Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 106 %

Procedure:
2-(6-Chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (106 mg, 183 μmol) was dissolved in dichloroethane (10 mL). To this mixture was added trifluoroacetic acid (2.09 g, 1.41 mL, 18.3 mmol) and the mixture was heated to 80° C. After 15 h, the mixture was concentrated in vacuo. The residue was dissolved in 60:20:1 dichloromethane:methanol:ammonium hydroxide (10 mL). After 2 h the mixture was concentrated in vacuo, then purified by chromatography (silica, Analogix 40 g, 0-5% methanol in dichloromethane, over 15 min) to give 2-(6-chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 194 μmol, 106%) as a yellow powder. MS (M+H)+=449; 1H NMR (CDCl3) δ: 11.90-12.06 (m, 1H), 8.97-9.07 (m, 1H), 8.27-8.35 (m, 1H), 8.11-8.17 (m, 1H), 7.95-8.05 (m, 1H), 7.72-7.82 (m, 1H), 7.05-7.13 (m, 1H), 6.94-7.03 (m, 1H), 6.81-6.92 (m, 1H), 5.69-5.83 (m, 2H), 4.17-4.38 (m, 1H), 3.72 (s, 3H), 1.24 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.Cl>[ClH:12].[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(CC)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 4-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×20 ml) and water (3×20 ml) and dried (MgSO4). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCl solution (15 ml). The acidic solution was concentrated and re-evaporated twice with acetonitrile to give 290 mg (81%) of the title compound as a solid. M.p. 251–253° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.O.[NH2:20][NH2:21].NN>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]#[N:9])[CH:4]=3)[NH:21][N:20]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: N#Cc1ccc(F)c(C(=O)c2ccc(F)cc2)c1
Solvent: O
Product: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 8 h

Procedure:
To a flask containing 4-fluoro-3-{(4-fluorophenyl)carbonyl}benzenecarbonitrile (4.2 g, 0.017 mmol) was added hydrazine monohydrate (15 mL) and anhydrous hydrazine (10 mL). In an addition flask the procedure was repeated. Both flasks were allowed to stir overnight exposed to the atmosphere. LCMS confirmed the reactions were complete. To the flasks were added an excess amount of water. The reactions were allowed to stir for two hours. The product of the reactions was collected via a fritted funnel by filtration and combined to yield the title compound. The product was allowed to dry under vacuum and taken on crude into the next step of the synthesis. 1H NMR (DMSO-d6) 8.7 (s, 1H), 8.1 (m, 2H), 7.7–7.8 (m, 2H), 7.3–7.4 (t, 2H), ES-MS m/z 238 [M+1]+
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C)c1
Yield: 72.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (442 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (571 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CC=C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC=C(C)C)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid was prepared staring from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid ethyl ester (6.2 g, 16 mmol) dissolved in ethanol (15 mL), 10 N sodium hydroxide (10 mL) and tetrahydrofuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21%). brown solid mp 196-197° C., MS: 367.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:4](=[S:12])[N:5]=[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=12.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[O:21].O>CN(C)C=O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][S:12][C:4]1[NH:5][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:3]=1
Reactant: S=C1N=C2CCCCC2=N1
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc2c([nH]1)CCCC2)C(=O)Nc1ccc(F)cc1F
Reaction time: 2 h
Yield: 18.2 %

Procedure:
Part B. To a suspension of sodium hydride (0.099 g, 0.004 mol; washed free of the mineral oil with hexane) in N,N-dimethylformamide (15 ml) under a nitrogen atmosphere, cooled to 0°, 4,5,6,7-tetrahydrobenzimidazol-2-thione (0.50 g, 0.0033 mol) was added slowly. The reaction mixture was stirred for two hours and then a solution of N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptyl urea (1.38 g, 0.0033 mol) in N,N-dimethylformamide (5 ml) was added. The reaction mixture was stirred at 0° for one hour, at ambient temperature for one hour, then was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give the crude product. The product was purified by flash chromatography on silica gel (250 ml) eluting with hexane: ethyl acetate (50:50::v:v) to give the title compound as a solid (0.30 g, 0.0006 mol), mp 98°-100°. 1H NMR (CDCl3) δ10.0-9.4 (bs,1H), 8.05-7.87 (m,1H), 6.91-6.75 (m,2H), 6.5-6.41 (d,1H,J=3.75 Hz), 3.42-3.2 (m,4H), 2.96-2.85 (t,2H,J=6.0 Hz), 2.61-2.45 (m,4H), 1.81-1.22 (m,20H), 0.88 (t,3H,J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Temperature: 50 °C
Yield: 56.3 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (100 mg, 0.162 mmol) in formic acid (3 mL) was added Zn dust (40.9 mg, 0.641 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 56.5% yield) as a white solid. LCMS: MH+ 548 and TR=1.399 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>FC(F)(F)CO.CCOC(C)=O>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:3]=3)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]ccc12
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]ccc12
Temperature: 90 °C
Yield: 15.8 %

