Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10][C:11]([O:13]CC)=[O:12])=[C:8]([S:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CSc1cccc(OCC)c1CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(SCC(=O)O)c1CC(=O)O

Procedure:
To a solution of ethyl 6-ethoxy-2-(ethoxycarbonyl-methylthio)-phenylacetate (17.8 g) in ethanol (112 mL) is added a solution of potassium hydroxide (85%, 7.21 g) in water (28 mL). The solution is refluxed for 2 hours, is concentrated in vacuo to remove the ethanol, and is diluted with water (200 mL). Hydrochloric acid (12 N, 10.0 mL) is added. The product which originally precipitates as an oil slowly crystallizes. After crystallization is complete the solid is filtered off, air-dried for 2 hours and then dried in vacuo at 50° to obtain 6-ethoxy-2-(carboxymethylthio)phenylacetic acid, m.p. 147°-150°.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH2:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.O>[Cl:31][C:32]1[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=1[CH2:34][S:35]([NH:10][C:9]1[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]2[S:12][C:2]([CH3:1])=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C:4]=12)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4Cl)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 2-chlorobenzylsulfonyl chloride (198 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 2-chlorobenzylsulfonyl chloride (79.2 mg, 0.352 mmol). The reaction mixture was then stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (6 mg). LCMS (A) m/z: 473 [M+1]+, Rt 1.07 min (basic).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][C@@H:22]3[CH3:33])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]([O:36]C)=[O:35])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+].O>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][C@@H:22]3[CH3:33])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]([OH:36])=[O:35])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCN(c4ccccn4)C[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.30 mmol) in methanol (20 ml) was added sodium hydroxide (36 mg, 0.90 mmol) and water (1 ml) The resulting solution was stirred overnight at room temperature and the mixture was concentrated under vacuum dissolved in water (30 ml), adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (44 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)([N:14]1C=CN=C1)=O.N>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([NH2:14])=[O:11])[NH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cc([N+](=O)[O-])n[nH]1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 5-nitro-3-pyrazolecarboxylic acid (6.28 mg, 40 mmol) in DMF (30 mL) was added carbonyldiimidazole (12.96 mg, 80 mmol) The mixture was allowed to stir for 30 min, and ammonia in MeOH (2M, 60 mL) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to afford the crude product which was then washed with ether to afford 3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 48%), which was used directly in the next step without further purification. LC-MS (ESI) m/z 155 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:27]2[CH2:28][CH2:29][CH:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH2:31][CH2:32]2)=[O:17])=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CS(=O)(=O)NC1CCNCC1
Agent: Cl
Product: CS(=O)(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
The title compound was prepared according to EXAMPLE 229 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228) and N-piperidin-4-yl methanesulfonamide hydrochloride (Preparation 92). Purification gave the title compound as an off-white powder. m/z (ES+)=522.30 [M+H]+; RT=3.29 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:23][NH2:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:24][N:23]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(C)c(C)c2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc(C)c(C)c3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(3,4-dimethylbenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [C:1](O)(=O)[C:2](O)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][NH2:19])[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1.C(C(CC)(CC)C([O-])([O-])[O-])C>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:1]([CH3:2])=[N:19][CH2:18][CH:16]3[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1
Reactant: O=C(O)C(=O)O
Reactant: NCC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC#N
Product: CC1=NCC2C[N+]([O-])=C(c3ccccc3F)c3cc(Cl)ccc3N12
Reaction time: 1 h

Procedure:
A slurry of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide oxalate salt (VIII, EXAMPLE 6, 35 g, 85 mmol) and triethylorthoacetate (23.5 ml, 128 mmol) in acetonitrile (175 ml) is stirred at reflux for 2 hr during which time the 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide (VIII) dissolves and ethanol/acetonitrile (about 75 ml) is removed by distillation under ordinary pressure. TLC and HPLC analysis shows the reaction is complete. The temperature is adjusted to 40° and methyl t-butyl ether (175 ml) is added dropwise over about 1 hr. The resulting slurry is cooled to 5°, stirred 1 hr, the solids are collected and are washed with t-butyl ether. The product is dried in the vacuum oven at 35° to give the title compound as the oxalate salt, mp=178-180°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.28.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]([CH3:61])([CH3:60])[CH3:59])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:58]([NH:55][C:56]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:57])([CH3:61])([CH3:60])[CH3:59]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanato-2-methyl-propane as starting materials in 32% yield. LCMS for C29H36ClN8O2 (M+H)+: m/z=563.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:36]=[CH:35][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:36]=[CH:35][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH3:27])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CN(CCNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cc(Cl)cc2cc[nH]c12)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
98 mg (0.50 mol) of 5-chloro-1H-indole-7-carboxylic acid, 165 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-(4-chloro-phenyl)-N-methyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 140 mg (55%) product as a colorless oil. MS (ISP) 508.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccccc1C(=O)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)N1CCC(CCN2CCC(C(N)=O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 70.9 %

