Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.O>C(OCC)C.CCCCCC.C(C1C=CC(C2(O)CCCC2)=CC=1)(C)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:17]2([OH:22])[CH2:21][CH2:20][CH:19]=[CH:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)c1ccc(C2(O)CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C2(O)C=CCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 34 g of 4-t-butylphenylbromide (0.16 mole) in 50 ml diethyl ether was slowly added to a stirred mixture of 100 ml of a solution of n-butyllithium in hexane (1.6 mole/l) and 50 ml diethyl ether, while the temperature of the mixture was kept at -25 ° C. After completion of the addition, the temperature of the resultant mixture was allowed to rise slowly to about room temperature. Subsequently the temperature was decreased to -25° C. and 13.2 g of 2-cyclopentene-1-one (0.16 mole) dissolved in a small volume of diethyl ether was slowly added. The suspension thus obtained, was allowed to reach room temperature and then stirred for one hour. An excess amount of water was added to the suspension to result in 1-(4-t-butylphenyl)cyclopentanol. The 1-(4-t-butylphenyl)cyclopent-2-en-1-ol product was isolated from the reaction mixture by extraction with diethyl ether and subsequently purified by chromatography over silica, using dichloromethane as the elution solvent.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]=[C:13]3[CH2:15][O:14]3)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:16][CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>O1CCOCC1.C(O)C>[CH:21]([N:19]1[CH2:20][CH:17]([NH:16][CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:10]2[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH2:18]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc2cccc(OC=C3CO3)c2s1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc2cccc(OCC(O)CNC3CN(C(c4ccccc4)c4ccccc4)C3)c2s1

Procedure:
The title compound was prepared according to Method A from 2-methyl-7-(oxiranyl-2-ylmethoxy)benzothiazole and 3-amino-1-benzhydrylazetidine with dioxane/ethanol (1:1) as the solvent. mp 55° C.; LSIMS m/z 460. The 3-amino-1-benzhydrylazetidine was prepared as described in Preparation 96.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc2c(c1)CCN=C2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2c(c1)CCNC2C

Procedure:
In close analogy to the procedure described above, 1-Methyl-6-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[N:15]1C=CC=CC=1>C(Cl)Cl>[NH2:15][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccnc(N)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a slurry of 2-chloro-4-cyanopyridine (10.00 g, 0.079 mol) and sodiumbicarbonate (19.92 g, 0.237 mol) in amine (0.174 mol) was added pyridine (35.0 mL) and the reaction was heated to 90° C. for 3 h. The reaction was then cooled to RT, diluted with the addition of CH2Cl2 (100 mL) and filtered. The solid was washed with EtOAc. Combined washes were concentrated in vacuo. A mixture of MeOH/hexanes was added and kept in the fridge for 12 h. The crystals that formed were filtered and washed with hexanes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Si:42]([O:49][CH2:50][CH2:51][CH2:52]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:52][CH2:51][CH2:50][O:49][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:43])[CH3:44])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with 3-{[tert-butyl(dimethyl)silyl]oxy}-1-propanol (J. Org. Chem. 1986, 51, 3388-3390)/triphenyl phosphine/diisopropyl azodicarboxylate as described in step a (Example 213) to provide the title compound as solid foam. 1H NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 0.8 (9H, s), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.8 (2H, quintuplet), 1.9-2.0 (1H, m), 2.38 (1H, dd), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.2-3.3 (2H, m), 3.35-3.45 (1H, m), 3.5-3.6 (3H, m), 3.7 (2H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d)Y 6.18 (2H, s), 6.75 (2H, d), 7.0-7.1 (3H, m), 7.18 (1H, d)Y 7.2 (1H, s), 7.28 (1H, d); MS: 765 (MH+)
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]([F:25])[F:24]>O.COCCOCCOCCOCCOC>[F:24][CH:23]([F:25])[N:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]=[C:2]1[CH3:1]
Reactant: FC(F)Cl
Reactant: Cc1nn(-c2ccccc2)c(=O)[nH]1
Agent: COCCOCCOCCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nn(-c2ccccc2)c(=O)n1C(F)F
Yield: 98.3 %

