Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C(O[CH2:9][Cl:10])C.[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=1)([CH3:13])[CH3:12].[C:23](Cl)(Cl)(Cl)[Cl:24]>>[Cl:24][CH2:23][C:17]1[CH:18]=[C:19]([CH2:9][Cl:10])[C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][C:16]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CCOCCl
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(CCl)cc1CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
55 ml (0.46 mol) of tin tetrachloride are added dropwise with cooling in an ice bath (exothermic reaction) to a solution of 230 ml (2.43 mol) of chloromethyl ethyl ether and 197 g (1.22 mol) of 1,3-diisopropylbenzene in 600 ml of carbon tetrachloride and the mixture is stirred at 0° C. for 1 h. After stirring overnight at +25° C., 142 g (1.5 mol) of chloromethyl ethyl ether and 74 ml (0.46 mol) of tin tetrachloride are again added dropwise at 0° C. and the mixture is stirred overnight at +25° C. The reaction mixture is added to ice/hydrochloric acid, and the organic phase is separated off, washed with water and dried using sodium sulphate. After concentrating, the residue is taken up with petroleum ether, filtered through 1 kg of silica gel (230-400 mesh) and distilled in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Yield: 62 %

Procedure:
A mixture of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (530 mg, 2.431 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (848 mg, 2.431 mmol) in chloroform (20 ml) and MeOH (1 ml) was stirred for 2 h before addition of NaBH(OAc)3 (1.546 mg, 7.293 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (833 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1OC)[CH:6]=[O:7].B(Br)(Br)Br.[OH2:23]>ClCCl>[OH:23][C:4]1[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1O
Temperature: -78 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
3,5-Bis(trifluoromethyl)anisaldehyde (prepared as in Sui and Macielag, Synth. Commun. 1997, 27, 3581-3590, which is expressly incorporated by reference herein; 2.0 grams (g), 7.7 millimoles (mmol)) was dissolved in dry dichloromethane (CH2Cl2; 15 milliliters (mL)), cooled to −78° C. and treated in portions with boron tribromide (BBr3, 1 M solution in CH2Cl2; 8.0 mL, 8.0 mmol). The mixture was stirred and allowed to warm to 25° C. After 20 hours (h), the mixture was cooled to −40° C., carefully treated with H2O (10 mL) and warmed to room temperature. The separated organic phase was washed with water (H2O; 10 mL), saturated (satd) sodium chloride (NaCl) solution (5 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with a 0 to 20% gradient of ethyl acetate (EtOAc) in hexane to give the purified aldehyde (1.4 g, 70%) as an oil: 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 10.02 (s, 1H), 8.07 (s, 2H). EIMS m/z 258.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH:32]1([NH:35][C:36](=[O:44])[C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40])[CH2:34][CH2:33]1>>[Cl:28][C:24]1[CH:25]=[C:26]([F:27])[C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]3[C:29]([NH:42][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:37](=[O:43])[C:36]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:44])=[O:31])=[O:17])[CH2:19][CH2:20]2)=[N:22][CH:23]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CC(C)[C@H](N)C(=O)C(=O)NC1CC1
Product: CC(C)[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-4-methyl-2-oxo-pentanoic acid cyclopropylamide in step 1. MS (m/e)=653.14 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[O:12]=[C:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH:3]=[C:2]1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1coc2ccccc2c1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1coc2ccccc2c1=O)C(=O)OCC
Temperature: 140 °C
Yield: 62.2 %

Procedure:
A mixture of 3-aminochromone (8.0 g, 0.05 mole) and diethyl ethoxymethylenemalonate (17.3 g, 0.08 mole) was heated under nitrogen at 140° C. for 2.5 hrs. The reaction mixture was cooled. The product, which crystallized out was filtered off and triturated with petroleum ether. Recrystallization from ethyl acetate - absolute ethanol gave white crystals (10.3 g, 62.5%), m.p. 155°-157° C.
