Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[NH:16][C:15]4=[O:23])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:39])[CH:34]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of 0.050 g of 1,3-dihydro-1-{trans-4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.023 mL of triethylamine in 1.5mL of dichloromethane was added 0.024 g of nicotinoyl chloride hydrochloride. After 12 h, 20 mL of saturated sodium carbonate was added, the organic layer was separated, and the aqueous layer extracted with two addtional 20 mL portions of chloroform. The combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol/10% conc. NH4OH in chloroform gave 0.024 g of 1,3-dihydro-1-{trans -4-[1-(3-pyridinecarbonyl)-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.04 (s, 1H), 8.68 (dd, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.06 (m, 3H), 4.67 (br s, 1H), 3.75 (br s, 1H), 3.18 (br s, 2H), 2.99 (br s, 1H), 2.87 (br s, 1H), 2.55 (q, 2H), 2.13-1.9 (m, 4 H), 1.72-1.3 (m, 7H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C24H29N5O2.2HCl.0.90 CHCl3.0.25 CH3CO2CH2CH3C: 50.02, H: 5.95, N: 11.26 found C: 51.28, H: 5.49, N: 11.53.
Reaction SMILES: [CH:1]1([C@@H:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:19]=[C:20]4[C:26]([C:27](O)=[O:28])=[CH:25][N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]4=[N:22][CH:23]=3)=[N:13][N:14]2[CH3:17])=[CH:10][CH:9]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C@@H:4]([NH:6][C:27]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:12]4[C:11]5[C:15](=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=5)[N:14]([CH3:17])[N:13]=4)[N:19]=3)[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)=[O:28])[CH3:5])[CH2:3][CH2:2]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@H](N)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1

Procedure:
A solution of (S)-1-cyclopropylethanamine (32 mg, 0.373 mmol), 3 mL of dichloromethane, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (77 mg, 0.169 mmol), 4-dimethylaminopyridine (21 mg, 0.169 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.371 mmol) was stirred 18 h, then concentrated to an off-white solid. The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution; dried over Na2SO4, filtered and concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification. MS: (M+Na)+=547.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH:7]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Fc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Nc2cc(I)ccn2)c1
Temperature: 130 °C
Yield: 16 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (500 mg, 2.24 mmol), 3-nitroaniline (620 mg, 4.49 mmol), and Cs2CO3 (1460 mg, 4.48 mmol) in dry DMF (12.5 mL) was heated for 1 h at 130° C. in a microwave oven. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (DCM/MeOH 100:0 to 95:5) to yield the desired product A5 as a white solid (122 mg, 16%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 7.21 (d, J=5.4 Hz, 1H), 7.29 (s, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.93 (m, 2H), 8.74 (t, J=2.1 Hz, 1H), 9.62 (s, 1H). MS (ES) C11H8IN3O2 requires: 341. found: 342 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:8][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 17 ml DCM and 0.5 ml pyridine, 1.5 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[C:9](O)[CH:10]=[C:11]([C:13]([N:15]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:12]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([N:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:10]=[C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH:8]=1
Reactant: C=CCN(C(=O)c1cc(O)cc(Cl)c1)C1CCCC1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCO)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of tetrahydrofuran (100 mL), 1,3-propanediol (1.6 mL, 30 mmol) and phenol 16 (4.3 g, 15 mmol) at 0° C., was added diethyl azodicarboxylate (DEAD, 3.6 mL, 23 mmol) dropwise over 10 min. The solution was warmed to ambient temperature and stirred for 16 h, prior to concentration in vaciio. The oil was partially purified by chromatography on silica gel to provide alcohol 17 (3.9 g) contaminated with Mitsunobu by-products. This material was used directly in subsequent experiments. 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 2H), 6.8 (s, 1H), 5.9 (bs, 1H), 5.18 (d, 2H), 4.4-3.8 (m, 7H), 2.05 (m, 2H), 1.4-1.9 (m, 10H). Mass spectrum (CI) calcd. for C18H24NO3Cl: 338 (M+H). Found: 338.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>ClCCl>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:5][C:4]=1[C:1](=[O:3])[NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)O)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Yield: 95.3 %

Procedure:
