Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:58][C:59]([NH2:61])=[O:60]>CN(C)C=O.C(OCC)(=O)C>[C:59]([CH2:58][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)(=[O:60])[NH2:61]
Reactant: NC(=O)CI
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (50.0 mg, 0.081 mmole, example 205) and potassium carbonate (22.4 mg, 0.162 mmole) in N,N-dimethylformamide (4 mL) was added iodoacetamide (29.8 mg, 0.162 mmole, Aldrich). The mixture was stirred at room temperature overnight and diluted with ethyl acetate, washed with water, brine and concentrated. The crude product was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in dichloromethane) to give the title compound (40.5 mg, 74% yield). HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2924.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C[C:32]1[N:33]=CC(C=O)=NC=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[CH:32][N:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:19]=2[N:20]=1
Reactant: Cc1cnc(C=O)cn1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 4.83-4.79 (m, 1H), 4.12-4.03 (m, 2H), 3.78-3.75 (m, 1H), 3.61-3.55 (m, 2H), 3.46-3.40 (m, 1H), 3.12-3.09 (m, 1H), 2.87 (m, 1H), 2.64 (m, 1H), 2.53 (m, 2H), 2.47-2.28 (m, 4H), 2.16 (m, 2H), 1.91-1.84 (m, 2H), 1.23-1.20 (m, 3H). MS: (M+H m/z 410.3).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[O:12][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])[C:8]([CH3:11])=[N:9][C:10]=2[C:2]=1[NH:1][S:33]([C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[Cl:25])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)nc3c2N)c(Cl)c1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(Oc2ccc3c(nc(C)n3S(=O)(=O)c3ccc(Cl)cc3Cl)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, methyl 2-(4-(4-amino-2-methyl-1H-benzo[d]imidazol-5-yloxy)-3-chlorophenyl)acetate (0.171 g, 0.495 mmol) was dissolved in pyridine (1.5 mL) and 2,4-dichlorobenzenesulfonyl chloride (0.267 g, 1.09 mmol) was added. The reaction was allowed to stir at room temperature for 3 h and then concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 50% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 763.7 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of methyl 6-chloropyridazine-3-carboxylate (36 mg, 0.2 mmol) in DME (6 mL) was added Pd(PPh3)4 (20 mg, 0.02 mmol) under N2. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one (96 mg, 0.2 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for another 2 h under N2. The reaction mixture was quenched by addition of H2O, and extracted by EtOAc. The combined organic phase was dried and concentrated to give the crude product, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-pyridazine-3-carboxylic acid (63 mg, 60%).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[N:10]1([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C=O)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([N:13]1[CH2:14][CH2:15][N:10]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12]1)=[O:7]
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CCC(C)/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)/C=C/C(=O)N1CCN(c2ccnc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4-Methylhex-2-enoic acid (26 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), HATU was added (76 mg, 0.2 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-piperazin-1-yl-7-(trifluoromethyl)quinoline (56 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), the two solutions were combined and stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 62.6 mg (0.16 mmol, 80%). MS (APCI) m/z=391.9 [M+1]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37]>ClCCl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=4[CH3:34])=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.8 %

Procedure:
To a mixture of 0.362 g of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride and 0.101 g of triethylamine in 5 ml of dichloromethane is added a solution of 0.129 g of 2-methylaniline in 3 ml of dichloromethane. The mixture is stirred 1.5 hr at room temperature and then washed with H2O 1N HCl, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give a solid. The solid is dissolved in dichloromethane and filtered through a thin pad of hydrous magnesium silicate with dichloromethane as eluent to give 0.025 g of crystals, m.p. 214°-216° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:45]([CH:42]4[CH2:44][CH2:43]4)=[O:46])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CC1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NC(=O)C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol), cyclopropanecarboxylic acid (4.79 mg, 0.056 mmol), and HATU (21.18 mg, 0.056 mmol) was added DIEA (0.013 ml, 0.074 mmol) and DMA (1 ml). The vial was capped and the contents heated to 60° C. and stirred for 16 h. The reaction mixture was concentrated to afford crude (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide which was taken forward without purification. MS ESI calc'd. For C38H35N6O2 [M+H]+ 607. found 607.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15])#[N:2].B.[H][H].Cl>O1CCCC1.CO>[NH2:2][CH2:1][CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15]
Reactant: [H][H]
Reactant: N#CCc1cc(F)c2c(c1F)OCCO2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1cc(F)c2c(c1F)OCCO2

