Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1.O>CS(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc2ccc(OCC3CC3)cc12
Reaction time: 2 h
Yield: 59.9 %

Procedure:
17.1 g (0.085 mol) of N-(7-hydroxynaphth-1-yl)acetamide in solution in 50 ml of dimethyl sulphoxide are added under a nitrogen atmosphere to a suspension of 3.4 g (0.085 mol) of sodium hydride in oil, washed beforehand with dry pentane), in 100 ml of dimethyl sulphoxide, while the mixture is cooled with an ice-water bath. Stirring is continued at room temperature for 2 h. 9.05 g (0.1 mol) of (chloromethyl)cyclopropane are added, and the mixture is stirred at room temperature for 4 h and left to stand overnight. The mixture is poured into 1 l of water, stirred for 1 h and left to stand overnight under cold conditions. The solid is separated by filtration, washed with water and dried. 13 g of a product melting point: 154°-155° C., are obtained which is used as it is in the following step.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1CC1CCOCC1
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2CC1CCOCC1
Temperature: 150 °C

Procedure:
4-Chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol (3.9 g, 12 mmol) and ammonia (70 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 150° C. overnight. The volatiles were removed under reduced pressure. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92). The chromatographed product was triturated twice with hot acetonitrile, collected by filtration, and dried in a vacuum oven to provide 800 mg of 4-amino-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:8]=[C:7]([Cl:12])[CH:6]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)Cc1cc(O)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(3-Chloro-5-hydroxy-phenyl)-acetic acid methyl ester (2.9 g, 14.5 mmol), 2-fluoro-5-nitrobenzaldehyde (2.7 g, 15.9 mmol), and potassium carbonate (4.0 g, 28.9 mmol) were combined in 1,4-dioxane (20 mL) and stirred at 100° C. overnight. Once no starting material was seen by analyical LCMS and tlc, the mixture was worked up with EtOAc and 10% aqueous HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][C:27]1([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([N:29]4[CH2:30][C:27]([CH3:26])([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28]4)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1

Procedure:
A mixture of 1 g (3 mmoles) of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.98 g (4.5 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.6 g (6 mmoles) of triethylamine is heated under reflux for 3 hours in 10 ml of pyridine.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4-fluoro-2-methoxyphenylboronic acid (CAS 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=233.108 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].Cl>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CC1(C)C=NC(C)(C)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 134.8 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 110 g (0.5 mol) of 3,3,12,12-tetramethyl-1-aza-1,5,9-cyclododecatriene, 41 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Distillation yields 85 g (0.337 mol) of 2,2,11,11-tetramethyl-11-amino-undeca-4,8-dienal oxime; yield 67.4% of theory; boiling point 130° C./7 Pa.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:9]([CH:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: Nc1ccccc1
Reactant: CCCCC(=O)CC
Product: CCCCC(CC)Nc1ccccc1

Procedure:
N-(1-ethylpentyl)aniline was prepared from aniline and heptan-3-one using the same method as in Example 2i).
Reaction SMILES: C([NH:5][C:6](=[O:38])[N:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH2:31]2)=[CH:26][CH:25]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:35]=[S:34]1(=[O:36])[CH:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:12][CH:11]=3)[C:6]([NH2:5])=[O:38])=[CH:25][CH:26]=2)[CH2:31][C:32](=[O:37])[NH:33]1
Reactant: CC(C)(C)NC(=O)N(CCc1ccc(Oc2ccccc2)cc1)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N(CCc1ccc(Oc2ccccc2)cc1)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Yield: 78.2 %

Procedure:
N′-(tert-butyl)-N-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl]-N-[2-(4-phenoxyphenyl)ethyl]urea (4.5 mg, 0.008 mmol) was heated in trifluoroacetic acid (1 mL) at 100° C. for 5 min in a microwave. The mixture was concentrated and purified by preparative LCMS to give the title compound as a white solid, (3.0 mg, 75%). LCMS found for C25H26N3O5S (M+H)+: m/z=480.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:49])([CH3:48])[CH3:50])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 49.9 %

