Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:28]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC[C@H](N(C)C)C3)cn2)c1O
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50.0 mg, 0.156 mmol), (S)—N,N-dimethylpyrrolidin-3-amine (26.7 mg, 0.234 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44.9 mg, 0.234 mmol) in DMF (1561 μl). HOBT (35.9 mg, 0.234 mmol) and DIPEA (136 μl, 0.781 mmol) were added. The reaction was allowed to stir overnight. Then 1N aqueous hydrochloric acid (21 ML) was added and reaction mixture was then purified using preparative HPLC eluting with 0.1% formic acid in water and 5-30% acetonitrile to give the title compound (30 mg, 0.072 mmol, 46.1%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.88 (m, 1H) 2.24 (br. s., 3H) 2.36 (br. s., 3H) 2.42 (s, 3H) 2.88-3.05 (m, 2H) 3.59-3.81 (m, 4H) 7.58 (d, J=7.83 Hz, 1H) 7.64 (s, 1H) 7.95 (d, J=7.83 Hz, 1H) 8.01 (s, 1H) 8.11 (d, J=9.09 Hz, 1H) 8.43 (d, J=8.84 Hz, 1H) 8.62 (s, 1H); ESI-MS m/z (M+H)+ calc'd for C23H24N6O2, 417.20. found 417.5.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=1[O:19][CH3:18])#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Temperature: 60 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (5.60 g, 0.0145 mol) and 2,4-dimethoxybenzylamine (3.51 mL, 0.0234 mol) were combined in tetrahydrofuran (100 mL) and stirred at 60° C. for three days. The reaction was concentrated in vacuo, diluted with dichloromethane and hexanes and the resultant precipitate was filtered to yield the title compound (5.56, 81%) as a yellow solid. LCMS: (FA) ES+, 473. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (s, 1H) 7.10 (d, 1H, J=8.57 Hz), 6.60-6.50 (m, 2H), 4.30 (s, 2H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.26-1.21 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)cc1Nc1cccc(Br)c1
Temperature: 150 °C
Yield: 61.1 %

Procedure:
(Method D-2) Under an atmosphere of nitrogen, 2,4-dichlorobenzoic acid (36 g, 0.19 mol), 3-bromoaniline (48 g, 0.28 mol), potassium carbonate (32 g, 0.23 mol), and copper powder (1 g, 0.016 mol, catalytic) were mixed in dry DMF (150 ml) and heated to 150° C. for 18 hrs. The DMF was removed under reduced pressure, water (200 mL) added and the mixture acidified with 2M HCl (400 mL) to give a brown solid which was collected by filtration. Recrystallisation from ethanol/water (60/40) gave the title compound (43 g, 0.116 mol 61%) as a grey solid. See, for example, Hodgeman et al., 1972.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2.I[CH3:20]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]2[CH3:20]
Reactant: CI
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 97.4 %

Procedure:
NaH (60% dispersion in mineral oil, 0.24 g, 6 mmole) was washed with hexanes, then was suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C., and ethyl 4,6-dichloroindole-2-carboxylate (1.03 g, 4 mmole) was added. After 2-3 min, iodomethane (1.3 mL, 20 mmole) was added, and the mixture was warmed to RT. The mixture became thick, and stirring became difficult for several minutes. After 0.5 hr, the reaction was cooled to 0° C. and quenched with 10% NH4Cl (2 mL). The mixture was concentrated to dryness, and the residue was partitioned between Et2O (50 mL) and H2O (10 mL). The layers were separated and the organic layer was washed with H2O (5 mL), dried (MgSO4), and filtered, and the filter pad was washed with a little CH2Cl2. Concentration afforded the title compound (1.06 g, 97%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1 H), 7.30 (s, 1 H), 7.17 (d, J=1.5 Hz, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 4.05 (s, 3 H), 1.42 (t, J=7.1 Hz, 3 H); MS (ES) m/e 272 and 274 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:19][N+:16]([O-:18])=[O:17])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CC(C[N+](=O)[O-])CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-5,6-dihydropyridin-2-(1H)-one (6.2 g, 30 mmol) in nitromethane (64.5 g, 1.06 mol) under an atmosphere of nitrogen was added DBU (4.59 g, 30.2 mmol). The reaction mixture was stirred overnight at room temperature. The product mixture was concentrated under vacuum. The residue was purified using column chromatography on silica gel eluting with 50%-100% ethyl acetate in hexanes. Collection and concentration of appropriate fractions provided the title compound as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 7.01 (t, J=8.7 Hz, 2H), 4.64 (d, J=14.6 Hz, 1H), 4.48 (d, J=14.5 Hz, 1H), 4.34 (m, 2H), 3.27 (m, 2H), 2.23 (dd, J=17, 10.6 Hz, 1H), 2.0 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:25][C:26]=2[NH2:31])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-ylmethyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains ˜15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[S:7][C:6]=2[CH:13]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].CCN(C(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][O:12][S:15]([CH3:14])(=[O:17])=[O:16])[S:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc2cc(CCO)sc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2cc(CCOS(C)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of 2-(6-methyl-benzo[b]thiophen-2-yl)-ethanol (3.22 g, 16.8) mmol) in dichloromethane (100 mL), methanesulfonylchloride (1.56 mL, 20.1 mmol) and DIEA (5.96 mL, 33.5 mmol) were added. The mixture was stirred for 15 min at 0° C. and then allowed to reach room temperature and stirred for an additional 2.5 hrs. It was washed with sat. NaHCO3 (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. Methanesulfonic acid 2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl ester was obtained as a solid and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Reactant: CCN1CCNCC1
Solvent: CCCCO
Product: CCN1CCN(c2cc(-c3ccccc3)nc(Nc3ccc(OC)c(Cl)c3)n2)CC1

