Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[NH:31][CH3:32].C(#N)C.O>CO.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[NH:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CNc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3mmol), KCO3 (1.4 g, 10.3mmol), 1-[4-(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux under nitrogen for 23hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, dried with MgSO4 and was concentrated to yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p.=151°-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCc2ccc(Cl)cc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 _mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-chlorobenzyl chloride (130 mg, 0.81 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (74 mg, yield 38%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)C.[Pt]=O>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([NH:2][CH3:1])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CN
Reactant: CC(=O)N1CCC(=O)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCN(C(C)=O)CC1

Procedure:
9.9 g of methylamine in 50 ml of ethanol are added to 14.4 g of 1-acetyl-4-oxopiperidine in 100 ml of ethanol. The mixture is then hydrogenated in the presence of platinum oxide at room temperature and atmospheric pressure, filtered and evaporated.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:28][N:29]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:30]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Reaction time: 0.67 h
Yield: 67.7 %

Procedure:
Benzyl chloroformate (0.40 mL, 2.79 mmol) and triethylamine (0.65 mL, 4.64 mmol) were added to a solution of 3-[(tert-butoxycarbonyl)amino]azetidine (400 mg, 2.32 mmol) in dichloromethane (23 mL) at room temperature, followed by stirring for 40 minutes. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 481 mg of the title compound as a white solid (68%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O.Cl.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidine (7, 306 g, 2.25 mol) was added in portions over 20 min to phosphorus oxychloride (1050 ml, 1727 g, 11.26 mol, 5.0 equiv). Stirring was continued at room temperature for 15 min then this suspension was slowly heated to reflux and the evolving hydrochloric acid was scrubbed through 20% sodium hydroxide solution. Reflux was continued for 30 min after all material went in solution. The reaction mixture was allowed to cool to 60° C. and it was poured onto ice (5 Kg) with stirring. Stirring was continued for 20 min and potassium carbonate was slowly added in portions to adjust pH to 7.5. Ice was added as needed to keep the temperature below 20° C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (30° C.). The crude material was taken in ethyl acetate and stirred at 50° C. for 1.5 hrs. This solution was treated with charcoal, stirred at 50° C. for an additional 20 min and filtered hot through celite. The resulting solution was concentrated to 900 ml and cooled in an ice bath with stirring. The precipitate was collected by filtration, washed with small volume of cold ethyl acetate and dried in a vacuum oven (40° C.) to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 227 g, 334.8 g theoretical, 67.8%) as yellow to brown crystalline solids. Further concentration of the mother liquor produces an additional crop of the desired product (5-10%) as yellow to brown crystals of less purity. For 1: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.58 (bs, 1H), 8.58 (s, 1H), 7.69 (d, 1H, J=3.5 Hz), 6.59 (d, 1H, J=3.5 Hz); C6H4ClN3 (MW, 153.57), LCMS (EI) m/e 154/156 (M++H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[N:47])=[CH:41][CH:40]=2)O1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[N:47])=[CH:41][CH:40]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccc(CC#N)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (60 mg, 0.12 mmol) in THF (2 mL) at room temperature under argon was added 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (87.9 mg, 0.36 mmol), Pd(dppf)Cl2.CH2Cl2 (9.8 mg, 0.011 mmol), and K3PO4 (77 mg, 0.36 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 48 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was still present and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 38 mg, 59%. HPLC/MS: retention time=3.94 min, [M+H]+=534. 1H NMR (CDCl3): δ 7.84 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.25 (m, 6H), 7.05 (d, J=8.4 Hz, 2H), 6.66 (d, J=7.1 Hz, 1H), 5.24 (s, 2H), 3.75 (s, 2H), 2.74 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH:9]([CH2:10][C:11](OC)=[O:12])[O:8][CH:7]([O:15][CH2:16][CH3:17])[O:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:16]([O:15][CH:7]1[O:6][CH:5]([CH2:4][CH2:3][OH:2])[CH:9]([CH2:10][CH2:11][OH:12])[O:8]1)[CH3:17]
