Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=O)[CH2:12][CH2:11]1.B(F)(F)F.CCOCC.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:16]1[C:15]2[C:13]3=[N:4][C:3]4[C:2]([C:1]([NH2:9])=[C:12]3[CH2:11][CH2:10][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=4
Reactant: O=C1CCCCc2ccccc21
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)-c1ccccc1CCC2
Yield: 86.1 %

Procedure:
To a solution of anthranilonitrile (0.69 g, 5.8 mmol) and 1-benzosuberone (1.03 g, 0.96 mL, 6.4 mmol) in 25 mL anhydrous toluene was added boron trifluoride etherate (0.91 g, 0.81 mL, 6.4 mmol) slowly via syringe under a nitrogen atmosphere. The reaction was heated to reflux for 22 h. After cooling, sodium hydroxide solution (25 mL, 2 M, 50 mmol) was added. The reaction was heated to reflux for 23 h. After cooling, the reaction was diluted with ethyl acetate, washed with water (3×50 mL), brine (20 mL), dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue (1.46 g) was dissolved in ethyl acetate:diethyl ether (1:1; 100 mL) with a trace of methanol (3 mL). To the solution was added 7 mL of a 1 N solution of HCl in diethyl ether. A resulting precipitate was collected by vacuum filtration and air-dried to provide the hydrochloride salt of the title compound as an off-white solid (1.30 g, 75%). MS (API+): M+1: 261 (100%); 1H NMR (300 MHz, DMSO-d6/TFA-d) d 2.13-2.29 (br m, 2H), 2.51-2.56 (br m, 2H), 2.56-2.75 (br m, 2H), 7.49 (d, J=7.0 Hz, 1H), 7.55-7.65 (m, 2H), 7.67-7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.05 (d,J=8.7 Hz, 1H), 8.57 (d, J=8.7 Hz, 1H).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2(O)[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:36]2=[O:50])=[C:30]([OH:52])[CH:29]=1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:36]2=[O:50])=[C:30]([OH:52])[CH:29]=1
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with ethyl [3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (83%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.39 (t, 1H), 7.34 (d, 1H), 7.26-7.22 (m, 1H), 6.92-6.82 (m, 2H), 6.73 (dd, 1H), 5.11 (br, 1H), 4.50 (d, 1H), 4.43 (d, 1H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: N1C2C(=CC=CC=2)C(CCS)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36](=O)[C:37]([O:39][CH2:40][CH3:41])=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]1[C:40]([CH3:41])([CH3:2])[O:39][CH2:37][CH2:36][C:30]2=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: SCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93° - 95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Pat. No. 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67- 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.S(=O)=O.[S:21](Cl)([Cl:24])(=[O:23])=[O:22]>CCOCC>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: O=S=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccc2c(c1)OC(F)(F)O2
Temperature: -30 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 2.37 g (10 mmol) 5-bromo-2,2-difluoro-1,3-benzodioxole in 25 ml anhydrous ether, cooled to −30° C., and 4 ml (10 mmol) n butyllithium (2.5 M in hexanes) was added at −30° C., over 10 minutes. The mixture was stirred at −30° C. for 1 hour, then sulfur dioxide gas was passed through the mixture at −20° C. for 5 minutes. The mixture then was allowed to warm up to −20° C., and the precipitate was filtered and washed with 20 ml hexane. The solid was suspended in 20 ml hexanes, 1.35 g (10 mmol) sulfuryl chloride was added, the mixture was stirred at 20° C. for 48 hours. The mixture then was filtered and the filtrate was concentrated under reduced pressure to obtain 1.6 g (62%) title compound. The product was used in the next step without further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 60 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 39) (250 mg, 0.379 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (220 mg, 0.666 mmol) in sodium carbonate (121 mg, 1.139 mmol), Pd(PPh3)2Cl2 (13.3 mg, 0.0189 mmol), toluene/ethanol/water (25/12.5/6 ml). This afforded 267 g (60% yield) after purification by column (Silica gel 60/120) using 1.5% of methanol in chloroform as eluent. MS: m/z=735.3 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:15])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:15])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 217.6 %

