Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (0.6 ml), and a solution of 4-fluorobenzoyl chloride (0.8 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][C:8]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[CH2:11][C:4]=2[CH:3]=1.C(O)(=[O:24])C.[Se](=O)=O>ClCCl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][C:8]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[C:11](=[O:24])[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1C)CCc1ccc(Br)cc1CC2=O
Agent: O=[Se]=O
Solvent: ClCCl
Product: COc1ccc2c(c1C)CCc1ccc(Br)cc1C(=O)C2=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 8-bromo-2-methoxy-1-methyl-11,12-dihydro-6H-dibenzo [a,e]cycloocten-5-one 12 (1.0 g: 2.9 mmol), acetic acid and selenium dioxide (0.64 g; 5.8 mmol) was stirred at 150° C. for 2 hr, cooled to room temperature, diluted with dichloromethane and filtered through silica gel to remove the suspended solids. The filtrate was evaporated to dryness. The residue was heated in ethyl acetate and crystallized by adding hexane to give compound 13 as grey needles, 0.71 g, 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCC(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Cl)c(N(CCCC(F)(F)F)c2cc(Cl)ncn2)c1
Temperature: 50 °C

Procedure:
4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12) (0.28 g, 1.1 mmol) and 1,1,1-trifluoro-4-bromobutane (0.32 g, 1.67 mmol) were dissolved in NMP (2 ml). Anhydrous potassium carbonate (0.31 g, 2.2 mmol) was added and the mixture heated to 50° C. for three hours. Following an aqueous work-up the product was obtained by column chromatography on silica gel using EtOAc-isohexane mixtures. (0.3 g, 75%). M/z 364 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 28.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.32 g, 29%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1)[C:5]#[N:6].[CH3:16][O-:17].[Na+]>CN(C=O)C>[CH3:16][O:17][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1)[C:5]#[N:6]
Reactant: Cc1ncn(-c2ccc(C#N)cc2F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1-n1cnc(C)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (0.51 g) in DMF (10 mL) was added sodium methoxide (5M methanol solution, 1.51 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was added to ice water, and the precipitated solid was collected by filtration, and washed with water to give the title compound (0.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13]C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)=[O:4].C(OC(=O)NCC#C)(C)(C)C.COC(C1SC(Br)=CC=1)=O>C(#N)C.CCOC(C)=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Agent: C#CCNC(=O)OC(C)(C)C
Agent: COC(=O)c1ccc(Br)s1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(CCCN)s1
Temperature: 25 °C

Procedure:
5-(3-tert-Butoxycarbonylamino-prop-1 ynyl)-thiophene-2-carboxylic acid methyl ester, A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2c(F)cc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)cc(F)c2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 74.8 %

Procedure:
To the mixture of 6-chloro-4-fluoroindolin-2-one (Natrochem, 85% purity) (1.1 g, 5.0 mmol) and 3-chloro-2-fluorobenzaldehyde (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was added piperidine (1.7 g, 20 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, washed with cold methanol, dried to give the first batch of desired product (1.22 g). The filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-35% EtOAc in hexanes) to give the second batch of desired product (0.32 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.54 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCC(c2ccc(N)cc2)CC1

Procedure:
4.3 g (19.5 mmol) 1-methyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 60 ml of ethanol and 60 ml THF, combined with 2 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 3.5 g
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH2:27][C:28]([OH:30])=O.[CH2:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:31]([N:38]1[CH2:43][CH2:42][N:41]([NH:2][C:28](=[O:30])[CH2:27][C:19]2[NH:18][C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1cc2ccccc2[nH]1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cc2ccccc2[nH]1)NN1CCN(Cc2ccccc2)CC1
Reaction time: 15 h
Yield: 28.7 %