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(2-methoxybenzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (323 mg, 0.68 mmol) was dissolved in THF (4 mL) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (165 mg, 0.69 mmol), water (1 mL), and sodium bicarbonate (105 mg, 1.25 mmol) were added and the solution was heated at reflux for 21 hours. The solution was concentrated in vacuo. The aqueous phase was extracted with dichloromethane (3×) and the organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient from ethyl acetate to 6% methanol in dichloromethane to give 280 mg (73%) of the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][C:18]5[N:23]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)[N:22]=[CH:21][C:19]=5[C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[C:24]1([N:23]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[C:19]=3[CH:21]=[N:22]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCc2c-4cnn2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-n2ncc3c2CCc2cnc4[nH]ncc4c2-3)cc1
Yield: 19.2 %

Procedure:
A solution of 3-(4-methoxybenzyl)-8-phenyl-3,6,7,8-tetrahydrodipyrazolo[3,4-c:4′,3′-f]isoquinoline (0.7 g, 1.72 mmol) in trifluoroacetic acid (4 mL) was heated at 100° C. for 2 hours. The reaction mixture was poured into water (50 mL) and basified with aqueous potassium carbonate to pH of 11. The reaction mixture was then extracted with dichloromethane (3×75 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give a residue, which was further purified by crystallization from methanol and isopropanol to give the desired product (0.095 g, 18%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.43 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.64-7.55 (m, 4H), 7.45 (t, J=3.2 Hz, 1H), 3.12 (s, 4H); LCMS [M+H]: 288.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][OH:12])[CH:9]=[CH:10][C:2]1=2>ClCCl.[O-2].[O-2].[Mn+4]>[S:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: OCc1ccc2c(n1)NCCS2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2c(n1)NCCS2
Yield: 50.3 %

Procedure:
The alcohol (a) (0.482 g) in dry dichloromethane (50 ml) was stirred with manganese dioxide (1.2 g) for 18 hours and the mixture was filtered. The filtrate was evaporated and chomatographed on silica gel, eluting with methanol-dichloromethane (1:50) to afford a yellow solid (0.24 g).
Reaction SMILES: [Li][C:2]#[N:3].C1(C)C=CC(S(O[CH2:14][C@H:15]([OH:26])[CH2:16][C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)(=O)=O)=CC=1.[C-]#N.[Na+]>CN(C=O)C>[OH:26][C@H:15]([CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:2]#[N:3]
Reactant: [Li]C#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)Cc2cc3ccccc3[nH]2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC[C@H](O)Cc1cc2ccccc2[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 0.5 M LiCN in DMF (30 mL) was added (R)-3-indol-2-yl-2-hydroxypropanyl p-toluenesulfonate (R)-2 (5.6 g, 16.2 mmol) and sodium cyanide (1.5 g, 30.6 mmol). The reaction mixture was stirred for 1 hour at 100° C., cooled to room temperature, poured into 80 mL ice-water, and extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with saturated sodium bicarbonate (2×50 mL), brine (2×30 mL), dried over anhydrous sodium sulfate, and evaporated to yield a deep red oil. The oil was purified by flash chromatography (hexane:ethyl acetate 2:3) to give 2.4 g (74%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C.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>[CH3:23][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:38]4[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CN(C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O
Temperature: 140 °C

Procedure:
A suspension of N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-N-methyl-methanesulfonamide (148 mg, 0.32 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (86 mg, 0.39 mmol), 1M Na2CO3 (1 ml, 1 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) in acetonitrile was heated in a microwave at 140° C. for 25 mins. The reaction was then acidified with 2N HCl (aq) extracted with ethyl acetate, the water layer separated and basified with K2CO3 (sat. aq) resulting in a white precipitate as 292 which was filtered and dried (120 mg, 72%). NMR (DMSO, 400 MHz), 1.62-1.67 (2H, m), 1.74-1.82 (2H, m), 2.18-2.24 (2H, m), 2.77 (3H, s), 2.95 (3H, s), 2.97-3.03 (2H, m), 3.57-3.66 (1H, m), 3.85 (4H, t, J=4.4), 3.89 (2H, s), 4.00 (4H, t, J=4.4), 6.37 (2H, s), 6.56 (1H, d, J=8.8), 7.36 (1H, s), 8.34 (1H, dd, J=8.8, 2.4), 8.99 (1H, d, J=2.4). MS: (ESI+): MH+ 518
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[C:5]([NH:7][NH:8][C:9](=O)[CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)[S:46]2)=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[C:5]1[S:46][C:9]([CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[N:8][N:7]=1
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Reactant: COc1ccccc1C(=O)NNC(=O)C(C(=O)OCc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1nnc(C(C(=O)OCc2ccccc2)c2ccccc2)s1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of compound 36 (539 mg, 1.02 mmol) in THF (4 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (539 mg, 1.02 mmol) and the reaction stirred overnight. The crude material was concentrated and purified by silica gel column chromatography with gradient of ethyl acetate (5-40%) in hexane to afford compound 37 (325 mg, 76%) as a white solid. LRMS (ESI): (calc) 416.4, (found) 417.4 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-5-methylbiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.2 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:16]I>CC(C)=O>[CH3:16][O:11][C:10](=[O:12])[CH2:9][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Reactant: CI
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 123.1 %

Procedure:
Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added, and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 (21.5 g) as a light yellow oil. 1H NMR (500 MHz, acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[CH2:26]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one. mp 95-110° C.