Procedure:
To a stirred mixture of 4-isopropoxy benzoyl chloride (15 mmol, 2.97 g) and hydroquinone (7.5 mmol, 0,825 g) in CH2Cl2 (50 ml), pyridine (2 ml) was added in 15 minutes. After stirring for 1 hour, the mixture was extracted with water, 10% HCl and water (100 ml each). Then the solvent was evaporated and the remaining solid recrystallized from ethanol/CH2Cl2 (70/30), giving 2.56 g of the product (yield 79%, melting point (mp) 195° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([CH:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([CH:25]5[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26]5)=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccc3nnc(C4CCNC4)n3c2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a suspension of 6-(4-fluorophenyl)-5-(3-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)imidazo[2,1-b]oxazole (0.100 g, 0.26 mmol; Example #M.1.1.3) in DCM (5 mL) was added TEA (0.04 mL, 0.26 mmol) and acetyl chloride (0.02 mL, 0.26 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by flash chromatography (silica gel; DCM/MeOH gradient from 99:1 to 90:10) to afford the title compound (0.02 g, 17%). LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 431.1 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[C:16]([N:18]3[C:26]4[CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22](=[O:29])[C:21]=4[C:20]([CH3:30])=[CH:19]3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:4][CH2:3]1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[H-].[Na+].[I-].[K+]>CN(C=O)C.O>[N:35]1([CH2:34][CH2:33][O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]3[CH:17]=[C:16]([N:18]4[C:26]5[CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][C:22](=[O:29])[C:21]=5[C:20]([CH3:30])=[CH:19]4)[CH:15]=[CH:14][C:10]=3[C:11]([NH2:13])=[O:12])[CH2:4][CH2:3]2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2c1C(=O)CC(C)(C)C2
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](OCCN4CCOCC4)CC3)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 180 °C

Procedure:
A microwave reaction vial was charged with the title compound of Example 3 [2-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide] (100 mg, 0.244 mmol), 4-(2-chloroethyl)morpholine hydrochloride (45.4 mg, 0.244 mmol), sodium hydride (17.3 mg, 0.732 mmol), and a catalytic amount of potassium iodide. After suspending in DMF, the reaction mixture was heated to 180° C. in the “Personal Chemistry” microwave for eight minutes. The solution was then diluted with water and extracted into EtOAc (2×). The organic layers were extracted with 2N HCl (2×). The aqueous extracts basified with aqueous sodium hydroxide, and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated, and purified by column chromatography (EtOAc/MeOH) to yield the title compounds as a white solid. LCMS m/z: (M+H) 523.9.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1.[Li+].[OH-:18]>>[OH:18][C:7]1[CH:2]=[C:3]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1csc(-c2ccccc2O)n1
Reactant: [OH-]
Agent: [Li+]
Product: O=C(O)Cc1csc(-c2cccc(O)c2)n1
Yield: 99 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4d (1.84 g, 7.00 mmol) and 2N LiOH (14.0 mL) to provide 5d (1.63 g, 99%) as a white solid, which was recrystallized from EtOAc/toluene. mp 172.0°-174.0° C.; IR (KBr) 3500-2400 (br), 3336 (br), 1689, 1442, 1276, 1231 cm-1 1H NMR (DMSO-d6) δ3.72 (2H, s, CH2), 6.81 (1H, d, J=7.4 Hz, Ar), 7.19-7.30 (3H m, Ar), 7.43 (1H, s), 9.67 (1H), br, s, OH), 12.40 (1H, br, s, CO2H); FDMS m/z 236 M+ +1); Anal. Calcd for C11H9NO3S: C, 56.14; H, 3.86; N, 5.95. Found: C, 56.11; H, 3.73; N, 5.80.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1([CH2:24][OH:25])[CH2:23][O:22][CH2:21]1.BrCC(CBr)(CO)CO>C1COCC1>[OH:25][CH2:24][C:20]1([CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)[CH2:23][O:22][CH2:21]1
Reactant: OCC1(CBr)COC1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: OCC(CO)(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(OCC2(CO)COC2)cc1
Temperature: 50 °C

Procedure:
Dissolve 4-hydroxybenzophenone in anhydrous THF and treat it with equimolar quantity of sodium hydride at 0° C. for 2 h. Stir and warm the suspension to 50° C. and treat it with an equimolar quantity of 3-Bromomethyl-3-hydroxymethyloxetane (readily prepared in one step by method described in U.S. Pat. No. 5,489,700 or Tet. Lett. 2011, 52, p. 565-567 from commercially available 2,2-bis-(bromomethyl)propane-1,3-diol). Stir overnight at 50° C., filter the reaction mixture, evaporate the filtrate to dryness and purify the residue by column chromatography to provide (4-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}phenyl)(phenyl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:14]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(-c2ncccc2CO)c1
Reactant: O=S(Cl)Cl
Product: COc1cccc(-c2ncccc2CCl)c1
Reaction time: 2 h
Yield: 55 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [2-(3-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to furnish 600 mg (55%) of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(C)c(C(C)=O)s2)cc1

