Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)[C:14](O)=[O:15]>>[CH:14]([C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:15].[CH:14]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])=[O:15]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C=O)c(O)c1
Product: COC(=O)c1cccc(O)c1C=O

Procedure:
Methyl 3-hydroxybenzoate (75.5 g) is dissolved in trifluoroacetic acid (2 L), thereto is added hexamethylene-tetramine tetramine (141.4 g) at room temperature, and the mixture is heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure and water is added to the resulting residue. The mixture is adjusted to pH 8 with potassium carbonate and sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1, 5/1, and then 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MS m/z: 179[M−H]−) and methyl 4-formyl-3-hydroxybenzoate (4.4 g) (ESI-MS m/z: 179[M−H]−).
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][O:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:33][C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[N:39][N:40]2[C:43]2[C:48]([NH2:49])=[CH:47][N:46]=[C:45]([NH2:50])[N:44]=2)=[CH:36][CH:35]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:50][C:45]1[N:44]=[C:43]([N:40]2[C:41]3[C:37](=[CH:36][CH:35]=[C:34]([I:33])[CH:42]=3)[CH:38]=[N:39]2)[C:48]([NH:49][C:6]([C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)=[O:8])=[CH:47][N:46]=1
Reactant: CC1(C(=O)O)COC1
Reactant: Nc1ncc(N)c(-n2ncc3ccc(I)cc32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(I)cc32)COC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-methyloxetane-3-carboxylic acid (8.7 mg, 0.075 mmol) and HATU (28.5 mg, 0.075 mmol) was added a solution of crude 4-(6-iodo-1H-indazol-1-yl)pyrimidine-2,5-diamine (11% purity, 120 mg, 0.037 mmol) in DMF (0.5 mL) followed by triethylamine (0.016 mL, 0.112 mmol). The mixture was stirred at RT for 10 min, then diluted with EtOAc (10 mL) and washed with water (2×3 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude compound. Purification by flash chromatography (Isolute column, 100% DCM to 3% MeOH in DCM) gave the title compound; m/z=+451.30 (M+H)+, (purity=76%). This intermediate was used in the next step without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[C:15]([CH3:16])=[C:14]([NH:17][S:18]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)(=[O:20])=[O:19])[O:13][N:12]=1.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[S:18]([NH:17][C:14]1[O:13][N:12]=[C:11]([CH3:10])[C:15]=1[CH3:16])(=[O:19])=[O:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
N,N-diisoproplyethylamine (222 μl, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 2-(trimethylsilyl)ethoxy methyl chloride (SEM chloride) (226 μl, 1.28 mmol) was added dropwise via syringe, and the resultant yellow solution was stirred at room temperature for 5 hours. Evaporation of solvents left an oil which was extracted into ethyl acetate, washed with water and brine solution and dried over magnesium sulfate. Flash chromatography of the residue using 10% ethyl acetate/hexanes yielded 321 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide as a clear colorless oil which solidified into a white solid upon standing (71% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]([O:14]CC(Cl)(Cl)Cl)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:33]=[N:34][C:35]([CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:36][CH:37]=2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:33]=[N:34][C:35]([CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[CH:36][CH:37]=3)=[CH:24][CH:23]=2)=[O:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reactant: Cc1ccc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reaction time: 1.5 h

