Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[S-:20][C:21]#[N:22].[K+]>CN(C=O)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:3]2[NH:2][C:21](=[S:20])[NH:22][C:4]=2[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1

Procedure:
With gentle heating, 23a (2.9 g; about 9.6 mmol) was dissolved in absolute DMF (75 ml). Potassium thiocyanate (1.9 g; 19.6 mmol) was introduced into the clear orange-red solution: immediate opalescence and a lighter color. The reaction mixture was stirred under reflux for 1.5 h. The suspension was cooled to room temperature and, with H2O cooling, diluted dropwise with H2O (about 140 ml). The yellow precipitate was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: OCCNCCO
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)N(CCO)CCO)C1
Reaction time: 2 h

Procedure:
A solution of p-menth-3-oyl chloride (4.0 g., 0.020 moles) in chloroform (30 ml.) was added dropwise to a stirred solution of diethanolamine (4.2 g., 0.044 moles) in chloroform (50 ml.). The reaction mixture goes cloudy and a yellow oil separates out. After 2 hours at room temperature, the yellow oil (upper layer) was separated. Infra red spectrographic analysis indicated this to be (HOCH2CH2)2NH2+Cl-. Removal of the chloroform left a viscous oil (6 g.). Thin layer chromatography (CHCl3 and CHCl3 +10% CH3OH) indicated it to consist of one major component and a minor component of larger Rf value. This was separated by column chromatography on neutral alumina (activity 1). Eluting with chloroform (200 ml.) removed the minor component and the major product was eluted from the column with chloroform+5% methanol. The major component was shown to be N,N-bis(2-hydroxyethyl)-p-menthane -3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[NH:10]3)=[CH:15][CH:14]=2)=[O:19])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N)cc1C
Reactant: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Product: Cc1ccc(NC(=O)c2ccc3cc(-c4c(C)cccc4C)[nH]c3c2)cc1C