Reactant: CCOC1OC(CC(=O)OC)C(CC(=O)OC)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC1OC(CCO)C(CCO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of (2-ethoxy-5-methoxycarbonylmethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester (Ex-14B, 11.0 g, 42 mmol) in tetrahydrofuran (75 mL) at 0° C. was added a solution of LAH in tetrahydrofuran (1 M, 63 mL, 63 mmol) dropwise over a 1 h period. The reaction mixture was allowed to warm to rt and stir for 2 h at which time the solution was then cooled back down to 0° C. and carefully quenched with sodium sulfate decahydrate. The mixture was concentrated under reduced pressure and the residue was diluted with equal portions of a saturated Rochelle salt solution and ethyl acetate (approx. 150 mL each) and the slurry was vigorously stirred overnight. The layers were then separated and the aqueous layer was extracted with ethyl acetate (4×100 mL), the organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Drying in vacuo gave 2-[2-ethoxy-5-(2-hydroxy-ethyl)-[1,3]dioxolan-4-yl]-ethanol (7.6 g, 88%) as a colored oil. This material was used without further purification. 1H-NMR (300 MHz, CDCl3) δ5.82(s, 1H), 4.11–4.17 (m, 1H,), 3.92–3.97 (m, 1H), 3.80–3.86 (m, 4H), 3.61 (q, 2H, J=7.0 Hz), 2.30 (brs, 1H), 2.22 (brs, 1H), 1.76–1.94 (m, 4H), 1.23 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C1COCC1.[Si:10]([O:17][CH2:18][CH:19]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:20]#[N:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[OH-].[Na+]>CCOCC.C(Cl)Cl>[Si:10]([O:17][CH2:18][CH:19]([C:20]1([NH2:21])[CH2:2][CH2:1]1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC[Mg+]
Reactant: CC(C)(C)[Si](C)(C)OCC(C#N)Cc1ccc(Cl)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccc(Cl)cc1)C1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of EtMgBr in THF (3.0M, 8.0 mL, 24 mmol) was added dropwise at room temperature to a stirred solution of 3-(tert-butyldimethylsilyloxy)-2-(4-chlorobenzyl)propanenitrile (3.7 g, 12 mmol) and Ti(i-PrO)4 (3.9 mL, 13 mmol) in Et2O (50 mL). After the mixture was stirred at room temperature for 1 hour, BF3OEt (3.0 mL, 24 mmol) was added at once. The mixture was stirred for an additional 1 hour. A solution of 10% NaOH (10 mL) was added, followed by DCM (300 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (30:1 DCM:MeOH) to give 1-(1-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)propan-2-yl)cyclopropanamine (2.6 g, 64%) as a colorless oil. LCMS: 340.2 (M+H)+ (APCI+); Rf: 3.17 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40].CO>C1COCC1>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:38](=[O:41])[CH:39]=[CH2:40])[CH:10]=1)[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3N)ncn2)c1Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2cccnc2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of 1-[6-(2-amino-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-pyridin-3-ylmethyl-urea (53 g, 0.1 mmol) in THF (10 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 0.5 mL, 0.1 mmol) at −10° C., and the mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-TLC to obtain the title compound (9 mg, yield: 15%). 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 6H), 5.01 (s, 2H), 5.69 (d, 1H), 5.75 (s, 1H), 6.10 (dd, 1H), 6.34 (d, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.09-7.24 (m, 2H), 7.28 (t, 1H), 7.32 (s, 1H), 7.47 (d, 1H), 7.69-7.71 (m, 2H), 8.31-8.34 (m, 2H), 8.40-8.42 (m, 1H), 12.60 (s, 1H); MS (ESI): 594 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]5[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=5[Cl:32])=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc(Cl)cc3Cl)cc2)C1
Temperature: 110 °C
