Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23]1>>[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][N:29]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:3][C:2]=3[F:1])[CH2:28]2)[CH2:24][CH2:23]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 52.6 %

Procedure:
Using 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (301 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (231 mg).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[NH2-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]>O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1)C(C)C

Procedure:
A solution of 20 parts of α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 4 parts of sodium amide in 180 parts by volume of toluene is heated to about 100° C. over a period of 15 minutes and then 18 parts of 2-chloro-N,N-diisopropylethylamine in 70 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 105°-110° C. for an hour and then cooled to room temperature when 200 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, concentrated and distilled to afford α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetonitrile as an oil. This compound is identical with the compound of Example 2, Method A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([O-:9])([OH:8])=[O:7]>C(OC(=O)C)(=O)C>[N+:6]([O-:9])([OH:8])=[O:7].[N+:6]([O:5][CH2:4][CH2:3][CH2:2][NH2:1])([O-:8])=[O:7]
Reactant: NCCCO
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: NCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 3-amino-1-propanol (6.17 g, 82.2 mmol) was added, drop-wise, to an ice-cooled solution of fuming nitric acid (90%, 12 mL) in acetic anhydride (50 mL). The reaction was stirred in an ice-bath for 10 minutes and then at room temperature for 10 minutes. The solvent was evaporated under vacuum at 40° C. The residue was stirred in diethylether (200 mL) until the product precipitated. The mixture was filtered and the white crystalline solid was dried in vacuo to give the title compound (12.1 g, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 4.57 (br. t, 2H), 2.8-3.0 (m, 2H), 1.98-1.93 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 70.9, 36.1, 24.5. MS m/z 121 (M−NO3)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26]/[C:27](/B(O)O)=[CH:28]/[CH3:29].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1/[C:27](/[CH3:26])=[CH:28]\[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C(/C)B(O)O
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 40.5 %

Procedure:
Methyl 4-benzyloxy-3-bromobenzoate (1.61 g, 5.0 mmol), caesium carbonate (4.89 g, 15.0 mmol), (E)-2-buten-2-yl boronic acid (600 mg 6.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocenyl]palladium (II) chloride (204 mg, 0.25 mmol) were dissolved in anhydrous tetrahydrofuran (100 ml), water (10 ml) was added and the mixture was stirred and held at reflux under an atmosphere of nitrogen for 16 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded methyl (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (600 mg, 41%) as a colourless solid. 1H NMR (DMSO-d6) 7.88 (1H, dd), 7.59 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.23 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 3.82 (3H, s), 1.94 (3H, s), 1.38 (3H, d).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]#N)=[CH:14][C:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.[K+]>C(O)=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18](=[O:2])[O:16][C:15](=[O:17])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: [K+]
Solvent: O=CO
Product: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Temperature: 50 °C

Procedure:
With stirring, 80 ml of concentrated sulfuric acid were added dropwise to 138 g (0.57 mol) potassium 3-(4-chlorophenyl)-3-cyanoacrylate in 1.2 l of 88% strength formic acid. During the addition, the temperature increased to 50° C. The mixture was refluxed for 3 h and, after cooling, put into 10 l of ice-water and then stirred for 1 h, and the product was filtered off, washed with water and dried under reduced pressure. Yield: 86.0 g of m.p. 144-145° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][N:8]=1.Br.O>C(O)(=O)C>[C:17]1([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH2:6])=[N:8][N:9]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CNc2nnc(-c3ccccc3)c3ccccc23)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1nnc(-c2ccccc2)c2ccccc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 150 mL sealed tube, dissolved N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine (3.00 g, 8.1 mmol) in acetic acid (40 mL). Hydrobromic acid (48% aqueous) (2.6 mL, 24 mmol) was added and the tube was stirred at 90° C. for 3 h. The solution was cooled to RT, and slowly poured into water, which caused a pink solid to crash out. The solid was filtered and rinsed with water. The product containing filtrate was slowly poured into saturated sodium carbonate. The aqueous phase was extracted with DCM, washed twice with water, dried with Na2SO4, filtered through flitted funnel, and concentrated to yield 4-phenylphthalazin-1-amine as light yellow solid. MS [M+H]=222; Calc'd 221.3 for C14H11N3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[NH:23][C:15]=23)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:43]([C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br)#[N:44].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[N:23]([CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[C:43]#[N:44])[C:15]=23)[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccccc1CBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(Cc3ccccc3C#N)c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
1.03 g (R)-1-[3-(2,4-dimethoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidine-3-carbamic acid tert-butyl ester (2.07 mmol) was dissolved in 5 mL DMF. 0.57 g potassium carbonate (4.14 mmol) was added, and then 0.45 g 2-cyano-benzyl bromide (2.28 mmol) was added. The reaction solution was stirred for 5 h at room temperature, and slowly poured into 100 mL water to precipitate a solid, filtrated, and dried to afford 1.24 g crude product with a yield of 97.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[C:43]=1[C:44](Cl)=[O:45]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])[N:10]([C:44]([C:43]3[C:47]([F:52])=[CH:48][C:49]([F:51])=[CH:50][C:42]=3[F:41])=[O:45])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: COc1cccc(C2NN=C(c3ccc(F)cc3)S2)c1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazole is added DIEA (3.09 mmol) and 2,4,6-tri-fluorobenzoyl chloride (3.09 mmol) and the reaction mixture is stirred for 12 hours at room temperature. After concentration, the residue is purified by automated column chromatography (hexane/EtOAc) to yield [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[CH2:12]([O:19][C:20](=[O:23])[NH:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:22][NH:21][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:23])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: NNC(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(NN=C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 101.5 %

