Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8](OC)=[O:9])[CH2:3][CH2:2]1.[BH4-].[Li+]>C1COCC1>[CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]([CH2:8][OH:9])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(CC2CC2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(CC2CC2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopropylmethyl)benzoate (9.06 g, 47.6 mmol) in THF (100 mL) was added lithium borohydride (2.0 M in THF, 71.4 mL, 142.9 mmol). After stirring at 50° C. for 1 h the reaction was cooled, quenched with excess methanol and concentrated under vacuum. Purification by silica gel chromatography (30% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [NH:1]([CH:5]([C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6](O)=[O:7])[C:2]([CH3:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH:1]([CH:5]([CH:9]([OH:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][OH:7])[C:2]([CH3:4])=[O:3]
Reactant: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCC(O)C(CO)NC(C)=O

Procedure:
As shown below, the ester and ketone groups in an ester of 2-acetamino-3-oxooctadecanoic acid are reduced in the presence of lithium aluminium hydride (referred to as LAH) to obtain a racemate of 2-acetaminooctadecane-1,3-diol, as follows: ##STR7##
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cnn(CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% paraffin oil dispersion, 0.507 g, 21.13 mmol) was added portionwise to a solution of 4-iodopyrazole in DMF at 0° C. The reaction mixture was stirred for 1 hour, treated with solution of 1-(2-chloroethyl)pyrrolidine (1.40 g, 10.56 mmol) in DMF, slowly warmed to RT and stirred for additional 16 hours. The reaction mixture was cooled to 0° C. and ice cold water was added, followed by extraction with EtOAc (2×40 mL). The combined organics were washed with water (3×40 mL), brine solution (40 ml), dried (Na2SO4), filtered, and concentrated to obtain 4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole, which was used as is for subsequent reactions without further purification; 1H-NMR (400 MHz, CHCl3): 7.60 (1H, s), 7.52 (1H, s), 7.49 (1H, s), 4.25 (2H, t), 2.95 (2H, s), 2.57 (4H, m), 1.79 (4H, m); ES-MS: 292.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Product: CCOc1cccc(-c2cc(Cl)c(N)c(Cl)c2)c1
Yield: 88.6 %

Procedure:
The title compound (0.550 g) was prepared from 4-Bromo-2,6-dichloroaniline (0.5 g, 2.2 mmol) and 3-ethoxyphenylboronic acid (0.447 g, 2.7 mmol) as a yellow liquid which was about 70% pure as adjudged by 1H-NMR data. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.56 (s, 2H), 7.28 (s, 1H), 7.16-7.08 (m, 2H), 6.83 (dd, J 2, 8.1, 1H), 5.62 (s, 2H), 4.10 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>CCOCC>[C:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: C=C1CC(=O)O1
Reactant: NCCNC(=O)OCc1ccccc1
Solvent: CCOCC
Product: CC(=O)CC(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of benzyl N-(2-aminoethyl)carbamate (54 g, 0.276 mole) in ether (250 ml) and a solution of diketene (25.2 g, 0.30 mole) in ether (250 ml) were added simultaneously, dropwise, to ether (600 ml) while stirring and cooling over a 30 minute period. A white precipitate appeared. The solution was stirred 30 minutes longer, and then filtered. One recrystallization from water gave pure benzyl N-(2-acetoacetamidoethyl)carbamate (m.p.=116°-118° C.) at a yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=2[F:9])[CH2:13][CH2:12]1
Reactant: Nc1cccc(Cl)c1F
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(Cl)c2F)CC1
Yield: 32.1 %

