Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc(Cl)ccc1C
Temperature: 0 °C

Procedure:
A mixture of 5-chloro-2-methylbenzoic acid (3.00 g, 17.5 mmol) in ethanol (30 mL) was cooled to 0° C. with an ice bath and thionyl chloride (12.5 mL, 105.5 mmol) was added dropwise, over 30 minutes. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath, and heated to 70° C. overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The solids obtained were then redissolved in diethyl ether (50 mL) and washed with 1 N sodium hydroxide (50 mL), brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to afford ethyl 5-chloro-2-methylbenzoate as a clear oil: 1H NMR (500 MHz, CDC13) δ 7.88 (d, J=2.5 Hz, 1H), 7.34 (dd, J=8.5, 2.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 4.36 (q, J=7.5 Hz, 2H), 2.56 (s, 3H), 1.39 (t, J=7.5 Hz, 3H); ESI MS m/z 199 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=O)[CH2:3][CH2:2]1.[F:14][C:15]([F:35])([F:34])[O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][NH2:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH:1]1([C:4](=[N:33][O:32][CH:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]([F:35])([F:14])[F:34])=[CH:22][CH:21]=3)(=[O:24])=[O:25])[CH2:31][CH2:30]2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: N#Cc1cccc(C(=O)C2CC2)c1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Product: N#Cc1cccc(C(=NOC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)C2CC2)c1

Procedure:
3-(Cyclopropanecarbonyl)benzonitrile was coupled with O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine to give 3-(cyclopropyl(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxyimino)methyl)benzonitrile as a mixture of stereoisomers.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:17])[N:14]=[N:15][CH:16]=2)=[C:7]([O:18][CH3:19])[CH:6]=1)=[C:3]=[S:4]>>[CH3:19][O:18][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[C:13]([CH3:17])[N:14]=[N:15][CH:16]=1
Reactant: COc1cc(N=C=S)ccc1-c1cnnc(C)c1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-c1cnnc(C)c1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Step L (5): Methanolic ammonia (2.0 M, 20 mL, 40 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylpyridazine (650 mg, 2.53 mmol). After 4 h, the reaction mixture was concentrated in vacuo to afford 1-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)thiourea (690 mg, 100% yield). LC-MS (M+H)+ 275.2.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([Br:18])=[CH:11]2)[S:5][CH3:6].[OH-].[Na+].Cl>C(O)C.O>[Br:18][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH:4]([S:5][CH3:6])[C:3]([OH:19])=[O:2])=[CH:17][CH:16]=2
Reactant: COC(=O)C(Oc1ccc2ncc(Br)cc2c1)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (3-bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid methyl ester (20 g) from Step 1, Stage 1 above in ethanol (150 ml) at R.T. a 2 M solution of sodium hydroxide in water (35.06 ml) was added. The reaction mixture was stirred at R.T. for 2 hours. The reaction mixture was poured into ice-could water (200 ml) and acidified with a 2 M solution of hydrochloric acid in water (35.06 ml). The precipitate was filtered off and washed with water to give (3-Bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid as yellowish solid (18.79 g). 1H NMR (CDCl3) δ ppm: 13.50 (1H, s br); 8.83 (1H, d); 8.59 (1H, d); 7.99 (1H, d); 7.57 (1H, dd); 7.50 (1H, d); 6.09 (1H, s); 2.17 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Brc1cccs1
Product: COC(=O)CCc1ccc(C#Cc2cccs2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromothiophene (60 μL, 0.62 mmol) according to the general procedure IF to give 97 mg (71%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.44 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.50-7.39 (m, 2H), 7.31-7.23 (m, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.00 (dd, J=5.1, 3.7 Hz, 1H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.1, 131.8, 131.6, 128.4, 127.1, 127.1, 123.4, 120.9, 92.9, 82.3, 51.6, 35.3, 30.8; ESI-MS m/z 293.1 (M+Na+).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[C:32]([NH:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 16 h

