Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:35])[C:30]1[O:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:34]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:29][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCc1ccco1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCc3ccco3)ccc21
Yield: 90.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide (108 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), furfurylamine (26 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 489.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.92 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.57 (s, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 6.39 (dd, 1H), 6.27 (d, 1H), 4.48 (d, 2H), 3.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[C:20]([O:27][CH3:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([NH:32][O:30][CH3:31])=[O:25])[CH:21]=[C:20]([O:27][CH3:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: COc1cc(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-methoxypyrimidine-4-carboxylic acid (Example 174) and methoxylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[OH:8].[OH-].[K+].Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[CH3:1][C:2]1[CH:3]=[C:4]([S:13][CH2:17][N:18]2[C:19](=[O:28])[C:20]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]3[C:22]2=[O:23])[CH:5]=[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:7]=1[OH:8]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1c2ccccc2C(=O)N1CCl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(SCN2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Yield: 46.3 %

Procedure:
The procedure of Example 1 was repeated using 8.46 grams of 3-methyl-4-hydroxy-5-tert-butylbenzenethiol, 1.72 grams of potassium hydroxide, and 8.43 grams of N-(chloromethyl) phthalimide . Recrystallization from ethyl acetate-heptane afforded 7.1 grams of product with m.p. 114°-116° C.
Reaction SMILES: [Li].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14]I)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1.[NH4+].[Cl-]>[Zn+2].[Br-].[Br-].Cl[Pd]Cl.C1COCC1.C1(C)C=CC=CC=1>[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:14][CH2:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]2)=[CH:21][CH:20]=1
Reactant: CCCCC[C@H]1CC[C@H](CCI)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.7 g of lithium and 5.7 g of ZnBr2 are added at 0° to a mixture of 15.4 g of trans-4-pentylcyclohexylethyliodide and 100 ml of THF/toluene (1:4), and the reaction mixture is treated with ultrasound at 0°-10° for 4 hours. 14.8 g of 4-trifluoromethoxybromobenzene and 0.88 g of PdCl2 (dppf) are subsequently added at 5°. The mixture is allowed to warm to room temperature and is stirred for a further 16 hours. The mixture is then poured into 100 ml of saturated NH4Cl solution, and the organic phase is worked up. After purification by chromatography and/or crystallization, 1-(4-trifluoromethoxyphenyl)-2-(trans-4-pentylcyclohexyl)-ethane is obtained.
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:11])[O:7][CH2:8][CH2:9]Cl)(=[O:4])=[O:3].[CH2:12]([C@H:14]1[C@@H:18]([C:19]2[N:23]3[C:24]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[C:25]=4[N:26]=[CH:27][C:22]3=[N:21][N:20]=2)[CH2:17][C@@H:16]([NH2:41])[CH2:15]1)[CH3:13]>C(Cl)Cl>[CH2:12]([C@H:14]1[C@@H:18]([C:19]2[N:23]3[C:24]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=5)(=[O:33])=[O:32])[C:25]=4[N:26]=[CH:27][C:22]3=[N:21][N:20]=2)[CH2:17][C@@H:16]([NH:41][S:2]([N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:11])(=[O:4])=[O:3])[CH2:15]1)[CH3:13]
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](NS(=O)(=O)N2CCOC2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a mixture of 2-chloroethyl chlorosulfonylcarbamate (prepared as detailed in Bioorg. Med. Chem. Lett., 2006 16, 3367-3370; 0.052 g, 0.236 mmol) and (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.100 g, 0.236 mmol, Example #8 Step M) in DCM (2.4 mL) was added TEA (0.098 mL, 0.71 mmol) and the reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.098 g, 65%) as a light brown solid: LC/MS (Table 1, Method a) Rt=2.18 min; MS m/z 574 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)co2)cc1
Yield: 30 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 4-[4-(4-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 30%. Pale yellow prisms. Melting Point: 182 to 183° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[NH2:14].C(O)(=O)C>O1CCOCC1>[Br:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: COc1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccnc(Nc2cc(C)cc(Br)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 10-20 mL microwave vial was charged with 2-chloro-4-methoxypyrimidine (0.835 g, 5.78 mmol), 3-bromo-5-methylaniline (1.075 g, 5.78 mmol), acetic acid (0.347 mL, 6.06 mmol) and dioxane (11.55 mL). The system was purged and flushed with Ar(g) three times before sealing and heating to 120° C. for 3 hours. The mixture was cooled and stirred overnight. The light brown solids were collected by filtration and were dried in a vacuum oven overnight to yield N-(3-bromo-5-methylphenyl)-4-methoxypyrimidin-2-amine (1.7 g, 5.78 mmol, 100% yield) as a tan solid. MS ESI: [M+H]+ m/z 296.0.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])#[N:2].[OH-].[Na+].Cl.[Cl-].[Na+]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: N#CCCCCCC(=O)NCC(=O)O
Agent: [Ni]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: NCCCCCCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.2 g (41.4·10-3 mol) of N-(6-cyanohexanoyl)-glycine are dissolved in 100 ml of ethanol, and 60 ml of 1M sodium hydroxide solution and 800 mg of Raney nickel are added. The mixture is then stirred under a hydrogen atmosphere, at room temperature and under a pressure of 3.5·105Pa, for 8 hours. When the reaction has ended, 20 ml of 1M hydrochloric acid are added and the mixture is concentrated under reduced pressure to give 10.2 g of a white pasty solid, which contains the expected salt and sodium chloride and which can be used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([NH:20][C:27]([NH:26][C:24](=[O:25])[C:23]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=3[Cl:21])=[O:28])=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: Nc1cnc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1cnc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)c1

