Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:4][C:5]([N:8](S(C)(=O)=O)[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:17]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:4][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N(c1cc(C(c2cc(C#N)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(c2cc(C#N)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
After N-[5-chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-fluorophenyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide (80 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 ml), a tetrahydrofuran solution (1.0M, 0.15 ml, 0.15 mmol) of tetrabutylammonium fluoride was added to the resulting solution at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to silica gel chromatography. The fraction obtained from the n-hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to afford a white solid. The resulting white solid was washed with ether to give the title compound (32 mg, 0.06 mmol, 46%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]#[N:30])=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21].N1C=CC=C(C)C=1.CS(Cl)(=O)=O.Cl>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:24][C:25]([C:29]#[N:30])=[CH:26][C:27]=2[CH3:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CNC(=O)c1cc(C#N)cc(C)c1N
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: Cc1cccnc1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -12 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (20.6 kg) and 2-amino-5-cyano-N,3-dimethylbenzamide (14.1 kg) in acetonitrile (114 kg) was added 3-picoline (22.2 kg). The mixture was cooled to −10 to −14° C., and then methanesulfonyl chloride (10.6 kg) was slowly added so that the temperature did not exceed 5° C. After reaction completion as ascertained by HPLC and NMR analyses, the mixture was worked up by successively adding water (72.6 kg) and concentrated hydrochloric acid (7.94 kg) at such a rate that the temperature did not exceed 5° C. After being maintained at a temperature not exceeding 5° C. for about 30 minutes, the reaction mixture was filtered to collect the solid product, which was successively washed with acetonitrile-water (2:1, 2×12.3 kg) and acetonitrile (2×10.4 kg). The solid was then dried at about 50° C. under reduced pressure and a flow of nitrogen gas to give the title product as a white crystalline solid, which was directly used in the present formulation Examples and Comparative Examples. With a moderate rate of heating (heating to about 150° C. over 5 minutes and then decreasing rate of heating from about 4-5° C./minute to about 3° C./minute to reach 210° C. over about 15 minutes more) to facilitate volatilization of loosely entrained solvents from the solid product, melting occurred in the range between 204 and 210° C.
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C=CC(OC(F)(F)F)=CC=3)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:47]2([CH2:71][CH2:70][C:50]3([O:55][C:54](=[O:56])[N:53]([C@H:57]([C:59]4[CH:64]=[CH:63][C:62]([O:65][C:66]([F:69])([F:68])[F:67])=[CH:61][CH:60]=4)[CH3:58])[CH2:52][CH2:51]3)[CH2:49][CH2:48]2)[O:46]C1>>[F:69][C:66]([F:67])([F:68])[O:65][C:62]1[CH:63]=[CH:64][C:59]([C@@H:57]([N:53]2[CH2:52][CH2:51][C:50]3([CH2:49][CH2:48][C:47](=[O:46])[CH2:71][CH2:70]3)[O:55][C:54]2=[O:56])[CH3:58])=[CH:60][CH:61]=1
Reactant: C[C@@H](c1ccc(OC(F)(F)F)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(OC(F)(F)F)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-(4-trifluoromethoxy-phenyl)-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-(4-trifluoromethoxy-phenyl)-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 57% of theory; LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=372 [M+H]+.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[S:29])=[CH:26][CH:25]=1>C(O)(C)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:28]([C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CC(C)O
Product: COc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccc(S(C)(=O)=O)cc3)s2)cc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 2-bromo-1- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) ethanone (Example 26, Step 2) (0.500 g, 1.35 mmol) in isopropanol (10 mL) in a 25 mL round bottom flask was added p-methoxythiobenzamide (0.230 g, 1.35 mmol). The solution was heated to reflux for 30 hours and cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(4-methoxyphenyl)thiazole (0.360 g, 61%) as a crystalline solid: mp 187°-189° C., 1HNMR (CDCl3) 300 mHz 7.99 (d, 8.82 Hz, 2 H), 7.93 (d, J=8.50 Hz, 2 H), 7.63-7.53 (m, 4 H), 7.09 (t, J=8.63 Hz, 2 H), 7.03 (d, J=8.82 Hz, 2 H), 3.92 (s, 3 H), 3.13 (s, 3 H); MS m/z 440 (M+H). HRMS Δ=2.0 mmu.