Procedure:
The compound of Example 11 (0.55 g) was dissolved in pyridine (10 ml) and benzoyl chloride (0.17 g) was added. The reaction was stirred for 16 hours and then partitioned between 10% citric acid (50 ml) and ethyl acetate (100 ml). The organic phase was washed with water (100 ml) and sodium bicarbonate solution (100 ml), dried (MgSO4) and evaporated to yield an oil which was purified by chromatography on silica using petroleum ether/ethyl acetate (1:3) to yield the title compound as a white solid, mp=119°-122° C.; found: C, 63.28; H, 4.25; N, 5.14; C28H22F6N2O2 requires C, 63.16, H, 4.16; N, 5.26%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[P:24]1(=[O:29])[O:28][CH2:27][CH2:26][O:25]1>C(OCC)C>[O:29]=[P:24]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)[O:28][CH2:27][CH2:26][O:25]1
Reactant: O=P1(Cl)OCCO1
Reactant: C=Cc1ccc(COCCCCO)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=Cc1ccc(COCCCCOP2(=O)OCCO2)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
4-Hydroxy-1(4′-vinylbenzyloxy)butane (5) (10.03 g; 48.69 mmol) and dried triethylamine (4.92 g, 48.69 mmol) were dissolved in dry diethyl ether (150 ml) and the resulting solution placed in a rigorously dried flask. The solution was cooled to -−30° and 2-chloro-2-oxo-1,3,2-dioxaphospholane (6.94 g; 48.69 mmol) added dropwise over 30 minutes, the temperature being held at −30°. The reaction mixture was then stirred for a further 2 hours, during which time the temperature was allowed to rise to 10°. The mixture was filtered and the precipitate washed with dry ether. The filtrate was evaporated (20°/21 mm) to give a cloudy oil. The residue was shaken with 50 ml of dry ether and refiltered. Evaporation of the filtrate gave the product as a viscous yellow oil (13.73 g; 90.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(Cl)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165 mg), and 4-dimethylaminopyridine (270 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (41 mg, yield 15%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:10]([CH3:16])=[N:11]2.C(O)C.[OH-].[Li+]>O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:9]2[C:10]([CH3:16])=[N:11][C:12]3[C:7]([CH:8]=2)=[C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])[CH:15]=[CH:14][CH:13]=3)=[CH:23][CH:22]=1
Reactant: COC(=O)COc1cccc2nc(C)c(Cc3ccc(Cl)cc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(OCC(=O)O)c2cc1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.11 g), ethanol (6.0 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and purification by preparative reverse-phase HPLC using a gradient over 37 minutes of acetonitrile in water (20% to 95% of organic modifier) gave title compound as a yellow gum, 0.028 mg.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:18]([CH3:46])[N:17]=[C:16]([NH2:47])[N:15]=1)(=O)=O.C(O)(C(F)(F)F)=O.[CH2:55]([NH2:60])[CH2:56][CH2:57][CH2:58][CH3:59]>CCOC(C)=O>[NH2:47][C:16]1[N:17]=[C:18]([CH3:46])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([P:36](=[O:37])([O:38][CH2:39][CH3:40])[O:41][CH2:42][CH3:43])([F:35])[F:34])=[CH:23][C:22]=2[O:44][CH3:45])=[C:14]([NH:60][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[N:15]=1
Reactant: CCCCCN
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC
Temperature: 100 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-5-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methoxybenzyl)-6-methylpyrimidin-4-yl 2,4,6-trimethylbenzenesulfonate (1 equiv.) in EtOAc (0.20 M) was added TFA (1.1 equiv.) and amylamine (3.3 equiv.). The reaction mixture was then heated to 100° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (76%) as a solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Br>CC(C)=O>[C:1]1(=[O:11])[N:5]([CH2:17]/[CH:16]=[CH:15]/[CH2:14][Br:13])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrC/C=C/CBr
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Temperature: 85 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Potassium phthalimide (18.5 g, 0.1 mol) was added in portions over 5 h to a stirred solution of (E)-1,4-dibromobut-2-ene (21.4 g, 0.1 mol) in acetone (200 ml) at 85° C. The suspension was stirred for 24 h at 85° C., then cooled and filtered. The filtrate was concentrated in vacuo to afford a white solid, which was recrystallised three times from acetone to yield (E)-1-phthalimido-4-bromobut-2-ene (15.76 g, 56.2%). δH (90 MHz, CDCl3) 3.88 (2H, d), 4.28 (2H, d), 5.92 (2H, m) and 7.80 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([S:33]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([Cl:22])[CH:24]=3)[CH:29]=2)(=[O:34])=[O:35])[CH2:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resultant solution of 1-(tert-butoxycarbonylamino)-2-piperazinone in ethyl acetate (20 ml) and a 10% aqueous solution of sodium carbonate (20 ml) was treated at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (1.36 g) and stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried and concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:2) to obtain 1-(tert-butoxycarbonylamino)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (848 mg) as a colorless amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
Triethylamine (17 ml) was added dropwise to a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (28.83 g) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes. Benzenesulfonyl chloride (14 ml) was added and the reaction allowed to stir at room temperature for 48 h. The mixture was washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml) then dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography (SiO2, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give the title compound (31.88 g, 77%) as a white crystalline solid.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([S:16][S:17][C:18]2[CH:29]=[CH:28][C:21]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=O)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>C(OC(C)C)(=O)C>[O:30]1[CH2:6][CH2:7][N:8]=[C:9]1[C:10]1[CH:11]=[CH:12][C:13]([S:16][S:17][C:18]2[CH:29]=[CH:28][C:21]([C:22]3[O:27][CH2:26][CH2:25][N:24]=3)=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=C(NCCO)c1ccc(SSc2ccc(C(=O)NCCO)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)OC(C)C
Product: c1cc(C2=NCCO2)ccc1SSc1ccc(C2=NCCO2)cc1
Reaction time: 72 h
Yield: 85.3 %

