Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:29])[C:7]([S:15][C@@H:16]1[CH2:20][NH:19][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])[CH2:17]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[C:31](=[NH:36])(OCC)[CH3:32].C(=O)([O-])[O-].[K+].[K+].Cl>O>[C:31]([N:19]1[CH2:20][C@@H:16]([S:15][C:7]2[C@H:6]([CH3:29])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:17][C@H:18]1[CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])(=[NH:36])[CH3:32]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=N)N1C[C@@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)C[C@H]1COCCNC(N)=O
Yield: 66.9 %

Procedure:
To a solution of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}-pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.15 g) in water (30 ml) was added ethyl acetimidate hydrochloride (1.65 g) by portions at 0°-5° C., keeping the pH between 8.4-8.6 with 10% aqueous potassium carbonate. After adjusting to pH 6.5 with lN aqueous hydrochloric acid, the solution was washed with 10% solution of tetrahydrofuran in ethyl acetate (50 ml) by four portions and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "HP-20" (30 ml), washed with water, eluted with 5% aqueous isopropyl alcohol and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-1-acetimidoyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[ (1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.11 g).
Reaction SMILES: [NH2:1][C:2](=[O:73])[C:3]([NH:6][C:7](=[O:72])[CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:71]=[CH:70][C:14]([CH2:15][C:16]2[C:17]([CH3:69])=[CH:18][C:19]([O:61]CC3C=CC=CC=3)=[C:20]([C@@H:22]3[O:51][C@H:50]([CH2:52][O:53]CC4C=CC=CC=4)[C@@H:41]([O:42]CC4C=CC=CC=4)[C@H:32]([O:33]CC4C=CC=CC=4)[C@H:23]3[O:24]CC3C=CC=CC=3)[CH:21]=2)=[CH:13][CH:12]=1)([CH3:5])[CH3:4]>[OH-].[Pd+2].[OH-].CO>[NH2:1][C:2](=[O:73])[C:3]([NH:6][C:7](=[O:72])[CH2:8][CH2:9][CH2:10][C:11]1[CH:71]=[CH:70][C:14]([CH2:15][C:16]2[C:17]([CH3:69])=[CH:18][C:19]([OH:61])=[C:20]([C@@H:22]3[O:51][C@H:50]([CH2:52][OH:53])[C@@H:41]([OH:42])[C@H:32]([OH:33])[C@H:23]3[OH:24])[CH:21]=2)=[CH:13][CH:12]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(C)C(N)=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCC(=O)NC(C)(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a methanol solution (1 mL) of (1S)-1-[5-(4-[(1E)-4-[(2-amino-1,1-dimethyl-2-oxoethyl)amino]-4-oxobut-1-en-1-yl]benzyl)-2-(benzyloxy)-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (75 mg, 0.0765 mmol) was added 20% palladium hydroxide (15 mg), and the mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=5:1, ethyl acetate:ethanol:water=20:2:1) to obtain the title compound (32 mg, 79%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc([C@H]2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H]1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 119° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (R)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH:19]=[CH:18][N:17]=[CH:16]5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 90.7 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(imidazole-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.14 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.75 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])(=[O:27])=[O:26])[CH:20]=[CH:19]2)=O)C>C1(C)C=CC=CC=1>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][S:25]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH2:14][OH:13])=[CH:24][CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of diisobutylaluminum hydride (82.9 mL, 1M in toluene, 82.9 mmol) was added slowly at 0° C. to the solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carboxylic acid ethyl ester (8.81 g, 25.9 mmol) in toluene (200 mL). After it was stirred at 0° C. for 45 min, the reaction was quenched by the addition of methanol (26 mL), pulverized sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed up to room temperature in 1 h and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a very viscous liquid, which solidified upon cooling. A white solid (8.08 g, 100% yield). 1H-NMR (CDCl3, 500 MHz) δ 7.87 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.35 (dd, J=8.6, 1.5 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 4.79 (s, 2H), 3.18–3.14 (m, 2H), 1.73 (s, 1H), 0.85–0.82 (m, 2H), −0.06 (s, 9H). Mass spec. 312.14 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].Cl.FC(F)(F)C(O)=O.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>ClCCl>[C:19]([S:4][CH2:3][CH2:2][NH2:1])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Hydrochloric acid 2-aminoethanethiol (5.16 g, 45.4 mmol) was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (7.0 mL, 90.8 mmol) and triphenylmethyl chloride (13.29 g, 47.7 mmol) were added, followed by stirring at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution (150 mL) was added, and extraction was carried out with dichloromethane (500 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, methanol (100 mL) was added to the resulting residue, and the deposited by-product was removed by filtration. 1N hydrochloric acid (300 mL) was added to make the solution acidic, and the deposit was filtered off. After the by-product was washed with dichloromethane (50 mL) to remove it, the solution was made alkaline with a 1N aqueous sodium hydroxide solution, and extraction was carried out with dichloromethane (600 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired product (8.77 g, yield 60%) as a white solid.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:6]([CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(O)(CC)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To ethyl 2-((cyclopentylamino)methyl)-2-hydroxybutanoate (2.7 g, 12 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (2.1 ml, 18 mmol) dropwise, followed by K2CO3 (5 g, 35 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 4:1) to give 2.9 g product (77%). [M+H] calc'd for C19H29NO3, 320. found 320.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A 6.0 g. portion of 3-chloro-6-(α ,α ,α-trifluoro-m-tolyl)pyridazine (prepared as in Example 11), 3.44 g. of acetylhydrazine and 75 ml. of n-butyl alcohol is refluxed for 48 hours. The solvent is removed under vacuum and the residue dissolved in ethyl alcohol and treated with activated carbon. The filtrate is concentrated, chilled and filtered to give an orange solid. Recrystallization from methyl alcohol affords the product of the example as crystals, m.p. 193°-194° C.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4].S(Cl)([Cl:17])=O>>[Cl:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([Cl:17])=[O:14])=[N:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(Cl)=C(Cl)Cl)cn1
Product: O=C(Cl)c1ccc(C(Cl)=C(Cl)Cl)cn1