Procedure:
A mixture of 0.5 g. of 2-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3-chloro-5-aminopyridine and 5 ml. of toluene was heated up to 50°. To this resulting solution was added 0.52 g. of 2-chloro-6-fluorobenzoyl isocyanate in 6 ml. of toluene. The mixture was heated at 80° for 1.5 hours, cooled, and filtered to give 0.7 g. of white crystals; mp. 243.5°-244.5°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:26]([OH:28])=[O:27])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2cccc(C(=O)O)c12
Temperature: -70 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.55 g) in tetrahydrofuran (30 ml) was added butyl lithium (3.0 ml, 1.6 M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture was then stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced to the reaction mixture over 10 minutes and the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (twice each with 40 ml). The aqueous layer was separated, after pH was adjusted to 4 with potassium dihydrogen phosphate, then extracted with ethyl acetate (twice each with 40 ml). The combined extracts were dried over anhydous magnesium sulphate, filtered and the solvent was evaporated under reduced pressure, to give 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-1,2-benzisoxazole and 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carboxyl-1,2-benzisoxazole as a colorless oily mixture (0.48 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([N:11]2[CH2:15][CH2:14][C@@H:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])[CH2:12]2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:11]2[CH2:15][CH2:14][C@@H:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])[CH2:12]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reaction time: 18 h
Yield: 32.3 %

Procedure:
A mixture of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]-3-nitro-pyridine (2.0 g, 6.89 mmol) and 10% Pd/C (200 mg) in ethanol (40 mL) was shaken on a parr shaker under 50 psi H2 for 18 h. The reaction mixture was filtered through a celite pad and concentrated to afford a dark red oil which was then purified by flash column chromatography (10% MeOH/CH2Cl2) to afford 580 mg (32% yield) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19](=[O:29])[N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]([CH2:40][OH:41])[NH:31]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH2:25]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:19]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10]([N:31]2[C@H:32]([CH2:40][OH:41])[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30]2)=[O:11])[N:4]=1)=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)O)c(C)c1Cl
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.5 %

Procedure:
To a stirred solution of 2-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-5-methoxy-benzoic acid (0.35 g, 0.82 mmol) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (0.13 g, 0.82 mmol) in dichloromethane (8 mL) under nitrogen atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.16 g, 0.82 mmol) and hydroxybenzotriazole (0.13 g, 0.82 mmol). The mixture was stirred at ambient temperature for 5 minutes. Triethylamine (0.34 mL, 2.5 mmol) was added to the mixture. The reaction was stirred for 60 hours at ambient temperature. The mixture was washed with water and purified by eluting through a silica gel column with a 10 to 100% ethyl acetate/heptane gradient to afford the title compound (21 mg, 4.5% yield). MS (ESI) [m/e, (M+H)+]=567.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.75-7.36 (m, 7H), 4.13-5.41 (m, 4H), 3.80-3.96 (m, 3H), 2.51-3.71 (m, 8H), 2.17-2.32 (m, 3H), 1.48-1.68 (m, 4H), 1.19-1.44 (m, 4H), 0.70-0.97 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2F)nc1
Reaction time: 8 h

Procedure:
Place 6-(2-fluoro-4-formylphenoxy)nicotinamide (Example 223, step 1) (0.700 g, 2.69 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.348 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (13.5 mL), cap and stir overnight. Add NaBH4 (0.204 g, 5.38 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate it. Purify by chromatography eluting with 0% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 1 hour at 20 mL/min to give 6-(2-fluoro-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)nicotinamide. (0.717 g, 71.3%). Dissolve the compound in dichloromethane: methanol (10 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.904 g): TOF MS ES+ 374.2 (M+H)+, HRMS calcd for C20H25N3O3F 374.1880 (M+H)+, found 374.1881, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=8.7 min, 100% purity.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([CH:32]1[CH2:34][CH2:33]1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][CH:7]([CH:32]2[CH2:34][CH2:33]2)[C:6]([OH:35])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC(C(=O)O)C2CC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-cyclopropyl-propionic acid tert-butyl ester (65 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 2 h. The mixture was subsequently concentrated and resulting residue was dissolved in EtOAc, washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate, filtered, concentrated and solids were treated with hot DCM/hexanes (1:1 by volume); solids after cooling were collected via filtration, giving desired product after air-drying as white solids (40 mg). LC-MS ESI+: 418 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=O)[CH3:2].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)/[CH:9]=[N:13]/[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(C=O)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(/C=N/c2ccc(C#N)cc2)c1
Yield: 72.5 %

