Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=3)=[CH:17][CH:16]=2)=[CH:11][C:10]([C:31]([F:34])([F:33])[F:32])=[N:9]1.CO.C=O.[C:39]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][N:14]([CH3:39])[C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][C:10]([C:31]([F:34])([F:32])[F:33])=[N:9]1
Reactant: [BH3-]C#N
Reactant: CS(=O)(=O)c1cccc(-c2ccc(NCc3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1cc(C(F)(F)F)nn1-c1ccccc1Cl)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Into an 8 mL vial was weighed 215 mg of N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3′-(methylsulfonyl)biphenyl-4-amine (0.42 mmol). Addition of 2 mL of methanol followed by 0.5 mL of acetic acid, and 150 μL of 37% aqueous formaldehyde solution afforded a solution that was treated with 40 mg of sodium cyanoborohydride (0.64 mmol). After 30 min. at room temperature the reaction was quenched by the addition of 6N HCl (aq.). After gas evolution had subsided, the reaction mixture was diluted with EtOAc and the aqueous was made basic by the addition of saturated aqueous NaHCO3. The basic aqueous was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford a colorless film. The crude product was purified by silica gel flash chromatography on a 12 g column using gradient elution from 0% to 100% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a colorless film. This material was impure by NMR analysis and was further purified by preparative reverse phase HPLC eluting with a gradient from 30% to 100% MeCN in H2O (each with 0.05% trifluoroacetic acid). The appropriate fractions were made basic by addition of saturated aqueous NaHCO3 solution and concentrated in vacuo to remove most of the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a brittle foam that was broken up into a white powder, yield 126 mg (57% yield): 1H NMR (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H, 7.84-7.79 (m, 2H, 7.62-7.56 (m, 2H, 7.52-7.40 (m, 5H), 6.72-6.67 (m, 2H), 6.52 (s, 1H), 4.43 (br s, 1H), 3.09 (s, 3H), 2.94 (S, 3H); MS (ESI) m/z 520.3 [M+H]+.
Reaction SMILES: C([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:23])(=O)C.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]O)=[CH:27][CH:26]=1>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:8]2[NH:7][C:6](=[O:23])[CH:5]([O:4][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([OH:24])=[CH:26][CH:27]=3)[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH:18]=1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: OCCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1OCCc1ccc(O)cc1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A solution of 10.0 grams (0.0309 mol) of 3-acetoxy-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-one and 11.0 grams (0.080 mol) of 4-hydroxyphenethylalcohol (Aldrich) in 50 ml. dry N,N-dimethylformamide was stirred in an ice bath and hydrogen chloride gas was bubbled into the solution for 5-10 minutes. After standing at room temperature for 18 hours, the reaction mixture was poured onto ice and the pH adjusted to 7.5 with ammonium hydroxide. The mixture was filtered and the gummy precipitate was stirred with 50 ml. dichloromethane and 50 ml. water for 5 minutes and filtered. The solid was crystallized from a mixture of dichloromethane and methanol to give 9.6 grams (77%) of the compound of Formula I (a) as white rods, m.p. 222°-230° C.; 1R (KBr) 3310, 3215, 3140, (OH,NH), 1685 cm-1 (C=O); NMR (DMSO-d6) 2.86 (t, 2H, CH2Ar), 3.77, 3.95 (2q, 2H, CH2O), 4.78 (s, 1H, CH), 6.68, 7.09 (2d, 4H, aromatics), 9.18 (s, 1H, OH), 10.81 (s, 1H, NH); mass spectrum m/e 406 (M+ ) Anal. Calcd for C23H19ClN2O3 : C, 67.90; H, 4.71; N, 6.89. Found: C, 67.91; H, 4.83; N, 6.80.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH:28]([F:30])[F:29])=[C:17]3[O:21][C:20]([CH:22]4[CH2:26][CH2:25][O:24][CH2:23]4)=[CH:19][C:18]=23)=[O:12])=CC=1)([O-])=O.[NH2:31][C:32]1[N:36]([CH3:37])[N:35]=[CH:34][C:33]=1[C:38]#[N:39]>O>[C:38]([C:33]1[CH:34]=[N:35][N:36]([CH3:37])[C:32]=1[NH:31][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:27][CH:28]([F:30])[F:29])=[C:17]2[O:21][C:20]([CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)=[CH:19][C:18]=12)=[O:12])#[N:39]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc(C3CCOC3)cc12
Reactant: Cn1ncc(C#N)c1N
Solvent: O
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2oc(C3CCOC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
Prepared from 7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (380 mg) and 5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (220 mg). The reaction was stirred for 2 hours at room temperature. Water (1 ml) was added and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×40 ml), followed by 1N hydrochloric acid (40 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 70% ethyl acetate in heptane, followed by trituration with diethyl ether afforded the title compound as a white solid (170 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:39].[K+].[K+].O1CCOCC1>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]3[NH:7][C:2](=[O:39])[N:3]=[CH:4][CH:5]=3)=[CH:17][C:14]=2[C:15]#[N:16])=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 90.8 %

Procedure:
A mixture of 5-{[(2-chloro-4-pyrimidinyl)oxy]methyl}-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzo-nitrile (2.30 g, 2.61 mmol), DABCO (0.147 g, 1.31 mmol) and potassium carbonate (1.08 g, 7.84 mmol) in a mixed solvents of 1,4-Dioxane (10 mL) and water (10 mL) was heated at 70° C. for 3 h, then concentrated and diluted with ethyl acetate (100 mL) and water (100 mL). Separated organic part was washed with water and brine, dried over sodium sulfate, concentrated. Purification via mass-directed autopreparation afforded the title product (1.0 g). LC-MS (ESI): m/z 420 [M−H]+; 3.89 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH2:30])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:29]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH:30][S:39]([C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:29]=1
