Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][C@H:8]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:47]1[C:48]2[CH:36]([CH2:35][O:34][C:32]([NH:31][C@H:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][C:6]([OH:49])=[O:5])=[O:33])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)O)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred solution of (R)-3-(9-fluorenylmethoxycarbonyl-amino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.34 g) in CH2Cl2 (20 ml) was added TFA (20 ml) dropwise. After being stirred for 1 h at room temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH/CH2Cl2, 1:20) to give (R)-3-(9-fluorenylmethoxycarbonylamino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid (2.07 g, 77% in 3 steps) as a white amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-chloropyridine (1.05 g, 8.2 mmol) was suspended in 15 mL dry DCM under Ar, added dry pyridine (0.66 mL, 8.2 mmol), cooled to 0° C. and added 4-nitrophenol chloroformate. A white precipitate forms rapidly. Stirred at ambient temperature for 1 hour, filtered off solid, washed with water and then DCM. A white solid recovered which is consistent with title compound. (2.1 g, 88%) 1H-NMR (D6-DMSO)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]1.[CH2:15]([S:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[CH2:15]([S:19][C:20]1[N:21]=[C:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]2)[CH:23]=[CH:24][N:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: NC(=O)c1c[nH]c2ccccc12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (480 mg, 12 mmol, 60% suspension) was added to a solution of 1H-indole-3-carboxylic acid amide (1.6 g, 10 mmol) in DMF (5 mL) at 0° C. and stirred for 20 min. A solution of 2-butylsulfanyl-4-chloro-pyrimidine (2.23 g) in DMF (5 mL) was added at 0° C., and the mixture allowed to warm to RT overnight. Water was added to the mixture, and the resulting white solid filtered off, washed with water (20 mL) and DCM (20 mL) and air-dried overnight to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (3.224 g, 98.77% yield) as a crude product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4](OC)=O.[F-].[Cs+].[C:17]1([CH3:28])[CH:22]=[C:21](C)[CH:20]=[C:19]([CH3:24])[C:18]=1B(O)O.CCCCCC.[C:35]([O:38][CH2:39]C)(=[O:37])C>C(COC)OC.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>[CH3:39][O:38][C:35]([C:8]1[C:3]([C:4]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:24])=[CH:18][C:17]=2[CH3:28])=[CH:2][CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13])=[O:37]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCCCCC
Product: COC(=O)c1c(-c2c(C)cc(C)cc2C)cccc1[N+](=O)[O-]

Procedure:
Under a nitrogen atmosphere in 20 ml of anhydrous dimethoxyethane (DME) was combined 1.44 g (5.54 mmol) of methyl 2-bromo-5-nitrobenzoate 1.68 g (11.1 mmol) of cesium fluoride and 192 mg of tetrakis(triphenylphosphine)palladium(0). The reaction was stirred for 5 minutes, at which point 1.00 g (6.09) of mesitylboronic acid was added. The solution was heated to reflux for 20 hours, and was then cooled and fractionated on silica gel using 6:1 hexane: ethyl acetate (EtOAc) to afford, after concentration in vacuo and refractionation using toluene, 5.65 g (54%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13]I>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+].[Ag+]>[CH3:13][O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccnc(O)c1
Reactant: CI
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(OC)c1
Yield: 86 %

Procedure:
A mixture of ethyl 2-hydroxy-pyridine-4-carboxylate (1.0 g, 6 mmol), (Chem. Abs. 1957, 8740c), methyl iodide (1 ml) and silver(I)carbonate (1.64 g) in toluene (20 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the insolubles removed by filtration through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was washed with water, dried (MgSO4) and the solvent removed by evaporation to give ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 86%) as a yellow oil. 1H NMR Spectrum: (CDCl3) 1.30(t, 3H); 3.90(s, 3H); 4.30(q, 2H); 7.24(s, 1H); 7.35(d, 1H); 8.20(d, 1H) MS-ESI: 182 [MH]+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH2:13][CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2ccc(C=O)cc2)CCN1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol) in DMF (10 mL) was added 2-methylpiperazine (1.9 g, 19.3 mmol) and K2CO3 (2.7 g, 19.3 mmol). The reaction was heated at 120° C. for 6 hours, diluted with H2O, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford 4-(3-methylpiperazin-1-yl)benzaldehyde (2.3 g, 69%): 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 3.67-3.83 (m, 2H), 3.07-3.18 (m, 1H), 2.81-3.06 (m, 3H), 2.50-2.62 (m, 1H), 1.46-1.73 (br s, 1H), 1.15 (d, J=6.3 Hz, 3H). ESI MS m/z 205 [M+H]+.
Reaction SMILES: O[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1ncc2c(n1)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncc2c(n1)CCCC2