Yield: 22.2 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (2,4-dichlorophenyl)boronic acid (98 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was heated in an aluminum block at 110° C. for 2 h. The cooled reaction was diluted with ethanol then evaporated under reduced pressure to a yellow residue. The residue was triturated from methanol and the filtered methanol layer was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-70% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired product fractions were combined and evaporated in vacuo to a residue that was recrystallized from hexanes/ethyl acetate to afford the title compound as a white solid (26 mg, 21.8%). MS(ES)+ m/e 457.0, 459.2 [M+H]+, chlorine pattern.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][CH:30]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][CH:30]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)C(CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)C(O)CCS(C)(=O)=O)nc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (1.43 g, 4.54 mmol) was added to a stirred solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)-4-(methylsulfonyl)butanamide (Step 3) (1.17 g, 3.03 mmol) in THF (10 mL). The reaction mixture was kept at ambient temperature for 30 minutes. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from EtOAc to give the title compound as colourless solid (0.57 g), 1H NMR (500 MHz, DMSO) δ 8.14 (d, 1H), 7.99 (d, 1H), 7.62 (dd, 1H), 4.23 (m, 1H), 3.17 (m, 2H), 2.96 (s, 3H), 2.24 (s, 3H), 2.16 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12.CI>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:17]([CH3:1])=[CH:18][C:11]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
1.8M Lithium diisopropylamide (270 ml) was added dropwise over 20 min to a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (82 g) in dry THF (820 ml) and the reaction was stirred at −45° C. for 30 min. Methyl iodide (90 ml) was added drop wise to the solution and the mixture was stirred at −45° C. for 45 min, then allowed to warm to RT. The reaction was quenched with water. The organic layer was collected and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with ethyl acetate:cyclohexane (3:1). The solid material was collected and washed with ethyl acetate:cyclohexane (3:1) and dried in vacuo at 35° C. This residue was dissolved in DCM, washed with water, dried over magnesium sulphate and the solvent removed in vacuo to give the title compound (37.6 g) as a cream solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Br:22][C:23]1[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[S:26][CH:27]=1.BrC1C=C(C=O)SC=1.C(N(CC)CC)C>CN(C=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:30](=[O:31])[CH:29]=[CH:28][C:25]4[S:26][CH:27]=[C:23]([Br:22])[CH:24]=4)[C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1NCCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Reactant: O=C(O)/C=C/c1cc(Br)cs1
Agent: Cl
Agent: O=Cc1cc(Br)cs1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
(S)-1-(4-chloroquinolin-7-ylmethyl)-3-methylpiperazin-2-one hydrochloride (0.35 g, 1.4 mmol), EXAMPLE 91, is treated with DMF (20 mL), 3-(4-bromothiophen-2-yl)-(E)-acrylic acid (0.32 g, 1.4 mmol), prepared according to EXAMPLE 26, using 4-bromothiophene-2-carboxaldehyde, triethyl amine (0.21 ml, 1.4 mmol) and 2-(1H-benzotriazol-1-yl)1,1,3,3-tertamethyluronium tetrafluoroborate (0.45 g, 1.4 mmol) and heated to 50° C. for 5 minutes. The reaction mixture is stirred at ambient temperature for 16 h then partitioned between ethyl acetate and water. The organic layer is concentrated and the residue is chromatographed (5% methanol/methylene chloride) to give crude title compound (0.5 g, 0.9 mmol). MS m/z: [M+H]+=504. 1H NMR (CDCl3, 300 MHz) δ8.9 (d, 1H), 8.2-8.3 (m, 2H), 8.0 (s, 1H), 7.7-7.8 (m, 1H), 7.4 (s, 1H), 7.3-7.4 (m, 1H), 6.7-6.8 (m, 1H), 6.6 (d, 1H), 5.1-5.2 (m, 1H), 4.6-4.7 (m, 2H), 3.4-3.6 (m, 2H), 3.0-3.3 (m, 2H), 1.5 (d, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:15](=[O:16])[NH:14][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(N3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A solution of crude 4-morpholin-4-yl-benzene-1,2-diamine (0.75 g, 3.9 mmol) in tetrahydroflran (4 mL) was treated dropwise with a solution of carbonyldiimidazole (0.76 g, 4.7 mmol) in tetrahydrofuran (12 mL). The reaction mixture was stirred for 16 h at room temperature, and the solid product was collected by filtration and recrystallized from ethanol to afford the white solid product (0.47 g, 55%). See, J. Am. Chem., Soc., 118:4018 (1996).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[C:23]([CH3:22])=[CH:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]=4)[CH2:33][CH2:34]3)[N:3]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl) -pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120°C. for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:23]=1
Reactant: O=Cc1cccnc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5cccnc5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-3-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-(pyridin-3-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.