Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC(Cl)C.C(=O)([O-])O.[Na+]>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4](=[O:21])[CH:3]2[NH:2][C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)C(NC(=O)OCc1ccccc1)C(=O)N2c1ccc(F)cc1
Yield: 93.9 %

Procedure:
A mixture of 30.0 g (0.0972 mole) of 3-amino-1-(4-fluorophenyl)-5-methoxy-2,3-dihydro-1H-indol-2-one hydrochloride, 18.2 g of benzyloxycarbonyl chloride, 200 ml of anhydrous dichloroethane and 200 ml of water was cooled in an ice-salt bath, and to the mixture was added 27.0 g of sodium hydrogen carbonate over 10 minutes under argon atmosphere while stirring. After the mixture was stirred at the same temperature for 20 minutes and at the room temperature for 20 minutes, the reaction mixture was washed with a 10% hydrochloric acid aqueous solution, water and then a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain 37.1 g of the title compound as colorless needle crystals. Melting point: 154.5° to 156° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([OH:26])[CH:20]=3)=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:20]=3)=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(O)c2)n1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of 2 g (4.88 mmol) of methyl 3,5-dichloro-2′-(4-chloro-3-hydroxyphenyl)-2,3′-bipyridine-6′-carboxylate in 20 mL of anhydrous DMF placed under argon are added 1.15 g (7.32 mmol) of 3-chloro-N,N-dimethylpropane-1-amine hydrochloride and 4.77 g (14.64 mmol) of cesium carbonate. The reaction medium is stirred for 18 hours at 90° C., cooled to room temperature and then concentrated under reduced pressure. The residue is taken up in 250 mL of EtOAc and washed with 250 mL of aqueous 5% Na2CO3 solution and then with 100 mL of water. After drying over Na2SO4 and concentrating under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a DCM/methanol gradient of from 0 to 15% methanol. After concentrating under reduced pressure, 1.82 g of methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate is obtained in the form of a gum.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C>[CH2:3]([O:10][C:11]1[C:20]([Cl:1])=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Solvent: CC(=O)O
Product: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)O
Temperature: 22.5 °C
Yield: 58.6 %

Procedure:
A solution of chlorine (5.1 g) in acetic acid (100 ml) was added dropwise to a solution of methyl 4-benzyloxy-2-methoxybenzoate (10 g) in acetic acid (40 ml) whilst maintaining the temperature at 20-25° C. The mixture was poured into ice-water and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting crude material was suspended in ethanol (500 ml) and treated with 10% aqueous sodium hydroxide (16 ml). The mixture was heated at reflux overnight and then concentrated in vacuo. The residue was treated with excess 5M HCl and extracted into dichloromethane. The extract was dried (sodium sulfate) and concentrated in vacuo to afford a white solid which was crystallised from ethanol to give the title compound (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].I[CH2:33]CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:29][CH3:33])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCCI
Product: CCCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 1-iodopropane and making non-critical variations provided the title compound as a light yellow syrup. IR (liq.) 3446, 2967, 2935, 2875, 1564, 1552, 1497, 1470, 1392, 1206, 1184, 1101, 1091, 1082, 748 cm−1; OAMS supporting ions at: ESI+ 469.9; MS (EI) m/z 469 (M+); [α]25D=−98 (c 0.91, methylene chloride); Anal. Calcd for C26H29Cl2N3O: C, 66.38; H, 6.21; N, 8.93. Found: C, 66.53; H, 6.15; N, 9.05.
Reaction SMILES: [ClH:1].O[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]>>[Cl:1][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cl
Product: O=C1c2ccccc2C(=O)N1CCl

