Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [AlH4-].[Li+].C([O:5][C:6](=O)[CH2:7][N:8]1[C:12]([CH2:13][CH2:14][C:15]2[N:26]=[C:18]3[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[C:22]([CH3:23])[N:17]3[N:16]=2)=[N:11][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:9]1)C>O1CCCC1>[CH3:25][O:24][C:19]1[C:18]2[N:17]([N:16]=[C:15]([CH2:14][CH2:13][C:12]3[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[C:10]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:11]=3)[N:26]=2)[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)nc1CCc1nc2c(OC)ccc(C)n2n1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCO)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1M of Lithium tetrahydroaluminate in Tetrahydrofuran (5.0 mL) was added to a stirred solution of {5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-1,2,4-triazol-1-yl}-acetic acid ethyl ester (950 mg, 2.2 mmol) in Tetrahydrofuran (3 mL) at rt. The reaction is exothermic. The solution was stirred at rt under Ar 3 h. The solution was diluted with THF (10 ml) and quenched by adding wet Na2SO4. The solution was filtered through dry Na2SO4, and was rotovaped. The crude product was purified by silica gel chromatography (Eluent: 0-30% MeOH in EtOAc). Yield: 710 mg (75%) of the title compound as a clear oil. LC-MS: m/z=379.4 (MH+), tR=0.51 min, Method B.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:10]2[S:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)=[N:12][CH:11]=2)[CH2:8][CH2:7][O:6][C@@H:5]([CH3:9])[CH2:4]1.Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C@:3]1([C:10]2[S:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][CH:17]=3)=[N:12][CH:11]=2)[CH2:8][CH2:7][O:6][C@@H:5]([CH3:9])[CH2:4]1
Reactant: CO[C@]1(c2cnc(Sc3ccc(C(C)=O)cc3)s2)CCO[C@@H](C)C1
Reactant: NO
Agent: Cl
Product: CO[C@]1(c2cnc(Sc3ccc(/C(C)=N/O)cc3)s2)CCO[C@@H](C)C1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-{5-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]thiazol-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]thiazol-2-ylthio}acetophenone oxime in 84% yield as a foam.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[N:9]1([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: Nc1cccc(N2CCCCC2)n1
Temperature: 205 °C
Yield: 94.9 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (500 mg, 4.4 mmol), piperidine (1.4 mL, 14.1 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-(piperidin-1-yl)pyridin-2-amine (740 mg, 94%) as a light yellow oil. LC-MS: [M+H]+, 178.1, tR=0.974 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:4]([OH:12])[O:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][CH:4]1[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:6][CH:2]([CH3:1])[O:3]1)(=[O:15])[CH3:14]
Reactant: CC1CC2(CCCCC2)C(O)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1OC(C)CC12CCCCC2
Temperature: 50 °C

Procedure:
A mixture of 11 g of 3-methyl-2-oxaspiro[4.5]decan-1-ol, 7.7 g of pyridine and 9.2 g of acetic anhydride was heated at 50° C. for 12 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 13 g (yield 960) of the target compound, 3-methyl-2-oxaspiro[4.5]decan-1-yl acetate.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N=C(c2ccccc2)C(c2ccccc2)=N1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O

Procedure:
4,5-Diphenylimidazol-2-one was treated with ethyl 8-bromooctanoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 78°-79° C, Found:C, 73.7;H, 7.4;N, 6.7%;C25H30N2O3 requires: C, 73.9;H, 7.4;N, 6.9%
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: CCOc1cccnc1CSCCN=C(NC#N)SC
Reactant: CN
Solvent: CCO
Product: CCOc1cccnc1CSCCN=C(NC)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 10 cc) was added to a stirred suspension of N-cyano-N'-[2-((3-ethoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (1.0 g) in ethanol (5 cc) and the mixture was left to stand overnight. Nitrogen was bubbled through the solution for one hour and the solution was concentrated and crystals which deposited were filtered off and recrystallised from ethanol/ether to give the title product (0.7 g) m.p. 126.5°-127.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([O-])=O.[H][H]>[Ni].CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1cccnc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1NCc1cccnc1

Procedure:
A mixture of 33 parts of N-(2-nitrophenyl)-3-pyridine-methanamine and 480 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 33 parts of N-(3-pyridinylmethyl)-1,2-benzenediamine as a residue.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:6]=[C:7]([Cl:11])[CH:8]=2)[NH:3]1.[OH-].[Na+].[O:22]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: O=C1Cc2cc(Cl)cc(Oc3ccccc3F)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cc(Cl)cc1Oc1ccccc1F

