Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][C:48]=1[N+:54]([O-:56])=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:51][C:50]1[CH:52]=[CH:53][C:47]([CH3:46])=[C:48]([N+:54]([O-:56])=[O:55])[CH:49]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 63.3 %

Procedure:
3-(2-cyanopropan-2-yl)benzoic acid 3 (25 g, 132 mmol), TBTU (63 g, 98 mmol), DIPEA (396 mmol, 65.4 mL) and 4-methyl-3-nitroaniline (20.1 g, 132 mmol) were dissolved in DMF (500 mL) and stirred for 72 h. The reaction mixture was poured into citric acid solution (3%) and extracted twice with EtOAc. The combined organic layers were washed with water (5×), brine (2×), dried, and evaporated. Purification by chromatography (CH2Cl2) gave 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-nitrophenyl)benzamide 4 (27 g, 63%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.60 (s, 3H), (d, J=8.5 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.73 (m, 1H), 7.80 (m, 1H), 7.90 (m, 1H), 7.99 (m, 1H), 8.06 (br s, 1H), 8.28 (m, 1H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][OH:20].[ClH:21]>CCOCC>[ClH:21].[ClH:21].[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][O:20][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Reactant: CN1CCC[C@H]1CO
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1

Procedure:
A sample of 3,5-dinitro pyridine from step 93a above is reacted with (S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedure of Example 3a, and the product is converted into the title compound by treatment with HCl in ether according to Example 14c.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[C:22]([NH:29][C@@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:25]([O:24][C:22]([NH:29][C@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]([NH:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21])=[O:39])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3(R,S)-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4.08 g) in anhydrous dimethyl formamide (30 ml), under an atmosphere of nitrogen, was added in succession Boc-D-phenylalanine (3.98 g), 1-hydroxybenzotriazole trihydrate (2.03 g) and 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (2.88 g). Triethylamine (2.09 ml) was then added and the resulting suspension stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (100 ml) and 10% citric acid solution (100 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with 10% sodium hydroxide solution (100 ml), water (50 ml) and brine (50 ml). The organic layer was separated, dried (Na2SO4) and evaporated in vacuo to afford crude 3(R,S)-[2(R)-(tert-butyloxycarbonyl)amino-3-phenylpropionylamino]-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.CC(O)=[O:38].[N+](=C)=[N-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][C@@H:19]([OH:38])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:28])[CH3:29])[CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
A mixture of (S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-butanoic acid, methyl ester (750 mg, 1.00 mmol) tetra-n-butylammonium fluoride (1.0M in THF, 3.50 mmol), and HOAc (330 mg, 5.50 mmol) in THF (12 ml) was stirred at room temperature for 15 hours. The solution was partitioned between 5% KHSO4 and EtOAc. The layers were shaken and separated and the EtOAc layer was washed again with 5% KHSO4. The pooled aqueous washings were back-extracted twice with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and removal the solvent afforded a yellow oil. The oil was dissolved in Et2O and treated with excess diazomethane for 20 minutes. The excess diazomethane was destroyed by the addition of HOAc and the solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 40% acetone in hexane followed by 1:1 acetone:hexane) to afford (S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (446 mg, 88%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (5.0 mg) with purity >90%. MS (pos) m/z 459.1, 461.1, 463.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[OH:27]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1cc(O)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cc(O)ccc1O
Yield: 16.1 %

Procedure:
To a mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (400 mg, 1.42 mmol) and 2-aminomethyl-benzene-1,4-diol hydrochloride salt (250 mg, 1.42 mmol) in N,N-dimethylformamide (DMF) (10 mL) is added triethylamine (Et3N) (0.3 mL, 2.13 mmol). The resulting precipitate is filtered to give 89 mg (16.1%) of the title compound as a beige solid. MS (ESI) m/z 387.0 (M−H)−1.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]>C(Cl)Cl>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:1])=[CH:6][C:5]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]
Reactant: ClI
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Solvent: ClCCl
Product: Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Yield: 56 %

