Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C(=CC=CC=2)CO1)=O.[C:11]([Cl:14])(Cl)=[O:12].Cl[C:16]1[C:24](C)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([Cl:20])=O>C1C=CC(P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=CC=1.B(F)(F)F>[Cl:20][CH2:18][C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:11]([Cl:14])=[O:12]
Reactant: Cc1cccc(C(=O)Cl)c1Cl
Reactant: O=C(Cl)Cl
Agent: FB(F)F
Agent: O=C1OCc2ccccc21
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(Cl)c1ccccc1CCl
Yield: 96 %

Procedure:
2 mol of phthalide (268 g) were initially charged with 27.8 g of TPPO (0.1 mol) and 7.9 g (0.04 mol) of BF3 etherate. At 140-150° C., a total of 233 g of gaseous phosgene (2.33 mol) were introduced over a period of 8 h. After an extra stirring time of 1 h at 140° C., the excess phosgene was stripped using nitrogen. The discharge (415 g) contained 88.4 GC area % of o-chloro-methylbenzoyl chloride and 0.1% of phthalide. Fractional distillation of the crude discharge gave 363 g (96% of theory) of o-chloromethylbenzoyl chloride of a purity of 99.8%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:14]=1>>[CH3:32][C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=4)[S:21][C:20]=13)=[CH:31][CH:30]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-formylbenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by a procedure analogous to example 17. RP18-HPLC RT: 5.391 minutes; API MS: 384.29 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.O>[CH2:29]([N:26]([CH2:27][CH3:28])[CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:9]=[N:10]1)[CH3:30]
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(N)cc2)c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(NS(C)(=O)=O)cc2)c1-c1ccccc1

