Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].[P:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]>>[CH3:9][O:8][P:7]1([O:12][CH3:13])([O:10][CH3:11])[O:6][C:2]([CH3:1])=[C:3]([CH3:4])[O:5]1
Reactant: CC(=O)C(C)=O
Reactant: COP(OC)OC
Product: COP1(OC)(OC)OC(C)=C(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
In a dried flask, 2,3-butanedione (17.20 g, 0.20 mol) was added very slowly at 0-5° C. to trimethyl phosphite (27.28 g, 0.22 mol). The reaction mixture was stirred at room temperature overnight and then distilled (40-47° C./0.1 Torr) using a Vigreux-column. Pure 2,2,2-tri(methoxy)-4,5-dimethyl-1,3,2-dioxaphosphole (35.04 g) was recovered (yield: 83%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:4]([O:18]C)[CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[C:4]([OH:18])[CH:3]=1
Reactant: COc1cc(C(=O)c2ccccc2)c(OC)cc1Br
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccccc2)c(O)cc1Br
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 90 %

Procedure:
A solution of [4-bromo-2,5-bis(methyloxy)phenyl](phenyl)methanone (400 mg, 1.245 mmol) in DCM (2.1 mL, C=0.6M) was added dropwise to a stirred solution of 1 M BCl3 in DCM (1.55 mL, 1.25 eq) while maintaining the reaction temperature at 0° C. The reaction mixture was stirred at 0° C. for 35 min and then quenched by slow addition of MeOH (0.7 mL) over 15 min at 10° C. Then, 2N HCl solution (1.4 mL) was added at r.t. over 15 min. The layers were separated, and the organic phase was concentrated to dryness by rotavap. The yellow oily product was purified by silica gel column flash chromatography (elution in pure DCM) to afford [4-bromo-2-hydroxy-5-(methyloxy)phenyl](phenyl)methanone in 90% yield (344 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.67 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.60 (t, J=7.3 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.29 (s, 1H), 7.02 (s, 1H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.4 (C═O), 157.5 (C), 148.3 (C), 137.6 (C), 132.3 (CH), 129.0 (CH), 128.5 (CH), 123.2 (CH), 121.9 (C), 117.8 (C), 114.7 (CH), 56.8 (OCH3); MS (ESI) m/z: 307.4, 309.1 [M+H, 79Br, 81Br]+; 229.1, 231.0 [M-Ph, 79Br, 81Br]1.
Reaction SMILES: C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:14](=[O:27])[NH:15][CH2:16][C:17]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])CC.[OH-].[Na+].Cl>CO.C1COCC1.O>[C:32]([O:31][C:29]([NH:28][CH:13]([C:14](=[O:27])[NH:15][CH2:16][C:17]1([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:18][CH2:19]1)[C@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCOC(=O)C1CCC(C(NC(=O)OC(C)(C)C)C(=O)NCC2(c3ccc(Cl)cc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)NCC1(c2ccc(Cl)cc2)CC1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C

Procedure:
4-(tert-Butoxycarbonylamino-{[1-(4-chloro-phenyl)-cyclopropylmethyl]-carbamoyl}-methyl)-cyclohexanecarboxylic acid propyl ester (2-2) (1.77 g, 0.0035 mol, 1 eq) was dissolved in MeOH (20 mL) and THF (6 mL). NaOH (0.42 g, 0.0105 mol, 3 eq) in H2O (2 mL) was added. The reaction mixture was stirred at RT and monitored by TLC and LC/MS. After stirring at RT for 20 hours, the reaction mixture was diluted with H2O. The pH was adjusted to pH=3 with 10% HCl while cooling with ice-H2O bath. The aqueous was extracted with EtOAc (3×60 mL). The combined EtOAc was washed with brine. After drying over Na2SO4 and filtration, the filtrate was concentrated under vacuum to dryness. The crude product was purified on silica gel column, eluted with 2% MeOH/CH2Cl2 to give trans-4-(tert-Butoxycarbonylamino-{[1-(4-chloro-phenyl)-cyclopropylmethyl]-carbamoyl}-methyl)-cyclohexanecarboxylic acid 0.56 g (2-3) (34.4%). 1H NMR (DMSO-d6) data is depicted in FIG. 19.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[NH:39]1[C:43]([CH2:44][NH2:45])=[N:42][CH:41]=[N:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:39]1[C:43]([CH2:44][NH:45][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[N:42][CH:41]=[N:40]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ncn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ncn[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), (1H-1,2,4-triazol-5-yl)methanamine (12.28 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, retention time=32.9 min) to give single enantiomer N-((1H-1,2,4-triazol-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (22 mg, 0.041 mmol, 58.8% yield): LCMS=512.2 [M+H]; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (3 H, m), 6.04 (1 H, s), 5.19 (1 H, s), 4.51 (2 H, s). HPLC Peak RT=8.4 min (Analytical Method C).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[CH3:25])=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:25])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2C)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2C)c2cccc(C(F)(F)F)c21
Yield: 117.6 %