Using methyl 3-(3-carboxy-4-methoxyphenyl)-2,2-dimethylpropanoate (204 mg, 0.766 mmol), triethylamine (135 ml, 0.969 mmol), ethyl chlorocarbonate (82.0 ml, 0.843 mmol), 4-(trifluoromethyl)benzylamine (120 ml, 0.842 mmol) and 8 ml of dehydrated dichloromethane and conducting the procedure similar to Example 7, 309 mg (95%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25]CC)=O)[O:20][N:19]=2)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:28][NH2:29])=[O:25])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (10.5 mmol, 4.0 g) in MeOH (50 mL) was cooled to 0° C., and 99% NH2NH2.H2O (62.8 mmol, 3.2 g) was then added dropwise. In the period of addition, lots of white precipitate was generated, kept stirring for 15 mins, the white solid was collected by filtration. The white solid was dispersed into MeOH again, sonicated for 10 mins, filtered, to give the final product (3.3 g, 86.0%). m/e+=369 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.9-10.5 (1H, D, brd, NH), δ 8.44-8.42 (1H, D, d, J=6.8 Hz, ArH), δ 7.87-7.85 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.67-7.64 (1H, D, d, J=9.2 Hz, ArH), δ 7.56-7.54 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.38-7.25 (1H, D, m, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.75 (2H, D, s, CH2).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:32]([O:34]C)=O)=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])[C:32](=[O:34])[NH:2][N:3]=2)=[O:14])[CH2:9][CH2:8]1)[CH3:5]
Reactant: NN
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
Hydrazine hydrate (0.037 mL, 0.49 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (53) (0.200 g, 0.45 mmol) in acetic acid (8 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford a crude gum, which was triturated with a mixture of NMP, DMSO and water to give a solid which was collected by filtration, washed with ether and dried under vacuum to give the desired compound as a white solid (0.112 g, 58.4% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.42 (1H, m), 1.71 (1H, m), 1.86 (1H, m), 2.27 (3H, s), 2.51 (3H, s), 3.04 (1H, m), 3.24-3.39 (2H, m), 3.46 (2H, m), 3.52 (1H, m), 3.97 (1H, s), 4.07 (2H, s), 7.13-7.30 (3H, m), 11.07 (1H, s), 11.94 (1H, s); m/z (LC-MS, ESI+), RT=1.62 min (M+H=427.12).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.O[N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:31]1([O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]5)=[CH:14][CH:13]=4)[CH2:20][CH2:19]3)=[CH:22][CH:23]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)C[C@H](C)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)On5nnc6ccccc65)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A mixture of 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid (1.01 g), 1-hydroxybenzotriazole (370 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (986 mg) in methylene chloride (100 ml) was stirred for 4 hours at room temperature then evaporated under reduced pressure. Water was added to the residue and the resulting precipitate collected by filtration, washed with water, then dried under hi-vacuum to give 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (1.197 g).
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH:1]1(/[CH:6]=[CH:7]/[C:8]([Cl:14])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/C1CCCC1
Solvent: ClCCl
Product: O=C(Cl)/C=C/C1CCCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2E)-3-cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0° C. was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0° C. for 40 minutes, then at room temperature for 2 hours. The volatiles were evaporated to afford (2E)-3-cyclopentylacryloyl chloride as a colorless liquid. A portion of this (2E)-3-cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was stirred for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49]O)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:49][CH:46]2[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:42])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: Oc1cccc(COc2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 272 mg (0.809 mmol) of 3-[(2-chlorophenoxy) methyl]phenol, as prepared in the preceding step, in methylene chloride (5 mL) containing 275 mg (1.05 mmol) of triphenylphosphine and 208 mg (0.97 mmol) of N-(tert-butoxycarbonyl)-4-piperidinemethanol, as prepared in step (b) of Example 1, was added slowly 165 μL (1.04 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and flash chromatographed (hexane/ethyl acetate (1:4 to 1:2)) to give 221 mg (58% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.38 (dd, 1 H, J=1.5, 7.8 Hz), 7.28 (t, 1 H, J=8.1 Hz), 7.15-7.21 (m, 1 H), 8.82-7.03 (m, 5 H), 5.13 (s, 2 H), 3.82 (d, 2 H, J=6.4 Hz), 2.74 (t, 2 H), 1.91-2.00 (m, 1 H), 1.84 (d, 2 H), and 1.47 (s, 9 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H30ClNO4S: 454.2 (M+Na). Found: 454.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1Br.[CH2:15](Cl)Cl.C([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[CH3:15]
Reactant: ClCCl
Reactant: CN1C(=O)CCc2cc(Br)c(N)cc21