Procedure:
1-Hydroxybenzotriazole (324 mg, 2.4 mmol) and triethylamine (446 μl, 3.2 mmol) were added to a solution of indole-2-acetic acid (350 mg, 2 mmol) and 1-benzylpiperazine (352 mg, 2 mmol) in THF (25 ml), followed after 5 min by 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (576 mg, 3 mmol) and the mixture stirred for 15 h. The mixture was concentrated in vacuo and the residue partitioned between citric acid (1M, 30 ml) and ethyl acetate (25 ml), the phases were separated and the aqueous layer extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with sodium bicarbonate (satd., 2×10 ml) and brine (satd., 20 ml), dried (Na2SO4) and evaporated in vacuo to give 1-benzyl-4-(2-indolylacetamido)piperazine as a pink solid (200 mg, 30%), m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Br:14]N1C(=O)CCC1=O>CC#N.C(C1C=C(O)C=C(C(C)(C)C)C=1C)(C)(C)C>[I:1][C:2]1[CH:7]=[C:6]([Br:14])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(OC)ccc1I
Agent: Cc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Solvent: CC#N
Product: COCOc1cc(OC)c(Br)cc1I
Temperature: 23 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of 2-iodo-5-methoxy-1-methoxymethoxybenzene (5.24 g, 17.8 mmol) in MeCN (55 mL) was added silica gel (1.32 g), 2,6-di-tert-butyl-4-hydroxytoluene (60 mg), and then N-bromosuccinimide (3.17 g, 17.8 mmol). The mixture was stirred at 23° C. for 1 hour and then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL). To this solution was added water (100 mL) and the resulting mixture was vigorously stirred for 5 min. The layers were then separated and the aq. phase was extracted with CH2Cl2 (2×100 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash-column chromatography (SiO2, petroleum ether:Et2O 8:1) to provide 2-iodo-4-bromo-5-methoxy-1-methoxymethoxybenzene as a yellow oil (5.05 g, 76%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]1[O:12][CH2:11]1.[C:20]1(C2NC=CN=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:12][CH:10]([CH2:9][O:13][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[C:4]([O:5][CH2:11][CH:10]([OH:12])[CH2:9][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Product: OC(COc1ccccc1)COc1cccc(OCC(O)COc2ccccc2)c1

Procedure:
Resorcinol (110 g), phenyl glycidyl ether (329.5 g) and 2-phenylimidazole (0.4 ) were stirred and heated at 130° for 2 hours, then at 150° for 31/2 hours. The product had a negligible epoxy content (only 0.2 equiv./kg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][O:39][CH2:40][CH2:41][N:42]([CH2:52][CH2:53][O:54][CH3:55])[C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:42]([CH2:52][CH2:53][O:54][CH3:55])[CH2:41][CH2:40][O:39][CH3:38])=[O:51])[CH2:46][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 797.4 [(M+H)+]
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].[CH3:14][CH2:15][CH3:16].C([S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])CC.C(N(CC)CC)C.CS(CC#N)(=O)=O>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:23]([S:20]([CH:15]([CH3:16])[CH3:14])(=[O:22])=[O:21])[C:24]#[N:25])=[C:3]1[Cl:13]
Reactant: CCC
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: CCCS(=O)(=O)CC#N
Agent: CS(=O)(=O)CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)S(=O)(=O)C(C#N)=Cc1c(Cl)n(C)c2ccccc12
Reaction time: 48 h