Procedure:
To a suspension of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine (75 mg, 0.24 mmol) and 4-aminobenzonitrile (113 mg, 0.96 mmol) in 2,2,2-trifluoroethanol (4 mL) in a sealed tube was added trifluoroacetic acid (0.15 mL, 1.92 mmol). The resulting solution was heated at 90° C. for 3 days. The reaction was diluted with EtOAc (50 mL), washed with NaHCO3 (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone=90:10) yielded 15 mg (16%) of 4-(4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzonitrile as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:10][N:8]([CH3:9])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]=[C:19]=[O:21])[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(F)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1ccc(F)c(N=C=O)c1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1.09 g (7.1 mmol) of 4-fluoro-N1,N1-dimethylbenzene-1,3-diamine followed by 4.6 cm3 of pyridine are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 18 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 40 cm3 of tetrahydrofuran. After filtration, a solution of 5-dimethylamino-2-fluorophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][OH:30].[CH2:31]([O:33][C:34](=[O:44])[C:35]1[CH:40]=[C:39](O)[C:38]([Br:42])=[C:37]([OH:43])[CH:36]=1)[CH3:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:31]([O:33][C:34](=[O:44])[C:35]1[CH:36]=[C:37]([OH:43])[C:38]([Br:42])=[C:39]([O:30][CH2:29][CH2:28][C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])[CH:40]=1)[CH3:32]
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Yield: 96.2 %

Procedure:
To a solution of 17.8 g (67.9 mmol) of triphenylphosphane, 8.8 ml (67.9 mmol) of 2-(2,4-dichlorophenyl)ethanol and 16 g (61.3 mmol) of 4-bromo-3,5-dihydroxybenzoic acid ethyl ester in 25 ml of THF was added a solution of 10.6 ml (67.9 mmol) of DEAD in 40 ml of THF within 45 min between 6° and 18° C. After 16 h at room temperature the solvent was removed and the residue was stirred with cyclohexane/ethyl acetate (1/1) and filtered. The solid residue was stirred with cyclohexane and filtered. The remaining solid was separated by chromatography (cyclohexane/ethyl acetate (1/1)) to give 25.6 g (96%) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[C:12]([Cl:37])=[C:13]3[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH3:28])=[CH:18][N:17]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[K+].Cl.[CH:42]([N:45](C(C)C)[CH2:46]C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O.C1COCC1.ClCCl>[Cl:37][C:12]1[C:11]([C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([N:45]([CH3:46])[CH3:42])=[O:3])=[CH:16][N:15]=[C:14]2[N:17]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])[CH:18]=[C:19]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[O:27][CH3:28])[C:13]=12
Reactant: CCOC(=O)c1cncc(-c2cnc3c(c(-c4cc(F)ccc4OC)cn3COCC[Si](C)(C)C)c2Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(=O)N(C)C)c3)c(Cl)c12
Reaction time: 8 h
Yield: 37.5 %