Procedure:
This compound was prepared in the manner of Example 3, with 50.0 grams of 4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (0.286 mole--1.0 equiv.), 11.4 grams (0.286 mole--1.0 equiv.) of sodium hydroxide in 50 mL of water, 9.9 grams (0.071 mole--0.25 equiv.) of potassium carbonate, and 37.1 grams (0.429 mole--1.5 equiv.) of chlorodifluoromethane in 333 mL of tetraglyme (% wt/vol. triazole to solvent--15%) as reagents. A yield of 63.2 grams of 96.3% pure 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (96.6% yield) was obtained. GC analysis of the product indicated the presence of about 0.9% O-isomer by-product.
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH3:18])[CH:3]([N:9]1[CH:12](Cl)[C:11]([Cl:15])([Cl:14])[C:10]1=[O:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(Cl)Cl.[B-](F)(F)(F)F.[Ag+]>[Cl:14][C:11]1([Cl:15])[C:10](=[O:16])[N:9]2[CH:12]1[O:1][CH:2]([CH2:17][CH3:18])[CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C(O)CC)N1C(=O)C(Cl)(Cl)C1Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1C(CC)OC2N1C(=O)C2(Cl)Cl
Reaction time: 0.5 h

Procedure:
All of the material produced in (g) was dissolved in methylene chloride (3 ml). To this solution was added AgBF4 (0.074 g) and Ag2O (0.44g). After stirring for 1/2 hour the suspension was filtered and the filtrate washed with NaHCO3 and water, dried and evaporated. Chromatography of the residue yielded the title compound (e17) (0.025 g), which was a mixture of the compound with the (2RS, 3SR, 5RS) stereochemistry and also the compound (2RS, 3SR, 5SR) stereochemistry in the ratio of 10:1.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[O:7])=[CH:4][CH:3]=1.[CH:28]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:28]1([O:1][C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:22][CH:23]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NCCCCCCCNC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCCCCCNC(=O)c1ccc(OC2CCCC2)cc1)c1ccc(OC2CCCC2)cc1

Procedure:
m.p. 153°-154° C., 18.8 g., was prepared as in Example 29 using 18.5 g. of N,N'-heptamethylenebis(4-hydroxybenzamide), 29.8 g. of cyclopentyl bromide, 20.7 g. of potassium carbonate, 500 ml. of isoamyl alcohol and recrystallization from acetonitrile.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCOCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)-morpholine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1([CH2:20][C@H:21]([NH:27]C(C2C=CC(C3CCOCC3)=C(OCC3CC3)N=2)=O)[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C@H:21]([NH:27][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): 384.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[C:10]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][C:21]2[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[NH2:1][C:2]1[S:3][C:4]([C:7]([NH:27][C:22]2[C:21]([NH:20][C:18](=[O:19])[C:17]3[CH:28]=[CH:29][C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:15][CH:16]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:9])=[CH:5][N:6]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: Nc1ncc(C(=O)O)s1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cnc(N)s2)cc1
Yield: 12.7 %

Procedure:
Using the procedure described in Example 102, Part A, 2-aminothiazole-5-carboxylic acid (1.0 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.5 mmol) yielded 50 mg (13%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19](O)=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:25]>>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19]([Cl:25])=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Product: O=C(Cl)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid (75 mg, 0.246 mmol) was dissolved in anhydrous MC (5 ml), SOCl2 (0.58 g, 4.92 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[NH:23][N:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:23]3[N:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(C(=O)O)n[nH]1
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Yield: 90.9 %

Procedure:
1-(3,4-Dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (1.00 g, 3.51 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (0.446 g, 3.51 mmoL) in acetic acid (100 mL) was heated at reflux for 48 hours. The reaction concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.20 g, 90%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24](O)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:4].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24]([Cl:7])=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccncc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccncc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 72 h
Yield: 126 %

Procedure:
1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH2Cl2. The solution was cooled at −10° C. and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[N:6]=[CH:7][C:2]([N:44]6[CH2:45][CH2:46][N:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]6)=[N:3][CH:4]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: CC(C)N1CCNCC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCN(C(C)C)CC5)cn3)C4)n[nH]c2c1
Yield: 19.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and 1-isopropyl-piperazine, (40 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method D to afford (18 mg, 19%) of the title compound as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:23][CH:22]5[N:24]([CH2:25][C:26](O)=[O:27])[CH:19]([CH2:20][CH2:21]5)[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH:72]1[CH2:75][CH:74]([OH:76])[CH2:73]1>CN(C)C=O.[Cl-].[Na+].O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:23][CH:22]5[N:24]([CH2:25][C:26]([N:72]6[CH2:75][CH:74]([OH:76])[CH2:73]6)=[O:27])[CH:19]([CH2:20][CH2:21]5)[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4CC(=O)O)cc12
Reactant: OC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4CC(=O)N3CC(O)C3)cc12