Procedure:
To 1 g of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of MeOH, was added 820 mg of propan-2-propylsulfonylacetonitril and 1.6 ml of triethylamine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 48 hours. The precipitate was collected by filtration to give (6a). Yield 1.13 g of (6a), m.p. 141C.
Reaction SMILES: [C:1]([S@@:5]([NH:7][C@H:8]([C:13]1([C:18]([O:20]CC)=O)[S:17][CH2:16][CH2:15][S:14]1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24].C(O)C>>[C:1]([S@@:5]([NH:7][C@H:8]([C:13]1([C:18]([NH:24][CH3:23])=[O:20])[S:17][CH2:16][CH2:15][S:14]1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)C1([C@H](CC2CC2)N[S@@](=O)C(C)(C)C)SCCS1
Solvent: CCO
Product: CNC(=O)C1([C@H](CC2CC2)N[S@@](=O)C(C)(C)C)SCCS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A heavy-walled glass tube was charged with ethyl (S,SS)-2-[1-(tert-butylsulfinylamino)-2-cyclopropylethyl]-1,3-dithiolane-2-carboxylate (2.00 g, 5.47 mmol) and a chilled 8.0 M solution of methylamine in ethanol (5 mL, 40 mmol). The mixture was allowed to warm to room temperature and was stirred for 2 hours at which time reaction was complete by HPLC analysis. Distillation of the solvent at reduced pressure afforded the title compound (1.79 g, 93%) as an amber glass.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][CH:18]([CH2:23][C:24]([O:26]C)=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][CH:18]([CH2:23][C:24]([OH:26])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3cc(N)ccn3)cc2CNC1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Solvent: O
Product: Nc1ccnc(NCCCOc2ccc3c(c2)CNC(=O)C(CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (±)-8-[3-[(4-amino-2-pyridyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as a white solid: MS (ES) m/e 385.4 (M+H)+. Anal. Calcd for C20H24N4O4.1.25 H2O: C, 59.03; H, 6.56; N, 13.76. Found: C, 58.80; H, 6.49; N, 13.62.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)O1>>[CH3:27][C:23]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]2[CH:18]=[C:17]([C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Nc1cccc(Br)n1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 2.30 g (13.0 mmol) of 6-bromopyridin-2-ylamine and 5.22 g (13.7 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].S(Cl)(Cl)=O.[CH3:25][N:26]([CH2:28][CH2:29]O)[CH3:27]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([O:19][CH2:29][CH2:28][N:26]([CH3:27])[CH3:25])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCO
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CN(C)CCOC(=O)Cc1ccc(OCc2ccccc2)c(Cl)c1
Product: Cl
Temperature: 5 °C
Reaction time: 2 h
Yield: 131.1 %

Procedure:
6.15 grams of 3-chloro-4-benzyloxyphenylacetic acid was converted into the corresponding chloride by treatment with 15 ml of thionyl chloride in 50 ml of benzene. A solution comprising 1.85 grams of dimethylaminoethanol in 10 ml of benzene was slowly added at 20° C. to the chloride solution. The mixture was then permitted to stand for 2 hours at that temperature and then cooled to 5° C., so yielding a precipitate which was filtered and washed with benzene. Two crystallizations from ethylacetate-isopropyl alcohol (1:1) yielded 5.6 grams (68.4%) of β-dimethylaminoethyl 3-chloro-4-benzyloxyphenylacetate hydrochloride, m.p. 138°-140° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:30]([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[O:31])[CH2:18]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: c1ccc(CN2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCOCC1)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, 1.35 mmol) in 4 mL of CH2Cl2 was added tetrahydro-pyran-4-carbonyl chloride (0.210 mL, 1.637 mmol) and Et3N (0.380 mL, 2.73 mmol). The reaction mixture was stirred at room temperature for 30 min then was quenched with H2O, extracted with CH2Cl2, filtered and evaporated under vacuum. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5) gave [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (420 mg, 73% yield) as a yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.37-1.64 (m, 4H) 1.95-2.29 (m, 2H) 2.56-2.83 (m, 4H) 3.28-3.91 (m, 13H) 5.54-5.68 (m, 1H) 7.24-7.36 (m, 5H) 8.54-8.59 (m, 1H). LCMS: [M+H]+=423.6, Rt(7)=0.68.
Reaction SMILES: OC(C(F)(F)F)=O.C([O:15][CH2:16][CH:17]1[CH2:20][CH:19]([C:21]2[CH:32]=[CH:31][C:24]([CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:22]=2)[CH2:18]1)C1C=CC=CC=1.CC(O)C>C(O)C.[Pd]>[N:26]1([CH2:25][C:24]2[CH:31]=[CH:32][C:21]([CH:19]3[CH2:18][CH:17]([CH2:16][OH:15])[CH2:20]3)=[CH:22][CH:23]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: c1ccc(COCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CC(C)O
Product: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Yield: 79 %