Procedure:
The title compound was prepared from 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid and 3,4-dimethylaniline analogous to Example 3-4. 1H NMR (CDCl3, 400 MHz): δ 8.38 (s, broad, 1H), 8.08 (s, 1H), 7.84 (s, broad, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.56 (dd, J=8.3, 1.6 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.37 (dd, J=8.1, 2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (m, 3H), 6.46 (m, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.17 (s, 61-1). MS (m/z) 369.2 (M+1), Retention time=1.73 min (Method 10).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)Cc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ncccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 2-(pyrimidin-2-yl)acetate (Example 31b, 410 mg, 2.47 mmol) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 72 hours, then concentrated under reduced pressure. The residue was triturated with ethanol and concentrated under reduced pressure to give the title compound, which was carried onto the next step without further purification. MS 139 (MH+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4])=[CH:11][CH:12]=1
Reactant: CC(=O)OCCC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.2 g. of 1 -acetoxy-3-(2',4'-difluoro-4-biphenylyl)-3-butanol and 2 g. of NaOH in 30 ml. of 80% aqueous ethanol is heated under reflux for 3 hours. Water is added; the product is extracted with chloroform, and the extract is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1.I[CH2:34][CH3:35].IC>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[C:24]([C:26]([O:29][CH2:34][CH3:35])([CH3:28])[CH3:27])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1
Reactant: CCI
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)O)c4)cc3c21
Solvent: CI
Product: CCOC(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 104 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 215.2, 0.063 mmol) and iodethane as replacement for the iodomethane to give the title compound as a film. (HPLC: tR 2.30 min (Method A); M+H=457 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.67 (m, 1H), 8.63-8.61 (m, 1H), 8.16-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.77-7.74 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.21 (q, 2H), 1.97 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H), 1.09 (t, 3H))
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-benzyl-benzenesulfonamide [CAS No. 303780-52-1] according to general procedure II. Light yellow solid. MS (ISP) 600.1 [(M−H)−]; mp 230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Product: COc1cc(OC)nc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)n1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-4,6-dimethoxy-pyrimidine
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:20]1([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:16]=[N:17][N:18]=2)[CH2:22][CH2:21]1
Reactant: c1ccc(COc2ccc(-n3nnnc3C3CC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(-n2nnnc2C2CC2)cc1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of 1-(4-benzyloxy-phenyl)-5-cyclopropyl-1H-tetrazole (2.3 g) in ethanol (75 ml) was added to a suspension of 10% palladium on charcoal catalyst (400 mg) in ethanol (10 ml) and the mixture was stirred under a hydrogen atmosphere for 1 h. The catalyst was removed by filtration and the solution concentrated in vacuo to afford the title compound (1.57 g) as a pale yellow solid, m.p. 184°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:23][CH:20]([NH:21][CH2:22]1)[CH2:19][O:18]2>>[CH:17]12[CH2:23][CH:20]([N:21]([C:14]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:16])[CH2:22]1)[CH2:19][O:18]2
Reactant: C1OC2CNC1C2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CC3CC2CO3)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 2-oxa-5-azabicyclo[2.2.1]heptane by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39])([CH3:32])[CH3:31].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[C:34](=[O:39])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)N1CCNCC1=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-isopropylpiperazin-2-one (0.082 g, 0.58 mmol) and 4 Å molecular sieves (0.718 g) in DCE (5 mL) and MeOH (1 mL) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 469 as an off-white solid (0.044 g, 22%). LCMS (Method I): RT=3.31 min, [M+H]+ 518.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-8.00 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.64-4.58 (m, 1 H); 4.28-4.25 (m, 4 H); 3.86 (s, 2 H); 3.81 (s, 3 H); 3.80-3.77 (m, 4 H); 3.27 (q, 7.5 Hz, 2 H); 3.17 (t, J=5.3 Hz, 2 H); 3.13 (s, 2 H); 2.73 (t, J=5.3 Hz, 2 H); 1.34 (t, J=7.5 Hz, 3 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NCCO)s1
Yield: 35 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (29 mg, 35%) which was obtained as a white solid MS: m/e=359.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:25])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=4[CH3:23])=[C:14]([CH3:24])[O:13][C:12]=23)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]([F:39])([F:38])C(OC)=O>CN(C=O)C>[F:38][CH:33]([F:39])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:11]3[N:10]=[C:9]([CH3:25])[C:8]([N:4]4[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]4)=[C:12]3[O:13][C:14]=2[CH3:24])=[C:17]([CH3:23])[CH:18]=1
Reactant: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(O)cc4C)c(C)oc23)n1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(OC(F)F)cc4C)c(C)oc23)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethylpyrazolo[5,1-b]oxazol-3-yl)-3-methylphenol (Step 1) (100 mg, 0.296 mmol) in dry DMF (4 ml) was treated with potassium carbonate (205 mg, 1.482 mmol) and stirred under N2 for 30 mins at 50° C. Methyl 2-chloro-2,2-difluoroacetate (428 mg, 2.96 mmol) was added and the reaction was heated to 90° C. for 1.5 hrs. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic portion was washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil. Purification of the crude product by reverse phase chromatography [prep-HPLC (Waters system)] yielded the title compound (TFA salt) as a colourless oil. The salt was taken up in DCM (2 ml) and MP-carbonate resin (macroporous polystyrene anion-exchange resin) (500 mg, 2.8 mmol/g, Argonaut) was added and the contents stirred at RT for 30 mins. The resin was filtered, washed with DCM and the filtrate was concentrated in vacuo to give the title compound as the free base. LC-MS Rt 4.86 mins; MS m/z 388.2 [M+H]+; Method=10minLC_v002. 1H NMR (400 MHz, CDCl3) δ 7.4 (1H, d), 7.15 (1H, s), 7.10 (1H, d), 6.6 (1H, t), 2.40 (6H, m), 2.35 (6H, m), 2.20 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:30])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[N:23]=[CH:22][C:21]([N:24]5[CH2:28][CH2:27][NH:26][C:25]5=[O:29])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:31]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:30])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[N:23]=[CH:22][C:21]([N:24]5[CH2:28][CH2:27][N:26]([CH3:31])[C:25]5=[O:29])=[CH:20][CH:19]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cn2)CC1