Procedure:
Prepared according to Method D step C from 1-allyl-3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.075 g, 0.22 mmol), boron tribromide (0.082 mL, 0.87 mmol) and 1.0 mL of cyclohexene to give the product (0.086 g) as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]2[C:24]([C:25]3[CH:39]=[CH:38][C:28]([O:29][C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH:32]=O)=[CH:27][CH:26]=3)=[CH:23][N:22]([CH:40]3[CH2:44][CH2:43][O:42][CH2:41]3)[C:18]=2[N:19]=[CH:20][N:21]=1.[CH2:45]([NH:47][CH2:48][CH3:49])[CH3:46]>ClCCCl>[Cl:15][C:16]1[C:17]2[C:24]([C:25]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH2:32][N:47]([CH2:48][CH3:49])[CH2:45][CH3:46])=[CH:38][CH:39]=3)=[CH:23][N:22]([CH:40]3[CH2:44][CH2:43][O:42][CH2:41]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: O=Cc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(Cl)c23)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium triacetoxyborohydride (264 mg) was added to a mixture of 2-[(4-(4-chloro-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde (330 mg) and diethylamine (121 mg) in 1,2-dichloroethane in a vial (5 ml) and the vial septum sealed. The mixture was stirred at ambient temperature for 20 hours then quenched with saturated aqueous sodium bicarbonate solution (5 ml). The mixture was extracted with ethyl acetate to give 2-[4-(4-chloro-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]-N,N-diethylbenzylamine.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].Cl[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)[nH]2)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
DIEA (1.23 mL, 7.08 mmol) was added to 1-(6-bromo-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.980 g, 2.70 mmol) in THF (13.5 mL), followed by (2-chloromethoxy-ethyl)-trimethyl-silane (0.500 mL, 3.27 mmol). The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was purified by FCC (0-20% EtOAc/hexanes) to yield the titled compound (1.27 g, 95% yield). MS (ESI/Cl): mass calcd. for C20H25BrN4O4Si, 492.1; m/z found, 435.1 [M−58+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:41]([C:38]5[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:45])[F:46])=[CH:40][CH:39]=5)(=[O:43])=[O:42])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-4-(trifluoromethyl)benzenesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and p-trifluoromethyl-benzenesulfonyl chloride following General Procedure U.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:25])CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:34]1[N:38]2[CH:39]=[C:40]([O:43][C@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C@@H:47]([NH2:54])[CH2:46][CH2:45]3)[CH:41]=[CH:42][C:37]2=[N:36][N:35]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[Cl:1][CH2:2][Cl:25].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:54][C@@H:47]2[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:44]([O:43][C:40]3[CH:41]=[CH:42][C:37]4[N:38]([C:34]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:28]5[CH3:27])=[N:35][N:36]=4)[CH:39]=3)[CH2:45][CH2:46]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A red-brown solution of Intermediate 33a (883 mg, 2.10 mmol), Intermediate 81d (755 mg, 2.00 mmol) and DIPEA (0.44 mL, 2.5 mmol) in dry dioxane (20 mL) was stirred at 70° C. for 16 h, and at 80° C. for 5 h. The cooled solution was concentrated in vacuo, suspended in water (15 mL) and extracted with DCM (2×15 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. Flash chromatography (silica 80 g, 4-8% MeOH in DCM) gave the title compound as a pale yellow foam (1.27 g, 87%). LCMS (Method 3): Rt 3.61 min, m/z 649 [MH+].
Reaction SMILES: CS(C)=O.[CH3:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[OH:20].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1.CC(C)([O-])C.[K+]>O.C(OCC)(=O)C>[CH3:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[O:20][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1
Reactant: COCCCOc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COCCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 150 °C
Reaction time: 14 h
Yield: 46 %

Procedure:
Dimethylsulfoxide (25 mL) was added to a mixture of 6-(3-methoxypropoxy)-1H-indol-5-ol described in Production Example 32-5 (3.81 g, 17.2 mmol), N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (3.23 g, 18.9 mmol), and potassium tert-butoxide (2.12 g, 18.9 mmol) under nitrogen atmosphere at room temperature. The liquid mixture was stirred at 150° C. for 14 hours. The reaction liquid was cooled to room temperature, and then ethyl acetate and water were added. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=49:1) to obtain the title compound (2.83 g, 46%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[O:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccco1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-furoyl chloride (0.26 g, 2.0 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.21 g, 63%)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][CH:12]=[N:11]1>C(#N)C>[I:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2ccnn2C)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1ccc(-c2c(I)cnn2C)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
N-Iodosuccinimide (95%, 756 mg, 3.19 mmol) was added to a solution of 1-methyl-5-(4-methylphenyl)-1H-pyrazole (500 mg, 2.90 mmol) in acetonitrile (15 mL), and the reaction was allowed to stir for 1 hour at 85° C. Removal of solvent in vacuo provided a residue, which was chromatographed on silica gel (Gradient: 20% to 50% ethyl acetate in heptane) to provide the product as a brown oil. Yield: 630 mg, 2.11 mmol, 73%. LCMS m/z 299.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.44 (br s, 3H), 3.83 (s, 3H), 7.26-7.33 (m, 4H), 7.57 (s, 1H).
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 64 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was conducted for 1 hr. through a solution of 9.64 g (0.354 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 210 ml of pyridine and 2.1 ml of triethylamine. The green solution was left to stand for 64 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The solid residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.41 g (87%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. An analytical sample was obtained from the organic phase after recrystallization in methanol. Yellow crystals; m.p. 300-302°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]([Cl:25])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:26](Br)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH:26]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([Cl:25])=[CH:14][CH:13]=2)[C:18]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[C:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)[nH]c2ccc(Cl)cc12
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 60 %

