Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]([O:30][C:31]([CH2:33][S:34](Cl)(=[O:36])=[O:35])=[O:32])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([S:34]([CH2:33][C:31]([O:30][CH2:28][CH3:29])=[O:32])(=[O:36])=[O:35])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccccc1NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc(Cl)cc1)c1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a stirred solution of 48 g of methyl 2-(4-chlorophenylmethylamino)-phenylacetate in 1.2 l of toluene containing 26 ml of triethylamine is added 31 g of ethoxycarbonylmethylsulfonyl chloride in 50 ml of toluene in a dropwise manner over a period of 15 minutes maintaining the temperature of the reaction below 10°. The reaction mixture is then allowed to stir overnight at room temperature and poured into 2 1 of ice-water and the organic layer separated. The toluene extracts are washed with 3×750 ml brine, separated, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 40 g of methyl 2-[N-(4-chlorophenylmethyl)-ethoxycarbonylmethylsulfonylamino]-phenylacetate which may be crystallized from ether-hexane (4:1); m.p. 86°-88°.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:32](=[O:36])[C:33]([NH2:35])=[O:34])=[C:9]([CH3:31])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Li+]>O1CCOCC1>[NH2:35][C:33](=[O:34])[C:32]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:37])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]=1[CH3:31])=[O:36]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1-c1ccccc1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1-c1ccccc1)CCC3
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A slurry of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-phenylbenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (18 mg, 0.036 mmol) in dioxane (3 mL) was warmed until a clear solution was produced. The mixture was treated with 1 N lithium hydroxide solution (0.5 mL) and warmed briefly. After 2 h the solution was adjusted to pH 3 and the resulting precipitate collected via vacuum filtration to provide 6 mg (34%) of the title compound. MS ES+ m/e 483 (p+1).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH:12](O)[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>CC#N>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][I:39])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A stirred solution of 33-5 (0.78 g, 3.8 mmol), PPh3 (1.1 g, 4.3 mmol), imidazole (0.40 g, 5.8 mmol), and CH3CN (20 mL) at 0° C. was treated with iodine (1.0 g, 4.3 mmol). After 15 min the cooling bath was removed and stirring continued for 5 h. The reaction mixture was then diluted with H2O and extracted with hexanes (5×25 mL then 4×50 mL). The combined extracts were dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 33-6 (0.99 g) as a colorless oil. Rf 0.44 (silica, 20% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][C:26]1([CH3:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:29]2[CH2:30][CH2:31][C:26]([CH3:32])([CH3:25])[CH2:27][CH2:28]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: CC1(C)CCNCC1
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC1(C)CCN(CCCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (100 mg, 0.23 mmol) and 4,4-dimethyl-piperidine (45.0 mg, 0.28 mmol). The title compound was afforded as a solid (30.0 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.43 (1H, s), 3.23 (2H, m), 2.95 (4H, m), 1.82 (2H, m), 1.35 (4H, m), 1.23 (2H, m), 0.94 (6H, s). MS m/z: 503.34, 505.37 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:8]2[CH3:21])=[CH:4][CH:3]=1)=[O:42]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1c(C)n(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
Into a dry reaction vessel, methyl 2-[1-(4-aminobenzyl)-2-methyl-1H-indol-3-yl]acetate (260 mg, 0.843 mmol) was added, and dissolved in 10 mL dichloromethane. Triethylamine (0.36 mL, 2.59 mmol) was added, and 2-naphthoyl chloride (195 mg, 1.02 mmol) was added slowly in an ice bath. Upon completion of addition, it was reacted for 1 h in an ice bath, and stirred at room temperature for 3 days. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 150 mg, at a yield of 38.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[C:11]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)cc(S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(C(=O)O)cc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2′,4′-difluoro-5-(methylsulfonyl)biphenyl-3-carboxylate (77 mg, 0.21 mmol) in dichloromethane (1.05 mL) was added trifluoroacetic acid (1.05 mL). The mixture was stirred at ambient temperature for 30 min. The mixture was concentrated to dryness to give the title compound.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[CH:8][CH:7]=1.O>C(#N)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]=2[CH:4]=[CH:3][CH:1]=[O:2])=[CH:8][CH:7]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC=O
Solvent: CC#N
Solvent: O
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Use of the crude acrolein coming from Example 3a. To a suspension of 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) phosphorus oxychloride (31.4 g) in acetonitrile (35 ml) cooled at 5° C. a solution of crude acrolein (32.3 g from Example 3a) in acetonitrile (40 ml) is added dropwise in 30 minutes. The reaction mixture is then warmed to 60° C. and kept under stirring at 60° C. for 4 hours; water (300 ml) is added and after 1 hour at 60° C. the formed solid is filtered on Buchner and washed with 75 ml of water. The wet solid (49.7 g) is dissolved in toluene (250 ml), celite (1 g) and charcoal (0.5 g) are added and the mixture is stirred at room temperature for 30 minutes. After filtration of the solid, the solvent is distilled off at reduced pressure and the residue is dissolved at 75° C. with isopropanol (72 ml). The solution is cooled at 20° C. and stirred at room temperature for 1 hour. The precipitate is filtered on Buchner, washed twice with isopropanol (15 ml) and dried at 60° C. under vacuum. 30.2 g (70% molar yield) of the product are obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=3)[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(N2CCCCc3ccccc32)CC1
Reaction time: 15 h
Yield: 49.4 %