Procedure:
Using 1-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (280 mg) described in Example 393 and methyl iodide (51 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (211 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.CO.[ClH:11]>O1CCCC1>[ClH:11].[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1
Reactant: N#CCc1ccsc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Slowly add borane methyl sulfide complex (30.4 mL, 304.4 mmol) to a solution of thiophen-3-yl-acetonitrile (25.0 g, 203.0 mmol) in tetrahydrofuran (450 mL). Heat the reaction at reflux for 16 h and then cool to RT. Slowly quench the reaction with methanol (50 mL) until no foaming is observed. To this mixture slowly add methanol (100 mL) which is saturated with hydrogen chloride. Stir the mixture at RT for 20 min before concentrating in vacuo. Add methanol (100 mL) to the mixture and concentrate in vacuo. Suspend the resulting solid in diethyl ether (200 mL) and filter to afford 31.1 g (94%) of the crude title compound. MS/ES m/z 128.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])=[CH:15][N:14](C4CCCCO4)[N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[C:5]([F:30])=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:16]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])=[CH:15][NH:14][N:13]=3)[NH:9][C:8]=2[CH:29]=1)[CH3:2]
Reactant: CCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)nc2cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)C3CC3)nc2cc1F
Reaction time: 5 h
Yield: 61.4 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [90 mg, Reference Example 48(d)] in a 1/1 mixture of trifluoroacetic acid and dichloromethane (30 mL) was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (30 mL) and aqueous sodium bicarbonate (30 mL). The organic layer was evaporated to give cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide (44 mg). LC-MS (Method E): RT=2.34 minutes, 330 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([C:24]#[N:25])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:24]([C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:11]=1)#[N:25]
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C#N)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C#N)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a mixture of methyl(4-cyano-6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (96 mg), THF (3 mL) and MeOH (3 mL) was added 1N NaOH (1.179 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The crystals were crystallized from EtOAc to give the title compound (80 mg).
Reaction SMILES: Cl.[O:2]1CCOCC1.C(OC(NC[C@H]1CC[C@H](C(N[C:26](=[O:36])[C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH2:28])=O)CC1)=O)(C)(C)C>CCCCCC>[NH2:28][C@H:27]([C:26]([OH:36])=[O:2])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCCCCC
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After evaporation of the solvent, the residue was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. After evaporation of the solvent, a white powder of N-(t-butoxycarbonyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide (I) (0.5 g) was obtained. After confirmation by NMR and IR, 4N hydrogen chloride/1,4-dioxane solution (5 ml) was added to the above compound (I) (0.5 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added and the solids precipitated were washed several times with diethyl ether to obtain white solids (0.45 g) of L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride (II). This structure was confirmed by NMR spectrum. To the mixture of 4-guanidino benzoic acid hydrochloride, dry pyridine (3 ml) and 1,3-dicyclohexylcarbodiimide (0.36 g), the above compound (II) was added under ice-cooling, and the mixture was left to stand at room temperature for 12 hours. After a conventional post-treatment, pale yellow solids of N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide (III) (0.5 g) were obtained. After confirmation by NMR, the above compound (III) (0.5 g) was added to a saturated sodium hydrogen carbonate solution (10 ml) and the mixture was stirred for 5 minutes, followed by a recovery of the precipitates. After washing several times with water, pale yellow solids of N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide carbonate (IV) (0.25 g). After confirmation by IR, the above compound (IV) (0.2 g) was added to a 4N hydrogen chloride/1,4-dioxane solution (1 ml) under ice-cooling, and the mixture was stirred for 20 minutes. Diethyl ether was then added, and the precipitated solids were washed several times with diethyl ether to obtain N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/transmethylcyclohexylamide hydrochloride (0.15 g) as pale yellow solids.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH3:29]>CN(C=O)C>[CH2:28]([N:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: CCBr
Reactant: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 35 °C

Procedure:
To 4 g (12.4 mmol) trans-N-(4-Hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide in 20 ml DMF were added 5.1 g (37.1 mmol, 3.3 eq) K2CO3 and 2.04 ml (27.2 mmol, 2.2 eq) ethyl bromide. The mixture was stirred at 35° C. over night, concentrated in vacuo and dissolved in CH2Cl2 and water. The phases were separated and the inorganic one was extracted CH2Cl2, the combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by column chromatography on silica gel with CH2Cl2/MeOH 95:5 to yield 1.6 g (38%) trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide as brown oil, MS: 351(M).