Procedure:
Thionyl chloride (20.0 g) was added to a stirred suspension of 13.3 g of N,N'-bis(2-hydroxyethyl)-4,4'-dithiobis[benzamide] in 250 ml of isopropyl acetate. The reaction mixture was allowed to stand for 3 days and the solid product was collected and dried to give 10.3 g of bis[4-(4,5-dihydro-2-oxazolyl)phenyl]disulfide, used directly in the next reaction.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]=1[CH3:8].Cl.[C-:16]#[N:17].[Na+]>CS(C)=O>[C:16]([CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]=1[CH3:8])#[N:17]
Reactant: [C-]#N
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1[nH]c(-c2ccccc2)nc1CC#N

Procedure:
A solution of 4-chloromethyl-5-methyl-2-phenylimidazole.HCl (40.5 g) in dimethylsulfoxide (400 ml) was added to a stirred solution of sodium cyanide (80 g) in dimethylsulfoxide (600 ml) over a period of 30 min. After 20 h the solids were filtered off, washed with water and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([CH2:10][C:11]#[N:12])[N:3]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:10][C:11]#[N:12])[CH:5]=1
Reactant: Cc1nn(CC#N)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1nn(CC#N)cc1N
Temperature: 80 °C
Reaction time: 48 h
Yield: 20.6 %

Procedure:
A mixture of (3-methyl-4-nitro-1H-pyrazol-1-yl)acetonitrile (2.6 g, 15.7 mmol), NH4Cl (3.4 g, 62.7 mmol) and Fe powder (3.5 g, 62.7 mmol) in MeOH (60 mL) and water (12 mL) was stirred at 80° C. for 2 days. The mixture was filtered, concentrated and the residue was purified by flash chromatography (MeOH: CH2Cl2 20:1) to give the title compound (440 mg, 15% yield) as brown oil.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH2:23]([SH:26])[CH2:24][SH:25]>C(Cl)Cl>[C:2]1([C:1]2([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[S:26][CH2:23][CH2:24][S:25]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCS
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(c3ccccc3)SCCS2)cc1
Reaction time: 8 h