Procedure:
A mixture of 2-oxo-5-chloro-7-(2-fluorophenoxy)indoline (4.0 g.), sodium hydroxide (1.2 g.), dioxane (25 ml.) and water (25 ml.) was refluxed under heating for 15 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water (200 ml.), washed with diethyl ether twice (200 ml. and 100 ml.) and then filtered. To the filtrate was added a mixture of diethyl ether (200 ml.) and ethyl acetate (200 ml.) and the mixture was adjusted to pH 4 with 5% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (200 ml.), dried over magnesium sulfate and then evaporated under reduced pressure. The resultant product was recrystallized from ethanol (30 ml.) to give 2-[2-amino-3-(2-fluorophenoxy)-5-chlorophenyl]acetic acid (2.7 g.), mp 154° to 156° C. Thus obtained compound was dissolved in 1N aqueous sodium hydroxide (9.13 ml.) and lyophilized to give sodium 2-[2-amino-3-(2-fluorophenoxy)-5-chlorophenyl]acetate (3.15 g.). mp>250° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21](CCOC)[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC1C2N(C)C3CCN(CC4N(COC)C=NC=4C)C(=O)C=3C=2C=CC=1.[OH-].[Na+]>Br>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCn1cnc(CN2CCc3c(c4cccc(F)c4n3C)C2=O)c1C
Agent: Br
Agent: COCn1cnc(C)c1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Agent: [Na+]
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O

Procedure:
A solution of 6-fluoro-2,3,4,5-tetrahydro-2-[[1-(methoxyethyl)-5-methyl -1H-imidazol-4-yl]methyl]-5-methyl-1H-pyrido[4,3-b]indol-1-one and 6-fluoro-2,3,4,5-tetrahydro-2-[[1-(methoxymethyl)-4-methyl-1H-imidazol-5-yl]methyl]-5-methyl-1H-pyrido[4,3-b]indol-1-one (32 mg) in 47% aqueous hydrobromic acid (4 ml) was heated on a steam bath for ca. 2 h. After cooling, the reaction mixture was added to 2N sodium hydroxide (50 ml) and extracted with ethyl acetate (2×50 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:8:1) to give the title compound (6.5 mg), m.p. 229°-232°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](=[O:47])[C:38](=[O:46])[N:39]2[CH2:42][C:43](O)=[O:44])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][N:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([F:32])[CH:41]=2)[C:37](=[O:47])[C:38]1=[O:46]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CN1C(=O)C(=O)c2ccc(F)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CN1C(=O)C(=O)c2ccc(F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol) in DCM (15 ml), DMAP (0.058. g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetic acid (0.127 g, 0.571 mmol) were added in one portion at room temperature. The resulting solution was stirred at room temperature for 24 hours; the solvent was removed under vacuum and the residue was dissolved in ethyl acetate (40 ml), washed with a saturated solution of NaHCO3 (20 ml), with 1N HCl (20 ml) and finally with brine (20 ml). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude was purified by preparative HPLC (Method 1) and two pure fractions were isolated:
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][S:13][CH:14]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:62])[CH3:61])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47]([CH:56]=O)=[CH:46][CH:45]=2)([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38](=[O:63])[NH:39][CH2:40][C:41]1[N:42]([CH2:59][CH:60]([CH3:61])[CH3:62])[C:43](=[O:58])[C:44]2[C:49]([C:50]=1[O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][C:47](/[CH:56]=[CH:9]/[C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[CH:46][CH:45]=2)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/c3cscn3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.7 %

Procedure:
A mixture of triphenyl(1,3-thiazol-4-ylmethyl)phosphonium chloride (0.44 g, 1.1 mmol), potassium carbonate (15 g, 1.1 mmol) and tert-butyl(4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.47 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{4-butoxy-2-isobutyl-1-oxo-6-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.46 g, 80.7%) as crystals.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][C:25]([OH:27])([CH3:28])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(O)CN
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 6 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of rac-2-amino-1-propanol, to the title compound (10 mg, 6%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=362.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(F)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1F

Procedure:
4-Fluoro-3-methoxybenzoic acid methyl ester (2.55 g, 13.85 mmol) (from Example 34a supra) was dissolved in a mixture of tetrahydrofuran (140 mL) and water (70 mL). Lithium hydroxide monohydrate (5.8 g, 138.5 mmol) was added and the mixture was heated at reflux for 3.5 hours. After quenching with 1 N aqueous hydrochloric acid (150 mL), the solution was extracted with dichloromethane. The phases were separated and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 4-fluoro-3-methoxybenzoic acid as an off-white solid. (Yield 2.26 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][S:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29]Br)[CH:23]=1)(=[O:20])=[O:19].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:24]2[CH:23]=[C:22]([O:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH:27]=[CH:26][C:25]=2[Cl:28])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CS(=O)(=O)Oc1ccc(Cl)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of piperazin-3-one-1-carboxylic acid tert-butyl ester (7.10 g, 35.3 mmol) in dry DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.10 g, 53.0 mmol). The reaction mixture was stirred for 15 min, and then a solution of the benzylbromide from Step B (10.0 g, 35.3 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction was poured into EtOAc (300 ml), and washed with H2O (3×50 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (60% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: [I:1]Cl.[Br:3][C:4]1[N:12]=[CH:11][C:10]2[NH:9][C:8]3[N:13]=[CH:14][CH:15]=[CH:16][C:7]=3[C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:3][C:4]1[N:12]=[CH:11][C:10]2[NH:9][C:8]3[N:13]=[CH:14][C:15]([I:1])=[CH:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: ClI
Reactant: Brc1cc2c(cn1)[nH]c1ncccc12
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A solution of iodine monochloride (32.5 g, 200 mmol) in acetic acid (120 mL) was added portionwise over 2 h to a mixture of 6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (5.0 g, 20 mmol) and sodium acetate (18.2 g, 221 mmol) in acetic acid (120 mL) at 100° C. The reaction mixture was cooled to ambient temperature and poured into saturated sodium metabisulfite solution (20% w/w, 400 mL). The resultant precipitate was collected by filtration and the solid was washed with water (50 mL) and diethyl ether (2×50 mL) then dried at 45° C. until constant weight was achieved, to afford the title compound as a grey solid (6.3 g, 83%). 1H NMR (DMSO-D6, 300 MHz) 12.49 (s, 1H); 9.14 (d, J=2.1 Hz, 1H); 8.79 (d, J=2.1 Hz, 1H); 8.71 (s, 1H); 8.49 (s, 1H). LCMS (Method B): RT=3.40 min, M+H+=374/376.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:19][O:20][CH3:21])[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:27]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]([CH2:19][O:20][CH3:21])[C:10]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCn1c(-c2ccncc2)cnc1-c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(-c2ccc(Cl)cc2)nc(C(=O)c2ccccc2)c1-c1ccncc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 26.7 %