Procedure:
6-Cyanomethyl-5,8-difluoro-1,4-benzodioxane (30.34 g, 0.158 mole) dissolved in 300 ml of dry tetrahydrofuran is treated with 308 ml of 1 M borane in tetrahydrofuran under nitrogen. After 2 hours of reflux 300 ml of methanol is added continuously (hydrogen evolution occurs, vigorously at first), then the mixture is refluxed for 30 minutes. Then 50 ml of 10% hydrochloric acid is added very carefully (hydrogen gas evolution again) and the mixture refluxed another 30 minutes. The reaction mixture is concentrated under vacuum to a small volume, then 300 ml of water is added and the mixture made basic with 40% sodium hydroxide. This is extracted with ether, dried, and concentrated to give 6-(2-aminoethyl)-5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C.[F:39][C:40]([F:45])([F:44])[CH2:41][CH:42]=O>ClCCCl>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:42][CH2:41][C:40]([F:45])([F:44])[F:39])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Reactant: O=CCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(C2=CCN(CCC(F)(F)F)CC2)cc1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
Sodium triacetoxyborohydride (6.2 g, 29.4 mmol, 2 eq.) was added to a solution of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.), DIEA (2.5 mL; 14.7 mmol; 1.0 eq.) and 3,3,3-Trifluoropropanal (2.4 mL; 29.4 mmol; 2.0 eq.) in DCE (60 mL). The reaction mixture was heated at 50° C. for 2 h and quenched by addition of a saturated solution of NH4Cl (50 mL). The phases were separated and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give a brown crude. Purification by flash chromatography on silica (EtOAc:heptane) afforded the title compound as a yellow solid (2.0 g, 45%). UPLC/MS: (MS+) 301.4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:14])=[CH:4][N:3]=1.O[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]3)[C:5]([F:14])=[CH:4][N:3]=1
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Reactant: CN(CCCO)c1nc(Cl)ncc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-1-propanol (Example 83, 0.60 g, 2.73 mmol) and methyl (5-hydroxy-1H-indol-1-yl)acetate (Example 9, 0.37 g, 1.82 mmol) in dichloromethane (9 mL) was added triphenylphosphine (0.70 g, 2.73 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.72 g, 2.73 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.42 g, 56%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 7.85 (d, 1H), 7.15-7.07 (m, 3H), 6.88-6.83 (m, 1H), 6.47-6.46 (m, 1H), 4.85 (s, 2H), 4.07 (t, 2H), 3.84 (t, 2H), 3.76 (s, 3H), 3.26 (d, 3H), 2.20-2.13 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:7]2.C1(C)C(S(O[CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH2:7]2
Reactant: Cc1ccccc1S(=O)(=O)OCCc1cccs1
Reactant: CCCNC1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCc1cccs1)C1CCc2c(O)cccc2C1

Procedure:
13.1 kg (63.9 mol) (−)-5-hydroxy-N-n-propyl-2-aminotetralin, 51.6 kg (182 mol) 2-(2-thienyl)ethanol toluenesulfonate, and 4.1 kg (38.6 mol) sodium carbonate (0.6 molar ratio Na2CO3/amine starting material) were mixed in a reactor under a nitrogen atmosphere using xylenes (150 kg) as a solvent with vigorous agitation and heated to a temperature of 120° C. to 125° C. for a period of 32 hours. HPLC analysis of the reaction mixture showed less than 2% of the starting material remaining, and the reaction was halted. The product, (−)-5-hydroxy-2-[N-n-propyl-N-2-(2-thienyl)ethylamino]tetralin, was isolated in the usual manner well known to those skilled in the art without chromatographic purification to yield product that was converted to its hydrochloride salt form, with a yield of 13.2 kg (59%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)#[CH:2].[CH3:13][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[C:36](I)[CH:35]=3)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[N:18]([C:22]2[CH:23]=[C:24]([NH:32][C:33](=[O:42])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[C:38]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)[CH:39]=3)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=2)[CH:19]=[CH:20][N:21]=1)[CH3:13]
Reactant: C#Cc1cncc2cccnc12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9]>CO>[CH3:12][O:11][C:7](=[O:10])[CH2:8][CH2:9][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: NC1CCCC1
Solvent: CO
Product: COC(=O)CCNC1CCCC1
Yield: 64.8 %

