Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH2:14][CH2:13]1)=[N:9][C:8]([O:28][CH3:29])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)=[N:9][C:8]([O:28][CH3:29])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(N3CCN(CCNC(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(N3CCN(CCN)CC3)c2n1
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl (2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)carbamate (725 mg, 1.79 mmol) in MeOH (9 mL) at 25° C. was added dropwise a 4M solution of HCl in dioxane (3.1 mL, 12.53 mmol). After 12 h, the solution was concentrated the residue neutralized using excess MP carbonate resin in DCM affording the free amine which was used without further purification: LCMS (ES) m/e 306 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]([NH:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)#[N:2].C(OCC)C>C(O)=O>[C:1]([C@@H:3]([NH:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: COCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)cc3)cc21
Solvent: O=CO
Solvent: CCOCC
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4)cc3)cc21
Yield: 86.9 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-cyano-2-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (38 mg) in formic acid (1 mL) was stirred at 50° C. for 10 min. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:24 2M ammonia in methanol/DCM to give, after trituration with diethyl ether, the title compound (27 mg) as a pale yellow solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:17]=[C:16]2[N:35]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:36]=[C:37]([CH2:38][CH:39]3[CH2:43][O:42]C(C)(C)[O:40]3)[C:15]=12>CO.[Cl-].[Na+].O>[Cl:13][C:14]1[N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[N:17]=[C:16]2[N:35]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:36]=[C:37]([CH2:38][CH:39]([OH:40])[CH2:43][OH:42])[C:15]=12
Reactant: COc1c(C)cnc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C)cnc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.76 g) was added to a solution of di-tert-butyl {4-chloro-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of 6) above (12.52 g) in methanol (250 mL), and the mixture was stirred at room temperature for seven hours. The reaction mixture was poured into brine, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain the title compound (9.64 g, 82%) as an amorphous substance.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH2:12](I)[CH3:13]>>[CH2:12]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1)[CH3:13]
Reactant: CCI
Reactant: O=c1ccc2c([nH]1)CCCC2
Product: CCOc1ccc2c(n1)CCCC2

Procedure:
Following the procedure described in Example 1A, step 2, 5,6,7,8-tetrahydroquinolin-2 (1H)-one and EtI gave the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28]C(=O)OCC)=S)=[N:23][CH:24]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.Cl.NO.C([N:46](CC)C(C)C)(C)C>CO>[NH2:46][C:26]1[N:25]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:36]=[CH:35][CH:34]=3)=[CH:24][N:23]2[N:28]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of the above-mentioned crude product, ethyl ({5-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]pyridin-2-yl}carbamothioyl)carbamate, in methanol (100 mL)/ethanol (100 mL) were added hydroxylamine hydrochloride (4.84 g, 69.6 mmol) and N,N-diisopropylethylamine (14.6 mL, 83.5 mmol), and the mixture was stirred with heating at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (3.65 g, 76%) as a pale-yellow amorphous solid.