Procedure:
The title compound was prepared by treating (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine (0.5 g, 1.4 mmol) with N-ethyl piperazine (0.16 g, 1.4 mmol) in n-butanol at refluxing temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[C:31]1[CH:32]=[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:34]=[CH:35][C:30]=1[Cl:29])[CH3:43]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 4-chloro-3-(ethoxycarbonyl)benzeneboronic acid, copper-(II)-acetate and pyridine to give the title compound as a off-white solid. MS (m/e, ISP neg. ion)=596.3 [M−H+]
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[CH:4]=1.Cl.C1(C)C=C[C:15]([S:18](O)=O)=CC=1>C(O)C>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[S:18][CH3:15]
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: Cc1cc(O)cc(=O)o1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CSc1c(O)cc(C)oc1=O
Yield: 64 %

Procedure:
A mixture of the monosodium salt of 4-hydroxy- 6-methyl-2-pyrone (14.8 g., 0.100 mol), methyl p-toluenethiolsulfonate (20.2 g., 0.100 mol), and 2B absolute ethanol (250 ml.) was heated at reflux for 21 hours. The ethanol was removed by distillation in vacuo; on attempted trituration with water (200 ml.), an oil separated. The oil was removed and the aqueous phase extracted with chloroform (2 × 100 ml.). The oil and chloroform washings were combined, dried over anhydrous Na2SO4, and the chloroform removed by distillation in vacuo. The resulting solid product, 4.5 g. (m. 130°-136°C., 26% yield) was twice recrystallized from 2-propanol to obtain the pure product, m. 141°-141.5°. The aqueous layer was acidified with dilute HCl producing 10.0 g. (64 percent yield) of the by-product p-toluenesulfinic acid, m. 79°-85°C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27].O>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:27][C:26]#[CH:25])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCn1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A solution of 2-chloro-6-benzylaminopurine (1.1 g, 3.8 mmol), in DMSO (5 mL) was cooled to 0° C., potassium carbonate (0.79 g, 5.7 mmol) and propargyl bromide (0.45 g, 3.8 mmol) was added to the contents, and stirred for 1 h at 0° C. Water (20 mL) was then added to the reaction mixture, and the resulting yellow precipitate was filtered and washed with excess water (50 mL). Compound 5 (1.1 g, 80%) was obtained as an off-white solid upon successive recrystallization from dichloromethane and ethyl acetate: mp 180° C.; EI/MS (m/z (relative %)): 297 (63, M+.), 298 (15), 299 (23), 258 (46), 91(100); 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 7.21-7.38 (m, 5H), 5.03 (bs, 2H), 4.62 (d, J=6 Hz, 2H), 3.51 (s, 1H). 13C NMR (100 MHz, DMSO) δ 155.6 (s), 154.0 (s), 150.3 (s), 140.7 (d, 1JC—H=214 Hz) 139.9 (s), 128.9 (d, 1JC—H=159 Hz), 127.9 (d, 1JC—H=157 Hz), 126.8 (d, 1JC—H=158 Hz), 118.1 (s), 78.5 (t, 2JC—H=9 Hz) 76.7 (dt, 1JC—H=252 Hz, 3JC—H=4 Hz), 43.8 (t, 1JC—H=126 Hz), 33.3 (t, 1JC—H=139 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.FC(F)(F)[C:13]([O:15]C(=O)C(F)(F)F)=[O:14].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Clc1cccc2cc[nH]c12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1c[nH]c2c(Cl)cccc12
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 7-chloroindole (7.1 g, 47.0 mmol) in dimethylformamide (60 ml) was cooled to 5° C. under nitrogen and trifluoroacetic anhydride (7.6 ml, 54.0 mmol) was added over 10 mins, maintaining the temperature below 10° C. The mixture was stirred at 5-10° C. for 2 h, then poured into water (600 ml). The resulting suspension was stirred for 15 mins and the 7-chloro-3-[(trifluoromethyl)carbonyl]-1H-indole precipitate was filtered off, washing with water to neutrality. The damp solid was suspended in 4 M aqueous sodium hydroxide (500 ml) and heated to reflux with stirring for 1 h. The mixture was cooled and washed with diethyl ether (2×100 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1H-indole-3-carboxylic acid as a pink solid (7.5 g, 38.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Yield: 22.2 %