Procedure:
To a cooled solution of 2-(4-chlorophenyl)-1-methoxymethyl-5-(4-pyridyl)imidazole from Step B (40 mg, 0.13 mmol) in THF (0.5 mL) at -30° C. was added dropwise a solution of n-butyllithium in hexanes (93 μL of a 2.5 M solution, 0.23 mmol). The reaction was stirred at -30 to -10° C. for 90 min. After cooling to -30° C., benzoyl chloride (47 μL, 0.40 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and the mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-4% methanol in methylene chloride to yield the title compound as a red-brown glass (14 mg, 26% yield), mass spectrum (CI) m/e=404 (M+1)+.
Reaction SMILES: O.[O:2]=[C:3]1[N:8]([Na])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1.[CH2:11](Br)[CH:12]=[CH2:13]>C(O)CO>[O:2]=[C:3]1[N:8]([CH2:13][CH:12]=[CH2:11])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1
Reactant: C=CCBr
Reactant: O=c1cn[nH]c(=O)n1[Na]
Solvent: O
Solvent: OCCO
Product: C=CCn1c(=O)cn[nH]c1=O
Temperature: 80 °C

Procedure:
A mixture of 6.12 g 3,5-dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine monohydrate, 5.81 g allyl bromide and 50 ml ethylene glycol was heated to 80° C. for 4 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.O>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([C:14]2[CH:13]=[N:12][C:11]([F:10])=[CH:19][CH:18]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Fc1ccc([Mg]Cl)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(F)nc1

Procedure:
A 2 M solution of 4-fluorophenyl magnesium chloride (7 ml, 14 mmol) was slowly added at −30° C. to a solution of 6-fluoronicotinoyl chloride (3.35 g, 21 mmol,) in ether (30 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a yellow solid. After purification by chromatography on silica gel (CH2Cl2/Hexane 85/15), the (4-fluorophenyl)(6-fluoro-3-pyridinyl)methanone 38 was obtained as a white solid (1.52 g, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:6][C:7]1[C:8]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][C:9]=2[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)#[N:2].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:6][C:7]1[C:8]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:9]=2[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:14][CH:13]=1)#[N:2]
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(C#N)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CC(Cl)Cl
Product: N#Cc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
3-[3-Cyano-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (60 mg, 0.11 mmol) in dichloroethane (4 mL) at 0° C. under argon was treated with ethanethiol (0.1 mL) and aluminum chloride (100 mg) for 3 h before quenching with saturated aqueous sodium bicarbonate solution (10 mL). The stirring was allowed to continue for 1 h at ambient temperature. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a white foam (40 mg, 68%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: CCCC(=O)Cl
Solvent: CN(C)c1ccccc1
Product: CCCC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Yield: 56.7 %

Procedure:
2.12 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol--isomer A; see Example 1--were treated with a mixture of 12.1 g (0.1 M) of N,N-dimethylaniline and 5.3 g (0.05 M) of butyryl chloride as indicated in Example 3--except heating at 100° for 3 hours--to give 1.6 g (57%) of the desired ester, b.p. 120°/0.5 Torr.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCCCO
Agent: Cl
Product: COc1ccc(N(C)c2nc(NCCCCO)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (81 mg, 0.24 mmol) and 4-amino-butan-1-ol (69 μL, 0.75 mmol) by a procedure similar to Example 180, yielding a pale yellow oil (55 mg; 65%). 1H NMR (CDCl3) δ 7.48 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.91 (m, 2H), 6.81 (m, 1H),6.69 (m, 1H), 3.84 (s, 3H), 3.78 (t, J=6 Hz, 2H), 3.60 (m, 2H), 3.53 (s, 3H), 1.82 (m, 2H), 1.73 (m, 2H); LC-MS (ESI+; 353 ([M+H]+)).