Procedure:
A mixture of 53.1 (600 mg, 3.6 mmol) and 4-aminobenzonitrile (421 mg, 3.6 mmol) in toluene (50 mL) was refluxed in a Dean-stark apparatus for 4 h. The reaction mixture was the concentrated and the resulted solid was washed with hexane to obtained Intermediate 53.2 (700 mg, 80%). 1H NMR (CDCl3) δ 1.42 (t, 3H), 4.08 (q, 2H), 7.05 (m, 2H), 7.27 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 8.69 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]OC(OC)N(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[C:10]([O:12][CH3:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(C)(C)[N+](=O)[O-])C(=O)O
Solvent: ClCCl
Product: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
(S)-2-t-Butoxycarbonylamino-6-methyl-6-nitroheptanoic acid (3.90 g, 12.81 mmol) was dissolved in dichloromethane (20 ml) and dimethylformamide dimethylacetal (2.6 ml, 19.22 mmol) was added. The mixture was stirred at room temperature for 20 h. Dimethylformamide dimethylacetal (1.74 ml, 12.8 mmol) was added and the mixture was stirred for 4 h. The mixture was washed with 0.5N hydrochloric acid (30 ml), saturated aqueous sodium hydrogencarbonate solution (30 ml) and saturated brine (30 ml). The solvent was evaporated by concentration under reduced pressure to give the objective compound (2.53 g, yield 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[C:10]([CH3:11])=[N:9][O:8][C:7]=3[C:12]3([NH:15][C:16](=O)[C:4]=2[CH:3]=1)[CH2:14][CH2:13]3.C(Cl)[Cl:21].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:21][C:16]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=2[C:6]2[C:10]([CH3:11])=[N:9][O:8][C:7]=2[C:12]2([N:15]=1)[CH2:14][CH2:13]2
Reactant: Cc1noc2c1-c1ccc(Cl)cc1C(=O)NC21CC1
Reactant: ClCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1noc2c1-c1ccc(Cl)cc1C(Cl)=NC21CC1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a vial containing 8-chloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropan]-6(5H)-one (0.0631 g, 0.230 mmol) was added CH2Cl2 (1 mL). The reaction mixture was heterogeneous and to aid in solubility CHCl3 (0.5 mL) was added. To the homogeneous mixture was added phosphorous pentachloride (0.092 g, 0.442 mmol) in one portion at room temperature. The reaction mixture eventually turned heterogeneous again (˜<10 min) and LC-MS analysis after ˜30 min indicated complete consumption of starting material and formation of desired product. The mixture was diluted with EtOAc and aqueous 10% Na2CO3 (2.8 mL). After initial effervescence, the mixture was stirred for an additional 5-10 min, and the aqueous layer was extracted with EtOAc (3×). The combine organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to give yellow solids. The solids were filtered over a plug of silica and eluted with 30% EtOAc:70% Hexanes. The product 6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (61.8 mg, 0.211 mmol, 92% yield) was obtained as off-white solids. LC/MS m/z 293 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([N+:21]([O-])=O)=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C.[Zn]>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OCC1CCCC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Temperature: 100 °C
Yield: 80 %

Procedure:
3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine (1.2 mmol) is dissolved in acetic acid (4 ml). After addition of water (4 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine is obtained as yellow powder in a yield of 80%. HPLC (method C): 1.83 min, LC-MS (method A): 1.486 min, 285.15 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26]([OH:33])=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=2)=[CH:18][CH:17]=1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:38].C(NC1C=CC(NC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=CC=1)(=O)C1C=CC=CC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>C1COCC1.O.C(OCC)C.C(OCC)(=O)C>[ClH:38].[ClH:38].[CH2:7]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]2[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[CH3:32])[C:26]([OH:33])=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=2)=[CH:20][CH:21]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)c1cc(Nc2ccc(NC(=O)c3ccccc3)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2ccc(NCc3ccccc3)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 466 mg of LiAlH4 in 30 ml of THF was added a solution of 1.7 g of 4-(4-benzoylaminophenylamino)-2,6-di-tert-butylphenol (free base of Compound 53) in 30 ml of THF, and the mixture was refluxed for 5.5 hours. After cooling, a solution of 15 g of Na2S2O4 in 60 ml of water was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 10 minutes. Then water was added thereto and the mixture was extracted with diethyl ether. The organic layer was dried over MgSO4 and concentrated. The oil thus obtained was dissolved in a small amount of diethyl ether. To this solution was added 2 ml of a solution of 4N hydrogen chloride in ethyl acetate, and the crystals thus precipitated were filtered and recrystallized from isopropanol-diethyl ether, giving 450 mg of the title compound as white crystals.