Reaction SMILES: Br.C[N:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[C@H:5]([CH2:17][O:18][CH2:19][CH3:20])[CH2:4]1.ClC(OC(Cl)=O)C.[OH-].[Na+].N>CO.C(Cl)Cl>[CH2:19]([O:18][CH2:17][C@H:5]1[C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:7][CH2:8][NH:3][CH2:4]1)[CH3:20]
Reactant: CCOC[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: Br
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCOC[C@@H]1CNCC[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of (13) 0.70 g and 1-chloroethylchloroformate (2.5 ml) was stirred at 100° C. for 2 days where after 4 N NaOH (25 ml) was added. The mixture was stirred with reflux overnight. After cooling, the mixture was extracted with toluene. The organic phase was dried and evaporated to give an oil which was subjected to column chromatography (SiO2, methylene chloride, MeOH, ammonia 9:1:1%) to give the product as pale crystals. Mp 68-70° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH2:17])[CH3:16]>CN(C)C=O>[CH2:15]([NH:17][C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:16]
Reactant: CCN
Reactant: Clc1nc2ccccc2n2cnnc12
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) in N,N-dimethylformamide (30 ml.) was saturated with monoethylamine gas and stirred at room temperature for 2 hours. Monoethylamine gas was again bubbled through the mixture and stirring was continued for 2 hours. The precipitate was removed by filtration and washed with N,N-dimethylformamide. Recrystallization from methanol afforded 680 mg. (32% yield) 4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 254°-256° C. Mass spectrum: m/e, 213 (P).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(OC1C=C(CC(O)=O)C=CC=1C(OCC)=O)C>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(=CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate, melting point 125-126° C., which in turn was prepared from (2-piperidino-phenyl)-isobutyl-ketimine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid analogous to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5](OC)=[O:6].O.[NH2:14][NH2:15].Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: NN
Agent: Cl
Solvent: O
Product: NNC(=O)c1ccc(O)c(F)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
10.00 g (58.8 mM) of methyl 3-fluoro-4-hydroxybenzoate and 17.5 ml of 80%-hydrazine hydrate were mixed and stirred for 1 hour and 20 minutes at 100° C., followed by cooling to room temperature. The resultant mixture was poured into 150 ml of iced water and 16.8 ml of concentrated hydrochloric acid was added thereto (pH=about 8), followed by addition of common salt and stirring at room temperature to precipitate a crystal. The crystal was recovered by filtration and stirred in methanol at room temperature. The resultant crystal was recovered from the above mixture by filtration to obtain 9.26 g of 3-fluoro-4-hydroxybenzohydrazide (Yield: 92.6%).
