Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[C:10](\[CH3:12])/[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=C(C)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 2-amino-5-bromopyridine (25 g, 140 mmole) in propionitrile (150 mL) was added ethyl methacrylate (50 mL, 400 mmole), DIEA (50 mL, 287 mmole), palladium(II) acetate (1.57 g, 7 mmole), and tri-o-tolylphosphine (4.3 g, 14 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The residue was taken up in 80% ethyl acetate/hexanes (100 mL), and the solution was filtered through a pad of silica gel, eluting with 80% ethyl acetatelhexanes (400 mL) until all the product was eluted off. The yellowish filtrate was concentrated under vacuum, and the residue was taken up in a small volume of 1:1 Et2O/petroleum ether. The precipitate which formed was collected and dried under vacuum to give ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (10.77 g, 37%) as a pale yellow solid: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.7 Hz, 1 H), 7.63 (dd, 1 H), 7.48 (s, 1 H), 6.75 (d, J=8.8 Hz, 1 H), 5.79 (br s, 2 H), 4.26 (q, 2 H), 2.10 (s, 3 H), 1.34 (t, 3 H). The filtrate was concentrated to dryness and purified by flash chromatography on silica gel (4:1 ethyl acetate/hexanes) to give additional ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (0.87 g, 3%) and ethyl 2-(6-aminopyridin-3-ylmethyl)acrylate (5.77 g, 20%) as a yellow oil: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J=2.1 Hz, 1 H), 7.32 (dd, 1 H), 6.53 (d, J=8.5 Hz, 1 H), 6.21 (d, J=1.8 Hz, 1 H), 5.48 (d, J=1.4 Hz, 1 H), 4.17 (q, 2 H), 3.47 (s, 2 H), 1.27 (t, 3 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)C)C3)cc1

Procedure:
Compound eq was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with isopropyl chloroformate. LC-MS: m/z=+483 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)=[O:41])[CH:35]=1)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:40]([C:36]3[CH:35]=[C:34]([C:29]4[C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=[CH:38][CH:37]=3)=[O:41])[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COC(=O)c1ccccc1-c1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccccc1-c1cccc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Yield: 64.5 %

Procedure:
(R)-2-Amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (40 mg, 0.107 mmol), 2′-(methoxycarbonyl)biphenyl-3-carboxylic acid (33 mg, 0.128 mmol), HOBT (20 mg, 0.128 mmol), EDC (25 mg, 0.128 mmol) and triethylamine (0.030 mL, 0.213 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then worked up by adding methylene chloride and washing with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (3:1 to 1:1 Hexanes/EtOAc) to obtain methyl 3′-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)biphenyl-2-carboxylate (40 mg, 0.069 mmol, 65.0% yield) as a white glass. MS found: (M+H)+=577.31.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:13])/[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](Cl)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C(OCC)(=O)C>[CH2:23]([C:24]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[N:13]=1)[C:22]([CH3:28])([CH3:27])[CH3:21]
Reactant: N/C(=N\O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)Cc1nc(-c2ccc([N+](=O)[O-])cc2)no1
Reaction time: 1 h

Procedure:
To a suspension of (Z)—N′-hydroxy-4-nitrobenzimidamide (0.500 g, 2.76 mmol) in dichloromethane (6 ml) was added 4-methylmorpholine (0.455 ml, 4.14 mmol) followed by 3,3-dimethylbutanoyl chloride (0.422 ml, 3.04 mmol). After 1 hour, the crude reaction mixture was purified by normal phase chromatography and the collected intermediate was dissolved in dichloromethane (8 ml) and treated with tetrabutylammonium fluoride (1.0M in THF) (8.28 ml, 8.28 mmol). After 3 hours at room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:14]/[C:15](/[C:18]([CH3:20])=O)=[N:16]\[OH:17]>CCOC(C)=O>[ClH:1].[CH3:14][C:15]1[N+:16]([O-:17])=[C:8]([C:7]2[CH:10]=[CH:11][C:4]([C:3]([F:12])([F:13])[F:2])=[CH:5][CH:6]=2)[O:9][C:18]=1[CH3:20]
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 5 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
HCl gas (21.2 g, 58.1 mmol) was bubbled via syringe into 0° C. solution of 4-trifluoromethylbenzaldehyde (50 g, 28.7 mmol), 2,3-butanedione monoxime (26.40 g, 26.1 mmol), and EtOAc (105 ml). The reaction was stirred at 5° C. for 3 h. Ice cold ether (575 ml) was then added, and the resultant precipitate was filtered, washed with ether, and dried at 25° C. for 16 h to give the product as a white solid (54.79 g 71% yield, mp 149°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([O:37]C)=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C1COCC1.CO>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.4 %