Procedure:
68 mg (0.12 mmol) of 5-[4-chloro-3-(5-fluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester was dissolved in methanol and 100 μL of 50% w/v of potassium hydroxide in water was added. The resulting mixture was left at room temperature for 8 h. The mixture was adjusted to pH 3 by addition of 100 μL of concentrated aqueous hydrochloric acid and the solvent completely evaporated. The residue was dissolved in 50 mL of 50% v/v methanol in diethyl ether. The insoluble residue was filtered off and the filtrate evaporated. The resulting material was dissolved in 10 mL of 50% v/v acetonitrile in dichloromethane. 100 μL (0.57 mmol) of di-iso-propylethylamine was added, followed by 92 mg (0.24 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate. The resulting suspension was sonicated until a homogeneous solution was obtained. 0.5 mL (1 mmol) of a 2 M solution of dimethylamine in anhydrous THF was added and the resulting mixture left at ambient temperature for 24 h. The resulting solution was distributed between dichloromethane and 10% w/v aqueous citric acid solution. The organic phase was dried over sodium sulfate and evaporated to afford 24 mg (45 μmol, 37%) of 5-[4-chloro-3-(5-fluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide. 1H-NMR [500 MHz, d6-DMSO] δ: 8.75 (d, 1H), 8.71 (d, 1H), 8.27 (s, 1H), 7.89 (t, 1H), 7.42 (s, 1H), 7.27 (s, 1H), 7.09-7.03 (m, 2H), 6.86 (dd, 1H), 5.74 (s, 2H), 3.74 (s, 3H), 3.64 (t, 2H), 3.15 (s, 3H), 3.08 (s, 3H), 0.97 (t, 2H), −0.2 (s, 9H); MS [MH+] m/z: 555.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C@H:9]([NH2:11])[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[NH2:13][C:14]([C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1)=[O:15]>CC(O)C>[NH2:13][C:14]([C:16]1[C:17]([NH:11][C@@H:9]2[CH2:8][C@H:7]3[N:3]([CH2:4][CH2:5][CH2:6]3)[C:2]([CH3:12])([CH3:1])[CH2:10]2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1)=[O:15]
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: CC1(C)C[C@H](N)C[C@@H]2CCCN21
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Cl)ncc2C(N)=O)C[C@@H]2CCCN21
Reaction time: 72 h
Yield: 54 %

Procedure:
A mixture of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine (1.25 g) and 5-aminocarbonyl-2,4-dichloropyrimidine (2.14 g, 1.5 eq.) in iPrOH (50 mL) was stirred at −10° C. to rt for 3 d. The solid was filtered off and washed with methanol (3×10 mL). The filtrate was evaporated under vacuum and the residue was purified by CombiFlash chromatography on silica gel (2N NH3 in MeOH/CH2Cl2=0-30%) to give the desired product (1.3 g, 54% over 3 steps).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[S:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:6]1[CH3:32].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2ccncc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccncc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
A mixture of {5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-4-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester (0.21 g) and tetrahydrofuran (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (3.0 mL), and the resulting mixture was stirred at 40° C. for 3 hours. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated to low bulk under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.094 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([C:15]2([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:13]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][N:12]1[CH2:13][CH:14]2[CH:16]([C:15]2([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:17]1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)C3Cc4ccccc4C3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CC3Cc4ccccc4C3)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of N-{3-[3-(2,3-dihydro-1H-inden-2-ylcarbonyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (Preparation 115, 94 mg, 0.23 mmol) in anhydrous tetrahydrofuran (2 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.40 ml, 0.40 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.40 ml), sodium hydrogen carbonate (400 mg) and ethyl acetate (15 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a colourless oil. This was purified by preparative HPLC (condition 8) to give a light brown oil which was partitioned between dichloromethane (10 ml) and aqueous potassium carbonate solution (4% w:v, 5 ml). The layers were separated and the organic layer was washed with water (3 ml) and saturated brine (2 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (62 mg, 68%). The free base (55 mg, 0.14 mmol) was dissolved in anhydrous diethyl ether (5 ml) and dichloromethane (1 ml) and the solution was treated with hydrogen chloride (1.0M solution in diethyl ether, 0.153 ml). The heterogeneous suspension was concentrated in vacuo to afford the hydrochloride salt of the title compound as a white solid (50 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[F:20][C:21]([F:31])([F:30])[O:22]C1C=CC=CC=1N>>[F:20][C:21]([F:31])([F:30])[O:22][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Product: O=C(Nc1ccccc1OC(F)(F)F)C1CCCCC1
Yield: 100 %

Procedure:
This compound was prepared following the procedure described for compound 26A of example 26, except that 2-trifluoromethoxyaniline was used in place of 2-trifluoromethylaniline. Yield: 100%.