Procedure:
reacting said mixture at a temperature of from about 45° to about 75° C at a pressure of from about 0 psig to about 50 psig which intimately contacting said reacting mixture with anhydrous HCl at a rate of from approximately 15 to approximately 65 pounds HCl per hour per pound-mole of N-hydroxymethyl phthalimide used to form the mixture in step (a), to maintain the concentration of said aqueous HCl at 35 to 40 wt.%, to form N-chloromethyl phthalimide in a first aqueous-organic mixture;
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si](C)(C)[O:24][C:25]1[CH:49]=[CH:48][C:28]([O:29][CH2:30][C:31]2[CH:47]=[C:34]3[C:35](=[O:46])[N:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=4)[CH2:37][CH2:38][N:33]3[N:32]=2)=[CH:27][CH:26]=1)(C)(C)C.O>C1COCC1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([N:36]2[CH2:37][CH2:38][N:33]3[N:32]=[C:31]([CH2:30][O:29][C:28]4[CH:48]=[CH:49][C:25]([OH:24])=[CH:26][CH:27]=4)[CH:47]=[C:34]3[C:35]2=[O:46])=[N:40][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cn2)C3=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cc(COc3ccc(O)cc3)nn2CCN1c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1M solution of TBAF in THF (0.14 mL, 0.144 mmol) was added to a stirred solution of 2-[4-(tert-butyl-dimethyl-silanyloxy)-phenoxymethyl]-5-(5-fluoro-pyridin-2-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (45 mg, 0.096 mmol) in THF (0.5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 N solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(5-fluoro-pyridin-2-yl)-2-(4-hydroxy-phenoxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.40-4.48 (m, 2H), 4.48-4.55 (m, 2H), 4.99 (s, 2H), 6.65-6.72 (m, 2H), 6.83-6.88 (m, 2H), 6.95 (s, 1H), 7.85 (td, J=8.7, 3.2 Hz, 1H), 7.93 (dd, J=9.1, 4.2 Hz, 1H), 8.50 (d, J=3.2 Hz, 1H), 8.96 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].O1CCCC1>C(Cl)(Cl)Cl>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:23][CH:24]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:46][CH:45]=[CH2:44])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCN1CCc2nc(CCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2C1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.20 g), potassium carbonate (0.082 g), allyl bromide (0.057 g) and tetrahydrofuran (2 ml) is stirred overnight at room temperature. To the mixture is added chloroform, and the mixture is washed, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-5-allyl-3-[2'-(t-butoxycarbonyl)biphenyl- 4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.128 g).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(CCc3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Nc2ncnc(CCc3ccc4[nH]ncc4c3)n2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To a solution of 4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.03 g, 0.064 mmol) in DCM (2 mL) cooled to 0° C., TFA (0.025 mL, 0.320 mmol) was added and the reaction mixture was stirred at 23° C. overnight. The reaction mixture was concentrated, washed with diethyl ether, and purified by preparative HPLC on a SY C18 column (20×19 mm) using 0-100% mobile phase B (ACN) in mobile phase A (10 mM NH4OAc) over 17 min to give 4-(2-(1H-indazol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a white solid (4 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)=[C:4]([O:17][CH3:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH3:18])[C:5]([CH:10]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1
Product: COc1cc(Cl)cc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(4-chloro-2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 444.09 g/mol.
Reaction SMILES: [C:1]([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C:16]1[N:17]=[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7]2)[CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(NC(=O)OC(C)(C)C)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of 114d (880 mg, 2.53 mmol) and TFA (2.0 mL) in DCM (10.0 mL) was stirred at rt overnight. The mixture was concentrated and diluted with EA (30 mL), neutralized with 1M NaOH. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE/EA=1/1) to give (S)—N-(1-(6-aminopyridin-2-yl)piperidin-3-yl)acrylamide 114e (440 mg, 70%) as yellow oil. MS-ESI: [M+H]+ 247.2
Reaction SMILES: [CH2:1](O)C.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([OH:20])[CH:10]=4)[C:7]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)C>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([O:20][CH3:1])[CH:10]=4)[C:7]=2[CH:6]=1
Reactant: COC(=O)C12CC(c3ccc(O)cc31)c1ccc(Cl)cc12
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(OC)cc12
Yield: 90 %

Procedure:
To an ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 90a) was added potassium carbonate and methyl iodide. The suspension was heated to reflux, cooled and diluted with diethyl ether, filtered to remove salts, and concentrated to a solid. The title compound was formed in 90% yield. TLC analysis (Rf 0.40, 20% ethyl acetate in hexane). MS (CI, CH4) m/z 315 (M+1,100), 343 (M+29,13), 301 (38), 287 (9), 279 (14), 265 (6), 255 (42).
Reaction SMILES: Cl.[CH:2]12[N:10]([CH2:11][C@@H:12]([C:14]3[CH:23]=[CH:22][C:17]4[C:18](=[O:21])[O:19][CH2:20][C:16]=4[C:15]=3[CH3:24])[OH:13])[CH:7]([CH2:8][CH2:9]1)[CH:6]1[NH:25][CH:3]2[CH2:4][CH2:5]1.[CH3:26][C:27]1[N:34]=[C:33]([CH:35]2[CH2:37][O:36]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[OH:36][CH:35]([C:33]1[N:34]=[C:27]([CH3:26])[C:28]([C:29]#[N:30])=[CH:31][CH:32]=1)[CH2:37][N:25]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH:2]1[N:10]([CH2:11][C@H:12]([OH:13])[C:14]3[CH:23]=[CH:22][C:17]4[C:18](=[O:21])[O:19][CH2:20][C:16]=4[C:15]=3[CH3:24])[CH:7]2[CH2:8][CH2:9]1
Reactant: Cc1c([C@@H](O)CN2C3CCC2C2CCC3N2)ccc2c1COC2=O
Reactant: Cc1nc(C2CO2)ccc1C#N
Agent: Cl
Product: Cc1nc(C(O)CN2C3CCC2C2CCC3N2C[C@H](O)c2ccc3c(c2C)COC3=O)ccc1C#N

Procedure:
6-(1-Hydroxy-2-{10-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl}ethyl)-2-methylpyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-2-(9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-1 hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 9) and 2-methyl-6-(oxiran-2-yl)nicotinonitrile (PCT Published Application WO 2010/129379).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 30 h