Reaction SMILES: [C:1]([C:3]1[C:20]([F:21])=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:22])#[CH:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[CH:26][N:25]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:32]1([CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:2]#[C:1][C:3]3[C:4]([F:22])=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])=[CH:19][C:20]=3[F:21])=[N:25][CH:26]=2)[CH2:33][CH2:34]1
Reactant: Brc1ccc(OCC2CC2)cn1
Reactant: C#Cc1c(F)cc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cc(F)c(C#Cc2ccc(OCC3CC3)cn2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A mixture of tert-butyl [(1S)-2-(4-ethynyl-3,5-difluorophenoxy)-1-methylethyl]carbamate (2.5 g), 2-bromo-5-(cyclopropylmethoxy)pyridine (1.8 g), copper iodide (I) (0.15 g), dichloropalladium-triphenylphosphine (1:2) (0.56 g) and triethylamine (2.2 mL) in toluene (20 mL) was stirred at 100° C. overnight under argon atmosphere. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (1.3 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4](OC)=[O:5].[NH2:27][C:28]([NH2:30])=[O:29]>C(O)C>[NH2:27][C:28]([NH:30][C:4](=[O:5])[C:3]1[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][C:10]([O:17][CH3:18])=[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:2]=1[OH:1])=[O:29]
Reactant: NC(N)=O
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Solvent: CCO
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)NC(N)=O)c1O
Temperature: 0 °C
Yield: 79 %

Procedure:
Dissolve compound 8 (1.0 g, 2.96 mmol) in anhydrous ethanol (20 ml), add in urea (0.27 g, 4.44 mmol), reflux to react for 12h, after completion of the reaction, pour the solution into ice water and extract three times with ethyl acetate, pool the organic layer, dry over anhydrous magnesium sulfate, filter and concentrate the solution, feed the solution to a silica gel column, evaporate the solvent in the eluent to obtain a white solid as the desired product (0.89 g, 80%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.82 (s, 3H), 3.34 (d, J=7.6 Hz, 2H), 3.83 (s, 3H), 5.21 (t, J=7.6 Hz, 1H), 6.20 (s, 2H), 6.65 (s, 1H), 6.81 (d, J=16.0 Hz, 1H), 7.26 (d, J=16.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 9.89 (s, 1H), 11.77 (s, 1H).
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[CH:7]=1>CO.[Pd]>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:8]1[CH:7]=[CH:6][N:11]=[N:10][C:9]=1[NH2:12]
Reactant: Cc1ccc(-c2cc(Cl)nnc2N)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2ccnnc2N)c(C)c1
Yield: 100.4 %

Procedure:
10% Pd—C (759 mg, 50 wt %) and ammonium formate (1.23 g, 19 mmol) were added to a solution of 6-chloro-4-(2,4-dimethylphenyl)-3-pyridazineamine (759 mg, 3.2 mmol) in methanol (40 mL), and the mixture was heated under reflux for 1 hour. The reaction solution was filtered through Celite, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (640 mg, 99%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:3]([OH:31])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=2)[N:9]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:8][CH2:7]1.[C:41](N(C(=O)C)OC)(=[O:43])[CH3:42]>ClCCl>[C:41]([NH:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:3]([OH:31])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=2)[N:9]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:8][CH2:7]1)(=[O:43])[CH3:42]
Reactant: CON(C(C)=O)C(C)=O
Reactant: CC(C)(C)Cc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCN(C(=O)OCc2ccccc2)c2ccc(CC(C)(C)C)cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of benzyl 4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-6-neopentyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.226 g) in dichloromethane (5 mL) was added N,N-diacetyl-O-methylhydroxylamine (0.064 9). The mixture was stirred over the weekend at room temperature. The solvent was then removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate, dried with magnesium sulfate, filtered, and concentrated to give 0.243 g of the title compound. (99% yield). MS (ESI+) for C34H41F2N3O4 m/z 594.31 (M+H)+.
Reaction SMILES: O=S(Cl)Cl.[C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:21]([OH:23])=[O:22])([CH3:8])([CH3:7])[CH3:6].[CH3:24]O>>[C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])([CH3:8])([CH3:6])[CH3:7]
Reactant: CO
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)O)c2[nH]1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc2cc(C(C)(C)C)[nH]c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
SOCl2 (3.6 g, 30 mol) was added dropwise to a solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 15 mol) and methanol (30 mL) at 0° C. The mixture was stirred at 80° C. for 12 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%). 1H NMR (CDCl3, 300 MHz) δ 9.99 (brs, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.04 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:10].[C:20]1([S:26]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([CH:38]=[O:39])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:38]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([S:26]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:28])=[O:27])[CH:30]=[CH:31]2)[OH:39])[CH3:10]