Procedure:
Combine 3-chloro-2-fluoroaniline (4.37 g, 30 mmol), 1-methylpiperidin-4-one (3.39 g, 30 mmol), sodium triacetoxyborohydride (5.26 g, 33 mmol), and acetic acid (5.4 g, 90 mmol) and stir at room temperature overnight. Partition the reaction mixture between dichloromethane and saturated aqueous NaCl containing NH4OH, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 2.34 g of the title compound (32% yield): mass spectrum (ion spray): m/z=243 (M+1); 1H NMR (CDCl3): 6.88 (ddd, 1H), 6.63 (ddd, 1H), 6.56 (dd, 1H), 3.85 (br d, 1H), 3.28 (m, 1H), 2.80 (m, 2H), 2.30 (s, 3H), 2.13 (m, 2H), 2.04 (m, 1H), 1.53 (m, 2H). (file: mn4-b6k-284-2)
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH2:17])([O-:13])=[O:12]>O>[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH:17][CH:5]=[O:7])([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (6.0 ml.) was added to formic acid (98- 100% w/v; 24.0 ml.) with swirling and cooling and the mixture was allowed to stand at room temperature for 30 minutes. 3,5-Dinitroaniline (6.0 g.) was then added. The reaction mixture was warmed for 5 minutes on the steam bath and allowed to stand for 40 minutes, allowing it to cool to room temperature. Water (100 ml.) was added, and the precipitate was filtered off and dried. Crystallisation from a mixture of petroleum ether (b.p. 60°-80°C.) and ethyl acetate (2:1 by volume) gave 3',5'-dinitroformanilide (4.1 g.), m.p. 121°-123°C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:47])[C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:47])[C:33]1[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.271 g (0.406 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.061 g (1.23 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR30## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.21, FD-MS: M+ =571.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][C:18]([OH:20])=[O:19]>C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH:16]([N:15]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])[CH2:17][C:18]([OH:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 79 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.54, 8.0 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid (1.56 g, 8.0 mmol) in 15 mL of acetic acid was refluxed for 3.5 h under nitrogen. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 2.34 g (79%) of 3-(4-methoxyphenyl)-3-(3-nitrophthalimido)propionic acid as a white powder: mp 178-180° C.; 1H NMR (DMSO-d6, 250 MHz) δ8.07-8.02 (m, 3H), 7.38 (d, 2H, J=8.7), 6.90 (d, 2H, J=8.7, 5.68-5.07 (m, 1H), 3.72 (s, 3H), 3.48-3.22 (m, 2H); 13C NMR (DMSO-d6) δ171.6, 165.7, 163.0, 158.8, 144.4, 136.4, 133.0, 130.2, 128.6, 128.5, 127.0, 122.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14N2O7. Theoretical: C, 58.38; H,3.81; N, 7.56. Found: C, 58.18; H, 3.79; N, 7.36.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12](N(OC)C)=[O:13].[OH-:18].[K+].Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12]([OH:13])=[O:18]
Reactant: [OH-]
Reactant: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 2-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylcyclopropane-carboxamide (304 mg, 1.0 mmol), 10 M potassium hydroxide (3.5 mL, 35 mmol), and dioxane (2.5 mL) was heated at 130° C. in a sealed tube for 19 h. Upon cooling to room temperature, the reaction mixture was acidified with 3 M HCl (20 mL), and the product was extracted with 5% methanol/dichloromethane (3×30 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated to afford the title compound as a white solid. MS m/z: 259 & 261 (M+1).
Reaction SMILES: [C:1]12([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4](=[O:11])[CH2:3][CH2:2]2.CO.[BH4-].[Na+].Cl>[Cl-].[Na+].O>[OH:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:2][CH2:3]1
Reactant: O=C1NC(=O)C2(CCC(=O)c3ccccc32)N1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C2(CCC(O)c3ccccc32)N1
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a slurry of 14.3 g. (0.062 mole) of 3',4'-dihydrospiro[imidazolidine-4,1'(2'H)-naphthalene]2,4',5-trione in 250 ml. of methanol at 0° C. was added in small portions over a period of 15 minutes 4.8 g. (0.13 mole) of sodium borohydride, and the reaction mixture allowed to stir in the cold for 60 minutes. The reaction mixture was added to 250 ml. of 10% hydrochloric acid and 50 ml. of a brine solution. The product was extracted with ethyl acetate (5×50 ml.) and the extracts combined and washed with a 10% hydrochloric acid solution. The extracts were dried over magnesium sulfate and concentrated to give an off-white solid. Triturations with diethyl ether followed by filtration gave 4.5 g. (31.9% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@H:11]([OH:13])C[C@@H]1C(O)=O)=O)(C)(C)C.Br[C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][O:36][CH3:37])=[O:29])[CH:27]=1)[C:21]([O:23]C)=[O:22].BrC1C=C(C=C(C(OC)=O)C=1)C(O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.COC[C@H]1CCCN1>ClCCl>[CH3:37][O:36][CH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28]([C:26]1[CH:25]=[C:20]([CH:19]=[C:18]([C:6]2[O:13][CH:11]=[CH:12][N:8]=2)[CH:27]=1)[C:21]([OH:23])=[O:22])=[O:29]
Reactant: COC[C@H]1CCCN1C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: COC[C@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Step H (1): (R)-methyl 3-bromo-5-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzoate. To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (1.8 g, 6.95 mmol) in dichloromethane (100 mL) and was added Hunig's base (2.7 g, 20.85 mmol) to make a clear solution and HATU (3.17 g, 8.34 mmol) was then added. After stirring for 30 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (800 mg, 6.95 mmol) and the reaction mixture was stirred at rt for 6 h. Dichloromethane (100 mL) was added and the mixture was washed with 1N NaOH, H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient) to give 1.8 g of the title compound (73% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 1.77-2.08 (4H, m), 3.14-3.47 (5H, m), 3.63 (2H, brd s), 3.82 (3H, s), 4.41 (1H, brd s), 7.83 (1H, s), 8.07 (1H, s), 8.20 (1H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[CH3:38])[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([CH3:38])=[C:29]([CH3:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: Cc1ccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)cc1C

Procedure:
Compound 58d was reacted with 3,4-dimethylbenzoic acid and subsequently hydrogenated according to the the procedure described in Example 58, to give Example 61. ESI-MS m/e 355.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cn2ccccc2n1
Yield: 8.4 %

