Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].C(OC)(C)(C)C>CN(C)C=O>[CH2:24]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][CH2:11][CH:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH2:14]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: CCC(CC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: C=CCO[C@@H]1CCC[C@H](CCC(CC)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.19 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate are dissolved in 50 ml of dimethylformamide, and 210 mg g of sodium hydride (60% strength in paraffin oil) are added. The suspension is stirred at room temperature for 15 minutes, and 1.6 ml of allyl bromide are then added. After one hour, a further 320 mg of sodium hydride are added. After 12 hours of stirring at room temperature, another 320 mg of sodium hydride and then 1.6 ml of allyl bromide are metered in. Stirring at room temperature is continued for a further 12 hours. After addition of 200 ml of methyl tert-butyl ether, the mixture is washed three times with in each case 100 ml of water and the organic phase is separated off and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=60:1=>30:1. This gives 770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate as an oil. C19H34O3 (310.48), Rf(n-heptane:ethyl acetate=5:1)=0.48.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:33][CH2:32][CH2:31][O:30][CH3:29])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: COCCN
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COCCNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 120 °C
Reaction time: 0.04 h
Yield: 33.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 2-Methoxy-ethylamine (147 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 2.5 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 110 mg of 275. (yield=34%). 1H NMR (CDCl3, 400 MHz): δ8.10 (s, 1H), 7.61-7.54 (m, 1H), 7.14-7.06 (m, 4H), 6.30 (d, J=8.8 Hz, 1H), 4.62-4.58 (m, 1H), 4.25-4.24 (m, 2H), 3.60-3.58 (m, 2H), 3.52-3.48 (m, 2H), 3.41 (s, 3H), 3.13-3.10 (m, 2H). LC-MS (ESI): m/z=456 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH2:43][CH:44]([CH3:46])[CH3:45]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)CI
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 66.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 1-iodo-2-methylpropane (0.115 mL; 1 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.140 g (66%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: CN1CCC(N)CC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CCC(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-methylpiperidin-4-amine (4.6 mg) in N,N-dimethylformamide (200 μL) were added a solution of N,N-diisopropyl ethylamine (8.7 μL) in N,N-dimethylformamide (50 μL) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 4-[2-(difluoromethyl)-1H-benzimidazolyl]-N-(1-methylpiperidin-4-yl)-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (11.1 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CCN1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2CCNCC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 5.13 g (14.3 mmol) ethyl 3-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-propionate and 1.0 g 10% Pd/C in 100 mL EtOH was hydrogenated for 2 h at 50° C. and 50 psi hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The oily product was reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C:21]([CH3:28])([CH3:27])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][C:42]([F:45])([F:44])[F:43])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][C:33]=1[O:41][C:42]([F:43])([F:44])[F:45])(=[O:39])=[O:38])[C:6](=[O:11])[C:5]2([NH:20][C:21]([CH3:28])([CH3:27])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(NC(C)(C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NC(C)(C)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 45.6 %

Procedure:
With 0.51 g of the compound obtained in Step 255-4 and 378 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 0.38 g of the title compound (colorless solid) was obtained by a similar procedure to Example 2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH2:30]([O:32][C:33]1[CH:38]=[C:37]([CH2:39][NH2:40])[CH:36]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[N:34]=1)C>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:40][CH2:39][C:37]3[CH:36]=[C:35]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:45][CH:46]=4)[N:34]=[C:33]([O:32][CH3:30])[CH:38]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(OC)nc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of acid 18 (281 mg, 0.90 mmol) in THF (20 mL) was added with DEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27L (300 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×35 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (4/6 EtOAc/Petroleum ether) to afford a white solid (130 mg) after crystallization from ethyl ether. Yield=25%. 1HNMR (DMSO, 200 MHz) δ 1.23 (m, 4H), 1.4 (m, 6H), 3.41 (m, 2H), 4.41 (m, 4H), 6.67 (s, 1H), 7.27 (d, 1H, J=3.8), 7.58 (m, 2H), 7.86 (d, 2H, J=8), 8.28 (m, 3H). [M+1] 587.80 (C25H25ClF3N3O4S2 requires 588.06).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5]CC)=[O:4].[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>C1COCC1.C(OCC)(=O)C.[Zn]>[F:9][C:2]([F:8])([CH:13]([OH:14])[C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1ccccc1C=O
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A solution of ethyl bromodifluoroacetate (5.6 g) and 2-methylbenzaldehyde (3 g) in THF (25 mL) is added dropwise to a refluxing suspension of activated zinc dust (2.1 g) in THF (25 mL) and refluxing continued for a further 4 hours. The reaction is allowed to cool to ambient temperature, filtered through hyflo and concentrated in vacuo to give a yellow solid. The solid is taken up in ethyl acetate (50 mL) and washed with brine which leads to the formation of a white precipitate which is filtered off then partitioned between ethyl acetate (50 mL) and 1 N HCl (50 mL). The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo to give (RS)-2,2-difluoro-3-hydroxy-3-(2-methylphenyl)propanoic acid as a yellow solid (2.4 g)
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH:2]([CH3:1])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: CCC(=O)c1ccc(OCC(=O)OC)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of RS methyl 4-(2-methylacetyl)phenoxyacetate (1.2 g) in acetonitrile (10 ml) was added dropwise over 30 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.3 g) in acetonitrile (30 ml) and the mixture stirred overnight. The mixture was then filtered and the filtrate evaporated to give an oil. Purification by flash chromatography, eluting first with dichloromethane then successively 2.5%, 3%, 4%, 5% and 10% v/v methanol/dichloromethane gave the title compound, 220 mg as a solid: m.p. 81°-83° C.; NMR (d6DMSO) δ8.13(2H,d), 8.06(2H,d), 7.02(2H,d), 6.77(2H,d), 4.92(2H,s) 4.33(1H,q), 3.72(3H,s), 3.26(4H,t), 2.63(4H,t), 1.16(3H,d); m/e 384(M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found C, 65.7; H, 6.8; N, 10.9%.
Reaction SMILES: [Br:1][C@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.Cl.O.CCOCC>C(O)(=O)C>[Br:1][C@@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C[C@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Yield: 75 %