Procedure:
A solution of compound 2 (1.0 g, 6.79 mmol), N-methyl-4-piperidone (1.00 mL, 8.15 mmol) and acetic acid (0.96 mL, 16.98 mmol) in dry methanol (10 mL) was treated with NaCNBH3 (0.51 g, 8.15 mmol) at 0° C. The reaction mixture was brought to room temperature and stirred overnight (15 hours). The reaction was quenched with 2N NaOH (100 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic fractions were washed with brine (30 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (2.0 N NH3 in MeOH:CH2Cl2, 3:97) to give compound 3 (0.82 g, 49.4%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.55 (m, 4H), 1.74 (m, 4H), 1.96 (td, 2H, J=11.3, 2.6 Hz), 2.15 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.17 (m, 1H), 6.74 (t, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.2 Hz), 7.01 (m, 2H); EI-MS (m/z, %): 244 (M+, 24), 97 (100), 71 (37).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[N:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][NH:26]3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:6]([OH:40])=[O:5])=[O:29])=[CH:12][CH:13]=3)[N:28]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1

Procedure:
A solution of 32-6 (221 mg, 0.39 mmol), TFA (5 mL) and CH2Cl2 (50 mL) was stirred under ambient conditions for 18 h. The reaction was concentrated and the solid residue purified by flash chromatography (silica, 19:1 EtOH/NH4OH) to give 32-7 as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:24]C(=O)C(C)(C)C)=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.C[O-].[Na+].Cl.[NH2:35][CH2:36][C:37]([OH:39])=[O:38]>CO>[CH2:17]([N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:5])[C:7]([OH:24])=[C:8]2[C:14]([CH3:15])=[C:13]1[CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)n(Cc2ccccc2)c2cnc(C(=O)NCC(=O)O)c(O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (70 mg, 0.171 mmol), NaOMe in MeOH (1.02 mL, 0.51 mmol, 0.5 M), and methanol (3 mL) was stirred overnight at 60° C.; then the reaction was cooled to room temperature and acidified to pH=6 with 2 M HCl aqueous solution. The solvents were then removed, and the residue was oil pumped to dryness. The left residue was then refluxed with glycine (257 mg, 3.42 mmol), NaOMe in MeOH (5.13 mL, 2.57 mmol, 0.5 M) overnight; the solvent was removed, the residue was dissolved in water and then extracted once with MTBE, the aqueous layer was acidified with HCl (2 M) aqueous solution to pH=1-2; the precipitated solids were collected by filtration, washed briefly with water and freeze-dried to give powder, the desired title compound (53 mg, 88%); ESI MS (m/z): 354 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].Cl.[F:14][C:15]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:16]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:15]=2[F:14])[CH2:23][CH2:22]1
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (492 mg, 2.460 mmol) in DCM (5 mL) at 0° C. was treated with 4-(2,4-difluorophenoxyl)piperidine hydrochloride (676 mg, 2.71 mmol) and DIPEA (1.29 mL, 7.38 mmol). The reaction mixture was allowed to stir overnight, gradually warming to room temperature. The reaction mixture was quenched with the addition of saturated aqueous NH4Cl and was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 20% to 60% EtOAc in heptanes to give the title compound as a pale yellow solid (736.2 mg, 79%). ESI-MS m/z [M+H]+ 377.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15](=[O:17])[CH3:16])[C@H:10]([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:15]([O:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:18])(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1CCN(Cc2ccccc2)C[C@H]1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)O[C@@H]1CCNC[C@H]1C