Procedure:
A solution of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(methoxycarbonyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (445 mg) in a mixture of 1N sodium hydroxide (5 mL), THF (5 mL), and methanol (5 mL) was stirred for 3.5 h at room temperature and the solvent was concentrated to ca. 5 mL. To the residue was added 5% potassium hydrogen sulfate and the precipitates formed were collected by filtration, washed with water, and dried to give 453 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N+:11]([O-])[CH:12]=1)[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:12]1[C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:24])=[CH:8][CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide (9 g, 26.7 mmol) in POCl3 (45 mL) was stirred at 80° C. for 5 h. After completion, reaction mixture was poured into ice water (150 mL), extracted with EtOAc (2×100 mL), combined extracts were treated with NaHCO3 solution, washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography by using (SiO2) EtOAc:Pet ether (2:98) to afford (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 67%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Yield: 90.3 %

Procedure:
To a solution of 2-amino-3-nitro-benzoic acid methyl ester (2 g, 10 mmol) in methanol, a suspension of 10% Pd/C (300 mg) in methanol 5 mL was added and hydrogenated with a hydrogen balloon over a period of 8 h. The reaction mass was filtered and the filtrate was concentrated under reduced pressure to obtain 1.5 g of the required compound as a brown coloured solid (88%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[F:1][C:2]1[C:3]2[C:4](=[CH:5][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C#CCCN
Reactant: O=Cc1cccc(F)c1[N+](=O)[O-]
Product: C[Si](C)(C)C#CCCn1cc2cccc(F)c2n1
Yield: 37.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 3-fluoro-2-nitro-benzaldehyde (0.2 g, 1.2 mmol) and 4-trimethylsilanyl-but-3-ynylamine (0.22 g, 1.5 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 7-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (117 mg, 0.45 mmol) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:18]#[N:19]>>[NH2:2][C:3]1[C:4]([C:18]#[N:19])=[CH:5][C:6]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CC(C)NCC(=O)c1cc(C#N)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)NCC(O)c1cc(C#N)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 224°-226° C. (decomp.), was prepared from 4'-amino-3',5'-dicyano-2-isopropylamino-acetophenone analogous to Example 48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[CH:38]1([S:41]([N:19]2[CH2:20][CH2:21][CH:16]([C:14]([N:12]3[CH2:13][CH:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:10]([N:22]([CH3:37])[C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=4)[CH2:11]3)=[O:15])[CH2:17][CH2:18]2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(S(=O)(=O)C4CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 140, the title compound N-[(3RS,4SR)-1-(1-Cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopropanesulfonylchloride instead of ethanesulfonyl chloride and was obtained as a off-white foam. MS m/e: 662.2 [M]+.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)=O.OO>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: OO
Solvent: O=CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Yield: 118 %