Procedure:
Methyl [2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (1 eq), Ph2CHBr (2 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.13M) under N2. The mixture was heated with stirring to reflux for 3 hrs. The reaction mixture was cooled to rt and filtered and solvent was removed. Resulting residue was purified using a column with 1:4Hexane/CH2Cl2 as eluent to give methyl [1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy }methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (yellow-brown solid) in 60% yield.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][CH:6]=[CH:7][C:8](=[O:10])[CH3:9].FC(F)(F)C(O)=O.O>C(OCC)C>[O:10]=[C:8]([CH3:9])[CH:7]=[CH:6][S:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CSC=CC(C)=O)OC
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C=CSCC=O

Procedure:
A solution of 3.0 g. (15.7 mmol) of (3-oxo-1-butenyl)mercaptoacetaldehyde dimethylacetal in 30 ml. of 10:1 trifluoroacetic acid/water at 0° was stirred 2 hours, poured into 150 ml. of water and extracted with CHCl3 (4×50 ml.). The CHCl3 was washed with cold aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and stripped in vacuo to afford 2.1 g. (93%) of the crude mixture of aldehyde double bond isomers (68:32::E to Z). Column chromatography on silica gel using ethyl ether as eluent afforded both isomers in a ratio of 4:1::E:Z. The (Z-3-oxo-1-butenyl)mercaptoacetaldehyde eluted first: Rf 0.45, 1H-NMR (CDCl3) delta 2.25 (s, 3), 3.45 (d, 2, J=3.2 Hz), 6.38 (d, 1, J=9.8 Hz), 6.80 (d, 1, J=9.8 Hz), 9.62 (t, 1, J= 3.2 Hz); IR (KBr) cm-1 1721 (m), 1659 (s); mass spectrum (70 eV) m/e 144.0240 (parent, calcd. for C6H8O2S; 144.0354), 126.0130 (p-H2O, calcd. for C6H6OS; 126.0198), 115.0230 (p-CHO), 97 (p-CHO and --OH2). The E olefin isomer (Rf 0.3) exhibited the following spectral characteristics: 1H-NMR (CDCl3) delta 1.94 (s, 3), 3.38 (d, 2, J=3.2 Hz), 5.85 (d, 1, J=15.9 Hz), 7.24 (d, 1, J=15.9 Hz), 9.35 (t, 1, J=3.2 Hz); IR (film) cm-1 1724 (m), 1660 (s); mass spectrum (70 eV) m/e 144.0242 (parent, calcd. for C6H8O2S: 144.0354), 101.0053 (base, p-CH2CHO, calcd. for C4H5Os; 101.0120).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCCl
Reactant: Cc1ccc(O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
12.1 g (65 mmol) of 3-bromo-4-methylphenol are placed in 100 ml of dry dimethylformamide in a round-bottomed flask and under a stream of nitrogen. At 0° C., 3.1 g (78 mmol) of 60% sodium hydride are added slowly. After 1 hour, 7.3 ml (78 mmol) of methoxyethyl chloride are added dropwise. The mixture is stirred at room temperature overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (85/15) to give 13.2 g (83%) of the expected product in the form of an oil.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:25]#[N:26])=O)(C)(C)C>CC(N(C)C)=O>[C:25]([C:9]1[NH:8][C:12]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:17][CH:18]=2)=[CH:11][CH:10]=1)#[N:26]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C(=O)OC(C)(C)C)cc1
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Temperature: 170 °C
Yield: 89.9 %

Procedure:
Tert-butyl-2-cyano-5-{4-{(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-carboxylate (2.3 g, 6.1 mmol) was dissolved in dimethylacetamide (60 mL) and heated to 170° C. for 30 minutes. The mixture was cooled and partitioned between water and ethyl acetate. The organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel Flash Chromatography (hexane/ethyl acetate; 1:1) to afford the title compound (1.51 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22]>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)I
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Powdered potassium carbonate (1.72 g, 12.5 mmol) and 2-iodopropane (1.16 mL, 1.98 g, 11.6 mmol) were added to a solution of 2-bromo-4-(trifluoromethyl)phenol (2.00 g, 8.30 mmol) in DMF. The mixture was stirred overnight at RT and then partitioned between hexane (100 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium chloride (50 mL) and the aqueous layers were extracted in succession with hexane (50 mL). The organic layers were dried over sodium sulfate, decanted, and evaporated. The crude product was purified by flash column chromatography, eluting with hexane, to give the title compound. Mass spectrum (EI): m/z=282 (M+).