Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:19])(=[O:20])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in the previous step, 17.8 mg, 0.0320 mmol) in DMF (35 μL) and ethylenediamine (13 μL, 0.18 mmol), solid tetrabutylammonium fluoride (TBAF) (25 mg, 0.090 mmol) was added. The resulting solution was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on silica (20-100% EtOAc-hexane) to afford the title compound (9.3 mg, 68%): 1H-NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 7.18 (dd, 1H, J=8.7, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.81 (br s, 1H), 3.62 (m, 2H), 3.35 (m, 2H), 2.93 (m, 1H), 2.24-2.34 (m, 4H), 1.82-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H22N6O3S, 427.1 (M+H), found 427.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 90 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and benzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 218-220° C. (Ethyl acetate-hexane).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:31]([OH:46])[CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)C1C=CC=CC=1>C(O)C.[Pd]>[C:42]([NH:41][C:39]([C@@H:34]1[CH2:35][CH2:36][CH2:37][CH2:38][N:33]1[CH2:32][C@@H:31]([OH:46])[C@@H:30]([NH:29][C:27](=[O:28])[C@H:22]([CH2:23][C:24](=[O:26])[NH2:25])[NH:21][C:19]([C:10]1[C:9]([OH:8])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:20])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2cc1O
Yield: 69.4 %

Procedure:
A solution of 181 mg of 1-[3(S)-[[N-(3-benzyloxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 5 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated. After trituration with diethyl ether there were obtained 110 mg of N-tert.butyl-1-[3(S)-[[N-(3-hydroxy-2-naphthoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide as a pale yellow solid; MS: m/e 632 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si](CC)(CC)CC)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=O)[CH3:33].[NH4+].[Cl-].CCOCC>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:32][CH3:33])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:24])([C:16]([F:18])([F:19])[F:17])[C:20]([F:21])([F:23])[F:22])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCN(Cc1ccccc1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 200 mg (0.43 mmol) of trans benzyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 3.1) in 2 mL of pyridine was treated with 0.05 mL of acetic acid anhydride (0.51 mmol), stirred overnight at RT and distributed between a saturated aqueous solution of NH4Cl and Et2O. After drying of the combined organic phases over Na2SO4 and evaporation of the solvent, the residue was dissolved in 3.5 mL of THF and treated with 0.86 mL of a 1M BH3-solution in THF. The mixture was stirred at RT for 2 hrs, and the solvent evaporated. The residue was redissolved in THF treated with an excess of TBAF and solution was stirred for 2 hrs. Evaporation of the solvent and chromatography on silica gel with hexane/EtOAc 4:1 gave 64 mg (39%) of trans 2-[4-(benzyl-ethyl-amino)-cyclohexyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol as a light yellow oil, MS: 384 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2ncccc2c1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncccc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromoquinoline (187 mg, 0.9 mmol; TCI-US) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.20 (m, 4H) 2.42 (s, 3H) 2.92-2.99 (m, 1H) 3.08-3.28 (m, 4H) 4.32 (s, 2H) 6.90-6.96 (m, 1H) 6.98-7.04 (m, 1H) 7.22 (s, 1H) 7.63 (dd, J=8, 4 Hz, 1H) 7.72 (dd, J=9, 2 Hz, 1H) 7.93 (d, J=2 Hz, 1H) 8.21 (d, J=9 Hz, 1H) 8.46 (d, J=7 Hz, 1H) 8.94 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1>>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)=[N:7][C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)[nH]n1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cc(C)n[nH]4)n3)cc2CC1

Procedure:
The title compound was prepared from was prepared from (2,5-dichloropyrimidin-4-yl)-(5-methyl-2H-pyrazole-3-yl) amine (137 mg, 0.56 mmol) and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (124 mg, 0.56 mmol) in an analogous manner to Example 946 to afford a white solid (110 mg, 46%). Mp: 198-9° C. LCMS (m/e) 428 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.46 (br s, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 2.93 (m, 4H), 2.82 (m, 7H), 2.33 (s, 3H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[CH3:33][C:34]([CH3:45])([NH2:44])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][C:34]([CH3:45])([CH3:33])[CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: CC(C)(N)CCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NC(C)(C)CCCc2cccnc2)c2cccc(OC)c2)c1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester 1.73 and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 30 hours at reflux and, after the usual work up, the product was crystallized from ethyl acetate-hexane to afford 1.6 g of (E)-5,5-bis(3-methoxyphenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 120°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Into a 2 L three-neck flask equipped with a stirrer, a thermometer and a nitrogen-introducing tube, 240.2 g (2.50 mol) of fluorobenzene was introduced, and was cooled to 10° C. in an ice bath. Then, 134.6 g (0.50 mol) of 2,5-dichlorobenzoic acid chloride, and 86.7 g (0.65 mol) of aluminum chloride were slowly added such that the reaction temperature would not exceed 40° C. After the addition, the mixture was stirred at 40° C. for 8 hours. After the disappearance of the raw materials was confirmed by thin-layer chromatography, the mixture was dropped in iced water, and extraction using ethyl acetate was carried out. The extraction liquid was neutralized by 5% sodium bicarbonate water, and the resultant was washed with saturated saline water. The liquid washed was dried with magnesium sulfate, and then the solvent was distilled away using an evaporator. The residue was allowed to recrystallize in methanol, thereby an intermediate product, 2,5-dichloro-4′-fluorobenzophenone, was obtained. Amount obtained was 130 g, and yield percentage was 97%. Note that, the yield percentage was calculated by following formula (hereinafter, the same): yield percentage (%)=(amount of product obtained/theoretical amount of product)×100.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17]C(=O)OC(C)(C)C)[N:16]=2)[N:13]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)=[N:13][N:12]2[CH:14]=1
Reactant: COc1cc(COc2ccc3nc(NC(=O)OC(C)(C)C)cn3n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(COc2ccc3nc(N)cn3n2)cc(OC)c1OC