Procedure:
A mixture of (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-one (398 mg, 2.12 mmol), PdCl2(Ph3P)2 (70 mg), Cs2CO3 (1.5 mL, 3.0 mmol) in 1,4-dioxane (15 mL) was heated under reflux for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (150 mg, 22%). 1H NMR (CDCl3): δ=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t, 3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41 (m, 1H), 2.92 (m, 1H), 3.63 (s, 3H), 5.69 (q, 1H), 6.69 (m, 1H), 6.99 (m, 4H), 7.18 (m, 2H) δ 7.27 (m, 2H) δ 7.42 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: C[Si](C)(C)CCCCl
Reactant: COc1ccc(N=Nc2ccc(O)cc2O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N=Nc2ccc(OCCC[Si](C)(C)C)cc2O)c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(4-methoxy-2-nitrophenylazo)benzene-1,3-diol (2.5 g, i.e. 0.0086 mol) and potassium carbonate (1.24 g) in 30 ml of dimethylformamide was brought to 70-75° C. 3-Chloropropyltrimethylsilane (1.24 g, i.e. 0.0086 mol) was added thereto over 20 minutes. The mixture was stirred at 75° C. for 6 hours. The reaction mixture was then poured into 50 ml of water and extracted with diisopropyl ether. The organic phase was dried, concentrated and purified by column chromatography (eluent: 50/50 heptane/CH2Cl2) to give compound (9) in the form of a red powder.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: CSCCCOc1ccc(Br)cc1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSCCCOc1ccc(-c2cc(CO)c(C)o2)cc1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (3.0 g), 1-bromo-4-[3-(methylsulfanyl)propoxy]benzene (2.8 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (0% ethyl acetate/hexane to 40% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.2 g, 84%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[Si:15]([O:14][C@H:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:10]([O:12][CH3:13])=[O:11])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H](O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Yield: 96.6 %

Procedure:
A solution of methyl (R)-2-(3,5-dichlorophenyl)-2-hydroxyethanoate (10.485 g), tert-butyidimethylsilyl chloride (8.07 g), and imidazole (3.64 g) in N,N-dimethylformamide (50 mL) was stirred under nitrogen for 18 h. Volatiles were then removed under vacuum and the residue was chromatographed on silica gel, eluting with hexanelethyl acetate (20:1) The title compound was obtained as a colorless oil (15.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].CO.ClCCl>CO>[C:1]([O:5][C:6]([N:17]([CH3:16])[NH2:18])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNN
Solvent: CO
Solvent: ClCCl
Product: CN(N)C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Di-tert-butyl-dicarbonate (0.23.69 g, 108.5 mmol) in methanol (40 mL) was added dropwise over a period of 1.5 h to a solution of methylhydrazine (5.00 g, 106.4 mmol) in methanol (20 mL) cooled to ˜5° C. When the addition was complete, tlc (10% methanol/dichloromethane) indicated that the reaction was complete. The reaction mixture was stored at −20° C. overnight, and then the solvent was evaporated to give N-methyl-hydrazinecarboxylic acid tert-butyl ester (14.34 g, 92%) as a colorless oil which was used directly in the subsequent step without further purification.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.[Na+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:28])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]([NH:1][NH2:2])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=S)N2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Hydrazine (4.5 ml) was added at room temperature to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepine-2(3H)-thione (described in Example B14) (0.0085 mol) in THF (50 ml). The mixture was stirred at room temperature for 30 min, poured out into ice water, saturated with NaCl and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 4.3 g (96.4%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-2-hydrazino-3,5dihydro-α-(1-methyl-1H-imidazol-5-yl)-4,1-benzothiazepine-7-methanol.