Reactant: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: C=CCCOCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCOC(C(=O)OCC)C(O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 17.7 ml lithium diisopropylamide (2 molar in tetrahydrofuran) in 40 ml tetrahydrofuran was added a solution of 5.61 g but-3-enyloxy-acetic acid ethyl ester [Tetrahedron (1982), 38(17), 2733-9] in 30 ml tetrahydrofuran at −78° C. After stirring for 30 min., a solution of 4.05 g 1-benzenesulfonyl-1H-indole-5-carbaldehyde in 30 ml tetrahydrofuran was added and stirring at −78° C. continued for additional 30 min. Then, the reaction mixture was quenched with 50 ml of saturated of ammonium chloride solution in water and warmed to ambient temperature. It was then extracted with ethyl acetate and the combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a crude product which was purified by chromatography (silicagel, eluent: gradient of n-heptane/ethyl acetate) to give 4.37 g of 3-(1-benzenesulfonyl-1H-indol-5-yl)-2-but-3-enyloxy-3-hydroxy-propionic acid ethyl ester (mixture of diasteromers) as colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(O)CNS(=O)(=O)c1ccc(N2CCN(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (4-fluoro-benzenesulfonylamino)-acetic acid was condensed with 4-phenyl-piperazine to give the title compound, mp=120-124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1>[Pt].C(O)C>[CH3:20][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1)[NH2:21]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C

Procedure:
3,5-Dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (6.0 g) and 600 mg of 10% platinum on carbon in 200 ml ethanol are hydrogenated on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate is stripped to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:36][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with tetrahydro-2H-pyran-4-amine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=497.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19]3)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(F)ccc1Cc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Product: CCOC(=O)/C=C/c1cc(F)ccc1Cc1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
The indole of Step 1 (621 mg; 1.92 mmol) was coupled with benzyl bromide according to the procedure described in step 1 of example 2 to yield 678 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.[Cl-].C([O:27][C:28](=O)[C:29](O)=[O:30])C>O1CCCC1>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:28](=[O:27])[C:29](=[O:30])[NH:1]2)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1NCCC(=O)O
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
At a bath temperature of +40° C., under argon and with exclusion of moisture, 211 mg (0.9 mmol) of 3-(2-amino-4-nitrophenylamino)propionic acid is combined with 200 mg (2 mmol) of triethylamine in 20 ml of dry tetrahydrofuran. A solution of 270 mg (2 mmol) of oxalic acid ethyl ester chloride and 5 ml of dry tetrahydrofuran is added dropwise to the batch, and the latter is stirred for 2 hours at room temperature. Furthermore, 0.05 ml of triethylamine and 0.05 ml of oxalic acid ethyl ester chloride are added to the mixture and the latter stirred for one hour at room temperature. The batch is filtered and the filtrate concentrated and distributed in water and ethyl acetate. The organic phase is concentrated. The residue is taken up in 15 ml of ethanol and 15 ml of 1N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110° C. The batch is concentrated, taken up in a small amount of water, and suctioned off, yielding 120 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)propionic acid, mp: 148-156° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:30]3([CH:34]=[O:35])[CH2:33][CH2:32][CH2:31]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:45][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([CH:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:30]3([CH:34]([OH:35])[CH3:45])[CH2:31][CH2:32][CH2:33]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C=O)CCC3)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C(C)O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3′-Fluoro-4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (14 g) was dissolved in tetrahydrofuran (150 mL), methylmagnesium bromide (35 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (13 g, 90%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])=[CH:11][CH:10]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC1CCc2ncnc(-c3ccc(O[C@@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)cc3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@H](Oc1ccc(-c2ncnc3c2C(C)CC3)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of (R)-tert-butyl 2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate (26 mg, 0.0498 mmol) in methylene chloride (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The contents were concentrated. The resulting residue was purified by reverse-phase HPLC to give (R)-N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine as TFA salt (7.5 mg, 23%). 1H NMR (d6-DMSO, 500 MHz) δ□(ppm): 8.9 (s, 1H), 8.7 (s, br, 2H), 7.8 (t, 2H), 7.5 (m, 4H), 7.1 (d, 2H), 5.7 (d, 1H), 3.8 (m, 1H), 3.4-3.5 (m, 2H), 3.3-3.4 (m, 1H), 3.0-3.1 (m, 1H), 2.9 (m, 1H), 2.3 (m, 1H), 1.7 (m, 1H), 1.3 (dd, 6H), 0.9 (dd, 3H). MS (422.3, M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(F)c(F)cc1O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl-silane as a clear oil (5.22 g, 81%).