Procedure:
Trifluoroacetic acid was added (2 mL) to 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (113 mg, 0.2618 mmol, see step (e) above) and one drop (ca. 0.05 mL) of anisole (ca. 0.05 mL) was added to the mixture. The reaction mixture was stirred under N2 atmosphere for 30 h and then evaporated and co-evaporated with acetonitrile until TLC showed that it was pure. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][CH:2](OC)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].CC(C)(CO)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:18][CH3:17])=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(CO)CO
Reactant: COC(Cl)CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Yield: 30.9 %

Procedure:
A solution of 45.96 g. (0.217 mole) of 4-chloro-4 -methoxybutyrophenone [prepared in (a), above], 28 g. (0.27 mole) of 2,2-dimethyl-1,3-propanediol and 0.53 g. of p-toluenesulfonic acid in 425 ml. of benzene is heated at reflux under a Dean-Stark trap for about 20 hours. The solution is allowed to cool, washed successively with aqueous sodium bicarbonate solution, water and brine and then evaporated to dryness. The residue is distilled at 174° C. at 1.5 mm. of mercury pressure and then recrystallized from petroleum ether to give 19.97 g. (30.9% yield) of 4-chloro-4'-methoxybutyrophenone, 2,2-dimethylpropylene ketal, having a melting point of 51.5 ° to 53.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C2CCN(C(=O)OC(C)(C)C)CC2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2(C(=O)O)CCCC2)CC1
Reaction time: 336 h

Procedure:
A solution of 1.2 g of 4-(1-ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxylic acid tert-butyl ester in a mixture of 100 ml of EtOH and 50 ml of an 1M aqueous NaOH is stirred at 70° for 14 days, EtAc is added and two phases obtained are are separated. The aqueous layer obtained is acidified with hydrochloric acid (pH 2-3) and extracted with EtAc. The organic layer obtained is washed with brine, dried and solvent is evaporated. 4-(1-Carboxy-cyclopentyl)-piperidine-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH3:18])[O:9][C:8]2[C:10]([CH3:17])=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[C:7]=2[CH2:6][CH2:5]1.[ClH:19].[NH:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:21]([NH2:23])=[NH:22].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CN(C)C=O>[ClH:19].[OH:15][C:12]1[C:11]([CH3:16])=[C:10]([CH3:17])[C:8]2[O:9][C:4]([CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([NH:20][C:21]([NH2:23])=[NH:22])=[CH:32][CH:31]=3)([CH3:18])[CH2:5][CH2:6][C:7]=2[C:13]=1[CH3:14]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN)O2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCNC(=O)c1ccc(NC(=N)N)cc1)O2
Reaction time: 60 h
Yield: 15.3 %

Procedure:
The amine (prepared in reference example 3, 1.0 g) and 4-guanidinobenzoic acid hydrochloride (0.95 g) were dissolved in the mixture of pyridine (5 ml) and dimethylformamide (5 ml). Dicyclohexylcarbodiimide (0.91 g) was added to the solution. The mixture was stirred for 2.5 days. The reaction solution was filtered. The filtrate was evaporated. The residue was dissolved in methanol (10 ml), and 1N hydrochloric acid (6 ml) was added to the solution. The solution was evaporated. The residue was purified by column chromatography on silica gel (methylene chloride: methanol=10:1) to give the title compound (275 mg) having the following physical data.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:22][CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCCCC(F)(F)F
Product: O=C(NCCCC(F)(F)F)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 166° C. and MS: m/e=321 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 4,4,4-trifluoro-butylamine.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[C:9]([C:19]#[CH:20])=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11]>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:10]2[C:9]=1[CH:19]=[CH:20][NH:11]2
Reactant: C#Cc1c(N)cc(C(F)(F)F)cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of potassium tert-butoxide (1.33 g) in NMP (30 mL) was added a solution of 3-bromo-2-ethynyl-5-(trifluoromethyl)aniline (1.56 g) in NMP (5 mL) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.08 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][N:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: Cc1ccc([Sn](C)(C)C)cn1
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)nc3)cccc2c1N
Yield: 76.5 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-methyl-5-(trimethylstannyl)pyridine (270 mg, 1.058 mmol) were reacted to afford the title compound (123 mg, 76% yield). 1H NMR (300 MHz, CDCl3) δ 8.75 (bs, 1H), 8.55 (br, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.84-7.70 (m, 2H), 7.30 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=322 (M+H). HPLC 1.41 min.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[F:24])=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C-]#N.[K+].[OH:35][C:36](C)(C)C#N>CO>[CH:1]1[C:6]2[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]([O:35][CH3:36])=[O:21])=[CH:18][C:17]=3[F:24])=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(C2=Nc3ccccc3Oc3ccccc32)c(F)c1
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)c(F)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A mixture of compound 102 (0.59 g, 1.90 mmol), triethylamine (1.6 mL, 11.48 mmol), potassium cyanide (0.061 g, 0.93) and 2-hydroxy-2-methylpropanenitrile (1 mL, 10.93) in methanol (15 mL) was stirred at 40° C. for 24 h then solvent evaporated. The resulting crude residue was purified on ISCO (0-100% EtOAc in Hexanes) to afford title compound 103 (0.364 g, 56%) as a yellow solid. LRMS (ESI): (calc) 347.10. (found) 348.4 (MH)+.