Procedure:
Under an argon atmosphere, a solution of 2-adamantanone (1.00 g, 6.70 mmol) in ethanol (40 mL) was added with benzylcarbazate (1.11 g, 6.70 mmol) at room temperature and the resultant was stirred at 80° C. for 12 hours. The reaction solution was concentrated in vacuo, and benzyl 2-(adamantan-2-ylidene)hydrazinecarboxylate (2.03 g, quant.) was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].Cl.[OH-:28].[Li+]>>[CH3:1][C:2]1[C:7]([C:8]([OH:9])=[O:28])=[C:6]([O:17][C:16]2[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=2[OH:10])[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1
Reactant: [OH-]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Agent: Cl
Agent: [Li+]
Product: COc1cc(C(=O)O)c(Oc2c(C=O)c(O)cc(C)c2C(=O)O)c(O)c1C
Reaction time: 8 h

Procedure:
Psoromic acid (35 mg, 1 mmol) was dissolved in 1 mol/L of aqueous lithium hydroxide (3 ml), and the reaction is allowed to stand overnight. The solution was acidified to a pH of 4 with 1 mol/L dilute HCl, filtered, and collected to give a white solid product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][OH:27])[CH3:28])=[CH:22][CH:23]=1
Reactant: CN(CCO)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 63 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 2-[(4-amino-phenyl)-methyl-amino]-ethanol (0.10 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[(2-hydroxyethyl)(methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.16 g, 64%) as a rust colored powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: C#CCCCCl
Product: ClCCCC#Cc1ccccn1
Yield: 60.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromopyridine (948 mg, 6.0 mmol) and 5-chloropent-1-yne (620 mg, 6.0 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 80/20 as eluent) to afford 655 mg of 2-(5-chloropent-1-ynyl)pyridine as a yellow oil (Yield: 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To 0.9 g. (0.0025 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 3, first paragraph) and 0.25 g. (0.0025 mole) of N-methyl piperazine in 40 ml. of ethanol was added 0.27 g. (0.0025 mole) of Na2CO3. The reaction mixture was refluxed for 3 hours after which time it was filtered and chilled in ice. The resulting precipitate was removed by filtration, and rinsed with diethyl ether, giving 0.7 g. of solid--m.p. 180°-185° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=[C:5]2[O:4][CH2:3]1.N[C:14](N)=[O:15]>CCOCC.CCCCCC>[CH3:1][CH:2]1[N:7]2[C:14](=[O:15])[NH:12][C:8]3=[CH:9][CH:10]=[CH:11][C:5](=[C:6]23)[O:4][CH2:3]1
Reactant: NC(N)=O
Reactant: CC1COc2cccc(N)c2N1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1COc2cccc3[nH]c(=O)n1c23
Yield: 52.6 %

Procedure:
3.3 g (0.02 mol) of 3-methyl-3,4-dihydro-1H-1,4-benzoxazin-5-amine are heated at 160°-165° C. in an oil bath for 1.5 hours in the presence of 1.7 g (0.028 mol) of urea. A solid is obtained which is taken up in a water/ether (50/50) mixture. The phases are separated, the organic phase is recovered, is washed, is dried and the solvent evaporated to dryness. The residue obtained is purified by chromatography on a column of silica gel, the eluent being ethyl ether. 2 g of product are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:25]([CH2:26][CH3:27])[C:24]([C@H:28]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)(=[O:33])=[O:32])[CH3:29])=[N:23][N:22]=2)[CH:15]=1)(C)(C)C>C(Cl)(Cl)Cl>[Cl:41][C:36]1[CH:35]=[C:34]([S:31]([NH:30][C@@H:28]([C:24]2[N:25]([CH2:26][CH3:27])[C:21]([O:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([OH:42])=[O:12])=[N:22][N:23]=2)[CH3:29])(=[O:33])=[O:32])[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: CCn1c(Oc2cccc(C(=O)OC(C)(C)C)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(Oc2cccc(C(=O)O)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 43.3 %