Procedure:
To a stirred solution of methyl oleate (MO) (200.00 g, 675 mmol) and formic acid (62.09 g, 1.35 mol) cooled in an ice bath (0° C.), H2O2 (30.0% in H2O, 306.00 mL, 2.70 mol) was added slowly. The reaction was then allowed to proceed at room temperature with vigorous stirring until LC/MS analysis indicated that MO had been consumed (around 19 hr). The reaction was then transferred to a separatory funnel, and ethyl acetate (500 mL) was added and the lower aqueous phase was removed. The organic phase was then washed with water, NaHCO3 and brine, dried with Na2SO4, filtered, concentrated using a rotary evaporator, and placed under vacuum until constant weight was achieved to yield epoxidized oleic acid (EMO) as a clear light yellow oil (225.0 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.[F:22]C1C=CC=CC=1NN>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[N:14]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Reactant: NNc1ccccc1F
Product: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1F

Procedure:
The title compound was prepared following procedure for 23a using 2-fluorophenyl hydrazine instead of phenyl hydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.37 (3H, m), 7.52 (2H, m), 7.81 (2H, m), 8.74 (1H, s). m/z 298.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:31])[CH2:29][CH3:30])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (1.30 g, 3.16 mmol) in pyridine (20 mL) was added propionyl chloride (330 μL, 3.80 mmol), and the mixture was stirred at room temperature for 4.5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→34/66) to give the title compound (1.30 g, 88%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cncs1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1

Procedure:
250 mg (0.964 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 242 mg (1.060 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 243 mg (2.892 mmol) of sodium bicarbonate, were stirred in 5 ml DMF at room temperature for 1 h. The reaction mixture was added to water, and the resulting precipitate was filtered off and washed with diethyl ether. Drying under reduced pressure gave 53 mg (12% of theory) of the target compound.
Reaction SMILES: N1C=CC([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=CC=1.Cl.[H][H]>[Pd].C(O)C>[N:9]1([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8](=[O:17])[CH:7]=2)[CH2:10][CH2:15][CH2:16][CH2:7][CH2:8]1
Reactant: O=c1[nH]c2ccccc2cc1-c1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1cc(N2CCCCC2)c2ccccc2[nH]1

Procedure:
A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.2 l of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10% palladium/charcoal was hydrogenated at a temperature of 40° C. until about 0.08 mol of hydrogen had been taken up. The mixture was freed from catalyst, the filtrate was evaporated down in vacuo, the residue was taken up in 200 ml of water and made ammoniacal. Common salt was added up to saturation point and the mixture was continuously extracted with dichloromethane using a perforator. The dichloromethane phase was evaporated down, the residue remaining was separated from byproducts by chromatography over silica gel using FM1 as eluant. The appropriate fractions were combined, freed from solvent, dissolved in a little isopropanol and converted with ethanolic hydrogen chloride solution into the hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCCC.C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([CH:26]([OH:27])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.2 g (11.8 mmol) 4-bromoanisole in 30 mL dry heptane under nitrogen was added 8.02 mL (1.6 M in hexane, 12.83 mmol) n-butyl lithium dropwise, and the mixture was stirred at room temperature for 30 minutes. The solution was then cooled to −78° C. and a solution of 2.0 g (10.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (route 18, step a) in 30 mL dry THF was added. The resultant mixture was allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate and extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 4:1 to 1:1).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C1(C)C=C[C:15]([S:18](O)(=O)=O)=CC=1.CS>>[CH3:15][S:18][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH2:9][CH2:10][OH:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CCCC(C)CCO
Agent: CS
Product: CSC(C)(C)CCCC(C)CCO

Procedure:
Twenty grams of citronellol, 2 g. of p-toluenesulfonic acid and 9 g. of methyl mercaptan are reacted as described in Example 44 except that a temperature of 140° is used instead of 220°, to give 7-methylthio-3,7-dimethyloctan-1-ol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[O:27][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-benzyl-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-4-amine (890 mg, 2.5 mmol) in methanol (10 mL) was stirred at room temperature for two minutes, and sodium methoxide (5 mL of a 25% w/w solution in methanol) was added. The resulting suspension was stirred at room temperature for one hour and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.3:4.7:95). The resulting off-white solid was triturated with hot acetonitrile, isolated by filtration, and dried under vacuum to provide 50 mg of 1-benzyl-2-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 240-242° C.