Procedure:
A solution of 8 lg (0.02 mol) of 4-(4-aminophenyl)-N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide of example 46 in 50 mL of pyridine was cooled to 5° C. and 4.6 g (0.04 mol) of methanesulfonyl chloride was added dropwise below 10° C. The reaction was stripped below 60° C. in vacuo, dissolved in about 75 mL of water, treated with excess saturated aqueous sodium bicarbonate, extracted into methylene chloride and stripped. The product was recrystallized from acetonitrile, 7.2 g, mp 179°-180° C.
Reaction SMILES: FC(F)(F)C(O)=[O:4].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2C)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50][N:49](C)[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH2:64]C2CCCC2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:47][CH2:48][NH:49][C:50](=[O:4])[CH2:51]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH3:64])=[CH:37][CH:38]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 17) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 471.1801, calculated for C24H28N4O4Cl [(M+H)+]471.1794.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:23][CH2:22][CH2:21][CH2:20]1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Nc1ccccc1OCCN1CCCC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 273 mg of 2-(2-pyrrolidin-1-yl-ethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours, and then concentrated under reduced pressure.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>C(#N)C>[C:13]([O:16][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1coc(CBr)n1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1coc(COC(C)=O)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
9.5 g (10.80 mmol) of ethyl 2-(bromomethyl)oxazole-4-carboxylate are dissolved in 135 mL of acetonitrile. 9.96 g (101.47 mmol) of potassium acetate are added and the medium is stirred at room temperature for 14 hours.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:25][CH:26]([N:22]1[CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20][CH2:21]1)[CH3:28]
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.20 g), acetone (0.23 mL) and acetic acid (1.0 mL) were dissolved in THF (10 mL), sodium triacetoxyborohydride (0.66 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and neutralized with saturated sodium hydrogen carbonate. Sodium chloride was added to saturation, and the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF) and recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[C:4]([O:8][C:9](=[O:12])[CH2:10]C)(=[O:7])[CH2:5][CH3:6].[C:13](=O)(O)[O-].[Na+]>>[C:1]([O:12][CH:9]([O:8][C:4](=[O:7])[CH2:5][CH3:6])[CH3:10])(=[O:3])[CH2:2][CH3:13]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C([O-])O
Reactant: CC=O
Agent: [Na+]
Product: CCC(=O)OC(C)OC(=O)CC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
An 88-g (2 mols) sample of acetaldehyde was added in small portions to a solution of 260 g (2 mols) of propionic anhydride at 60°C. The reaction mixture was then stirred at about 25°C for 7 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with methylene dichloride. The methylene dichloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was distilled through a 16-inch column to give 316.5 g of ethylidene bispropionate, b.p. 57°C. (1 mm/Hg).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: C1CNCCNCCNCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(CN2CCNCCNCCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
In 50 ml of chloroform was added 3.5 g (20.3 mmole) of 1,4,7,10-tetraazacyclododecane and 1.7 g (7.87 mmole) p-nitrobenzyl bromide and the mixture stirred under nitrogen for 24 hours at 25° C. The chloroform slurry of hydrobromide salt was then applied to a 1 in.×17 in. column of flash silica gel (Solvent System 3). There was obtained 2.13 g (6.93 mmole) of the title product as a pale yellow solid of analytical purity in 88 percent yield (Rf =0.58, Solvent System 3), MP=128°-129° C., and further characterized by:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(O)cc1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(O)cc1
Yield: 69 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and alanine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]alanine benzyl ester is obtained in a 69% yield, the characteristics of which are as follows: Rf =0.22 [hexane/ethyl acetate (65:35 by volume)].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][OH:15])[CH2:10][CH2:9][C:8]=1[S:7]2.C(N(CC)CC)C.Cl.[N:24]1([CH:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C.C(Cl)Cl>[N:24]1([CH:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:2]3[N:3]=[CH:4][N:5]=[C:6]4[C:13]=3[C:12]3[C@@H:11]([CH2:14][OH:15])[CH2:10][CH2:9][C:8]=3[S:7]4)[CH2:34][CH2:35]2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NC1CCC(N2CCOCC2)CC1
Reactant: OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a 100 mL round-bottom flask containing a solution of [(3S)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol (100 mg, 0.42 mmol, 1.00 equiv) in anhydrous DMF (8 mL) was added triethylamine (372 mg, 3.68 mmol, 9.00 equiv) and 4-(morpholin-4-yl)cyclohexan-1-amine hydrochloride (214 mg, 0.83 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at 80° C. After cooling, the resulting solution was diluted with DCM (50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 130 mg (81%) of [(3S)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol as a yellow oil. MS (ES): m/z 389 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1>>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1nccs1
Reactant: NCCN
Product: NCCNCc1nccs1

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole, by the procedure of Example 34 gives N-(2-thiazolylmethyl)ethylenediamine. Reacting this intermediate with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[C:22](O)(=[O:26])[C:23]([NH2:25])=[O:24].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:23](=[O:24])[C:22]([N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1)=[O:26]
Reactant: NC(=O)C(=O)O
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCO[C@@H]1CN(C(=O)C(N)=O)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), oxamic acid (26 mg, 0.29 mmol) and WSC hydrochloride (120 mg, 0.626 mmol) were suspended in DMF (3 mL). Triethylamine (0.040 mL, 0.29 mmol) and HOBT (40 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=1/0→9/1) to obtain 64.7 mg of the title compound as a colorless solid (59%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(C(=O)CCCCl)cc1
Reaction time: 1 h

Procedure:
To a solution of 100 g (1.1 mole) of toluene and 146 ml (1.3 mole) of 4-chlorobutyryl chloride in 470 ml of carbon disulfide at 10° C. under N2, is added in portions, 180 g (1.4 mole) of aluminum chloride. Stir 1 hr. at 0° C., then discontinue the stirring and allow the reaction mixture to settle for 1/2 hr. Decant the top carbon disulfide layer and pour the lower layer into concentrated HCl/ice. Extract with two 600 ml portions of methylene chloride. The combined extracts are washed with 1 L of 10% potassium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1C(OCC)=O.Cl>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@](C)(CCC(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of Example 40D (2.60, 8.22 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (1.60 g, 80%). 1H NMR (300 MHz, CDCl3): δ ppm 0.44 m, 0.5 H) 0.73 m, 3.5 H) 0.80 m, 3 H) 1.06 m, 1 H) 1.39 m, 1 H) 1.56 (s, 1.5 H) 1.59 (s, 1.5 H) 2.04 m, 1 H) 2.30 m, 1 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.63 (s, 0.5 H) 7.46 (m, 2 H) 7.66 (m, 1 H) 8.08 m, 0.5 H) 8.20 m, 0.5 H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:26]C(=O)OC(C)(C)C)[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1)[CH3:2].CCOC(C)=O.C1COCC1>C(Cl)Cl>[NH2:26][C@@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1
Reactant: CCOC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@H](N)CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.9 %