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.6 mg) with purity >90%: MS (pos) m/z 339.2; HEMS m/z 338.0748 (calc. of monoisotopic mass for C15H18N2O3S2 gives 338.0759).
Reaction SMILES: O=C1[N:6]([S:7]([NH:10][C@@H:11]([CH2:22][C:23]2[O:24][C:25]([CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:35]=[CH:34][C:32]=4[N:33]=3)=[N:26][N:27]=2)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])(=[O:9])=[O:8])[CH2:5][CH2:4]O1.[CH:44]1(N)CC1>C(#N)C>[CH:5]1([NH:6][S:7]([NH:10][C@@H:11]([CH2:22][C:23]2[O:24][C:25]([CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][C:32]=4[N:33]=3)=[N:26][N:27]=2)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])(=[O:8])=[O:9])[CH2:4][CH2:44]1
Reactant: NC1CC1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)N1CCOC1=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)NC1CC1
Temperature: 70 °C
Yield: 46.4 %

Procedure:
To a solution of 2-chloroethanol (0.10 mL, 1.3 mmol) in DCM (1 mL) at rt was added a solution of sulfurisocyanatidic chloride (180 mg, 1.3 mmol) in DCM (1 mL) and the reaction mixture was stirred for 6 h. The resulting mixture was added to a solution of Compound 181a (300 mg, 0.65 mmol, prepared as described in Example 45) and TEA (0.45 mL, 3.2 mmol) in DCM (4 mL) and the mixture stirred for 30 min then heated at 35° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-100% hexane/EtOAc to afford (S)-benzyl 2-(2-oxooxazolidine-3-sulfonamido)-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (230 mg, 57% yield) as a yellow foam. LCMS=1.2 min using analytical method (B), 620.2 (M+H). A portion of (S)-benzyl 2-(2-oxooxazolidine-3-sulfonamido)-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (93 mg, 0.15 mmol) was dissolved in ACN (3 mL) then TEA (0.031 mL, 0.23 mmol) was added followed by cyclopropanamine (0.053 mL, 0.75 mmol) and the reaction mixture heated at 70° C. for 16 h. The reaction mixture was allowed to cool to rt then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% hexane/EtOAc to give Compound 181b (41 mg, 46% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.13-7.97 (m, 2H), 7.72 (dd, J=8.5, 1.9 Hz, 1H), 7.67-7.59 (m, 2H), 7.51-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.34-7.31 (m, 3H), 7.30-7.27 (m, 2H), 5.53 (d, J=8.1 Hz, 1H), 5.23 (s, 1H), 5.18 (s, 2H), 4.68 (d, J=4.4 Hz, 2H), 3.43 (dd, J=5.7, 1.8 Hz, 2H), 2.51-2.35 (m, 1H), 0.65-0.43 (m, 4H). LCMS=1.2 min using analytical method (B), 590.2 (M+H)±.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([CH3:14])([NH2:13])[CH3:12])=[CH:2]1.[F:15][C:16]1[CH:17]=[C:18](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:19]=[C:20]([F:24])[C:21]=1[CH:22]=O>C(O)(=O)C>[CH3:12][C:11]1([CH3:14])[NH:13][CH:22]([C:21]2[C:20]([F:24])=[CH:19][C:18](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])=[CH:17][C:16]=2[F:15])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: CC(C)(N)Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
1-(1H-Indol-3-yl)-2-methylpropan-2-amine (807 mg, 4.29 mmol) and (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (obtained as described in Example 1, preparation of starting materials) (970 mg, 4.29 mmol) were combined in acetic acid (15 ml) and the mixture heated to 80° C. for 2 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 2M NH3 in methanol and product-containing fractions were evaporated to dryness to afford (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (1610 rag, 95%) as a yellow foam. 1H NMR (500 MHz, DMSO, 20° C.) δ 1.15 (3H, s), 1.27 (3H, s), 2.23 (1H, s), 2.61 (2H, s), 3.75 (3H, s), 5.46 (1H, s), 6.84 (1H, d), 6.97 (2H, dtd), 7.18 (1H, d), 7.39 (1H, d), 7.58 (2H, s), 7.67 (1H, d), 10.60 (1H, s). m/z: ES− [M−H]− 395.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH2:16]C)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO>[C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure E, ethyl 6-phenyl-5-(4-trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 25, 110 mg, 0.29 mmol) and conc. H2SO4 (5 drops) in MeOH (5 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[CH:20]([C:18]1[CH2:17][N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(=Cc1cccn2cc(C(C)C)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C(C)C)=N3