Procedure:
The above reaction is repeated on 12.3 g. of 5-trichlorovinyl pyridine-2-carboxylic acid and 145 ml. of thionyl chloride affording a tan solid with a m.p. 89°-90° C. The crude 5-trichlorovinyl pyridine-2-carboxylic acid chloride are used without further purification in subsequent steps.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=2[O:27]1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:31]2[CH:30]=[CH:29][C:28]3[O:27][CH2:26][O:34][C:33]=3[CH:32]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc3c(c2)OCO3)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (200 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 150 mg of (3,4-methylenedioxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 100 mg of 2,2-dimethyl-4-(3,4-methylenedioxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.60 (s, 6H), 3.07 (s, 3H), 5.99 (s, 2H), 6.74 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H). IR (cm−1): 1697, 1503, 1404, 1245, 1148, 959, 770.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.08 g) in dichloromethane (2 ml) was added TFA (2 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.036 g, 15%). MS (ISP) 472.2 [(M+H))+]; mp 255° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:36]([F:35])([F:46])[F:47])=[CH:38][CH:39]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred suspension of [4,6-bis-dimethylamino-2-(4-aminobenzyl)pyrimidin-5-yl]acetic acid methyl ester (100 g, obtained according to step C) in 700 mL of methanol in a 1500 mL double jacketed vessel at 20±5° C. is added diisopropylethylamin (41.4 g) over a period of 30 minutes while heating the reaction mixture to 50±5° C. 4-Trifluoromethylbenzoic acid chloride (63.8 g) is added during further 30 minutes. The reaction mixture is stirred for 15 minutes at 50±5° C. and subsequently heated to 65±5° C. (reflux conditions) and stirred for another 30 minutes. The resulting suspension is gradually cooled to 5±5° C. over a period of 2 hours and stirred at this temperature for 1 hour. The solid is filtered off, washed with 200 mL of isopropanol and dried in vacuo at 50° C. to yield [4,6-bis-dimethylamino-2-[4-(4-trifluoromethylbenzoylamino)benzyl]pyrimidin-5-yl]acetic acid methyl ester in an amount of 135.8 g (yield: 90%; HPLC-purity: 99.5%).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[C:9]1=[O:37])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:9]1[N:10]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:23][CH:24]=2)[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]([OH:38])=[O:5]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Reaction time: 18 h

Procedure:
A stirred solution of {2,4-dioxo-3-[4-(phenethylcarbamoyl-methyl)-phenyl]-3,4-dihydro-2H-quinazolin-1-yl}-acetic acid tert-butyl ester (Intermediate E) (470 mg, 0.916 mmol) and triethylsilane (0.37 ml, 2.9 mmol) in dry DCM (2.5 ml) under argon is treated dropwise with TFA (2.5 ml). After 18 hours, the reaction mixture is evaporated in vacuo and the residue is triturated with MeOH resulting in a white solid. The solid is filtered and dried under vacuum to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[N:22]1>>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([C:25]2[N:21]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)[N:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=[N+]([O-])c1ccc(-c2ccnn2C2CCCCO2)cc1C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared from 5-bromo-2-nitrobenzotrifluoride (5 g, 18.52 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.67 g, 20.37 mmol) using the method of Example 34(a). Reaction afforded 3.90 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49-1.68 (m, 3H), 1.82 (m, 1H), 1.94 (m, 1H), 2.38 (m, 1H), 3.61 (m, 1H), 3.99 (d, 1H), 5.31 (m, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 8.10 (m, 1H), 8.19 (m, 1H), 8.32 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Yield: 99.2 %

Procedure:
40.58 g (128.7 mmol) of ethyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 300 ml of ethanol and 32.5 ml (130 mmol) of 4N sodium hydroxide solution were heated to reflux on a steam bath for 1.5 hours. The alcohol was evaporated on a rotary evaporator. The aqueous phase was washed twice with methylene chloride and acidified to pH 3-4 with 32.5 ml (130 mmol) of 4N hydrochloric acid. The suspension obtained was cooled and filtered. The filter residue was washed with a small amount of ice water and dried. There were obtained 36.67 g (99%) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of m.p. 159°-160°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:49][C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1cnccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnccn2)cc1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 148A, 375 mg, 1.0 mmol) and triphenylphosphine (446 mg, 1.7 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of the N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminopyrazine (238 mg, 2.5 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. Biotage chromatography (FLASH 40S, Silica, 2/3 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide (72 mg, 16%) as pink foam: EI-HRMS m/e calcd for C19H22BrN3O3S (M+) 451.0565, found 451.0547.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)Cl>[CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23]([CH3:24])=[O:42])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Solvent: ClCCl
Product: Cc1nc(N(CCCO)Cc2ccccc2)c2c(S(C)=O)nn(-c3c(Cl)cc(Cl)cc3Cl)c2n1
Yield: 110.9 %

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}propanol (42 mg, 0.077 mmol) and m-chloroperbenzoic acid (14 mg, 0.081 mmol) in 0.5 ml of methylene chloride was stirred at room temperature for 3 hours. The mixture was quenched with water and saturated sodium thiosulfate, and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give an oil which was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 46 mg of the title compound as a white glass form. 1H NMR (CDCl3): 1.88(m,2H), 2.54(s,3H), 2.73(s,3H), 3.5-3.7(m,4H), 4.3(m,1H), 5.15(ABq,JAB=16Hz,2H), 7.2-7.4(m,5H), 8.47(ABq,2H)ppm.