Procedure:
To a solution of (R)-tert-butyl 1-ethoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (109 mg, 0.239 mmol) in DCM (1 mL) was added a TFA/DCM solution (1/1, 10 mL). The mixture was stirred at RT for 2 h. After removal of the solvent, the resulting crude material was reconstituted in a solution of MeOH/DCM (1/1, 5 mL) and was purified via reverse phase preparative HPLC. The fractions were collected, and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (11 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.18 (m, 3H), 1.25-1.44 (m, 4H), 2.26-2.32 (m, 3H), 4.07-4.17 (m, 3H), 4.19-4.29 (m, 2H), 6.03 (s, 1H), 6.78 (d, J=7.83 Hz, 1H), 7.06 (br s, 1H), 7.12-7.22 (m, 1H), 7.48 (s, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.66-7.75 (m, 2H), 7.99 (s, 1H), 8.83-8.97 (m, 1H). [M+H] calc'd for C19H25N5O2, 356. found, 356.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[OH:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][OH:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-7-fluoro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 7 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].[CH3:15][C:16]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH2:29]Br)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:29][CH2:28][CH2:27][O:26][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:15])[CH:25]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: Cc1cc(OCCCBr)c2ccccc2n1
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCOc1cc(C)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.539 g, 3.5 mmol) and lithium hydroxide monohydrate (0.294 g, 7.0 mmol) in DMF (10 mL) was stirred at 25° C. for 1 hour after that 3-(2-methylquinolin-4-yloxy)propyl bromide (0.980 g, 3.5 mmol) was added to the reaction mixture and the reaction mixture was left to stir at 25° C. overnight. Two thirds of the DMF was evaporated under vacuum and the reaction mixture was poured in water, solid was separated by filtration and dried in oven at 80° C. The crude product was purified by column chromatography on silica gel (4% MeOH: 96% CH2Cl2 as eluent) to obtain title compound as light yellow solid (0.5814 g, 47%). 1H NMR (400 MHz, DMSO-d6): 0.90 (3H, t, J=7.6 Hz), 2.30 (4H, m), 2.60 (3H, s), 3.86 (2H, t, J=5.9 Hz), 4.41 (2H, t, J=5.9 Hz), 5.59 (2H, s), 6.16 (2H, s), 6.97 (1H, s), 7.46 (1H, t, J=7.7 Hz), 7.67 (1H, t, J=7.7 Hz), 7.84 (1H, d, J=8.4 Hz), 8.09 (1H, d, J=8.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([C:12]#[C:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2].[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 4-(4-((4-((5-(2-ethoxy-2-oxoethyl)pyrimidin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I111) (0.108 g, 0.177 mmol) was dissolved in dry DMF (10 mL) under an atmosphere of nitrogen. Pd/C (10 wt. %; 0.040 g) in EtOAc (2 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with balloon and stirred at room temperature for 22 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×20 mL). The solvent was removed in vacuo to give a greyish semi-solid which was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I112) (0.096 g, 88% yield) as a pale yellow foam; 1H NMR (400 MHz, de-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 4.11-4.04 (m, 4H), 3.83 (s, 2H), 3.28-3.21 (m, 4H), 2.79 (brs, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=13.1 Hz, 2H), 1.52-1.38 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.65 min; m/z 615.1 [M+H]+.