Procedure:
A mixture of trans-1-benzyl-4-(RS)-acetoxy-3-(RS)-methylpiperidine [7 g, 28.5 mmole {prepared according to literature procedure described in A. F. Casy and W. K. Jeffery, Can.J.Chem., 50 (1972), 803}] and 20% palladium hydroxide (1.8 g) in methanol (25 ml) was stirred at 50-55° C. under hydrogen (1 atmosphere) for 20 hr. The catalyst was filtered off and washed with methanol. Filtrate was concentrated to give trans-4-(RS)-acetoxy-3-(RS)-methyl piperidine as oil. Yield 4.41 g (100%), C8H15NO2, m/z 158 (M+1), PMR (CDCl3): 0.94 (3H, d, CH3, j=8 Hz), 1.42 (1H, m, H3), 1.67 (1H, m, H5), 1.98 (1H, m, H5), 2.08 (3H, s, COCH3), 2.3 (1H, t, H2, j=12 Hz), 2.68 (1H, dt, H2, j=3 Hz, 12 Hz), 3.04 (2H, in, H6), 4.5 (1H, dt, H4, j=3 Hz, 12 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14](Cl)[N:13]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:24])[N:13]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc(C(F)(F)F)c(Cl)n2)C1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N2CC(NC(=O)OC(C)(C)C)C2)ccc1C(F)(F)F
Yield: 72.9 %

Procedure:
A mixture of D13 (1.92 g, 5.55 mmol), methylboronic acid, (490 mg, 8.19 mmol) and tetrakis(triphenylphosphine) Pd(0), (315 mg) in dioxan (25 ml) was treated with aqueous sodium carbonate (7 ml). The mixture was heated at reflux for 16 h, allowed to cool, then diluted with water and extracted with DCM (2×50 ml). The organic phase was washed with brine, dried and concentrated to give a solid. T.I.c anlaysis showed that substantial quantities of starting material remained. The crude material was treated again with methylboronic acid, (490 mg, 8.19 mM) and tetrakis(triphenylphosphine) Pd(0), (315 mg) as above. T.I.c. showed complete conversion to the product which was purified by column chromatography to give the title compound as a colourless solid (1.34 g, 74%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH2:3]1.[OH-].[Na+]>C(O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)-pyrimidine-5-carboxylate (5 g, 16.06 mmol) was dissolved in ethanol (50 mL) before adding sodium hydroxide solution (2 M in water, 20 mL, 40.0 mmol) and stirring at room temperature. After 30 min, LCMS shows mostly desired product mass. The reaction mixture was neutralized by addition of saturated aqueous citric acid solution. The resulting precipitate was filtered and dried to give 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol, 99% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (br. s., 1H), 8.44-8.54 (m, 2H), 4.74 (d, J=3.90 Hz, 1H), 3.97-4.12 (m, 1H), 3.56 (d, J=3.12 Hz, 1H), 2.46 (s, 3H), 2.05-2.16 (m, 1H), 1.84 (d, J=10.15 Hz, 1H), 1.65-1.80 (m, 2H), 1.11-1.36 (m, 4H); MS (ESI) m/z 284.1 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:6][CH:7]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(NNc1ccc(Br)cn1)c1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccccc1-c1nnc2ccc(Br)cn12
Temperature: 85 °C
Yield: 30.3 %