Reaction SMILES: C(N1[CH2:8][CH2:7]CCC1)=O.Cl.[Br:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=[O:17].S(C1C=CC(C)=CC=1)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)CO>[Br:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]1[O:19][CH2:8][CH2:7][O:17]1
Reactant: O=Cc1sccc1Br
Reactant: O=CN1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: Brc1ccsc1C1OCCO1

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: ClC1C=C(NC2C=CC(C(F)(F)F)=CC=2)C=CC=1C(C1C=C([N+]([O-])=O)C=CC=1C)=O.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[CH3:49])=[O:39])=[C:34]([Cl:50])[CH:33]=1.[Cl:51][C:52]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:53]=1[NH2:54]>>[Cl:50][C:34]1[CH:33]=[C:32]([NH:54][C:53]2[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:52]=2[Cl:51])[CH:37]=[CH:36][C:35]=1[C:38]([C:40]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=1[CH3:49])=[O:39]
Reactant: Nc1ccc(F)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.28 mmol) and 2-chloro-4-fluoroaniline (0.28 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.[CH3:18][C:19]([CH3:21])=O>O1CCCC1>[CH:19]([NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1)([CH3:21])[CH3:18]
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NCC1CNC(=O)c2cccc3[nH]cc1c23
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
0.82 g of borane-dimethylamine complex was added to a stirred solution of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole hydrate (see Example 1C for preparation) in 80 ml of tetrahydrofuran. The solution was heated under reflux for 1 hour and subsequently, at a temperature of 45° C., 10 ml of acetone were added dropwise. The reaction mixture was stirred at a temperature of 60° C. for 2.5 hours. To work up the reaction mixture it was subsequently evaporated to dryness, and the residue was dissolved in a mixture of water and dichloromethane. The dichloromethane phase was separated, and the aqueous phase was extracted three more times with 50 ml portions of a 9:1 dichloromethane/methanol mixture. The organic phases were combined and evaporated to dryness. The crude product which remained as residue was purified by chromatography under slightly elevated pressure (=flash chromatography) on silica gel using methanol/ethyl acetate 4:1 as eluent. The title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.P(Br)(Br)[Br:12].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:12][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CC(O)c1ccc(Cl)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of the above product 1-(4-chlorophenyl)ethanol in 100 ml of diethyl ether was slowly added a solution of 13.5 g (50 mmoles) of phosphorus tribromide in 50 ml of diethyl ether. The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into ice water. Sodium hydrogencarbonate was added to the resulting solution for neutralization, and the organic layer was extracted with diethyl ether. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate and concentrated in a vacuum, giving 9.00 g (41 mmoles, 82% in yield) of 1-(1-bromoethyl)-4-chlorobenzene [1H-NMR (300 MHz, CDCl3) 2.02 (d, J=6.9 Hz, 3H), 5.1 (q, J=6.9 Hz, 1H), 7.26-7.40 (m, 4H)] in a nearly pure form.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([O:12][C:13]([C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=3[CH:23]=[C:22]([C:31](O)=[O:32])[CH:21]=2)=[CH:17][C:16]=1[F:36])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:14])[C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:29])([CH3:30])[O:28][C:24]=3[CH:23]=[C:22]([C:31](=[O:32])[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)[CH:21]=2)=[CH:17][C:16]=1[F:36])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)OC(C)(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 15 except that the reaction was carried out at 75° C. for 2 hr, from 1-methyl-3-aminopyrazole (892 mg, 9.18 mmol) and 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (66b) (2.46 g, 6.11 mmol) to give a white solid (1.77 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H) 7.87 (t, J=8.59 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (s, 1 H) 7.04 (s, 1 H) 6.79 (d, J=2.02 Hz, 1 H) 6.75 (dd, J=8.84, 2.27 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1H) 3.80 (s, 3 H) 2.87 (s, 2 H) 1.60 (s, 9 H) 1.49 (s, 6H); LCMS for C26H28FN3O5 m/z 505.00 (M+Na)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[N:6][N:5]=[N:4]1)[CH3:2].[CH2:19]([N:21]1[N:25]=[N:24][C:23]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)=[N:22]1)[CH3:20]>C(O)(=O)C>[CH2:1]([N:3]1[C:7]([CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[N:6][N:5]=[N:4]1)[CH3:2].[CH2:19]([N:21]1[N:25]=[N:24][C:23]([CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)=[N:22]1)[CH3:20]
Reactant: CCn1nnc(CSc2ccc([N+](=O)[O-])cc2)n1
Reactant: CCn1nnnc1CSc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: CCn1nnc(CSc2ccc(N)cc2)n1
Product: CCn1nnnc1CSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 1-ethyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole and 2-ethyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (4.2 g) was added acetic acid (42 ml), reduced iron (12.6 g) was added to the mixture, and the mixture was stirred for 40 hours at room temperature. The mixture was filtered with Celite, and the mixture was washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and the mixture was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(1-ethyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (1.1 g) and 4-[[(2-ethyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (2.2 g).
