Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1>>[Br:6][C:7]1[S:8][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:10]([Br:12])[N:11]=1
Reactant: Brc1csc(Br)n1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1sc(Br)nc1Br
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
To a flask containing chlorosulfonic acid (51.0 mL, 767 mmol) was added 2,4-dibromothiazole (10.2 g, 42.0 mmol) with stirring over 15 minutes. The resulting solution was heated to 150 degrees overnight. The reaction was quenched by carefully and slowly pouring onto ice (500 mL). The resulting precipitate was extracted with ethyl acetate (2×200 mL) and the combined organic layers were washed with water, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→15/85) to give 8.1 g (56% yield) of the title compound as a yellow oil which partially solidified. 13C NMR (400 MHz, CDCl3) δ: 145.04, 138.78, 131.81.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[C@H:26]([OH:30])[CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[CH3:32]I>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[C@H:26]([O:30][CH3:32])[CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CI
Product: CO[C@@H](C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C(C)C

Procedure:
The title compound, white solid (6 mg, 50.5%), MS (ISP) m/z=446.3 [(M+H)+], was prepared in accordance with the general method of example 62 from (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide (11.5 mg, 26.6 mmol) and methyl iodide.
Reaction SMILES: Br[C:2]1[N:27]=[C:5]2[CH2:6][CH:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]3[S:20][CH:21]=[C:22]([CH:24]([F:26])[F:25])[N:23]=3)=[O:12])[CH2:8][CH2:9][N:4]2[N:3]=1.[CH3:28][O:29][CH2:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>C(OCC)(=O)C>[F:25][CH:24]([F:26])[C:22]1[N:23]=[C:19]([C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:11]([NH:10][CH:7]2[CH2:8][CH2:9][N:4]3[N:3]=[C:2]([N:32]4[CH2:33][CH2:34][CH2:35][C@@H:31]4[CH2:30][O:29][CH3:28])[N:27]=[C:5]3[CH2:6]2)=[O:12])[S:20][CH:21]=1
Reactant: Cn1ncc(-c2nc(C(F)F)cs2)c1C(=O)NC1CCn2nc(Br)nc2C1
Reactant: COC[C@H]1CCCN1
Solvent: CCOC(C)=O
Product: COC[C@H]1CCCN1c1nc2n(n1)CCC(NC(=O)c1c(-c3nc(C(F)F)cs3)cnn1C)C2
Temperature: 150 °C

Procedure:
The N-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (20 mg) obtained in (Example 5.16) <Step 7> and (R)-2-(methoxymethyl)pyrrolidine (0.5 ml) were heated at 150° C. for 4 days. Thereafter, ethyl acetate (50 ml) and a saturated saline (20 ml) were added to the reaction solution, and an organic layer was then extracted. The obtained organic layer was dried over sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by preparative thin-layer chromatography (silica gel: eluent; ethyl acetate), so as to obtain the title compound (2.1 mg) in a yellow amorphous form.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.C([O-])(=[O:12])C.[Na+]>C(O)(=O)C>[OH:12][C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CSc1ccc(Cl)nn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1ccc(O)nn1
Yield: 65.4 %

Procedure:
A solution of 96 g (0.6 mol) of 3-chloro-6-methylthiopyridazine and 98.4 g (1.2 mols) of sodium acetate in 500 ml of glacial acetic acid was boiled for 2 hours under reflux. The solvent was then distilled off in vacuo, the residue was triturated with water and the reaction product was filtered off. In this way, 55.8 g (65% of theory) of 3-hydroxy-6-methylthiopyridazine were obtained in the form of a beige powder of melting point 119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].N12CCCN=C1CCCCC2>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:11]([O-:13])=[O:12])[CH2:16][CH2:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC[N+](=O)[O-])c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.2 %

Procedure:
To a solution of 1-methoxy-3-(2-nitroethyl)benzene (22.59 g) and tert-butyl acrylate (15.98 g) in dichloromethane (180 ml) was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.90 g) in dichloromethane (45 ml) in an ice bath. After stirring for 18.5 hours at ambient temperature, ice water (70 ml) was added to the solution. The organic layer was separated, washed successively with 1N hydrochloric acid, and brine. The solution was treated with silica gel (70 g) and evaporated in vacuo to give tert-butyl 5-(3-methoxyphenyl)-4-nitrovalerate (29.39 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Li+].[CH3:22][O:23][CH2:24]OC>>[CH3:22][O:23][CH2:24][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Product: COCOCCc1cccs1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
150 g of 2-thiopheneethanol was dissolved in 2,250 mL of dimethoxymethane, and 22.3 g of p-toluenesulfonic acid and 20.3 g of lithium chloride were added thereto. The resulting mixture was refluxed for 5 hours and concentrated by evaporation under reduced pressure. To the residue, 1,000 mL of water and 1,500 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 193 g (yield of 96%) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11](=[S:14])([S-:13])[NH2:12].[NH4+]>C(O)C>[CH3:10][C:8]1[NH:12][C:11](=[S:13])[S:14][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1sc(=S)[nH]c1C
Yield: 40.5 %

