Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)C(=O)Nc1ccc(I)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a dispersion of p-iodoaniline (219.0 g, 1 mol) in acetonitrile(1000 ml) was added pyridine (81.0 ml, 1 mol). Isobutyryl chloride (100.5 ml, 1 mol) was added dropwise to the mixture over 1 hour in an ice bath. The mixture was further stirred for one hour following the addition of isobutyryl chloride and to the mixture was added water (3000 ml). Precipitated crystalline solids were collected by filtration to give N-(4-iodophenyl)isobutyramide (281.7 g, Yield: 97%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].CC(C)=O.C(=O)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -68 °C
Reaction time: 0.15 h

Procedure:
A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 minutes (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)(Cl)Cl>[ClH:20].[N:1]1([CH2:7][C:8]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cccc2c1CCNC2CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CCNC2(CN1CCCCC1)C(=O)Cc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
Prepared as Ex. No. 33, from 600 mg (2.31 mmoles) of 1-(piperidin-1-yl)methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline and 630 mg (2.82 mmoles) of 3,4-dichlorophenyl acetyl chloride in 20 ml of dry chloroform.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[C:21]#[CH:22])[CH2:8][CH2:7]1.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:27]([N:34]1[C@@H:39]2[C@H:40]([S:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH2:41][C@@:35]1([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:36](=[O:51])[CH2:37][CH2:38]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[C@@H:39]2[C@H:40]([S:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)(=[O:43])=[O:44])[CH2:41][C@@:35]1([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@:36]([C:22]#[C:21][C:11]1[CH:12]=[C:13]([O:16][C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:15][C:10]=1[O:9][CH:6]1[CH2:7][CH2:8]1)([OH:51])[CH2:37][CH2:38]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6M, 5 ml, 8 mmol) was added dropwise to a stirred solution of 2-cyclopropyloxy-5-trifluoromethoxyphenylethyne (Description 4; 2.0 g, 8.2 mmol) in tetrahydrofuran (30 ml) at −78° C. to form an orange solution that turned violet at the end of addition. The mixture was stirred for 10 minutes and solid anhydrous cerium(III) chloride (2 g, 8.1 mmol) was added. The mixture was stirred for 30 minutes at −78° C. and a solution of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 7; 2.9 g, 6.7 mmol) in tetrahydrofuran (25 ml) was added dropwise. The reaction mixture was warmed to 0° C. over 30 minutes, stirred at 0° C. for 15 minutes, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (2.4 g, 53%) which was recrystallised from ethyl acetate:iso-hexane.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>CC(N(C)C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([O:6][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CNCC[C@@H](O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CNCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over be magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D -2.16° (c 1.62, MeOH); (lit.133b [α]23D -1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit. [α]23D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2 H), 7.40-7.43 (d, J=8.7 Hz, 2 H), 7.25-7.33 (m, 5 H), 6.88-6.92 (d, J=8.7 Hz, 2 H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 H), 3.12 (br, s, 2 H), 2.55-2.62 (br, s, 3 H), 2.42-2.52 (m, 2 H); Anal. Calcd. for C17 H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].NCCCOC1C=CN2C(C=1)=CC(C(NC[C@H](NS(C1C=CC=CC=1)(=O)=O)C(O)=O)=O)=CC2=O.C([O:46][C:47](=[O:88])[C@@H:48]([NH:78][S:79]([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:81])=[O:80])[CH2:49][NH:50][C:51]([C:53]1[CH:54]=[C:55]2[N:60]([C:61](=[O:63])[CH:62]=1)[CH:59]=[CH:58][C:57]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][NH:70]C(OC(C)(C)C)=O)=[CH:56]2)=[O:52])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:57]1[CH:58]=[CH:59][N:60]2[C:55]([CH:56]=1)=[CH:54][C:53]([C:51]([NH:50][CH2:49][C@H:48]([NH:78][S:79]([C:82]1[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1)(=[O:81])=[O:80])[C:47]([OH:88])=[O:46])=[O:52])=[CH:62][C:61]2=[O:63]
Reactant: CC(C)(C)OC(=O)NCCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc2c1
Agent: NCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCOc1ccn2c(=O)cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2c1
Yield: 86 %

