Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][C:10](=O)[C:4]=2[CH:3]=1.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][C:10](=[N:26][C:20]#[N:21])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)COc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)COc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (158 mg, 0.5 mmol) in DCM (5 mL) was added TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.25 mL, 1.11 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (160 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]([OH:19])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]([N:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:35])[CH3:23])[CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1
Reactant: CN(C)CCCNCCCN(C)C
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CN(C)CCCN(CCCN(C)C)C(=O)c1c(COc2ccc(Cl)cc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-carboxy-1H-indole (0.100 g, 0.317 mmol) was dissolved in 3.2 ml of N,N-dimethylformamide. To this solution were added N,N-bis(3-dimethylaminopropyl)amine (0.074 ml, 0.0623 g, 0.332 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.091 g, 0.475 mmol), and hydroxybenztriazole (0.0642 g, 0.475 mmol). The resulting mixture was then heated for 6 hours and then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][CH:16]([F:36])[C:17]1[N:22]=[C:21]([C:23](O)=O)[N:20]=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:18]=1>>[F:36][CH:16]([F:15])[C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[N:20]=[C:21]([C:23]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:22]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 6-difluoromethyl-4-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.3) (0.16 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.12 g, 49%). MS (ISP) 498.3 [(M+H)+]; mp 217.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH3:17][N:18]([CH3:20])[NH2:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:19][N:18]([CH3:20])[CH3:17])=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Br
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NN(C)C
Temperature: 110 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 3-Bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.500 g, 1.68 mmol) in toluene (10 ml) was added N,N-Dimethyl-hydrazine (0.121 g, 2.02 mmol), cesium carbonate (0.767 g, 2.36 mmol), BINAP (0.106 g, 0.17 mmol) and paladium(II) acetate (0.019 g, 0.08 mmol). The reaction mixture was stirred for 16 h at 110° C. The mixture was partitioned between toluene (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with toluene (2×10 mL) and the combined toluene layer was dried (MgSO4), concentrated and the residue was purified by preparative tlc (10% EtOAc/Hexane) to obtain 0.350 g (75%) of 3-(N′,N′-Dimethyl-hydrazino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): δ 7.71 (d, 2H), 7.40 (m, 3H), 7.13 (s, 1H), 3.87 (s, 3H), 2.65 (s, 6H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)[CH3:19]>>[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[CH3:19]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: CCc1ccccc1CBr
Product: CCc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-ethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](F)=[CH:18][N:19]=1)[C:5]([C:7](=[CH:13]N(C)C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH3:21][O:22][CH2:23][CH:24]([NH2:28])[CH2:25][O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][N:19]=1)[N:28]([CH:24]([CH2:25][O:26][CH3:27])[CH2:23][O:22][CH3:21])[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Reactant: COCC(N)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(COC)COC)c2cnc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 65, 1 g, 2.9 mmol, 1 equiv.) in THF (7 mL) was added 1,3-dimethoxypropan-2-amine (451 mL, 2.9 mmol, 1 equiv.). This reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and re-suspended in DMF (7 mL). Potassium carbonate (1.2 g, 8.69 mmol, 3 equiv.) was added, and the reaction mixture was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and quenched with water. 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-(1,3-dimethoxypropan-2-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (963 mg, 83%).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: COCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: COCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.9 mg (0.23 mmol) of 3-methoxypropylamine are reacted together by general method E. 22.7 mg (36.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[F:40])[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[N:27]=1>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:37]=[CH:38][C:39]([F:40])=[C:18]([NH:17][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:19]=4)=[N:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 39.2 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.171 mL, 2.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methylpyrrolidone (5 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with 1N aqueous sodium hydroxide solution (10 mL) and water (10 mL×3). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and recrystallized from ethyl acetate to give the title compound (88 mg, yield 39%) as a white solid. melting point 205° C.
Reaction SMILES: CS(C[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1NC1C=CC(OC)=CC=1)=O)=O.CS([CH2:25][C:26]([C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=[O:27])=O>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([N:36]2[C:29]3[C:28](=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=3)[C:26](=[O:27])[CH:25]=[C:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:38][CH:39]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)CS(C)=O)c1
Reactant: COc1ccc(Nc2ccccc2C(=O)CS(C)=O)cc1
Product: COc1ccc2c(c1)c(=O)cc(-c1ccccc1)n2-c1ccc(OCc2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 12, Procedure 3, but substituting for 2-(methylsulfinyl)-2'-(4-methoxyanilino)acetophenone an equivalent amount of 2-(methylsulfinyl)-2'-(4-benzyloxyanilino)-5'-methoxyacetophenone there can be obtained 1-(4-benzyloxyphenyl)-2-phenyl-6-methoxy-4(1H)-quinolone.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH2:17][CH:18]3[CH2:20][O:19]3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=3>>[NH2:1][CH2:20][CH:18]([OH:19])[CH2:17][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([Br:16])[CH:12]=2
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: N
Product: NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of NH3 (9.4 mL of 7M in MeOH, 65.6 mmol) was added to 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.500 g, 1.31 mmol). The vial was tightly sealed and the reaction mixture was heated to 100° C. and stirred for 1 hour. Volatile components were removed under vacuum. The residue was suspended in CH2Cl2 and the white precipitate was filtered. The filtrate was saved and CH2Cl2 was removed under vacuum to afford 0.3413 g white solid as crude product, which contained about 50% unidentified side-product. This crude product was used as is in next step without any further purification. Purification by flash chromatography on silica gel provided pure material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21]CC2C=CC=CC=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 96.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoyl]morpholine (1.27 g, 2.59 mmol) was dissolved in ethanol (50 ml) and the resulting solution was added to an ethanol suspension (5 ml) of 5% Pd—C (0.200 g) and stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was recrystallized from ether to obtain the titled compound (1.00 g, 2.49 mmol, 96%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[CH3:28][C:23]1[CH:22]=[C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=3)[N:16]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(C)cc(C)c3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3cc(C)cc(C)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][NH2:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.O[CH:14]1[O:18][C:17](=O)[CH2:16][CH:15]1[CH2:20][CH2:21][CH3:22]>ClCCCl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:14][CH:15]([CH2:20][CH2:21][CH3:22])[CH2:16][C:17]1=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: NCc1c(F)cc2ccccn12
Reactant: CCCC1CC(=O)OC1O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC1CC(=O)N(Cc2c(F)cc3ccccn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g, 2.3 mmol) and 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.33 g, 2.3 mmol) in DCE (12 ml) is kept at room temperature for 2 h, then STAB (0.74 g, 3.5 mmol) is added, and the mixture is stirred overnight. The reaction mixture is kept under stirring at 50° C. for 2 h, cooled to room temperature, and diluted with dichloromethane (10 ml). The mixture is washed with a 20% K2CO3 solution (2×15 ml), and the aqueous layer is washed with brine (25 ml), dried over anhydrous Na2SO4 and evaporated. The residue (0.60 g) is purified by chromatography on silica gel (gradient: chloroform to chloroform/methanol 50/1) to isolate a product of approximately 80% purity (0.162 g). This product is purified by chromatography on silicagel (hexane/ethyl acetate 5/2) to afford pure 1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264 (0.126 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:13]2[CH2:12]1)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([C:19]1[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[N:14]2[CH2:15][CH2:16][N:11]([C:10](=[O:33])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:12][C:13]=12)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89 %

