Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:2]([C:6]([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@H:2]([C:6]([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of Z-Val-Pro-Val-Pro-OtBu [SEQ ID No: 9] (1.1 mmol) was treated with trifluoroacetic acid (2.76 mL, 3.58 mmol) in dichloromethane (4.85 mL), the reaction was stirred at room temperature for 3 h. Then, the solution was evaporated to dryness and the residue was lyophilized to give Y (84% yield).
Reaction SMILES: [C:1]([N:4]1[CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][N+:41]([O-:43])=[O:42])=[CH:35][C:34]=1[O:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:9]([CH:8]1[CH2:7][O:6][C:5](=[O:16])[N:4]1[C:1](=[O:3])[CH2:2][CH:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:34]([O:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:35]=1)[CH2:40][N+:41]([O-:43])=[O:42])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Reactant: CC(=O)N1C(=O)OCC1Cc1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CC(C[N+](=O)[O-])c1ccc(OCc2ccccc2)c(OC2CCCC2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Yield: 76.2 %

Procedure:
A mixture of 3-acetyl-4-benzyl-oxazolidin-2-one (2.1 g, 9.4 mmol) in THF (40 mL) was stirred under N2 at −78° C. Lithium diisopropyl amine (5.2 mL, 10.3 mmol, 2.0 M in heptane/THF/ethylbenzene) was then added dropwise. The mixture was stirred for 20 min. 1-Benzyloxy-2-cyclopentyloxy-4-(2-nitrovinyl)benzene (3.2 g, 9.4 mmol) dissolved in 20 mL THF was cannulated over and the mixture was stirred for 2 h at −78° C. After quenching the reaction sat. NH4Cl, the mixture was warmed to r.t., extracted with CH3Cl, washed with water and brine, dried and concentrated. Filtration of the solids with 1:1 hexane/EtOAc, afforded 4 g of white solids. Yield: 75%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][C:33]([CH:35]=O)=[CH:32][N:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]3[NH:34][C:30]([CH3:29])=[N:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ncc(C=O)[nH]1
Product: Cc1ncc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)[nH]1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methyl-3H-imidazole-4-carbaldehyde. MS (ESI) m/z 473.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH2:4][CH2:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH2:17][N:18]=[C:19]=[S:20]>C(O)C>[SH:20][C:19]1[N:18]([CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[CH:15]=2)[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][N:12]=1
Reactant: CN1CCN(CC(=O)NN)CC1
Reactant: Fc1cccc(CN=C=S)c1
Solvent: CCO
Product: CN1CCN(Cc2nnc(S)n2Cc2cccc(F)c2)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide (2.58 g., 0.015 mole) and 3-fluorobenzylisothiocyanate (2.51 g., 0.015 mole) in ethanol (30 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ether and the resulting solid was filtered and recrystallized from ethyl acetate to give 3-mercapto-4-(3-fluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole as a solid melting at 179.5°-180.5° C. (2.30 g., 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH:30][CH3:31])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:39]OC(OC)OC.II>C(#N)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[N:29]=[CH:31][N:30]([CH3:39])[C:22]=5[C:21]=4[O:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: CNc1c(N)ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: II
Solvent: CC#N
Product: Cn1cnc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a stirred solution of {1-[4-(7-amino-8-methylamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (95 mg, 0.19 mmol) in acetonitrile (3 mL) was added trimethylorthoformate (24 μL, 0.22 mmol) and iodine (5 mg, 0.02 mmol) at RT. After 1 hour, the reaction mixture was quenched with Na2S2O3. The resulting mixture was extracted with ethyl acetate (2×30 mL) and the combined organics washed with brine, dried (Na2SO4) and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, ethyl acetate) to give the title compound as a white solid (67 mg, 68%). LCMS (Method G): RT=3.63 min, [M+H]+=522.
Reaction SMILES: ClC1C=C(C)C=C(C)C=1N1CCCC2=C(N)N(C)N=C12.C[N:22]1[C:30]([NH2:31])=[C:29]2[C:24]([N:25]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=3[CH3:40])[CH2:26][CH2:27][CH2:28]2)=[N:23]1.C(Cl)(=O)CC.[CH3:46][O:47][CH2:48][C:49](Cl)=O>>[CH3:46][O:47][CH2:48][CH2:49][NH:31][C:30]1[NH:22][N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][N:25]2[C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40]
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(C)c1
Reactant: COCC(=O)Cl
Agent: CCC(=O)Cl
Agent: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Product: COCCNc1[nH]nc2c1CCCN2c1c(C)cc(C)cc1C