Procedure:
Iodine monochloride, 15 ml (21 g), was added to a solution of 23 g (0.1 mol) of (2-aminophenyl)(2 chlorophenyl)methanone [ref. E. Reeder and L. H. Sternbach, U.S. Pat. No. 3,371,085; February 1968] in 500 ml of methylene chloride cooled to -60° C. After stirring with cooling for 5 hours, the cooling bath was removed and the temperature of the reaction mixture was allowed to reach 0° C. Following the addition of 300 ml of aqueous sodium bisulfite solution, the two phase system was stirred for 10 minutes. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was crystallized from ether/hexane to yield 20 g (56%) of (2-amino-5-iodophenyl) (2-chlorophenyl)methanone with m.p. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:44]1[C:56]2[NH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[C:47]([O:57][CH2:58][CH:59]([OH:63])[CH2:60][NH:61][CH3:62])=[CH:46][CH:45]=1>CN(C=O)C.C(Cl)Cl>[CH:44]1[C:56]2[NH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[C:47]([O:57][CH2:58][CH:59]([OH:63])[CH2:60][N:61]([CH3:62])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:46][CH:45]=1
Reactant: CNCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)CC(O)COc2cccc3[nH]c4ccccc4c23)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
To a solution of 3,4-Dimethoxybenzoic acid (0.2 g, 1.11 mmol) in DMF (5 mL) was added DIPEA (0.48 mL, 2.8 mmol), EDCI (0.355 g, 1.85 mmol), HOBt (0.05 g, 0.37 mmol) followed by 1-(9H-carbazol-4-yloxy)-3-(methylamino)propan-2-ol (0.25 g, 0.925 mmol) prepared following the procedure described above in step I, example 72. The reaction was stirred at room temperature for 12 hours and was diluted with DCM (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated. The crude compound was purified by dissolution in dichloromethane (3 mL) and precipitation by adding diisopropyl ether (5 mL) and hexane (10 mL). The resulting white solid was filtered, and dried to afford the desired compound (0.15 g, 38%) with m.p.: 77-80° C. 1H NMR (400 MHz, CDCl3) δ (ppm): 3.10-3.40 (m, 3H), 3.70-4.10 (m, 7H), 4.07 (s, 1H), 4.20-4.25 (m, 1H), 4.38 (s, 1H), 4.56 (s, 1H), 4.76 (s, 1H), 6.74 (s, 1H), 6.87 (s, 1H), 6.90-7.15 (m, 4H), 7.20-7.49 (m, 3H), 8.17 (s, 1H), 8.30 (s, 1H). MS m/z: 435.0 (M+).
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:3]([O:5]CC)=O.[NH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>C(O)C>[OH:23][CH:21]([CH3:22])[CH2:20][NH:19][C:3](=[O:5])[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:1]
Reactant: CC(O)CN
Reactant: CCOC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CC(O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Ethanol (1.27 L) and ethyl oxo{[3-(trifluoromethyl)phenyl]amino}acetate (243.15 g, 1 eq) were heated to reflux. 1-Amino-2-propanol (73.2 g, 1.05 eq) in ethanol (0.29 L) was added to the reaction mixture over 1 hour. The reaction mixture was held at reflux for a further 3 hours and then cooled to 20-25° C. The solvent was removed on a rotary evaporator and the resulting white solid was dissolved in ethyl acetate (1.6 L). The solution was reduced in volume by 80% by distillation at atmospheric pressure. Heptane (1.29 L) was then added and the product precipitated. The mixture was cooled further to 0-5° C. and held at this temperature for 1 hour. The mixture was filtered and the filter cake washed with heptane (0.24 L). The damp product was dried at 50° C. for 16 hours in a vacuum oven. The title compound (227.88 g, 84.3%) was isolated as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[C:20]([O:25][CH2:26][CH:27]1[O:29][CH2:28]1)(=[O:24])[C:21]([CH3:23])=[CH2:22]>O1CCCC1>[C:20]([O:25][CH2:26][CH:27]([OH:29])[CH2:28][C:7]1[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:16][C:17]=2[CH:18]=[CH:19][C:6]=1[C:3](=[O:5])[CH3:4])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: C=C(C)C(=O)OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC(O)Cc1c(C(C)=O)ccc2c1Nc1ccccc1S2
Reaction time: 48 h
Yield: 72.3 %

Procedure:
0.20 g (0.0086 mol) of sodium hydride was added carefully to a solution of 2-acetylphenothiazine (2 g, 0.0083 mol) in 150 ml tetrahydrofuran under agitation below 5° C. A solution of glycidyl methacrylate (1.88 g, 0.013 mol) in 10 ml tetrahydrofuran was added dropwise to above solution. The reaction was kept at room temperature for 48 hours. After the solvent was removed, the residue was washed with dilute HCl and water. Dried. 2.3 g of product was obtained by recrystallization with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([CH2:32][N:33]2[CH2:49][CH2:48][C:36]3([O:41][CH2:40][CH2:39][N:38](C(=O)C(F)(F)F)[CH2:37]3)[CH2:35][CH2:34]2)[CH:31]=1)[CH2:5][CH2:6][N:7]([CH2:15][C@H:16]([OH:28])[C:17]1[C:25]2[S:24][C:23](=[O:26])[NH:22][C:21]=2[C:20]([OH:27])=[CH:19][CH:18]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]>N>[O:41]1[C:36]2([CH2:35][CH2:34][N:33]([CH2:32][C:30]3[CH:29]=[C:4]([CH:3]=[C:2]([F:1])[CH:31]=3)[CH2:5][CH2:6][N:7]([CH2:15][C@H:16]([OH:28])[C:17]3[C:25]4[S:24][C:23](=[O:26])[NH:22][C:21]=4[C:20]([OH:27])=[CH:19][CH:18]=3)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:49][CH2:48]2)[CH2:37][NH:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N(CCc1cc(F)cc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: N
Product: CC(C)(C)OC(=O)N(CCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reaction time: 0.67 h