Procedure:
A solution of 14.6 g of 2-aminopyridine and 25.5 g of ethyl 4-chloroacetoacetate in 200 ml of acetonitrile was heated under reflux for 14.5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue thus obtained was mixed with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 2.65 g of the title compound having Rf=0.33 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN[C@H]1CCCC[C@@H]1NC.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CS(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(I)c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(-n2cccn2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To a solution of tert-butyl-3-iodobenzylcarbamate (550 mg, 1.65 mmol) in Dioxane (1.2 mL) and DMSO (1.2 mL) was added CuI (16 mg, 0.083 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.052 ml, 0.33 mmol), pyrazole (135 mg, 1.98 mmol) and K2CO3 (479 mg, 3.47 mmol). After stirring at 120° C. for 3 h, it was concentrated and the residue was purified by column chromatography to give tert-butyl-3-(1H-pyrazol-1-yl)benzylcarbamate (317 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+].C(O)CCC>ClCCl.C(=O)([O-])O.[Na+].CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([S:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Sc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCCCO
Solvent: CCCCCC
Product: c1ccc(Sc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Uniformly mixed were 3.0 parts of 4-bromobiphenyl, 1.7 parts of thiophenol, 2.5 parts of sodium tert-butoxide, 0.15 parts of tetrakis(triphenylphosphine)palladium, and 64.3 parts of 1-butanol, and allowed to react at 120° C. for 2 hours. The reaction solution was cooled to room temperature (about 25° C.) and then filtered. The filtrate was transferred to a rotary evaporator, and the solvent was removed by distillation, so that a red-brown, crystalline product was obtained. The product was dissolved in 70 parts of dichloromethane, and 50 parts of an aqueous saturated sodium hydrogen carbonate solution was added thereto. After washing three times by liquid-liquid separation, the dichloromethane layer was washed with 70 parts of distilled water until the pH became neutral. The dichloromethane layer was transferred to a rotary evaporator, and the solvent was removed by distillation, so that a brown, crystalline product was obtained. Twenty parts of hexane was added thereto, and the product was dispersed in hexane using an ultrasonic cleaner. The operation of standing for about 15 minutes and then removing the supernatant was repeated three times to wash the resulting solid, and the solvent was removed with a rotary evaporator, so that brown crystalline 4-(phenylthio)biphenyl was obtained in a yield of 84%. The product was identified by 1H-NMR {d6-dimethylsulfoxide, δ (ppm) 7.6-7.7 (4H, m), 7.3-7.5 (10H, m)}.
Reaction SMILES: C1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)CCCCC1>C1(C)C=CC=CC=1>[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:7][CH:8]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To reactor-1 was charged III (35 g, 140.95 mmol) in toluene (140 g). The mixture was heated to 50° C. to obtain a clear solution. To a second reactor was charged IV (36.4 g, 169.10 mmol) and toluene (300 g), followed by addition of a solution of dicyclohexyl carbodimide (11.6 g, in 50% toluene, 28.11 mmol) at 0-10° C. The mixture was stirred at the same temperature for 15 min, then charged in parallel with the content of reactor-1 and the solution of dicyclohexyl carbodimide (52.4 g, in 50% toluene, 126.98 mmol) within 1 hr while maintaining the batch temperature at 0-10° C. The mixture was agitated at the same temperature for 3 hrs, and warmed to 25° C. for another 1 hr. Once III was consumed, toluene (˜300 mL) was distilled off under reduced pressure at 70-80° C. n-Butanol (200 g) was added, followed by 3 M HCl solution in n-butanol (188 g) while maintaining the temperature at 70-80° C. (Gas evolution, product precipitates). After stirring for over 30 min at 70-80° C., the mixture was cooled to 20-30° C. over 1 hr. The precipitate was filtered and washed with acetone (172 g) and toluene (88 g). The wet cake was dried in vacuo at ˜60° C. to give V toluene solvate as off white solid (60-72 g, 85-95% yield). Compound V could be used directly for the next step or basified prior to next step to obtain the free base compound VI used in the next step.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:16][C:17]1[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O>CC(O)C>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:18]3[C:17](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 90.3 %

Procedure:
694.1 kg of methyl 3-cyclopropyl-3-oxopropionate and 1447.8 kg of 2-amino-4′-fluorobenzophenone methanesulfonate were added to 8455 kg of 2-propanol, and 2-propanol was distilled off at 79 to 87° C. After distilling off 7553 kg of 2-propanol, 66.1 kg of methyl 3-cyclopropyl-3-oxopropionate was added and the mixture was heated at 79 to 81° C. for 4 hours. An analysis of the mixture with HPLC showed that the residual amount of 2-amino-4′-fluorobenzophenone as a raw material was 0.5%. 8455 kg of toluene was added into the reaction solution, and the reaction solution was washed with 4620 kg of 4% aqueous solution of sodium hydroxide, then 2010 kg of 2% aqueous solution of sodium hydroxide, and finally 1585 kg of 5% brine solution. The reaction solution was dried over 158 kg of anhydrous magnesium sulfate to obtain 10220 kg of a toluene solution containing 1350 kg of methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate (converted yield: 90.4%). A part of the solution was concentrated, and the concentrated residue was recrystallized from toluene having the same mass as that of the residue and heptane having five times mass of the residue to obtain methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate of HPLC purity 99.7%. The substance has the same properties as the substance of Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.7 %

Procedure:
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine hydrochloride salt (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76% yield).