Procedure:
6β-Bromo-1,2β-methylenandrost-4-ene-3,17-dione (200 mg) in acetic acid (15 ml) at 15°-20° is treated with a steady stream of dry hydrogen chloride for 1 hour and then kept an additional hour at room temperature. Then water is added and the product isolated with ether. The combined ether extracts are washed with saturated salt solution, 5% sodium carbonate solution, water; dried and evaporated. Column chromatography of residue over silica gel using benzene/ethyl ether as eluant affords pure 6α-bromo-1,2β-methylenandrost-4-ene-3,17-dione (150 mg, 75%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[CH:17][CH:16]=1>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9](=[O:11])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cc1

Procedure:
4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: CN(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1ccc(N)c(N)c1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a Parr hydrogenation bottle was added 3.5 g of 4-(2-(dimethylamino)ethoxy)-2-nitroaniline, 10% palladium in carbon (50% w/w water, 1.0 g) and methanol (100 mL). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was carried out on the Parr shaker at 40 psi at room temperature for 1 hour. The reaction mixture was filtered through a plug of Celite. 2.0 g of sodium bicarbonate was subsequently added to the filtrate, which was stirred for 10 minutes. The filtrate was concentrated reduced pressure and the resulting residue was triturated with diethylether to give 4-(2-(dimethylamino)ethoxy)benzene-1,2-diamine (2.2 g, 73%). 1H-NMR (400 MHz, MeOH-d4): δ 6.67 (d, 1H), 6.44 (d, 1H), 6.27 (dd, 1H), 4.18 (t, 2H), 3.50 (t, 3H), 2.92 (s, 6H). MS (EI): 196 (MH+).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([NH:20][C:21]([C:23]1[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[CH:26]=[CH:25][CH:24]=1)=[O:22])[CH2:13]2.CN(C)C=O.Cl>O1CCCC1>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@H:14]([N:20]1[CH:1]=[C:31]3[CH2:30][CH2:29][CH2:28][C:27]4[C:32]3=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]1=[O:22])[CH2:13]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2c1CCCC2
Reactant: [Li]CCCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=c1c2cccc3c2c(cn1[C@@H]1CN2CCC1CC2)CCC3
Temperature: -10 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of n-butyllithium in hexane (60 mmol) was added dropwise at -70° C. to a solution of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro1-naphthalenecarboxamide (7.70 g, 21 mmol), prepared as in Example 3, in dry tetrahydrofuran (400 mL). The reaction mixture was stirred at -10° C. for one hour, cooled to -70° C., and dimethylformamide (100 mmol) added in one portion. The reaction mixture was allowed to warm to room temperature over 1.5 hours, then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was washed with ethyl acetate, then made basic with 10N aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and evaporated to give 7.58 g (95% yield) of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro1H-benz[de]isoquinolin-1-one as white crystals; m.p. 117°-118° C.; [α]D25 +43.2° (c=0.98, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]([C:19](OC(C)(C)C)=O)[NH:11][C:12](OC(C)(C)C)=O)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:26]OC(OC)CC(OC)OC.CCO.OS(O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:10]2[CH:19]=[CH:26][CH:12]=[N:11]2)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cnc(F)c1F
Reactant: COC(CC(OC)OC)OC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ncc(Cl)c(-n2cccn2)c1F
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
To a stirred mixture of di-tert-butyl 1-(5-chloro-2,3-difluoropyridin-4-yl)hydrazine-1,2-dicarboxylate (4.0 g, 0.010 mol, 1.0 equiv) and 1,1,3,3-tetramethoxypropane (17 mL, 0.10 mol, 10 equiv) was added a mixture of EtOH (100 mL) and concentrated H2SO4 (28 mL). The vessel was then sealed and heated to 45° C. After stirring for 45 minutes, the mixture was diluted with EtOAc (300 mL) and washed with water (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified over silica gel using 100% dichloromethane as eluent to give the desired product (1.6 g, 70%).
Reaction SMILES: S=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][N:3]=1
Reactant: COC(CN)OC
Reactant: CCOC(=O)c1ncn2c1CNC(=S)c1sccc1-2
Product: CCOC(=O)c1ncn2c1CN=C(NCC(OC)OC)c1sccc1-2