Procedure:
A solution of 1 g of 2-hydroxy-5,6,7,8-tetrahydroquinazoline and 0.1 g of diethylaniline in 10 mL of phosphorus oxychloride is refluxed for 2 h, and subsequently cooled and concentrated. The residue is taken up in chloroform and washed with excess 3 N NaOH solution. The organic layer is dried and concentrated to provide 2-chloro-5,6,7,8-tetrahydroquinazoline (1.1 g) as an orange solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3].[CH:25](N(C(C)C)CC)(C)C.CI>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNCC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Reaction time: 12 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-piperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (6.37 g) in dichloromethane (60 ml) were added N,N-diisopropyl-N-ethylamine (3.38 ml) and methyl iodide (1.64 ml) under ice cooling with stirring, and the mixture was allowed to stay in a refrigeration for 12 hours. The mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, methanol and isopropylamine (10:1:0.3 v/v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([CH2:21][N:22]=C=O)(=O)=O)=CC=1.[C:26](=O)([O-])[O-].[K+].[K+].O>CO>[O:3]1[C:1]([C:4]2[CH:11]=[CH:10][C:7]([C:8](=[O:9])[CH3:26])=[CH:6][CH:5]=2)=[CH:2][N:22]=[CH:21]1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: CC(=O)c1ccc(C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
4-Acetylbenzaldehyde (2.96 g) and p-toluenesulfonylmethylisocyanate (4.69 g) were dissolved in methanol (200 mL). Potassium carbonate (3.32 g) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The solvent was evaporated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=100:1), followed by concentration under reduced pressure, to thereby yield the title compound (3.14 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[N:19][C:4]1=2)[CH3:2].[C:25]([O-])(=[O:27])[CH3:26].[K+]>C(OC(=O)C)(=O)C>[C:25]([N:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[CH:13]=[CH:12][CH:11]=[N:10][C:9]=4[N:3]([CH2:1][CH3:2])[C:4]=3[N:19]=2)[CH:24]=[N:23]1)(=[O:27])[CH3:26]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cnn(C(C)=O)c3)nc21

Procedure:
The title compound (mp 186°-188° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one by heating in acetic anhydride under reflux for 1 hour in the presence of potassium acetate.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)[CH3:21].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([CH2:3][C:4]2[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[C:24]([OH:36])[N:23]=1)[CH3:21]
Reactant: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 (323 mg, 1.07 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 94:6) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided, after evaporation, 60 mg of 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.04 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 43 as a yellow solid (69 mg, 12% yield).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[NH2:15][C:16]1[C:17]([O:31][CH3:32])=[C:18]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1.N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([NH:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:24])([CH3:25])[CH3:23])[CH:19]=[C:18]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=1[O:31][CH3:32])=[O:9])=[N+:2]=[N-:3]
Reactant: Cc1c(F)cc(C(=O)O)cc1N=[N+]=[N-]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc(F)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamide was prepared from 3-azido-5-fluoro-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][C:8]1[O:9][C:10]([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH:4]([OH:6])[CH3:5].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][CH2:2][CH:3]([CH2:7][C:8]1[O:9][C:10]([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH:4]([OH:6])[CH3:5])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(CO)Cc1ccc(C(=O)Nc2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
645 mg of (2RS,3SR)-3-(hydroxymethyl)-4-{5-(phenylcarbamoyl)-2-furyl}butan-2-ol in 12 ml of dimethylformamide was mixed with 305 mg of imidazole and 372 mg of tert-butyldimethylsilyl chloride under cooling with ice and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=3/1] to give 805 mg of the title compound as a colorless oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[C-:20]#[N:21].[Na+].O>CS(C)=O>[CH3:19][C:4]1[C:3]([CH2:2][C:20]#[N:21])=[CH:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: [C-]#N
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
27.2 g of the above (example 1N]) prepared 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (95.2 mmol) was dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured onto a mixture of ice and water and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic layers were washed with water, then with brine, and dried over sodium sulfate. After evaporation of the solvents, 25.2 g of the title compound was obtained as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C([O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[C:39]([F:44])[CH:38]=1)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([C:36]([OH:35])=[O:45])=[CH:38][C:39]=3[F:44])=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 24.7) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as yellow liquid. MS: m/e=570.2 [M+H+].
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:25][CH:26]([C:31]([OH:33])=[O:32])[CH2:27][C:28]([OH:30])=O>>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:25][CH:26]([C:31]([O:33][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:32])[CH2:27][C:28]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:30]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CC(CSc1nc2ccccc2s1)C(=O)O
Agent: Cl
Product: CCCCCCCCCCCCOC(=O)CC(CSc1nc2ccccc2s1)C(=O)OCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
125 parts of dodecan-1-ol are saturated with dry hydrogen chloride gas at room temperature. 13.5 parts of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic acid are then added and the mixture heated to 85°. The resulting solution is stirred for 4 hours at 85°. Excess dodecan-1-ol is removed by heating at 90° under a vacuum of 0.01 mm Hg to give di-dodecyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([OH:28])=O.[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([NH:1][C:26]([C:22]6[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=6)=[O:28])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:12][CH:13]=3)=[O:16])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: Cn1cccc1C(=O)O
Reactant: Nc1ccc2c(-c3ccc(C(=O)O)cc3)c[nH]c2c1
Product: Cn1cccc1C(=O)Nc1ccc2c(-c3ccc(C(=O)Nc4ccc(N5CCC(O)CC5)cc4)cc3)c[nH]c2c1