Procedure:
Trifluoroacetic acid (0.12 ml) was added to a solution of the compound (260 mg) of Example 18 in chloroform (12.0 ml), and the mixture was stirred at room temperature for five days. The mixture was evaporated to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-20%) and then recrystallized (methanol/chloroform/hexane) to give the titled compound (Compound 113) (101 mg, colorless powder).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]([CH3:13])=[CH2:12])[C:6]=2[CH:14]=1.C[O-].[Na+].[O:18]1[CH2:20][CH2:19]1>C(O)C>[OH:18][CH2:19][CH2:20][N:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=2[N:7]([C:11]([CH3:13])=[CH2:12])[C:8]1=[O:10]
Reactant: C1CO1
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)n1c(=O)n(CCO)c2ccc(C)cc21
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred mixture of 37.6 parts of 1,3-dihydro-6-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 2 parts of sodium methoxide solution 30% and 320 parts of absolute ethanol is added a solution of 22 parts of oxirane in 40 parts of absolute ethanol. Stirring is continued first overnight at room temperature and further for 3 hours at reflux. The ethanol is evaporated, yielding 46 parts (100%) of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:12])[N:10]=1)[C:5]([OH:7])=O.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH2:22][CH2:21]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([N:11]([CH3:12])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:4]([C:5]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([F:17])=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[O:7])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(c1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.30 g (1.1 mmol) 2-chloro-6-(methanesulphonyl-methyl-amino)-isonicotinic acid, 0.16 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 4.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 2 h at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[H-].[Na+].[CH3:25][C:26]([CH3:36])([CH3:35])[C:27](N1CCSC1=S)=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:27](=[O:28])[C:26]([CH3:36])([CH3:35])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)C(=O)N1CCSC1=S
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (500 mg) in tetrahydrofuran (15 ml) was added 60% sodium hydride (75 mg) under a nitrogen atmosphere, the solution was stirred for 30 minutes at room temperature, then 2,2-dimethyl-1-(2-thioxothiazolidin-3-yl)propan-1-one (380 mg) was added thereto on an ice bath followed by stirring for 25 minutes. A saturated aqueous solution of ammonium chloride was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (640 mg).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[NH:14][C:13](=[O:15])[CH:12]=[CH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[CH3:21][O:15][C:13]1[CH:12]=[CH:11][CH2:10][CH2:9][CH:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:14]=1
Reactant: O=C1C=CCCC(Cc2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(Cc2ccccc2)CCC=C1

Procedure:
The product of Example 187 is reacted with one equivalent of trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)COCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COCc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
2.00 g (12.0 mmol) of benzyloxyacetic acid was dissolved in 40 mL of dichloromethane and 2.77 g (14.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2.21 g (14.4 mmol) of 1-hydroxybenzotriazole 1 hydrate, 2.52 mL (18.1 mmol) of triethylamine and 2.52 g (13.2 mmol) of 4-amino-1-benzylpiperidine were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 18 hours. Dichloromethane was added to the reaction mixture and the mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate/methanol=100/0-90/10) to obtain 2.82 g (yield: 69%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5](=[O:10])[C:4]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3]1.CCN(CC)CC.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:27]=1[C:28]([N:14]1[CH2:13][CH2:12][N:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)[CH2:16][CH2:15]1)=[O:29]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nc(N2CCN(C(=O)c3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
The compound 40 is prepared according to the synthesis method 2: 0.16 g (0.72 mmol) of derivative 12a is placed in 1 mL of dichloromethane in the presence of 0.15 mL (1.08 mmol) of NEt3 at 0° C. 0.2 g (0.72 mmol) of 2,5-bis-trifluoromethyl-benzoyl chloride is added. This mixture is stirred for 15 min at 0° C., and then for 1 h at room temperature. The medium is taken up with water and extracted with CH2Cl2. After drying on MgSO4, the organic phase is concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2-AcOEt: 90-10). 0.24 g of white crystals are isolated (yield: 71%).