Procedure:
Methyl 4-benzoylbenzoate 64a (2.08 mmol, 0.50 g) and BF3.(OAc)2 (5.2 mmol, 0.73 mL) were dissolved in dry CH2Cl2 under N2. Ethane-1,2-dithiol (3.95 mmol, 0.333 mL) was added and the solution was stirred overnight. The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to afford compound 64b.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:2]2[CH2:7][CH2:6][N:5]([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[C:24]([O:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][C:21]=3[N+:31]([O-:33])=[O:32])[CH2:4][CH2:3]2)=[N:9]1
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)N2CCN(c3nsc4ccccc34)CC2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-piperazin-1-yl-benzoisothiazole hydrochloride (5.29 g, 20.7 mmol) and 4,5-dimethoxy-2-nitrophenylacetic acid (5 g, 20.7 mmol) were combined in 200 mL methylene chloride with triethylamine (5.77 mL, 41.4 mmol). This solution stirred for 15 min before bis-(2-oxo-3-oxazolidinyl) phosphinic chloride (5.26 g, 20.7 mmol) was added. After stirring overnight at rt, the reaction was quenched with water and extracted into methylene chloride. The organic layer was washed with 0.5 N HCl, water, sodium bicarbonate then water before it was dried over Na2SO4 and concentrated. The residue was taken up in methylene chloride and washed with water. The organic layer was dried over sodium sulfate, and concentrated then purified by MPLC using a Biotage prepacked silica gel cartridge eluting with 3% methanol in methylene chloride to afford 6.5 g of a tan solid. Yield 71%; 100% purity at 214 nm; LCMS (APCI): 443 [M+H]+; mp 170° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24](OS(C(F)(F)F)(=O)=O)[CH:25]=3)[C:20]2=[O:38])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>CN(C)C=O.C(Cl)Cl>[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:25]=3)[C:20]2=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium hydride (2.88 g., 120 mmole) in dry dimethylformamide (20 ml), under dry nitrogen and cooled in an ice-bath is added dropwise, a solution of diethyl malonate (19.2 g., 120 mmole) in dimethylformamide (30 ml). The mixture is stirred for one hour in the ice-bath and another hour at room temperature, then is cooled in the ice-bath again and 2-cyclopentyl-6,7-dichloro-2-methyl-5-trifluoromethylsulfonyloxy-1-indanone (12.93 g., 30 mmole) in dimethylformamide (25 ml) is added dropwise over 1-1/2 hours. The mixture is stirred at room temperature overnight and then poured into a mixture of ice-water (750 ml), methylene chloride (200 ml) and 6 N hydrochloric acid (20 ml). The methylene chloride layer is separated and the aqueous layer extracted with methylene chloride (50 ml). The combined extract is washed with water (500 ml), dried (MgSO4) and evaporated under vacuum, finally at 70°/0.05 Torr, to give an oil (18.28 g.). This is purified by chromatography on Merck silica gel (1.04 Kg) using 1,1,1-trichloroethane as the solvent. The product is accompanied by some diethyl malonate which is removed at 125°/0.05 Torr to give a viscous oil, 10.25 g. (77%),
Reaction SMILES: [CH3:1][N:2]([C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[S:48]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=S)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide (Compound 149) (273 mg, 0.5 mmol) (i.e. the product of Example 6, Step D) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (202 mg, 0.5 mmol) (Lawesson's reagent) in 5 mL of toluene was heated at 100° C. for 3 days. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in 10 mL of dichloromethane and washed with 1 M aqueous solution of potassium carbonate, and dried over magnesium sulfate. The filtered residue was concentrated in vacuo and purified by medium-pressure liquid chromatography on silica gel using 50-100% of ethyl acetate in hexanes as eluant to give 70 mg of the title compound, a compound of the present invention as a white foam.