Procedure:
Following the procedure in Example 147d, and starting with 149c (120 mg, 0.42 mmol, 1 eq.) and 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid (116c) (485 mg, 1.18 mmol, 2.8 eq.), afforded 149d as a yellow solid (120 mg, 50%). MS-ESI: [M+H]+ 573.3.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][CH2:37][O:38]C1CCCCO1>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:37][OH:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: OCCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 142, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran to give 179 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 9.86 (s, 1 H); 8.44 (s, 1 H); 8.29 (s, 1 H); 7.84 (td, J=8.75, 5.94 Hz, 1 H); 7.72 (td, J=9.64, 2.83 Hz, 1 H); 7.43-7.37 (m, 1 H); 7.21 (d, J=2.28 Hz, 1 H); 7.09 (dd, J=8.45, 2.36 Hz, 1 H); 6.96 (d, J=8.40 Hz, 1 H); 5.37 (t, J=4.89 Hz, 1 H); 4.21 (t, J=5.01 Hz, 2 H); 3.83 (d, J=5.48 Hz, 2 H); 3.65 (d, J=12.04 Hz, 2 H); 3.23 (m, 2 H); 3.10 (m, 4 H); 2.69-2.60 (m, 1 H); 2.01-1.80 (m, 4 H). LCMS: RT=7.55 min, M+H+=493
Reaction SMILES: Cl.[O:2]=[C:3]([NH:18][CH:19]1[CH:23]([O:24][CH2:25][CH2:26][CH3:27])[CH2:22][NH:21][CH2:20]1)[CH2:4][NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][N+:39]([O-:42])=[CH:38][CH:37]=2)[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>>[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][N+:39]([O-:42])=[CH:38][CH:37]=2)[CH2:30][CH2:31][CH:32]([N:21]2[CH2:22][C@H:23]([O:24][CH2:25][CH2:26][CH3:27])[C@@H:19]([NH:18][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:17])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[CH2:20]2)[CH2:33][CH2:34]1
Reactant: CCCOC1CNCC1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(O)(c2cc[n+]([O-])cc2)CC1
Agent: Cl
Product: CCCO[C@H]1CN(C2CCC(O)(c3cc[n+]([O-])cc3)CC2)C[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
This compound was synthesized from N-(2-oxo-2-{[4-propoxypyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide hydrochloride and 4-hydroxy-4-(1-oxidopyridin-4-yl)cyclohexanone according to typical reductive amination procedure. MS (m/e): 565 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 60 °C
Reaction time: 30 h
Yield: 11.8 %

Procedure:
2-Chloro-5-trifluoromethylpyridine (5 g) was dissolved in chloroform (150 mL) and m-chloroperbenzoic acid (14.3 g) was added thereto. The mixture was stirred at 60° C. for 30 hr. Aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and after stirring, the mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 2-chloro-5-trifluoromethylpyridine 1-oxide (0.64 g).
Reaction SMILES: CO[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[Cl:13][C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnn(C)c(=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(Cl)cc1=O
Temperature: 110 °C
Yield: 58.4 %