Procedure:
(R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 21a (0.1 g, 0.16 mmol) was added to a solution of 2.2 N hydrochloric acid in 10 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (pyridin-2-yl)amide dihydrochloride 21 (80 mg, yield 89%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13](=O)[CH3:14].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[CH2:14]
Reactant: OCC1CCNCC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: C=C(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(CO)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)phenyl]ethanone (10.0 g) and piperidin-4-ylmethanol (5.40 g) in THF (368 mL) was added titanium (IV) isopropoxide (34.6 mL). The reaction mixture was stirred at 70° C. overnight, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution and the insoluble material was filtered through celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound so (12.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Reactant: OB(O)c1ccccc1
Product: O=S(=O)(NC1CNc2ccc(-c3ccccc3)cc2C1)c1ccccc1

Procedure:
Compound 170A was prepared from 87A and phenylboronic acid by procedures analogous to those described in Example 91A.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:7]([N:6]1[C:2]([NH:1][C:10]2[C:11](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1cc(OC)c(OC)cc1C(=O)O
Yield: 97.6 %

Procedure:
A mixture of 5-amino-1-ethylpyrazole (5.0 g, 45 mmol), 2-bromo-4,5-dimethoxybenzoic acid (11.76 g, 45 mmol), K2CO3 (6.21 g, 45 mmol), Cu(OAc)2 (0.8 g, 400 mmol) and DMF (125 ml) is refluxed overnight. The reaction mixture is cooled, poured into water and acidified with acetic acid. The resulting solid is collected by filtration and dried to afford 12.8 g (97%) of N-(1-ethylpyrazol-5-yl)-4,5-dimethoxyanthranilic acid.
Reaction SMILES: [ClH:1].[CH2:2]([CH:5]1[NH:11][C:10](=[NH:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:3]=C.[BH4-].[Na+].C([OH:17])C.O.Cl>C(Cl)Cl.CO.O.C(O)(=O)C>[ClH:1].[NH:12]=[C:10]1[NH:11][CH:5]([CH2:2][CH2:3][OH:17])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCO
Reactant: C=CCC1CCCCC(=N)N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: N=C1CCCCC(CCO)N1
Temperature: -78 °C
Reaction time: 10 h

Procedure:
Hexahydro-7-(2-propenyl)-1H-azepin-2-imine, monohydrochloride (the product of EXAMPLE 108) (3.0 g, 14.7 mmol) is dissolved in a mixture of methylene chloride (100 mL) and methanol (50 mL) and cooled to −78° C. Ozone is then bubbled through until a blue color is observed. The reaction is flushed with N2 to remove excess ozone. The reaction mixture is warmed to room temperature and concentrated in vacuo to a residue. The residue is dissolved in ethanol (100 mL), cooled to 0° C., and vigorously stirred as a cold solution of sodium borohydride (0.7 g, 18.5 mmol) in 1:1 ethanol-water is added. The pH of the reaction mixture is maintained by the concomitant addition of 2 M acetic acid in water, maintaining the pH (pH paper) at 8 to 9. After the addition is complete, the mixture is stirred at room temperature for 10 hr, the reaction mixture is acidified to pH 2 with dilute HCl, and the reaction mixture is concentrated in vacuo to a gum. The gum is dissolved in a small amount of ethanol, filtered, evaporated in vacuo to a solid, dissolved in water and applied to an ion exchange column of Dowex 50 (H+). The column is washed with deionized water, and the title compound eluted with 2 N HCl. The eluate is concentrated in vacuo to a solid, dissolved in a small amount of water, filtered, and lyophilized to give the title compound. C8H16N2O.HCl mw=192.69