Reactant: COC(=O)CCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
5-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:6]([CH3:12])=[N:7]2.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline (0.3907 g, 1.433 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.2458 g, 0.8596 mmol) were suspended in carbon tetrachloride (14.33 mL, 1.433 mmol). To the mixture was added benzoyl peroxide (0.04627 g, 0.1433 mmol) and the mixture was heated at reflux. After 24 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 1.3 min, then 9% isocratic of EtOAc for 7.6 min, then 9 to 100% gradient of EtOAc in hexane over 12.7 min, then 100% isocratic of EtOAc for 10 min as eluent to give 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1 H, dd, J=8.4, 1.2 Hz), 8.12 (1 H, dd, J=7.6, 1.4 Hz), 7.92 (1 H, dd, J=8.4, 7.8 Hz), 7.64-7.70 (3 H, m), 7.43-7.50 (1 H, m), 4.91 (2 H, s); LC-MS (ESI) m/z 351.0 and 352.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1)[C:5]#[N:6]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-4-fluorobenzonitrile (1.09 g, 7.00 mmol) in DMSO (25 mL) was added 4-hydroxy-1-napthaldehyde (1.20 g, 7.0 mmol) and caesium carbonate (4.55 g, 14.0 mmol). The reaction mixture was heated to 80° C. for 24 h. After cooling to rt the mixture was partitioned between EtOAc (40 mL) and saturated NaHCO3 (50 mL), and the aqueous phase washed with EtOAc (50 mL). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane, 2:8) to give the title compound: RT=4.10 min; m/z (ES+)=NO IONISATION [M+H]+. δH(DMSO) 7.10 (1H, t), 7.46 (1H, d), 7.78 (1H, t), 7.88 (1H, t), 7.94 (1H, d), 8.19 (1H, d), 8.32 (1H, d), 8.37 (1H, d), 9.28 (1H, d), 10.33 (1H, s).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]2[O:4][C:27](=[O:28])[NH:2][N:1]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]\1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO/N=C1\C[C@@H](c2n[nH]c(=O)o2)N(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 1.84 mmoles; 500 mg) and triethylamine (2.76 mmoles; 27 mg) in THF (25 mL) at 0° C. was added 1,1′-carbonyldiimidazole (2.76 mmoles, 448 mg). The stirring was continued for 5 hours. Another portion of triethylamine and 1,1′-carbonyldiimidazole were added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed with NH4Clsat., and 10% NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated to dryness to give the desired N-protected intermediate, tert-butyl (2S,4E)-4-(methoxyimino)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidinecarboxylate, as a white foam (460 mg, 84%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Si@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1F
Reactant: CC(C)CCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
2.5 g (20 mmol) of 3-methylbutyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (21 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,4-difluorobiphenyl to obtain 4'-(trans-4-(3-methylbutyl)-4-silacyclohexyl)-3,4-difluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.5 g of the trans isomer (yield 90%). The results of its analysis are shown below.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:12]([CH2:13][CH2:14][C:15]#[N:16])[N:67]=[N:66][N:65]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide (18 g, 45.7 mmol) in THF (375 mL) under nitrogen is added triphenylphosphine (12 g, 45.7 mmol). The solution is cooled to 0° and treated with diethyl azodicarboxylate (DEAD, 7.2 mL, 24.3 mmol) followed by trimethylsilyl azide (3.2 mL, 24.3 mmol). The solution is warmed up to room temperature and stirred for 18 hours. One additional equivalent of triphenyl phosphine (12 g, 45.7 mmol), DEAD (7.2 mL, 24.3 mmol) and trimethylsilyl azide (3.2 mL, 24.3 mmol) are added and stirring is continued for 3 days. The solution is cooled to 0°. Ceric ammonium nitrate (2.2 L; 10% aqueous solution) is added dropwise. After 20 minutes of stirring, extraction is carried out with methylene chloride (3×200 mL). The combined organic layers are dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo. The residue is taken up in ethyl acetate (500 mL) and hexane (50 mL). A small amount of (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile crystallizes out. The filtrate is concentrated and the residue purified by flash-chromatography eluting with a gradient of ethyl acetate in hexane (30% to 50%). The pure fractions of product (Rf=0.6 in 1/1 ethyl acetate/hexane) are combined and concentrated under reduced pressure to give (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)tetrazol-1-yl]-propionitrile as a colorless crystalline solid, m.p. 184°-185°, [α]D =-2.90° (c 0.89, CHCl3).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44]12([C:54](Cl)=[O:55])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]12([C:54]([NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=4)=[O:24])[CH2:18][CH2:19]3)=[O:55])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(CC(C5)C3)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added, in portions, 1-adamantanecarbonyl chloride (0.199 g, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.565 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.267 g colorless crystals. Mp 228° C. Mass spectrum, m+ =491. Anal (C31H43N5O6) theory C, 64.01; H, 7.45; N, 12.04; found C, 63.89; H, 7.53; N, 12.12.