Procedure:
A mixture of 59.605 g (0.70 mole) cyclopentylamine (Aldrich), 72.299 g (0.84 mole) of methyl acrylate (Aldrich) and 250 mL of methanol was heated at reflux under an argon atmosphere for 14 hours, then ca 200 mL of solvent was distilled out at atmospheric pressure. The residue was distilled under vacuum (12 mm Hg, bp 112-114 degrees) to give 77.616 g (64%) of 3-cyclopentylamino-propanoic acid methyl ester.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1>[Si:13]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OCc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a solution of 1,3-benzenedimethanol (1 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 318 mg) under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction mixture was added tert-butyldimethylsilyl chloride (1.09 g), and the mixture was stirred at room temperature for 4 days. Ice water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (528 mg).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N([CH2:12][CH3:13])CC)C>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]1(=[O:6])[O:5][CH:2]1[CH2:12][CH3:13]
Reactant: CCN(CC)CC
Agent: C=C(C)C(=O)O
Product: CCC1OC1=O
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml 3N-RB flask fitted with a gas inlet, thermometer, overhead stirrer and a 125 ml pressure equalizing dropping funnel was added 26.5 g triethylamine. The triethylamine was cooled to 5° C. using a water/ice bath. Once the triethylamine was at 5° C. the methacrylic acid was added dropwise over a 20-25 min period. The mixture exothermed ˜10° C. After the addition was complete the water/ice bath was removed. While the solution was stirring (20 min) the dropping funnel was removed and replaced with a clean 125 ml pressure equalizing dropping funnel. The bromolactone (41.25 g)/THF (62.5 ml) was added dropwise over a 30 min. The mixture warmed from ˜18° C. to ˜30° C. with a precipitate forming. The reaction was heated to 55° C. and held at 55° C. for 16 hrs using an oil bath/hot plate. After heating for 16 hrs the mixture was cooled to 20° C. using a water/ice bath. The solid (44.5 g) was removed by vacuum filtration. The filtrates were reduced under partial pressure at 33-34° C. The resulting dark amber/brown oil was diluted with 90 g of methylene chloride. This solution was slowly poured onto a plug of silica gel (180 g, Baker 40 um flash chromatography packing) which had been pre-conditioned with methylene chloride. The crude mixture was allowed to pass into the silica gel plug by gravity. Once the crude mixture had passed the surface of the silica gel plug a fresh portion of methylene chloride was slowly poured onto the plug. The methylene chloride was pulled through the silica gel plug using reduced pressure. Once the methylene chloride had passed the surface of the silica gel plug the vacuum was removed then the next portion of methylene chloride was slowly poured onto the plug. This procedure was followed until all the product was extracted. The total filtrate was 850 ml. [The product was detected by spotting an aliquot on a TLC plate then illuminating with short UV.] To the orange filtrate was added 36 g of activated charcoal. The mixture was stirred for 1.5 hrs then filtered through a Celite plug (pre-conditioned with methylene chloride). The charcoal/Celite was washed with (2×100 ml, 1×50 ml methylene chloride). The filtrate was then washed with 2×200 ml D.I. water. The layers were separated and the organic layer was dried over 100 g of sodium sulfate. The mixture was stirred for 15-30 min. The sodium sulfate was removed and washed with 2×50 ml methylene chloride. The pale yellow filtrate (1.2 L) was stripped under reduced pressure at 33-34° C. leaving 36.4 g of a pale orange oil, Yield 85.6%.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28]
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Reaction time: 1.5 h
Yield: 136.7 %

Procedure:
To a chilled solution of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl}{[(5-chloro(2-thienyl))sulfonyl]amino}carboxamide (0.246 g, 0.55 mmol) in CH2Cl2 (5 mL) was added neat TFA (1.1 mL). The reaction mixture was stirred cold for 1.5 hr, concentrated in vacuo, azeotroped with heptane and dried to give N-(4-amino-3-methylphenyl) {[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide (0.26 g) as the mono TFA salt. ES-MS (M+H)+=346.