Procedure:
A mixture of 1.50 g (10.70 mmol) of 5-methoxy-2-methyl-2H-pyridazin-3-one and 7.8 ml (13.1 g, 85.6 mmol) of phosphorus oxychloride was heated at 110° C. for 2 h. After allowing to cool to room temperature, the mixture was poured into 100 ml of ice/water with vigourous stirring. After neutralization by addition of saturated sodium carbonate solution, the compound was worked up with methylene chloride/water, dried over magnesium sulfate and concentrated in vaccuo. The crude material was purified by flash chromatography on silicagel using a 80:20 mixture of ethyl acetate and heptane as eluant to yield 904 mg (6.25 mmol, 58%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[C:30]([CH3:35])([CH3:34])[CH2:29][C:28]3([CH3:37])[CH3:36])O1.C([O-])=O>>[CH3:36][C:28]1([CH3:37])[C:27]2[C:31](=[CH:32][C:33]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)=[CH:25][CH:26]=2)[C:30]([CH3:35])([CH3:34])[CH2:29]1
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Reactant: CC1(C)CC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: O=C[O-]
Product: CC1(C)CC(C)(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described above starting from 110 mg (0.29 mmol) of 2-[1-(4-bromothiazol-2-yl)piperidin-4-ylamino]ethanol and 98 mg (0.29 mmol) of 4,4,5,5-tetramethyl-2-(1,1,3,3-tetramethylindan-5-yl)-1,3,2-dioxaborolane. The product is in the form of the formate.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11].[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([OH:16])=[C:7]([Br:6])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
Sulfuric acid (conc., 10 ml) was added to a solution of 3-bromo-4-hydroxybenzoic acid (10.0 g, 46 mmol) in methanol (100 ml) and the mixture was stirred at room temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The mixture was washed with saturated aqueous sodium bicarbonate (2×250 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (8.83 g, 83%). 1H NMR (250 MHz, CDCl3) δ8.19 (1 H, d, J 2.0 Hz), 7.92 (1 H, dd, J 8.5, 2.0 Hz), 7.05 (1 H, d, J 8.5 Hz), 5.91 (1 H, s), and 3.90 (3 H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:12][CH:11]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:11][CH:12]=3)[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCBr)cc1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 30.3 %

Procedure:
A solution of 4-(8-bromooctyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (36.3 mg, 0.06 mmol, e.g. which can be as prepared in Intermediate 41) in N,N-dimethylformamide (6 ml) was treated with morpholine (0.021 ml, 0.24 mmol) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (11 mg). LCMS showed MH+=605; TRET=2.39 min.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][O:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:1]1[C:3]2[N:4]=[CH:5][O:6][C:7]=2[N:8]=[CH:9][N:2]=1
Reactant: CCOC=Nc1ocnc1C#N
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3ocnc13)C2
Yield: 14.7 %

Procedure:
4-cyano-5-ethoxymethyleneaminooxazole (240 mg, 1.5 mmol) (see, J. Am. Chem. Soc., 88, 3829 (1966), Bull. Chem. Soc. JAPAN, 43, 187 (1970), Bull. Chem. Soc. JAPAN, 43, 3909 (1970)) and 2-aminoindan (580 mg, 4.4 mmol) in dry ethanol (2 ml) were heated to reflux for 6.5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (methylene chloride:ethyl acetate=1:4) to obtain the title compound (56 mg, 0.22 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1[O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:11]
Reactant: OCc1ccccc1
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(COCOC)nn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.38 g, 4.91 mmol) and benzylalcohol (797 mg, 7.37 mmol) in dry DMF (10 ml) was added 60% sodium hydride (294 mg, 7.35 mmol) at 5° C. The reaction solution was stirred at 0° C. for 1 hour. The reaction solution was diluted with water, and extracted with tert-butyl methyl ether 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.12 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (yield: 99%) as oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:27])[CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(S(C)(=O)=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 98.2 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 30.0 ml) was dissolved methyl 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (354 mg). To the solution was added 1N sodium hydroxide solution (7.7 ml), and the mixture was stirred at room temperature for 15.5 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (337 mg, 98%) as white crystals.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-])=O.[ClH:11].[H][H]>[Pt].C(O)C>[ClH:11].[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: O=C1CCCCC1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: NC1CCCCC1=O
Reaction time: 3 h
Yield: 40 %

Procedure:
Add 2-nitrocyclohexanone (7.0 g, 48.9 mmol), 5% platinum sulfided on carbon (500 mg), ethanol (120 mL) and concentrated hydrochloric acid (6 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen and stir the mixture for 3 h. Filter the mixture through Celite® and wash with ethanol followed by DCM under a nitrogen atmosphere. Concentrate the filtrate in vacuo. Slurry the residue in acetone (50 mL) and filter. Collect the solid to obtain the desired intermediate (2.2 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2
Reactant: CCN(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-bromo-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine is treated with a cold mixture of N,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl] -6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.