Reaction SMILES: [CH:1]1([C@H:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[N:13]([CH2:25][CH2:26]Br)[N:14]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=O)C.[I-].[K+]>C(#N)C>[CH:1]1([C@H:4]([N:6]2[CH2:26][CH2:25][N:13]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[C:12]3[C:10]2=[O:9])[CH3:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCBr
Reactant: C[C@@H](N)C1CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](C1CC1)N1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 90 °C
Reaction time: 20 h

Procedure:
(R)-1-Cyclopropylethylamine (0.3 mL, 2.82 mmol) was added to a suspension of 2-(2-bromo-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.128 mmol) and potassium iodide (9.36 mg, 0.056 mmol) in ACN (1 mL). The mixture was stirred at 90° C. for 20 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield (R)-5-(1-cyclopropyl-ethyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one as a orange oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.29-0.37 (m, 1H), 0.38-0.49 (m, 2H), 0.60-0.70 (m, 1H), 0.86-0.97 (m, 1H), 1.28 (d, J=6.9 Hz, 3H), 3.75 (ddd, J=12.9, 7.6, 4.9 Hz, 1H), 3.87 (ddd, J=12.9, 7.4, 5.2 Hz, 1H), 4.07 (dq, J=9.2, 6.9 Hz, 1H), 4.32-4.44 (m, 2H), 5.09 (s, 2H), 6.92 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 6.98-7.03 (m, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]2[C:21](=[CH:20][CH:19]=1)[NH:24][C:2]([CH3:15])=[C:3]2[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Product: Cc1[nH]c2ccc(Cl)cc2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 4-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])([O-])=O.[OH-].[Na+:23]>O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)[C:11]([O-:13])=[O:12].[Na+:23]
Reactant: O=C(O)C(=Cc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1C(=Cc1ccc(Br)cc1)C(=O)[O-]
Temperature: 80 °C

Procedure:
To a mixture of FeSO4.7H2O (163 g, 0.586 mol) in 180 ml of water was added 720 ml of 2.5N NaOH and the mixture was stirred and heated at 80° C. A solution of cinnamic acid derivative 1 (20.40 g, 0.05859 mol) in 180 ml of 0.5N NaOH was added dropwise. After the addition was complete, the temperature was increased to 100° C. and maintained for 30 min. The mixture was filtered while hot, and the filtrate was allowed to cool gradually to room temperature. The resulting solid was isolated by filtration to yield, after drying in vacuo, 12.1 g (61%) of the title compound as a tan solid which was used in the next reaction without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:27][CH:26]=2)[C:12](=[O:23])[NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(O[C:50]1[C:55]([F:56])=[C:54]([F:57])[C:53]([F:58])=[C:52]([F:59])[C:51]=1[F:60])=O>CN(C=O)C>[F:56][C:55]1[C:50]([O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][C:12]([N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[CH:27][CH:26]=3)=[O:23])[CH:15]=2)=[C:51]([F:60])[C:52]([F:59])=[C:53]([F:58])[C:54]=1[F:57]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzoic acid was added a solution of pyridine (500 μL) in DMF (5 mL) followed by pentafluorophenyl trifluoroacetate (850 μL). The mixture was shaken for 4 hours at 25° C., filtered and washed with DMF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:32])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1
Reactant: CCOC(=O)CN
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CNc1nc(SC)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C), (3.0 g 8.14 mmol) in 80 mL of acetonitrile at 0° C. was added glycine ethyl ester hydrochloride, a compound of formula (D), (1.14 g, 8.14 mmol), followed by the addition of cesium carbonate (6.1 g, 18.7 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred for 2 hours. The volatiles were evaporated to yield 3.6 g of 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxy)pyrimidine, a compound of formula (E).