Procedure:
A solution of (R)-tert-butyl 3-fluoro-5-((4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (examples 116-182, step a) (0.7 g) in 35% aqueous ammonia solution (15 mL) was allowed to stand at 20° C. for 40 minutes. The reaction mixture was evaporated to half the initial volume under reduced pressure. Water (10 mL) was added and this solution was passed through a 10 g C18 silica cartridge which had been pre-wetted with water. The column was flushed with water (20 mL). The column was then flushed with methanol (50 mL) to bring off the product. The solvent was evaporated under reduced pressure and the residue was azeotroped with acetonitrile (×2) to afford the subtitled compound. Yield 0.580 g.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[CH2:7]([N:9]1C(=O)C(O)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:10]1(=[O:27])=[O:26])[CH3:8].CN(C=O)C>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:9]([CH2:7][CH3:8])[S:10](=[O:27])(=[O:26])[C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1
Reactant: CCN1C(=O)C(O)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Cl)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Yield: 60.5 %

Procedure:
Oxalyl chloride (0.379 g, 2.99 mmol) was added dropwise to a solution of 2-ethyl-4-hydroxy-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (0.480 g, 1.49 mmol) and DMF (0.109 g, 1.49 mmol) in DCM (12 mL). The mixture was refluxed for 1 h. It was evaporated and water was added. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and evaporated to give the title compound (0.306 g, 71%) as a solid; 1H NMR (500 MHz, DMSO-d6): δ 8.07-8.11 (m, 4H), 3.81 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:13]C(=O)C)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[ClH:17]>O>[ClH:17].[C:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH:12]([NH2:13])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCCc2sc(C(C)=O)cc21
Agent: Cl
Solvent: O
Product: CC(=O)c1cc2c(s1)CCCC2N

Procedure:
The product from Example 31, N-(2-acetyl-4,5,6,7-tetrahydrobenzo[b] thien-4-yl)acetamide (7.25 grams), is heated with 90 ml. of 1N hydrochloric acid at reflux temperature for 8.5 hours and cooled. The mixture is diluted with water and extracted with methylene chloride. The aqueous layer is then evaporated to dryness using 2-propanol for facilitating removal of water. This gives 4.85 grams of 2-acetyl 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34]Cl.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][CH2:41][N:36]1[CH2:34][CH2:33][O:39][CH2:38][CH2:37]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: ClCCBr
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (67 mg) was dissolved in N,N-dimethylformamide (5 ml) to prepare a solution. Potassium carbonate (225 mg) and 1-bromo-2-chloroethane (0.15 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Morpholine (0.3 ml) was added to the reaction solution, and the mixture was further stirred overnight at 70° C. Potassium carbonate (354 mg) and morpholine (0.2 ml) were further added to the reaction solution, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 12%) (2 steps).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2CCN(C(OC(C)(C)C)=O)C[C@H]2OC)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[C:28]([O:31][CH2:32][CH3:33])(=O)C.[C:34]([N:41]1[CH:45]=[CH:44]N=C1)([N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1)=[S:35]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:44][CH2:45][N:41]([C:34]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[S:35])[CH2:33][C@H:32]2[O:31][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(C)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=S)n3ccnc3)C[C@H]2OC)nc1Cl
Reaction time: 0.25 h

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (130 mg, 0.34 mmol) was dissolved in methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (3 mL) was added, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and then the same operation as in Example (64a) was performed using 1,1′-thiocarbonyldiimidazole (81 mg, 0.45 mmol), to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]1[CH2:18][OH:19])=[O:9])[CH:5]=[CH2:6].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(OCC)(=O)C.O>[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]1[CH2:18][O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:9])[CH:5]=[CH2:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N1CC(C(C)=O)=CC1CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1CC(C(C)=O)=CC1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
To a methylene chloride solution (50 ml) of 1-allyloxycarbonyl-4-acetyl-2-hydroxymethyl-3-pyrroline (2.5 g) and imidazole (1.51 g) was added tert-butyldimethylsilyl chloride (2.5 g) under ice-cooling. The mixture was then stirred at room temperature for one day, followed by addition of water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate twice. The organic layers were combined, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-4-acetyl-2-tert-butyldimethylsilyloxymethyl-3-pyrroline (1.45 g).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:34](#[N:38])[CH2:35][C:36]#[N:37].O>CS(C)=O>[F:24][C:8]([F:25])([C:9]([F:22])([F:23])[C:10]([F:20])([F:21])[C:11]([F:18])([F:19])[C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH2:7][CH:35]([C:34]#[N:38])[C:36]#[N:37]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
14.6 g of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl trifluoromethanesulfonate was dissolved in 20 ml of dimethyl sulfoxide, and 5.5 g of potassium carbonate was added. 2.6 g of malononitrile dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl)malononitrile.