Procedure:
5. By reacting ethyl 5,6-dihydro-6-thioxo4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate with aminoacetaldehyde dimethyl acetal in an analogous manner to that described in Example 5 there is obtained ethyl 6-[(2,2-dimethoxyethyl)amino]-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepine-3-carboxylate of m.p. 134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)(=O)[CH3:13].[ClH:16]>>[ClH:16].[CH3:12][C:13]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CC(=O)O
Agent: Cl
Product: Cc1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
After a mixture of 5.0 g (32.8 mmols) of 3,4-diaminobenzoic acid, 50 ml of conc. hydrochloric acid and 10 ml (0.175 mol) of acetic acid was heated at 100° C. for 24 hours, the solvent was distilled off under reduced pressure to give 6.6 g (94.5%) of 2-methylbenzimidazole-5-carboxylic acid hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=O)[CH:7]=[CH:6]2>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:12][C:3](=[O:2])[CH3:4])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Solvent: CC(C)=O
Product: COc1ccc2cc(C=CC(C)=O)ccc2c1
Reaction time: 24 h
Yield: 169 %

Procedure:
6-Methoxy-2-naphthaldehyde (110 g, 0.591 mol), basic alumina (175 g; Aldrich Chemical Co. Inc.), and acetone (1000 mL) were added to a 2-L 3-neck flask with condenser, mechanical stirrer, and thermocouple attached. The reaction was heated to reflux for 22 hrs, filtered while still hot, and washed with hot ethyl acetate (3×100 mL). The combined organics were concentrated and then put under high vacuum for 24 hours, affording 113.0 g (85%) of 4-(6-methoxy-2-naphthyl)-but-3-en-2-one (93% GC purity). mp 114°-115.5° C.; DSC 114.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.80 (s,1H), 7.72-7.55 (m,4H), 7.17-7.08 (m,2H), 6.74 (d,1H, J=10 Hz), 3.89 (s,3H), 2.38 (s,3H); 13 C NMR (75 MHz, CDCl3) δ 198.7, 159.4, 144.1, 136.3, 130.5, 130.2, 129.1, 128.0, 126.7, 124.6, 119.9, 106.5, 55.8, 27.9.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:23][N:24]([CH3:26])[CH3:25])[CH:14]=[O:16])=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (92 g) was added dropwise to stirred DMF (78 ml) between 10°-15° C. To the resulting slurry was added 4-chlorophenylacetic acid (34.12 g). The resulting mixture was stirred at room temperature for one half hour and then heated to 70°-80° C. during 5.5 hours, during which time the mixture became effervescent. The reaction mixture was cooled and poured slowly onto cracked ice. The resulting suspension was brought to pH 10 with solid potassium carbonate. Ice was added intermittently during this addition to maintain the temperature below 15° C. ToIuene (150 ml) was added and the resulting mixture heated at 100° C. for one hour. The mixture was cooled and allowed to stand overnight. The two resulting layers were separated and the aqueous layer extracted with toluene (2×100 ml). The combined organic layers were washed with water (5×200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the resulting yellow solid was triturated with hexane to yield 26 g of 2-(4-chlorophenyl)-3-dimethylaminopropenal as a tan solid mp. 120°-125° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]1
Reactant: CCI
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 2: 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.30 g, 1.50 mmol), acetonitrile (3 mL), potassium carbonate (0.21 g, 1.50 mmol), iodoethane (0.12 mL, 1.50 mmol). Microwave irradiation at 100° C. for 20 minutes. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 1:1). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 119-120° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 14), 212 (11), 141 (14), 127 (11), 71 (bp).