Procedure:
A solution of 5-t-butyl-2-methyl-1-(2,2,2-trichloroethoxycarbonyl)aminobenzene (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55-60° C. and held for 1.5 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:6][C@@H:4]([CH2:3][C@H:2]([O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:1])[CH3:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)C[C@@H](C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C[C@@H](C)OS(C)(=O)=O)OS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of (2R,4R)-2,4-pentanediol (15.0 g), triethylamine (45.2 mL) and dichloromethane (350 mL) is cooled at a temperature close to 0° C. Methanesulfonyl chloride (24.5 mL) is added dropwise. The mixture is stirred for 3 h at a temperature close to 0° C., hydrolysed with a 1.5 N aqueous hydrochloric solution (100 mL) and extracted with dichloromethane. The organic extracts are pooled, washed with a saturated aqueous solution of sodium hydrogenocarbonate, then a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 36.06 g of (2R,4R)-2,4-pentanediol dimethanesulfonate as a brown oil used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:32]=[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:14]([CH2:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:32]=[C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:14]([CH2:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(C)C(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
In 3 ml of ethanol is dissolved 0.55 g of ethyl 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-2-methylpropanoate, to which is added 1.5 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for two hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 0.45 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-2-methylpropanoic acid as a white solid product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]=5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:31])=[O:32])[CH:3]=2)[CH:47]=[N:46]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 88 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 66C) (250 mg, 0.381 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (172 mg, 0.571 mmol) using Pd(PPh3)2Cl2 (14 mg, 0.019 mol) and sodium carbonate (121 mg, 1.143 mmol) in toluene/ethanol/water (20/10/4 ml) to afford 237 mg (88% yield) of the titled. MS: m/z=704.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1cccnc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1cccnc1
Yield: 81.9 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 3-aminopyridine (60 mg, 0.64 mmol) to give 170 mg of the title compound (80%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 10.58 (s, 1H), 8.31 (d, 1H, J=4.6 Hz), 8.07 (t, 2H, J=8.1 Hz), 7.79 (t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.10 (dd, 1H, J=4.6, 8.1 Hz), 5.17~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J=17.1 Hz), 2.76 (dd, 1H, J=13.5, 7.2 Hz), 2.57 (dd, 1H, J=13.5, 5.4 Hz), 2.07 (dm, 1H, J=13.5 Hz), 1.80~1.94 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Mg]Cl)(C)C.[CH2:27]([O:34][C:35](=[O:47])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]=[O:45])[C:38]=1[F:46])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1[Mg]Cl>O1CCCC1>[CH2:27]([O:34][C:35](=[O:47])[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[OH:45])[C:38]=1[F:46])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ncnc32)cc1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Agent: CC(C)[Mg]Cl
Agent: Cc1ccccc1[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c3c(Cl)ncnc32)cc1
Temperature: -50 °C
Yield: 26.9 %

Procedure:
In a round bottom flask, 4-chloro-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (29, 1.549 g, 3.572 mmol) is combined with 25.0 mL of tetrahydrofuran and the solution is cooled to −50° C. under nitrogen. Isopropylmagnesium chloride (2.76 mL, 2.0 M in tetrahydrofuran, 5.00 mmol) is added slowly and the reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C. In a separate vessel, (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (33, 805 mg, 2.76 mmol) in 5 mL of tetrhydrofuran is cooled to −5° C. and o-tolylmagnesium chloride (2.76 mL, 1 M in tetrahydrofuran, 2.76 mmol) is added dropwise slowly, maintaining the temperature at −5° C. for 1 hour. This is then cooled to −30° C. and added to the above 4-chloro-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine reaction mixture. The resulting reaction mixture is warmed to room temperature over 2-3 hours, then quenched with the addition of 1 M aqueous citric acid and extracted with ethyl acetate. The organic layer is washed with water, brine and dried over magnesium sulfate, then filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (34, 445 mg). MS (ESI) [M+H+]+=598.8.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=O)=[CH:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:18]3[CH:19]=[CH:20][O:16][CH:17]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Fc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.O>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:1][CH:2]2[CH2:3][CH2:4][C:5]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCC(N)CC1
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C)CCC(Nc2ncc(Br)cn2)CC1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
To an ice-cold solution of ethyl 4-amino-1-methylcyclohexanecarboxylate (0.18 g, 0.97 mmol) in EtOH (5.0 mL) was added DIPEA (0.52 mL, 2.91 mmol) followed by the addition of 5-bromo-2-chloropyrimidine (0.185 g, 0.97 mmol). The mixture was heated to 80° C. for 6-8 h after then cooled to rt, water added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 4% EtOAc:hexane to obtain the desired product (0.064 g, 19%). MS: 342.01 [M+H]+.
Reaction SMILES: [I-].[CH:2]1([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: c1ccc([PH](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphine iodide (725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. and then treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The resulting red reaction mixture was stirred at 0° C. for 45 minutes and then slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction mixture was warmed to 25° C. where it was stirred for 20 h. The reaction mixture was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (Flash 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%) as a yellow oil consisting of a 2:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c(C)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(-c2ccccn2)c(C)c1C=O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Dissolve dimethylsulfoxide (0.324 mL, 4.56 mmol) in DCM (10 mL) and cool the solution to −78° C. Add oxalyl chloride (0.239 mL, 2.74 mmol) to the mixture dropwise and stir at −78° C. for 20 min. Add (3,5-dimethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol (0.369 g, 1.82 mmol) in DCM (10 mL) and stir the mixture at −78° C. for one hr. Add triethylamine (1.27 mL, 9.12 mmol) to the mixture and warm to room temperature then stir for 18 hr. Add saturated aqueous sodium bicarbonate and extract the aqueous 3 times with DCM, dry organic solution then filter and concentrate. Purify using silica gel chromatography, eluting with 20:80 hexanes:ethyl acetate to give the title preparation as a yellow solid (0.358 g, 97%). MS (APCI): m/z=202 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)N.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([S:18][CH3:17])[CH:15]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 504.3 %