Procedure:
Using the procedure described for the preparation of compound XXX (step E), (S)-2-benzenesulfonylamino-3-{[8-(5-tert-butoxycarbonylamino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid tert-butyl ester (42 mg, 0.063 mmol) was treated with trifluoroacetic acid in dichloromethane to afford compound XXXIV (34 mg, 86%) as a yellow solid which was characterized by 1HNMR (400 MHz, CD3OD) δ: 9.04 (1H, d, J=7.9 Hz), 7.86 (2H, dd, J=1.2, 7.7 Hz), 7.46-7.54 (3H, m), 7.21 (1H, d, J=2.5 Hz), 7.06 (1H, d, J=1.1 Hz), 7.02 (1H, dd, J=2.7, 8.0 Hz), 6.58 (1H, d, J=1.6 Hz), 4.21-4.25 (3H, m), 3.79 (1H,dd, J=5.0, 13.5 Hz), 3.52 (1H, dd, J=8.5, 13.4 Hz), 2.99 (2H, t, J=7.4 Hz), 1.92-1.99, 1.74-1.82, 1.61-1.68 (6H, 3 multiplets).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C.Cl>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]2[C:15]3([O:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:3]1=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1cccc1-c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cn1ccc2c1-c1ccccc1OC21CCNCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(1-methylpyrrol-2-yl)phenol (1.20 g, 6.90 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6.93 mmol), 4-methylbenzenesulfonic acid hydrate (264 mg, 1.39 mmol), and dichloroethane (24 mL) was heated at 80° C. for 2 h. To the mixture was added HCl (1.7 mL of 4.0 M, 6.9 mmol) and the mixture was allowed to stir at 50° C. for 1 h. The mixture was cooled to 25° C. and was concentrated in vacuo. The residue was taken up in dichloromethane and was washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 1-methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]. ESI-MS m/z calc. 254.3. found 255.2 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([CH3:14])[O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][N:4]=[CH:3]1.[Na].O[C:17](P(O)(=O)O)(P(O)(=O)O)COC(C)CN1C=CN=C1.[CH2:36]1O[CH:37]1C>>[N:2]1([CH:7]([CH3:17])[CH2:8][OH:9])[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:36]([O:12][C:11](=[O:13])[CH2:10][O:9][CH:8]([CH3:14])[CH2:7][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)[CH3:37]
Reactant: CC1CO1
Reactant: CC(Cn1ccnc1)OCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: CC(Cn1ccnc1)OCC(=O)O
Agent: Cl
Agent: [Na]
Product: CC(CO)n1ccnc1
Product: CCOC(=O)COC(C)Cn1ccnc1

Procedure:
The 5-(imidazol-1-yl)-4-methyl-3-oxa-pentanoic acid-hydrochloride used as the starting material was prepared in the following manner: reaction of the sodium salt of the imidazole with propene oxide yields the 2-(imidazol-1-yl)-1-propanol (b.p.0.1 : 147°-150° C.) from which the 5-(imidazol-1-yl)-4-methyl-3-oxa-pentanoic acid-ethyl ester (oil) is obtained by reaction with ethyl bromoacetate in dimethyl formamide in the presence of sodium hydride which is then saponified with 3N hydrochloric acid to form the desired acid.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=O)[CH:17]=[CH:16]3)=[CH:9][CH:8]=1.N>>[Br:3][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)[CH:14]=2)[N:19]=1
Reactant: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Reactant: O=P(Br)(Br)Br
Agent: N
Product: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Temperature: 110 °C

Procedure:
50 g (0.174 mol) phosphorus oxybromide are heated to 65° C., combined with 10 g (0.039 mol) 6-(4-chloro-phenyl)-1H-quinolin-2-one and heated to 110° C. for 3 h. The reaction mixture is then poured onto ice water and made alkaline with ammonia solution. The precipitate is filtered off and dried in the drying cupboard at 60° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:17][CH2:16]C[C@H:11]1[C:12](O)=[O:13].C(=O)([O-])[O-].[K+].[K+].N1CCOCC1>CS(C)=O.[Cu]I>[F:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:16][CH2:17]2)=[CH:5][N:4]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1cc(Br)cnc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: Nc1cc(N2CCOCC2)cnc1F
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of 3-amino-5-bromo-2-fluoropyridine (0.96 g, 5.02 mmol), L-proline (0.12 g, 1.01 mmol), potassium carbonate (1.39 g, 10.1 mmol), copper(I) iodide (0.096 g, 0.50 mmol), and morpholine (1.31 mL, 15.04 mmol) in dry DMSO (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentration the residue was purified on basic alumina (10-50% EtOAc in hexanes) to afford a white solid as 2-fluoro-5-morpholinopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.96 (1H, t, J=2.6 Hz), 6.75 (1H, dd, J=9.6, 2.7 Hz), 5.25 (2H, br. s.), 3.80 (4H, m), 3.08 (4H, m). Mass Spectrum ESI (pos.) m/e: 198.1 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[N:39][CH:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[C:16]4[N:17]([N:38]=[N:39][CH:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cnnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2cnnn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
A mixture of hydroxylammonium chloride (438 mg), sodium hydrogen carbonate (706 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (192 mg) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (83 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (78 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] and crystallized from diisopropyl ether to give the title compound as colorless crystals (137 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]([CH2:6][CH2:7][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:28])[CH:3]=1.C1(O[C:36](=[O:45])[NH:37][C:38]2[CH:43]=[N:42][C:41](Cl)=[CH:40][N:39]=2)C=CC=CC=1.[CH3:46][N:47](C=O)C>>[Cl:28][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:37][C:38]2[CH:43]=[N:42][C:41]([C:46]#[N:47])=[CH:40][N:39]=2)=[O:45])[C:25]([O:26][CH3:27])=[CH:24][C:5]=1[CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C)C=O
Reactant: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1N
Reactant: O=C(Nc1cnc(Cl)cn1)Oc1ccccc1
Product: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Yield: 47 %