Procedure:
t-Butyl N-[6-(3,4,5-trimethoxybenzyloxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (Example 13, 0.43 g, 1 mmol) was dissolved in dichloromethane (2 ml) and treated with trifluoroacetic acid (1 ml). After 2 h at ambient temperature the mixture was evaporated in vacuo to give a brown oil which was triturated with diethyl ether to give the title compound (0.25 g) as a cream solid, m.p. 150°-157°, NMR δH (DMSO) 8.0 (1H, JAB 8.8 Hz, 8H), 7.48 (1H, s, 3H), 7.16 (1H, JAB 8.8 Hz, 7H), 6.44 (2H, s, CH2), 4.5 (brs, NH3), 3.89 (6H, s, OMe) and 3.75 (3H, s, OMe).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:12]([C@@H:13]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][Cl:35]>>[CH2:1]([O:8][CH2:9][N:10]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:12]([C@@H:13]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]2[O:15][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])[C:11]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCBr
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n(COCc2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCCl)c(=O)n(COCc2ccccc2)c1=O
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of 3-benzyloxymethyl-5-methyluridine (25.9 g, 68 mmol) was treated with NaH (60% oil, 7.9 g, 200 mmol) for 1 hr at room temp. 1-Bromo-4-chlorobutane (19.7 g, 115 mmol) was added slowly and the reaction stirred at room temp. for 16 hrs. The reaction was then quenched (MeOH), concentrated in vacuo and the residue chromatographed on silica gel CHCl3/MeOH 95/5 to give the title compound in 41% yield. 1H NMR (DMSO-d6) δ 5.87 (d, 1H, C1′H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:40])[CH3:39])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47) but using acetyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][N:17]=1>>[F:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([C:3]2[CH2:4][CH2:5][C:6]3[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=3[C:2]=2[OH:1])=[O:21])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Product: CC(=O)Nc1nc2c(s1)C(O)=C(C(=O)c1ccc(F)nc1)CC2

Procedure:
The title compound is synthesized according to general procedure A1 starting form 21.0 g (100 mmol), N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 20.2 g (120 mmol, 95% pure) 6-fluoro nicotinic acid chloride. Yield: 27.0 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine (product of Example 3C, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound 1H NMR (300 MHz, CD3OD) 1.08 (m, 1H), 1.19 (m, 1H), 1.32 (d, J=6 Hz, 3H), 1.42 (m, 1H), 1.63 (m, 1H), 1.99 (m, 3H), 2.20 (m, 1H), 2.65 (m, 1H), 2.94 (m, 1H), 3.07 (m, 1H), 3.34 (dd, J=9 Hz, J=6 Hz, 1H), 3.51 (m, 1H), 7.24 (d, J=9 Hz, 2H), 7.60 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[NH:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]1=[O:33])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH:26]([CH2:24][CH3:25])[C:27](=[O:33])[N:28]([CH3:32])[C:29]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CCC1NC(=O)N(C)C1=O
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 64.7 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (113 mg) was obtained.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][C:17]([C:10]1[N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:12]=[C:8]([C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH:9]=1)=[O:19]
Reactant: CCCCn1cc(C(=O)C2CCCC2)cc1C(=O)O
Reactant: Nc1nccs1
Product: CCCCn1cc(C(=O)C2CCCC2)cc1C(=O)Nc1nccs1
Yield: 23.2 %

Procedure:
4-Cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid (132 mg) was obtained following the hydrolysis of the ester intermediate via the general procedure E. 4-Cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid thiazol-2-ylamide (40 mg) was prepared from 4-cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid (132 mg, 0.5 mmol) and 2-aminothiazole (51 mg, 0.5 mmol) following the general procedure F.
Reaction SMILES: [CH2:1]1[C:6](=O)[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][CH:6]3[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2][CH2:1]3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CCN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
1-(2-Phenethyl)-4-piperidone (142 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (104 mg, yield 65%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9]1
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Reactant: BrCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 1,8-dibromooctane and potassium carbonate in butanone to give after chromatographic work up the title compound, m.p. 90°-91° C., Found: C, 64.0; H, 6.5; N, 10.1; Br, 19.8%; C22H26BrN3 requires: C, 64.1;H, 6.4; N, 10.2; Br, 19.4%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[C-:16]#[N:17].[Na+]>CN(C=O)C>[F:15][C:2]([F:14])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:16]#[N:17])[N:11]=[CH:10]1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccccc1-n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
A mixture of 4-(chloromethyl)-1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole (1.1 g), NaCN (1.2 g, 24.5 mmol), and dry DMF was stirred at 100° C. for 12 h. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc, the phases were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with water, brine, dried over sodium sulfate, and evaporated in vacuo. The crude product was purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to give 1-(1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile (730 mg, 74%) as a white solid. MS (ESI) 482 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 76 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.