Procedure:
Compound 5-54 was prepared according to the procedure described in Example 15, steps 1 and 2, except that in step 1, 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45) was replaced with 2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-52) and propionyl chloride was replaced with methoxyacetyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[C:23]5[C:27]=4[NH:26][CH:25]=[CH:24]5)=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[OH-].[K+].Cl>CO>[C:42]([O:41][C:39]([NH:38][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[C:23]5[C:27]=4[NH:26][CH:25]=[CH:24]5)=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2cccc4cc[nH]c24)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Temperature: 40 °C
Yield: 69.2 %

Procedure:
2-tert-Butoxycarbonylamino-5-[3-(1H-indol-7-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester (605 mg, 0.95 mmol) was suspended in methanol (10 mL), potassium hydroxide (50% w/v in water, 2 mL) was added and the resulting suspension was heated to 40° C. for 1 hour. Hydrochloric acid (1 N) was added to adjust the pH to 6. The mixture was extracted with ethyl acetate (10 mL×4). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 2-tert-butoxycarbonylamino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid as a pale yellow powder (308 mg, 69%). MS: m/z 469 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 58 %

Procedure:
Using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 160 and isothiazolidine 1,1-dioxide (94 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (128 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH:25]=[CH:26][CH3:27].[Cl-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2/[CH:25]=[CH:26]/[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CC=Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.96 g (5.52 mmol) of 3-bromopyridin-2(1H)-one is dissolved in 17 ml of DMSO. The mixture is cooled to 0° C., and 1.00 g (5.52 mmol) of potassium tert-butoxide is added such that the internal temperature does not exceed 30° C. After 1 h at room temperature, a solution of 1.00 g (5.52 mmol) of the compound from Example 43A in 5 ml of DMSO is added. After 3 h at 80° C., 200 ml of water and 50 ml of sodium chloride solution are added and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=4:1). This gives 935 mg (49% of theory) of the desired compound as an E/Z isomer mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 340 mg (72%) of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][N:37]=3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(C3SC(C)=CN=3)=CC=2)NS(C2C=CC=CN=2)(=O)=O)N=1)(C)(C)C>>[Cl:38][C:35]1[S:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:11]3[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=3)=[CH:32][CH:31]=2)=[N:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ncc(Cl)s3)cc2)NS(=O)(=O)c2ccccn2)n1
Agent: Cc1cnc(-c2ccc(CC(NS(=O)(=O)c3ccccn3)c3cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)cc2)s1
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ncc(Cl)s3)cc2)NS(=O)(=O)c2ccccn2)n1
Yield: 66 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 22-(d) except for using tert-butyl[tert-butoxycarbonyl(6-{[4-(5-chlorothiazol-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (265 mg, 0.386 mmol) obtained in Example 24-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(5-methylthiazol-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate to afford the title compound (135 mg) as a slightly brown solid. (Yield: 66%)
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)c2cccnc2)cc1
Yield: 83.6 %