Procedure:
A solution of tert-butyl 4-amino-2-chloro-5-methoxyphenethyl(3-fluorobenzyl)-carbamate (0.3 g, 0.74 mmol) and phenyl-5-chloropyrazin-2-ylcarbamate (0.18 g, 0.74 mmol) in DMF (30 mL) was heated to 100° C. for 2 hours. The mixture was partitioned between water (200 mL) and EtOAc (50 mL) and the separated aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 20-30% EtOAc in hexane to give the title compound (0.19 g, 47%) as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)C1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[O:20]=[C:19]1[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]2[N:39]=[CH:40][N:41]=[C:15]2[N:14]1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4.82 g), 10% palladium-carbon (containing water by 50%, 2.39 g), tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/100→5/95 (volume ratio)] to give the title compound as a colorless amorphous compound (2.97 g, 74%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:18]=1[C:26](O)=O)[CH3:15].CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[CH2:14]([S:16][C:17]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:18]=1[C:26]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1cc(C(F)(F)F)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1cc(C(F)(F)F)sc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 80 °C
Reaction time: 6 h
Yield: 116.2 %

Procedure:
A mixture of 0.12 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.2 g of 3-ethylthio-5-trifluoromethylthiophene-2-carboxylic acid, 0.15 g of EDCI hydrochloride, 9 mg of HOBt and 3 ml of pyridine was stirred at 80° C. for 6 hours. Water was poured into the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and applied to a silica gel column chromatography to obtain 0.3 g of 2-(3-ethylthio-5-trifluoromethylthiophen-2-yl)-3-methyl-6-t rifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (5)).
Reaction SMILES: [Mg].Br[C:3]1[CH:17]=[CH:16][C:6]([CH:7]([CH3:15])[O:8]C2CCCCO2)=[CH:5][CH:4]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]#N.[Cl-].[NH4+].[O:27]1CCCC1>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([OH:8])[CH3:15])=[CH:16][CH:17]=1)=[O:27]
Reactant: CC(OC1CCCCO1)c1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: N#Cc1cccs1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CC(O)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 4 h

Procedure:
A Grignard-complex is formed starting from 7.2 parts of magnesium and 93.9 parts of 2-(p-bromo-α-methylbenzyloxy)tetrahydropyran in 200 parts of dry tetrahydrofuran. To this stirring and refluxing complex is added dropwise a solution of 32.7 parts of 2-thiophenecarbonitrile in 70 parts of dry tetrahydrofuran and stirring at reflux is continued for 4 hours. The reaction mixture is stirred overnight at room temperature. After cooling, it is decomposed with 150 parts of a saturated ammonium chloride solution at a temperature of about 15° C. The whole is poured onto water and extracted with ether. The organic phase is washed four times with water, dried, filtered and upon acidification of the filtrate with 2-propanol, previously saturated with gaseous hydrogen chloride, an oil is separated. The ether is decanted and the oil is triturated twice in ether. The latter is decanted each time and the oily product is dissolved in water. Concentrated hydrochloric acid solution is added (150 parts) and the whole is stirred with activated charcoal. The latter is filtered off and the filtrate is boiled for 10 minutes and extracted with ether. The combined extracts are washed with water, dried, filtered and evaporated, yielding p-(1-hydroxyethyl)phenyl 2-thienyl ketone, as an oily residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C([Li])CCC.[CH2:13]([O:17][C:18]1[C:22](S(C)(=O)=O)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]>C1COCC1.CCCCCC>[CH2:13]([O:17][C:18]1[C:22]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CN1CCC(O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1nsnc1OC1CCN(C)C1

Procedure:
A solution of 1-methyl-3-pyrrolidinol (0.6 g, 0.0059 mol) in THF (20 mL) was treated with 1.6M n-butyllithium in hexane (3.1 mL), 0.005 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, and the extracts washed with water. The extracts were dried and the solvent evaporated to give a liquid. The HCl salt (0.7 g) crystallized from EtOAc, m.p. 157°-158° C. (Compound 28).