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[CH2:1]([C:3]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:15][CH2:16][OH:17])[C:4]1=[O:12])[CH3:2]
Reactant: CCC1(C)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CCC1(C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-ethyl-3-methylindol-2(3H)-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described in above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:22]=1[N+:28]([O-:30])=[O:29]>CS(C)=O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=2[N+:28]([O-:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.204 g, 1.1 mmol) in 1 mL dimethylsulfoxide was added potassium carbonate (0.303 g, 2.2 mmol) followed by 1,3-difluoro-2-nitro-benzene (0.159 g, 1 mmol). The solution was stirred 30 minutes at room temperature, and was then diluted with 50 mL ethyl ether. The organic phase was washed three times with 50 mL water and once with 50 mL brine, dried over sodium sulfated, and concentrated in vacuo to give 0.314 g (0.965 mmol, 96.5%) of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. MS: 226 (M−BOC+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([S:49][CH2:50][CH3:51])=[N:47][N:48]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:43][C:44]2[S:45][C:46]([S:49][CH2:50][CH3:51])=[N:47][N:48]=2)=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCSc1nnc(N)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCSc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethylthio-1,3,4-thiadiazole (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 31 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[OH:28])[CH:21]=[CH:20][C:19]=1[OH:29].N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[NH:18][C:19](=[O:29])[CH:20]=[CH:21]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccc(O)c2n1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.10 g, 0.39 mmol) and 2,8-quinolinediol (0.075 g, 0.46 mmol, Fluka) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.069 mL, 0.46 mmol, Aldrich). The mixture was heated to reflux for 6 h, allowed to cool to room temperature, and diluted with EtOAc. The solids were filtered, washed with EtOAc and dried in vacuum for 16 h to yield the title compound as long white needles. Mp: 312° C., MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH2:16][OH:17])=[C:9]4[CH:18]=[CH:19][N:20]=[CH:21][C:8]4=[C:7]([CH3:22])[C:6]=3[C:5]=2[CH:4]=1.CC(C)=O.[CH3:27][N:28]=[C:29]=[O:30].OCC1C2NC3C=CC=CC=3C=2C(C)=C2C=NC=CC=12>N1C=CC=CC=1>[CH3:27][NH:28][C:29](=[O:2])[OH:30].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH2:16][OH:17])=[C:9]4[CH:18]=[CH:19][N:20]=[CH:21][C:8]4=[C:7]([CH3:22])[C:6]=3[C:5]=2[CH:4]=1
Reactant: CN=C=O
Agent: COc1ccc2[nH]c3c(CO)c4ccncc4c(C)c3c2c1
Agent: Cc1c2cnccc2c(CO)c2[nH]c3ccccc3c12
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CNC(=O)O

Procedure:
The above alcohol 36 was dissolved in dry pyridine and dry acetone and treated with methyl isocyanate as in the case of the carbinol 25. The mixture was stirred until no further alcohol 36 could be detected on thin layer chromatography. The solvents were evaporated and the residual solid was crystallized from ethyl acetate-methanol to give the desired carbamate 37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)N3CCOCC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 14.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.060 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.098 g, 0.304 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and morpholine (0.062 g, 0.304 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.41 (s, 6H), 2.96 (s, 2H), 3.37 (s, 4H), 3.56 (s, 4H), 6.64 (s, 1H), 8.40 (s, 2H), 10.82 (s, 1H), 11.26 (s, 1H); MS [M+H]+: 462.23.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:24][CH3:25])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>N1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:13][CH:14]=2)[N:9]([CH2:24][CH3:25])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCS(=O)(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(NS(=O)(=O)CC)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 μL, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg, 83%).