Procedure:
A solution of ethyl 2-chloroacetoacetate (5 g) and ammonium dithiocarbamate (3.37 g, prepared as reported in Synthesis (1985), (10), 948-9) in ethanol (20 mL) was refluxed overnight. The solvent was evaporated under vacuum and the crude product purified by flash chromatography on silica gel (eluting with cyclohexane:ethyl acetate from 1:0 to 7:3) to give the title compound (2.5 g). MS (m/z): 204 [MH]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](OCC)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[O:28].O>CN(C)C=O>[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]/[C:14](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:33][CH:32]=1)=[O:28]
Reactant: CN(C)C(=O)CNc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CNc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
6.0 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-2-indolinone (educt IX) and 3.9 g of N-(dimethylcarbamoylmethyl)-p-phenylenediamine (educt XV.208) are dissolved in 50 ml of dimethylformamide and stirred for 4.5 hours at 120° C. After cooling water is added, the precipitate formed is suction filtered and washed with methanol. The product is purified through a silica gel column with methylene chloride/methanol (100:1) as eluant and finally recrystallised from ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]>CCO.O.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccc(O[C@@H](C)C(=O)OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccc(O[C@@H](C)C(=O)O)cc1)OCC
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of (R,S)-3-[4-(1-benzyloxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.05 g, 2.63 mmol) in EtOH (20 ml) and H2O (0.5 ml) was added a slurry of Pd—C (5%, 100 mg) in EtOH (10 ml). The suspension was hydrogenated under balloon pressure for 2 hours. The mixture was filtered through a pad of celite and concentrated to a residue, the residue was then purified by silica gel chromatography with EtOAc/Hexanes (25% to 100%) to afford the acid product (550 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:21][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoic acid (3.0 g, 8.67 mmol) in a mixture of THF (15 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.63 ml, 2 M in Hexanes, 11.3 ml). After stirring for 4 h, the reaction was quenched with AcOH and diluted with EtOAc (100 ml). The organic solution was washed with H2O (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated to dryness to give 2.83 g (91%) of methyl 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoate as a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.C[C:31]1[O:35][C:34]([C:36]2C=C(C=CC=2)N)=[CH:33][CH:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:31]3[O:35][C:34]([CH3:36])=[CH:33][CH:32]=3)[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1ccc(-c2cccc(N)c2)o1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1ccc(-c2cccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)c2)o1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methylfuran-2-yl)aniline in step 1. MS: 407.5 (M+H).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].CC(C)=O.C(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C@:32]1([CH2:2][C:1]([O:4][CH3:5])=[O:3])[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetate (0.25 mL, 3.2 mmol) was dissolved in THF (3 mL) under an atmosphere of Ar and cooled to −78° C. (acetone/dry ice). A solution of LHMDS (3.13 mL, 1M/THF) was added dropwise. After 15 minutes, a solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (5, 1.35 g, 2.5 mmol) in THF (7 mL) was added dropwise. After 3 hr, the reaction mixture was quenched with NH4Cl (aq), warmed to room temperature and extracted with EtOAc (1×). The organic layer was washed with brine (1×), dried (Na2SO4), and concentrated to a syrup (1.4 g, 92%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.15-7.31 (m, 20H), 2.26 (d, J=1.5 Hz, 1H), 4.81-4.97 (m, 4H), 4.45-4.66 (m, 4H), 3.98 (m, 1H), 3.58-3.75 (m, 7H), 3.31 (dd, J=9.6, 1.5 Hz, 1H), 2.73 (d, J=15.6 Hz, 1H), 2.30 (d, J=15.6 Hz, 1H). LC/MS tR=3.16 min, calcd for C37H40O8: 612.27, found 635.6 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([OH:17])[CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:17][C:20](=[O:22])[CH3:21])[CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc([C@H](O)C[C@@H]2CCCN2C)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc([C@@H](C[C@@H]2CCCN2C)OC(C)=O)c1