Procedure:
Compound 981 was prepared according to the procedure described in Scheme IV from 4-(6-amino-1H-indol-3-yl)benzoic acid, 1-methylpyrrole-2-carboxylic acid, and 4-(4-hydroxypiperidin-1-yl)aniline. [M+H]+ calcd for C32H31N5O3: 534.15; found: 534.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O-:16].[Na+].[C:18](OCC)(=[O:20])C>CO>[CH3:18][O:20][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[O-]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h

Procedure:
To 20.0 g (0.084 moles) 1,5-dichloro-2,4-dinitrobenzene in 200 ml methanol is added 22.7 g (0.42 moles) sodium methoxide. The mixture is heated to reflux and the reaction is monitored by TLC (ethyl acetate). TLC after approximately 12 hours shows the reaction is complete. The host mixture is poured into 750 ml ice/H2O. The pale yellow precipitate is collected by vacuum filtration and dried in the vacuum oven at 50° C. Yield is 16.3 g (85.7%). Recrystallization using toluene and 1 g decolorizing charcoal yields 11.5 g product, m.p. 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1Br
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-3-hydroxy-6-iodopyridine (11-2, 40 g, 133 mmol) in DMF (80 ml) was added K2CO3 (16.77 g, 121 mmol) and methyl iodide (66.3 g, 467 mmol). The system was stirred for 45 minutes at 100° C., cooled to room temperature and then treated with water (650 mL) and stirred for 0.5 h. The resulting solids that precipitated from solution were isolated by filtration and dried to give the title compound (11-3) as a pale brown solid. ESI+MS C6H5BrINO: 313.8 found, 313.9 required.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:4]=1
Reactant: Clc1ccncc1
Reactant: CCCCC[Mg]Br
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 4-chloropyridine hydrochloride (3 g, 20 mmol) in 200 mL of THF at −78° C. was added 24 mL (48 mmol) of pentylmagnesium bromide (2M soln in ether) slowly dropwise. After being stirred at −78° C. for 20 minutes, phenyl chloroformate (2.51 mL, 20 mmol) was added and the mixture was stirred for 30 minutes at −78° C. The cooling bath was removed and the reaction mixture was allowed to stir while slowly warming to room temperature. Aqueous 20% NH4Cl (50 mL) and ether (80 mL) were added, the layers were separated, and the queous phase was extracted twice with ether. The combined organic extracts were washed successively with 50 mL portions of saturated aqueous CuSO4, water, saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered through Celite, and evaporated to give 6.2 g (quantitative) of the crude product. This crude material was used directly in the next step to make the N-Boc derivative. 1H NMR (250 MHz) d 7.45-7.05 (m, 5H), 5.68 (d, 1H), 5.33 (m, 1H), 4.92 (m, 1H), 1.9-1.1 (m, 8H), 0.87 (t, 3H).