Procedure:
In the manner described in Example 99, (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester (0.295 g) was saponified in a refluxing mixture of methanol (1.5 mL) and 1N NaOH (1.5 mL). After the cooled reaction was neutralized with 1N HCI (1.5 mL), the crude acid was filtered off and crystallized from methanol to afford 0.235 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid as its 0.33 molar hydrate, mp 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH:21][CH3:22]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:21]([CH3:22])[CH3:20])=[O:10])[CH2:6]1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A stirred solution of 5 g (0.016 mol) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 5.5 ml (0.048 mol) of 40% aqueous dimethylamine. After stirring for 16 h, the reaction mixture was diluted with 200 ml of water and the solid which precipitated was collected by filtration (4.8 g). The crude product was crystallized from benzene/ligroin to yield 4.3 g (83.3%) of fine white crystals, mp 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](OCC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.O.[NH2:22][NH2:23].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:16]([NH:22][NH2:23])=[O:17])=[N:4][C:5]([C:12]([F:14])([F:15])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (Int. G1)(455 mg, 1.501 mmol) in MeOH (10 ml) was treated with hydrazine monohydrate (0.147 ml, 3.00 mmol) and stirred at RT overnight. The reaction mixture was diluted with water (50 ml) and the pH was adjusted to pH4-5 using 1M HCl. A yellow precipitate formed which was filtered under vacuum, washed with water and air dried to afford the title compound which was used without further purification;
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:5]=1[CH2:6][OH:7].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].CC(=O)OCC>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[C:9]([F:13])[CH:10]=[C:11]([F:12])[C:4]=2[F:3])[C:16]=1[C:17]#[N:18]
Reactant: OCc1cc(F)cc(F)c1F
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a cold (ice water) suspension of sodium hydride (407 mg; 10 mmol) in anhydrous DMF (4 mL) is added a solution of 2,3,5-trifluorobenzyl alcohol (1.62 g; 10 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.56 gm; 11 mmol) in anhydrous DMF (5 mL), and allowed to room temperature over 3 hours. TLC (25% EA/Hex) was incomplete so the reaction was continued at room temperature for an additional 2 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 4.5 hours to give 2.05 grams of 2-fluoro-6-(2,3,5-trifluorobenzyloxy)-benzonitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>ClCCl>[C:1]1([CH2:7][CH2:8][NH:9][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85617.8 %

Procedure:
174.9 ml (1.39 mol) of phenylethylamine were dissolved in 600 ml of dichloromethane and admixed with 196.0 ml (1.41 mol, 1.01 eq.) of triethylamine. Subsequently, 221.0 g (1.39 mmol) of 3-fluorobenzoyl chloride were added dropwise to the solution at 0° C. such that the temperature did not rise above 40° C. The mixture was stirred at RT for 18 h and the precipitated solid was dissolved in 1000 ml of dichloromethane. The mixture was washed four times with 200 ml of dilute NaOH, 1N HCl and saturated NaHCO3 solution. The organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The solid was filtered off with suction and washed twice with a little dichloromethane. 289.52 g of a white solid were obtained with >99% purity (by HPLC), corresponding to 85.4% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=O)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.[NH2:22][NH2:23]>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[NH:23][N:22]=1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Product: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 0 °C

Procedure:
A stirred mixture of 2-(3-nitrophenyl)indan-1,3-dione (85 g, 0.318 mol) and hydrazine hydrate (450 ml) was heated under reflux for 2 hours then cooled to 0° C. The resulting solid was collected by filtration, washed with water (500 ml), ground to a fine powder, mixed with sufficient cold ethanol to give a thick paste, collected by filtration and dried in vacuo at 55° C. The crude solid was then recrystallised from ethanol to give 4-(3-aminobenzyl)-2H-phthalazin-1-one (32.6 g) as a pale brown solid, m.pt. 175–177° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Yield: 39 %

Procedure:
N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (1.0 g, 3.5 mmole, Example 15), ethanol (100 mL) and Pt/C were placed in a Paar apparatus. The mixture was hydrogenated at 50 psi (3.44×105Pa). The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 0.35 g of N5 -(2-methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine as off white needles, m.p. 148-150° C. Analysis: Calculated for C13H16N6 : %C, 60.92; %H, 6.29; %N, 32.79; Found: %C, 60.94; %H, 6.25; %N, 32.93.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)COC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Treatment of L-phenylalanine with isobutyl chloroformate in a manner analogous to that described above, yielded yielded the desired acid as an oil [MS: 266 (M+H)+ ] which crystallized out upon standing and which was used directly in the next step.
Reaction SMILES: [OH:1]C1CCN(C)CC1.FC1C=C(C=CC=1F)C#N.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[C:23]#N>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[CH:23]=[O:1]
Reactant: CN1CCC(O)CC1
Reactant: CN1CCC(Oc2ccc(C#N)cc2F)CC1
Agent: N#Cc1ccc(F)c(F)c1
Product: CN1CCC(Oc2ccc(C=O)cc2F)CC1

Procedure:
Synthesized from 4-hydroxy-1-methylpiperidine and 3,4-difluorobenzonitrile according to an analogous synthetic method to Preparation Example 15, 3-fluoro-4-(1-methylpiperidin-4-yloxy)benzonitrile (1.1 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.1 g).