Procedure:
t-Butyl nitrite (4 ml) was added to a mixture of 5-chloro-2-methylaniline (4 g) and dimethyl disulphide (26.3 g) in chloroform. After the reaction started t-butyl nitrite (17.7 ml) and 5-chloro-2-methylaniline (16 g) were added simultaneously. The mixture was stirred at room temperature for 2 hours and left to stand overnight. The mixture was washed with water, aqueous hydrochloric acid (2M), water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-(methylsulphenyl)toluene (24.6 g) as a red oil, NMR (CDCl3): 2.2 (s,3H), 2.4 (s,3H), 6.85 (s,2H), 7.0 (s,1H).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6]O[Si](C)(C)C)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[C:6]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C#C[Si](C)(C)C
Temperature: 70 °C
Yield: 66.4 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:9]=12)[CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([N:6]1[C:17](=[O:18])[C:16]2=[CH:15][NH:14][C:10]3[C:9]2=[C:8]([CH:13]=[CH:12][N:11]=3)[CH2:7]1)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 49.8 %

Procedure:
Into a 8 mL scintillation vial equipped for stirring was added (S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (6 mg, 0.018 mmol). N,N-dimethylformamide (2 mL), HATU (8.29 mg, 0.022 mmol) and 4-methylmorpholine (2.2 mg, 0.022 mmol) were added and the solution was allowed to stir at room temperature for 1 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow solid (2.8 mg, 49.4%). 1H NMR (500 MHz, CD3OD) δ 0.97 (t, J=7.32 Hz, 3 H) 1.74-1.98 (m, 5 H) 1.98-2.14 (m, 1H) 3.08-3.22 (m, 1 H) 3.37-3.47 (m, 1 H) 3.65-3.77 (m, 1 H) 4.07 (s, 1 H) 5.05 (s, 2 H) 5.62 (dd, J=8.54, 7.08 Hz, 1 H) 7.11 (d, J=4.88 Hz, 1 H) 7.80 (s, 1 H) 8.29 (br. s., 1 H). [M+H] calc'd for C17H20N4O2, 313; found, 313.6.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[CH:12]([NH2:14])=O>>[Cl:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:14][CH:12]=[N:1][C:2]=2[CH:6]=1
Reactant: NC=O
Reactant: COC(=O)c1sc(Cl)cc1N
Product: O=c1[nH]cnc2cc(Cl)sc12
Temperature: 205 °C

Procedure:
In a 50 ml round bottom flask equipped with a mechanical stirrer and a reflux condenser, a mixture of 7.0 g (0.036 mole) of methyl 3-amino-5-chloro-2-thiophenecarboxylate and 15 ml of formamide was heated at 205° C. for 7 hours. Upon cooling to room temperature, the reaction solution afforded a precipitate which was filtered: yield about 3.3 g. The crude tan solid was taken up in hot methanol, treated with activated carbon, and filtered. Upon cooling to room temperature, the filtrate afforded yellow crystals of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one: m.p. 238°-239° C.; yield 2.5 g (36%); ir (KBr) 3427 cm-1, 1688, 1659, 1600, 1510, 1476, 1410 among others; 1H-nmr (CDCl3 +some trifluoroacetic acid) delta 7.5 ppm (s, 1H), 9.1 (s, 1H); mass spectrum 186 (molecular ion and parent peak with the expected isotope pattern), 159 (-27), 131 and others.