Procedure:
To a stirring solution of crude 1-[4-(3-benzyloxymethyl-cyclobutyl)-benzyl]-pyrrolidine TFA salt prepared above (61.5 mmol) in 250 mL of ethyl alcohol was added palladium black (4.0 g, 20% by wt). The Parr bottle was then pressurized with H2 to 45 psi. After complete consumption of starting material as evident by LRMS the reaction vessel was evacuated (removal of H2 gas), then the reaction was filtered through a plug of Celite, and concentrated under reduced pressure. The residual was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3. The aqueous layer was back extracted with 3:1 CHCl3:iPrOH. The organic layers were dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography, using a Biotage column 75 large, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.2% NH4OH, through 20% MeOH/CH2Cl2 w/0.2% NH4OH. The product containing fractions were collected and concentrated, 13C NMR revealed the presence of TFA. The product was free based by reaction with aqueous K2CO3, and extracted with 3:1 CHCl3:iPrOH to yield the title compound (11.9 g, 79% yield) as a colorless oil and a mixture of cis:trans isomers.
Reaction SMILES: C(OC([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[C:27]([O:33]C)(=O)[CH2:28][C:29]([CH3:31])=O>C(Cl)Cl>[C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:27](=[O:33])[CH2:28][C:29]([CH3:31])=[N:8]2)[CH2:15][CH2:14]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)NNC1CCC(C(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=NN(C2CCC(C(C)(C)C)CC2)C(=O)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To the N′-(4-tert-butyl-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester (7.61 g) in CH2Cl2 (30 mL) was added TFA (10 mL). After 5 h at RT, the solvent was removed under reduced pressure. The residue was dissolved in glacial acetic acid (100 mL), methyl acetoacetate (4.46 g, 38.4 mmol) was added and the reaction was heated to 100° C. for 18 h. After allowing the reaction to cool to RT, the solvent was removed under reduced pressure. Flash chromatography of the residue (50% to 80% EtOAc/hexanes, silica gel) gave the two isomers of 2-(4-tert-butyl-cyclohexyl)-5-methyl-2,4-dihydro-pyrazol-3-one as pale yellow oils. Isomer 1: 2.67 g; TLC Rf 0.30 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.0 (M+H+). Isomer 2: 0.66 g; TLC Rf 0.15 (silica gel, 1:1 EtOAc/hexanes); MS (ES+) m/z 237.4 (M+H+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[S:11](=[O:21])[C:12]([C:18]([NH2:20])=[O:19])=[C:13](OC(C)C)[C:9]=2[CH:8]=1>C(#N)C>[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[S:11](=[O:21])[C:12]([C:18]([NH2:20])=[O:19])=[C:13]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]=2[CH:8]=1
Reactant: CC(C)N
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(N)=O)S2=O
Solvent: CC#N
Product: COc1ccc2c(c1)C(NC(C)C)=C(C(N)=O)S2=O
Reaction time: 16 h
Yield: 64 %

Procedure:
Isopropyl amine (379 μL, 4.45 mmol) is added to a room temperature solution of 5-methoxy-(3-(1-methylethoxy))benzo[b]thiophene-2-carboxamide-1-oxide (250 mg, 0.89 mmol) in 25 mL of acetonitrile. Stirring is continued for 16 hours. The reaction mixture is concentrated and recrystallized from acetonitrile to provide 5-methoxy-3-[(1-methylethyl)amino]benzo[b]thiophene-2-carboxamide-1-oxide in 64% yield; mp=193.5°-194.5° C.