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2c(cc1N)N(C)C(=O)CC2
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 7-amino-6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one 1 (57 mg, 0.615 mmol) dissolved in 4 ml degassed dioxane was added 50 mg (0.0615 mmol) PdCl2dppf.CH2Cl2, K2CO3 (255 mg 1.845 mmol), 400 ul H2O, and 86 ul (0.615 mmol) trimethylboroxine. The mixture was heated to 110° C. and stirred for 12 hours, then cooled and partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 75 mg of 7-amino-1,6-dimethyl-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1.[Cl:24]C(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:24][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 110 (1.25 g, 3.77 mmol) was added to toluene (20.0 mL) under an atmosphere of nitrogen at room temperature. Isopropyl chloroformate in toluene (1.0 M, 4.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours to provide a solution of 3-chloromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:12][CH2:13][C:14]3([CH3:18])[CH2:17][O:16][CH2:15]3)=[CH:6][C:7](C#N)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[CH:21]([OH:23])=[O:22]>C(O)C>[CH:1]1([C:4]2[C:5]([O:12][CH2:13][C:14]3([CH3:18])[CH2:15][O:16][CH2:17]3)=[CH:6][C:7]([C:21]([OH:23])=[O:22])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=CO
Reactant: CC1(COc2cc(C#N)ncc2C2CC2)COC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinonitrile (1.73 g, 7.08 mmol) in ethanol (20 ml) in a microwave vial was added a 4.0M aqueous solution of potassium hydroxide (6.2 ml, 24.8 mmol). The vial was sealed and mixture was stirred at 85° C. overnight. The reaction was cooled down to 0° C. followed by addition of formic acid (1.14 g, 951 μl, 24.8 mmol) to acidify the reaction mixture. The crude solution was then evaporated to dryness and the crude material was directly purified by preparative HPLC to yield the title compound (1.34 g, 72%) as white solid. MS (ESI, m/z): 264.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:19])=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(C(=O)OC(C)(C)C)oc2ccc(Br)c(O)c12
Temperature: 0 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To 200 mg (0.81 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 2 mL of carbon tetrachloride. The mixture was cooled with water/ice bath while 1 equivalent of N-bromosuccinimide was added in small portions. After stirring at 0° C. for 6 h, the reaction mixture was filtered and the filtrate was loaded onto a column and purified by column chromatography to give 225 mg (85% yield) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].Cl[CH2:35][CH2:36][N:37]=[C:38]=[S:39]>C(Cl)Cl.CCN(CC)CC>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:38]3[S:39][CH2:35][CH2:36][N:37]=3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Reactant: S=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCS3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure AA. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 39 mg, 0.086 mmol) in CH2Cl2 (1 ml) was added 2-chloroethyl isothiocyanate (25 μl, 0.26 mmol) and Et3N (1 drop). The reaction was stirred at room temperature for 16 h and was purified directly by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH:1]#[C:2][C:3]#[CH:4].[OH-].[K+].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([C:1]#[C:2][C:3]#[CH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Reactant: C#CC#C
Agent: [K+]
Agent: [OH-]
Product: C#CC#Cc1ccccc1

Procedure:
The thus-obtained diacetylene derivative represented by the formula (IX) is then dissolved in benzene and refluxed while being heated for 30 min. to 1 hour in the presence of potassium hydroxide. After the reaction has been completed, the reaction mixture is filtered, and the solvent is then evaporated. The residure is then purified by silica-gel column chromatography to obtain a phenylbutadiyne derivative represented by the formula (X).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([O:69][CH3:70])[CH:63]=2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH2:58][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH:68][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:10]=5)[N:23]4[N:22]=3)=[C:64]([O:69][CH3:70])[CH:63]=2)[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (120 mg, 0.3464 mmol) and N,N-Diisopropylethylamine (0.242 mL, 1.39 mmol) in 3.0 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (136 mg, 0.381 mmol). After stirring at room temperature for 30 minutes, 4-(4-Amino-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.460 mmol) was added. The reaction mixture was heated at 65° C. for 2.5 days. The reaction mixture was purified via silica gel column chromatography using 100:1 DCM:MeOH as the eluant. The collected fractions afforded impure 4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperidine-1-carboxylic acid tert-butyl ester as a sticky brown solid.