Procedure:
A mixture of 2-chloro-benzoic acid N′-(5-bromo-pyridin-2-yl)hydrazide (2.96 g, 9.1 mmol) in POCl3 (15 mL) was heated at 85° C. for 48 hours. The solvent was removed in vacuo, and the residue quenched with saturated Na2CO3 and EtOAc. The layers were separated, and the organic layer concentrated in vacuo to minimal volume. The resulting solid was filtered and purified by flash chromatography to give the title compound (0.85 g, 30%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-:18].[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+].[OH-].[Na+]>O>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: c1ccc2sc(SN3CCOCC3)nc2c1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=S(c1nc2ccccc2s1)N1CCOCC1
Temperature: 25 °C
Yield: 93 %

Procedure:
37.8 parts of 2-morpholinosulphenyl-benzothiazole are suspended in 65 parts of water containing 5 parts of sodium carbonate and 1 part of sodium bicarbonate. 90 parts by volume of an aqueous solution of sodium hypochlorite titrating 177 g. of NaClO and 3 g. of free caustic soda per liter are slowly introduced in a period of one hour into the well stirred suspension. The temperature is maintained at 25° C. and the mixture is stirred for 20 hours at this temperature. It is filtered, the solid is washed until neutral and dried under vacuum. 37 parts of 2-morpholinosulphinyl-benzothiazole melting at 93°-94° C. are obtained, that is a yield of 93%. On recrystallisation from a benzene/petrol ether mixture, the melting point is 99° C. (uncorrected).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>S1(CCCC1)(=O)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 160 °C
Reaction time: 14.5 h
Yield: 85.4 %

Procedure:
To a solution of 38.1 g of 4-chlorophenyl methyl sulfone and 37.2 g of 4-methoxyphenol dissolved in 150 ml of sulfolane was added 41.5 g of K2CO3. The mixture was heated at 160° C. for 7 hrs and then at 170° C. for 14.5 hrs and cooled. The mixture was poured into aqueous NaOH and the crystalline product collected by filtration, washed well with water and dried, which gave 47.5 g (85.3% yield) of product. Recrystallization from ethanol gave purified 4-(4-(methylsulfonyl)phenoxy)-1-methoxybenzene, mp 151.5°-153° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH:4]=1)#[N:2].C(O)C.O.[Cl-].[NH4+]>[Zn].C(OCC)(=O)C.O1CCCC1>[NH2:21][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: N#Cc1cn(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)c(N)c2)c2ccccc12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 27.7 %

Procedure:
To a solution of 4-(3-cyanoindol-1-yl)-2-nitrobenzoic acid (0.012 g) in a mixed solvent of ethanol (1 mL), water (0.5 mL) and tetrahydrofuran (0.5 mL) were added zinc powder (0.041 g) and ammonium chloride (0.004 g) at room temperature, and this mixture was stirred at 80° C. for 2.5 hours. After cooling to ambient temperature, to this reaction mixture was added ethyl acetate. This insoluble material was removed by filtration and this filtrate was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.003 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][C:30]([CH3:36])([OH:35])[C:31]([F:34])([F:33])[F:32]>>[F:32][C:31]([F:34])([F:33])[C:30]([OH:35])([CH3:36])[CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CC(O)(CCN)C(F)(F)F
Product: CC(O)(CCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1)C(F)(F)F

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 4-amino-1,1,1-trifluoro-2-methylbutan-2-ol in a manner similar to that described in Example 11.