Reaction SMILES: NN1C(C)=NN=N1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH+]1C=CC=CC=1>C(O)C>[CH3:18][C:8]1[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1nnnn1N
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
2,2′-[[3-[N-(3-Hydroxypropyl)-N-methylamino]phenyl]methylene]bis[4-[[(5-methyl-1H-tetrazol-1-yl)imino]methyl]]phenol. 1-Amino-5-methyltetrazole (71 mg, 0.72 mmol) and pyridinium para-toluenesulfonate (6 mg, 0.024 mmol) were dissolved in absolute ethanol (10 ml) and heated to reflux for 15 minutes. Compound 37(f) (0.17 g, 0.41 mmol) in ethanol (6 ml) was added dropwise to the solution. The reaction was stirred at reflux for 3 hours, and then cooled to room temperature overnight. The solvent was removed in vacuo and diluted with t-butyl methyl ether to provide the tosic acid salt, which was isolated by filtration and dried in vacuo. This solid was treated with sodium bicarbonate (20 mg) in water (6 to 7 ml) and ethyl acetate to form the free base. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered, and concentrated by rotary evaporation to provide 0.12 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl.O>[C:21]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])(=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (200 mg, 0.689 mmol) in dichloromethane (4 mL) was added isobutyryl chloride (0.08 mL, 0.76 mmol, 1 equiv.) and TEA (0.23 mL, 1.72 mmol, 2.5 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then diluted with dichloromethane and water. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography (silica gel, EtOAc/hexanes) to afford tert-butyl (2-isobutyramido-4-(thiophen-2-yl)phenyl)carbamate (0.2 g, 81% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CNc1ccc(CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1ccc(CC(=O)O)cc1
Reaction time: 3 h
Yield: 46.8 %

Procedure:
Methyl 2-(4-(methylamino)phenyl)acetate (721 mg, 4.0 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with a 1 M aqueous solution of lithium hydroxide (4.4 mmol). After 3 hours, the mixture was acidified with 1 N aqueous hydrochloric acid and concentrated to remove tetrahydrofuran. The aqueous phase was extracted with dichloromethane (2×20 mL) and the organic layer was dried and concentrated to give 2-(4-(methylamino)phenyl)acetic acid (309 mg, 1.87 mmol).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[NH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:3]1
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: c1cc(NC2CCCNC2)ccn1

Procedure:
Reaction of tert-butyl 3-oxopiperidine-1-carboxylate and 4-aminopyridine using the method of Example 3 followed by deprotection using the method of Example 4 affords the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]#[N:10].[BH4-].[Na+].O>CC(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]#[N:10]
Reactant: N#C/C=C/c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: N#CCCc1ccccn1
Temperature: 80 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
(E)-3-(2-Pyridyl)acrylonitrile (0.50 g, 3.8 mmol) was dissolved in 2-propanol (10 ml), and sodium borohydride (0.50 g, 13.2 mmol) was added thereto. The reaction mixture was stirred at 80° C. for 14 hrs and cooled under ice cooling condition, combined with water, concentrated to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.42 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28]I)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)CCC(CCCI)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1

Procedure:
To a solution of 0.32 g (0.57 mmol) of t-butyl 8-(p-chlorophenylsulfonamido)-4-(3-iodopropyl)-octanoate in 3 ml dry dimethylformamide is added 0.116 g (1.7 mmol) imidazole and the mixture is then refluxed with ethyl acetate and washed with water and brine. The organic layer is dried, filtered, concentrated and then subjected to chromatography using ethyl acetate as eluent to yield t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]-octanoate; IR (neat): 1718, 1337, 1164 cm-1 ; NMR (CDCl3): delta 7.5 (br,1H), 7.1 (s,1H), 6.9 (s,1H), 4.2 (t,2H).
Reaction SMILES: [CH2:1]([S:13](Cl)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[NH:23][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH2:34])[CH:33]=1)=[CH:21]2.O.Cl>N1C=CC=CC=1>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[NH:23][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH:34][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:33]=1)=[CH:21]2
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(-c2cc3cc(F)c(F)cc3[nH]2)ccc1OC
Yield: 44.9 %

Procedure:
1-Dodecanesulfonyl chloride (0.3 g, 1.1 mmol) was added to a stirred solution of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl-amine from Example 3 (0.3 g, 1.11 mmol) in pyridine (3 mL) under an inert atmosphere at room temperature. After approximately 20 hours the mixture was poured into water (30 mL), stirred, and acidified with aqueous HCl. After several hours the precipitate was filtered off, rinsed three times with water, and dried. Recrystallization from ethanol afforded the product (0.25 g), mp 148-149° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[CH:12])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]([CH2:10][C:11]#[CH:12])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[O:9])[N:7]=1
Reactant: C#CCN(C)c1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C#CCN(C)c1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
2-(N-Methyl-2-propynylamino)-4-hydroxymethylthiazole (i) (4.36 g) was dissolved in methylene chloride (20 ml) and manganese dioxide (10 g) was added thereto. The mixture was stirred at room temperature for 16 hours and filtered off. The filtrate was evaporated and the residue was applied to column chromatography on silica gel (50 g) to give 2-(N-methyl-2-propynylamino)-4-formylthiazole (j) (2.56 g, yield 59%) from chloroform-ether (3:1) eluate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][NH:10][CH2:11][CH3:12].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]Br.CN(C)C=O>[CH2:11]([N:10]([CH3:9])[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: Brc1ccc(I)cc1
Reactant: CCNC
Agent: [Cu]Br
Agent: O=P([O-])([O-])[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CN(C)C=O
Product: CCN(C)c1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A mixture of 1-bromo-4-iodobenzene (2.0 g, 7.07 mmol), N-methylethylamine (3.0 ml, 35.3 mmol), copper(I) bromide (203 mg, 1.41 mmol), 1,1′-bi-2-naphthol (405 mg, 1.41 mmol), tripotassium phosphate (3.0 g, 14.1 mmol) and anhydrous N,N-dimethylformamide (20 ml) was stirred at 70° C. for 2 days. After cooling to room temperature, the mixture was filtered through a Celite pad, and the insoluble material was washed with ethyl acetate. The filtrate and washing solution were combined and washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100→2:98) to give N-ethyl-4-bromo-N-methylaniline (1.04 g, yield 69%) as a yellow oil.
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([CH3:29])[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH:14]=2)=[CH:9][CH:8]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:33])=O>ClCCl>[CH3:29][N:20]([CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([Cl:33])=[O:4])=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=1)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(Cc1cccc(-c2ccc(CCC(=O)Cl)cc2)c1)C(=O)c1ccccc1

Procedure:
By reacting 1.6 g (4.1 mmol) of 2-methyl-3-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-yl)propionic acid with 390 μl (4.5 mmol) of oxalyl chloride in dichloromethane, and after evaporation, 1.7 g (100%) of 3-(3′-{[methyl-(1-phenylmethanoyl)-amino]methyl}biphenyl-4-yl)propionyl chloride are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[N:13]1([CH2:18][CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:17]=[CH:16][N:15]=[N:14]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:19][CH2:18][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: C=CCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CSCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a mixture of 13.0 g (50.5 mmol) (4-allyloxy-phenyl)-methanethiol and 13.5 g (50.5 mmol) toluene-4-sulfonic acid 2-[1,2,3]triazol-1-yl-ethyl ester in 125 ml N,N-dimethylformamide was added under argon at −30° C. 2.42 g (101 mmol) sodium hydride. The mixture was allowed to warm up to room temperature and was stirred under argon for 12 hours. After quenching with 100 ml water, the mixture was diluted with dichloromethane, washed with water, dried and evaporated. Purification on silica after elution with ethyl acetate/heptane 1:1 yielded 12.0 g (86%) 1-[2-(4-allyloxy-benzylsulfanyl)-ethyl]-1H[1,2,3]triazole as slightly yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([S:21][CH3:22])[N:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O1CCCC1>[NH2:20][CH2:19][C:18]1[C:13]([NH:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:14][C:15]([S:21][CH3:22])=[N:16][CH:17]=1
Reactant: CSc1ncc(C#N)c(NC2CCCC2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ncc(CN)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a stirred 0° C. suspension of 1.7 g (44.8 mmol) of LAH in 70 mL of tetrahydrofuran is added dropwise a solution of 5.0 g (21.3 mmol) of 4-(cyclopentylamino)-2-(methylthio)-5-pyrimidinecarbonitrile in 250 mL of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature overnight. The mixture is recooled to 0° C., and treated with a saturated solution of ammonium sulfate until there is no more effervescence. After stirring for another 15 minutes, the gray solids are filtered and washed four times with hot ethyl acetate. The combined organic washes are concentrated, and the residue is chromatographed on silica gel eluting with 1:1:8 methanol/hexane/chloroform to obtain 4.0 g (79%) of the title compound: mp 58-60° C.