Procedure:
3,5 g of (R*,S*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 40 ml of acetic acid anhydride are stirred for 15 minutes at room temperature. 6 N sodium hydroxide solution is added with cooling up to a pH of 8-9. The mixture is extracted with diethyl ether, and the organic layer is concentrated to the oily title compound. The hydrochloride (from methanol/diethyl ether) melts at 155°-157°.
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH3:30])=[C:20]=[S:21]>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:19][C:20]([NH2:1])=[S:21])=[C:23]([CH3:30])[CH:24]=1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(N=C=S)c(C)c1
Product: COc1ccc(NC(N)=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-isothiocyanato-4-methoxy-2-methyl-benzene. Title compound: ES-MS: 196.9 [M+H]+; single peak at tR=2.46 min (System 2).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]([C:31](=[O:34])[CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:26][C:20]=3[CH2:19][S:18](=[O:37])(=[O:36])[C:17]=2[CH:38]=1)=[O:12]>CN(C=O)C>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]4[CH2:28][CH2:29][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:32][C:31]4=[O:34])=[CH:26][C:20]=3[CH2:19][S:18](=[O:36])(=[O:37])[C:17]=2[CH:38]=1)=[O:12]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzylamine (0.17 mL, 1.581 mmol) was added to a solution of Example 57k (0.4 g, 0.79 mmol) in DMF (5 mL) and stirred at 80° C. for 5 h. The reaction mixture was concentrated, treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried and concentrated to obtain the crude title compound which was purified using flash chromatography (silica gel, 1% methanol/chloroform). Yield: 125 g, (29.2%); 1H NMR (DMSO-d6,): δ 2.68 (s, 3H, CH3), 2.8 (t, 2H, CH2), 3.2 (s, 2H, CH2), 3.63 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 5.31 (s, 2H, CH2), 7.29-7.38 (m, 5H, Ar), 7.66 (s, 1H, Ar), 7.73 (s, 1H, Ar), 8.16 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 541 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:45]([OH:47])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:48][CH2:49][CH:50]([CH2:52]O)[OH:51].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:45]([O:47][CH2:52][CH:50]([OH:51])[CH2:49][OH:48])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:38])[CH2:25][CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27]2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: OCC(O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC2C=Nc3ccccc32)NS(=O)(=O)c2ccccc2)C(=O)OCC(O)CO)cc1
Yield: 79.3 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(N′α-benzenesulfonyl-L-tryptophanyl)-L-lysine (170 mg, 0.25 mmol) dissolved in a solution of DMF (1 mL) was treated with glycerol (100 μL, 1.37 mmol) and EDC (100 mg, 0.5 mnol) and stirred overmght. Them, the solution was poured in 5% citric acid and extracted with EtOAc. The solvent was evaporated and the residue purified by preparative HPLC to give 150 mg (79%) of the final product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].Cl[CH2:31][O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:31][O:32][CH2:33][N:11]1[C:10](=[O:21])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]2[N:18]=[CH:19][N:20]=[C:12]12
Reactant: COCCl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(COC)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), chloro(methoxy)methane (0.12 mL), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% 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 column chromatography to give the title compound as a colorless solid (0.38 g, 69%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:17])([F:18])[F:19])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20])=[O:31]
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S(=O)CC(F)(F)F
Yield: 37.2 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the present invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([NH:47][C:48]2[S:49][CH:50]=[CH:51][N:52]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1nccs1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of triphenylphosphine (847 mg, 3.2 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (575 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-acrylic acid (507 mg, 1.9 mmol) in methylene chloride (4 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (476 mg, 4.75 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (75 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (2×30 mL), a saturated aqueous sodium bicarbonate solution (2×30 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 4/1 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-N-thiazol-2-yl-acrylamide (520 mg, 78%) as an amorphous solid: EI-HRMS m/e calcd for C18H18F2N2OS (M+) 348.1108, found 348.1104.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([CH:11]3[CH2:10][CH2:9][C:8]4[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[CH2:13][CH2:12]3)[CH2:25][CH2:24]2)[CH2:19][CH2:18]1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(C3CCc4ccc([N+](=O)[O-])cc4CC3)CC2)CC1

Procedure:
1-Methyl-4-[1-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperidin-4-yl]-piperazine was prepared from 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 1-methyl-4-piperidin-4-yl-piperazine in an analogous manner to Example 178a. Product was isolated as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.97 (d, 1H, J=8.08 Hz), 7.24 (d, 1H, J=8.08 Hz), 2.95 (dd, 2H, J=7.32, 12 Hz), 2.84 (d, 2H, J=12 Hz), 2.74 (m, 3H), 2.60 (broad s, 4H), 2.47 (m, 3H), 2.29 (s, 5H), 2.11 (m, 2H), 1.82 (d, 2H, J=12 Hz), 1.67 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H).