Procedure:
A mixture of Example 304A (0.100 g, 0.225 mmol), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.141 g, 0.270 mmol), triethylamine (0.157 mL, 1.126 mmol), and azetidin-3-ol.hydrochloride (0.030 g, 0.270 mmol) in N,N-dimethylformamide (2.5 mL) was stirred for 3 hours. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using the ISCO Companion flash system eluting with dichloromethane/methanol/ammonium hydroxide (18:1:0.1 to 12:1:0.1) to give the title compound. 1H NMR (500 MHz, Methanol-d4) δ 1.60-1.70 (m, 1H), 1.91-1.99 (m, 1H), 2.06-2.17 (m, 2H), 2.16-2.27 (m, 1H), 2.82-2.91 (m, 1H), 3.26-3.34 (m, 1H), 3.51-3.58 (m, 1H), 3.63-3.70 (m, 1H), 3.76-3.78 (m, 4H), 4.00 (td, J=9.9, 4.3 Hz, 1H), 4.21 (dd, J=10.6, 6.9 Hz, 1H), 4.33-4.46 (m, 1H), 4.49-4.69 (m, 2H), 6.23 (s, 1H), 6.48-6.53 (m, 1H), 7.07 (d, J=5.1 Hz, 1H), 7.09-7.20 (m, 3H), 8.15 (d, J=5.1 Hz, 1H). MS (ESI+) m/z 463.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-phenoxybenzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was add to the obtained residue, and a solid substance was separated by filtration to obtain 13 mg of (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:17]([O-:19])=[O:18])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)(Cl)Cl>[CH2:30]([O:29][C:27]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:17]([O-:19])=[O:18])[CH2:9]1)=[O:28])[CH3:31]
Reactant: O=[N+]([O-])c1cccc2c1CN(Cc1ccccc1)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 20 h
Yield: 73.3 %

Procedure:
2.54 g of 2-benzyl-4-nitroisoindoline was dissolved in 10 ml of chloroform, and 1.27 g of sodium carbonate was added to the solution. To the mixture was added dropwise 1.30 g of ethyl chloroformate under ice-cooling while stirring. After the addition, the stirring was continued for 20 hours at room temperature. The insoluble materials were removed by filtration and the filtrate was washed with water, 5% hydrochloric acid, and then with water. The mixture was concentrated and recrystallized from a chloroform-ether mixed solvent to obtain 1.73 g of 2-ethoxycarbonyl-4-nitroisoindoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[CH3:19][C:16]([Si:13]([CH3:14])([CH3:15])[O:20][CH2:21][CH2:22][N:23]([CH3:24])[S:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])([CH3:17])[CH3:18]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.7 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (1 g, 4.70 mmol) in DCM (2 mL) was added slowly to a solution of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (980 mg, 5.17 mmol) in DCM (65 mL) and 10% sodium hydroxide solution (65 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL). The combined organics were washed with brine (80 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a colourless oil (0.7 g). 1H NMR δ (CDCl3): 0.00 (s, 6H), 0.83 (s, 9H), 2.91 (s, 3H), 3.24 (t, 2H), 3.73 (t, 2H), 6.87-6.96 (m, 2H), 7.82-7.88 (m, 1H)
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][CH:13]=1>ClCCCl>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]cc1C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c(C=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 0.92 mL (12 mmoles) of N,N-dimethylformamide in 10 mL of 1,2-dichloroethane was added dropwise 1.0 mL (12 mmoles) of phosphorus oxychloride at 0° C. The ice-bath was removed and the reaction mixture was further stirred for 30 min. 3,4-Dimethylpyrrole (960.0 mg, 10 mmoles) was added to the above solution portionwise and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was poured into ice-cold 1 N sodium hydroxide solution (pH=9 after mixing) and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine until pH=7, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with a solvent mixture of ethyl acetate and hexane to afford 610 mg (50%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=O.[NH3:29].[K+].[Br-]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH2:29])=[O:2])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: N
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CSc1nc(C(N)=O)c2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 3 g (0.007 mole) of 8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 60 ml of 25% solution of ammonia in methanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give light tan crystals, which were recrystallized from methanol/methylene chloride to yield light tan prisms with mp 270°-274° (dec.). Uv λ max 217 mμ (ε=47,200) infl 242 (23,200) sh 270 (11,500), ir (KBr) 3365, 3250, 3215, 3150 cm-1 (NH2) 1675, 1650, 1590 (CON).