Procedure:
From 6f (yield: 87%); mp 207-209° C.; IR (KBr) 3285, 1681, 1248 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, 3H, J=7 Hz), 1.34 (d, 6H, J=7 Hz), 3.11 (sept, 1H, J=7 Hz), 4.42 (q, 2H, J=7 Hz), 6.82 (d, 1H, J=7 Hz), 7.17 (s, 1H), 7.56 (s, 1H), 7.73 (d, 1H, J=7 Hz), 11.40 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 22.5, 28.3, 61.0, 101.0, 107.5, 108.1, 114.1, 123.3, 126.2, 133.2, 141.31, 151.4, 161.9; MS m/z 271 (M+, 82), 256 (40), 225 (42), 210 (100), 182 (20). Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C, 66.68; H, 6.41; N, 15.57.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O)=[CH2:2]>[Pd].C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9])[CH3:2]
Reactant: C=Cc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(N2CCN(C(C)C)CC2)ccc1N
Yield: 62.7 %

Procedure:
A solution of 1-(3-ethenyl-4-nitrophenyl)-4-(1-methylethyl)piperazine (1.4 g, 5.1 mmol) and 10% palladium on carbon (0.5 g) in degassed ethanol was maintained under an atmosphere of hydrogen (60 psi) overnight. The next morning, the reaction was filtered through celite, concentrated, and purified via chromatography on SiO2 to afford 2-ethyl-4-[4-(1-methylethyl)-1-piperazinyl]aniline (0.8 g, 3.2 mmol, 64% Yield). 1H NMR (400 MHz, CDCl3) d ppm 0.92 (t, J=7.3 Hz, 3 H), 1.51-1.60 (m, 2 H), 1.81 (dd, J=7.7, 2.9 Hz, 4 H), 1.98-2.06 (m, 2 H), 2.30-2.37 (m, 2 H), 2.40 (t, J=7.9 Hz, 1 H), 3.06 (d, J=11.7 Hz, 2 H), 3.67 (s, 2 H), 3.82 (s, 3 H), 6.63-6.70 (m, 3 H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.6 Hz, 6 H), 1.07 (td, J=7.5, 0.7 Hz, 3H), 2.37 (q, J=7.3 Hz, 2 H), 2.51 (s, 4 H), 2.59-2.67 (m, 1 H), 2.86 (s, 4 H), 4.29 (s, 2 H), 6.48 (s, 1H), 6.51 (d, J=19.0 Hz, 2 H).
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([CH2:14][C:15](O)=O)[N:12]=[C:11]([CH2:18][O:19][CH3:20])[S:10]1)=O)(C)(C)C.C(N(CC)CC)C.P(Cl)(Cl)([Cl:30])=O.O>C(#N)C>[Cl:30][C:15]1[N:8]=[C:9]2[N:13]([CH:14]=1)[N:12]=[C:11]([CH2:18][O:19][CH3:20])[S:10]2
Reactant: COCc1nn(CC(=O)O)c(=NC(=O)OC(C)(C)C)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCc1nn2cc(Cl)nc2s1
Temperature: 80 °C
Yield: 36 %

Procedure:
To {2-[(tert-butoxycarbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3 (2H)-yl}acetic acid a14 (418 g, 1.38 mol, 1 eq) in acetonitrile (2.5 l) at room temperature, are successively and slowly added triethyl amine (278.9 g, 2.76 mol, 2 eq), then phosphorous oxychloride (633.9 g, 4.13 mol, 3 eq). The reaction mixture is heated at 80° C. for one hour. After reaction completion, water (2.2 l) is slowly and carefully added at 50° C. The reaction mixture is extracted with dichloromethane (2×1.2 l), the combined organic layers are washed by a NaOH/NaCl aqueous solution (1.4 l of saturated NaCl solution+400 ml 2N NaOH), dried over MgSO4, filtered and condensed under reduced pressure. The residue is recrystallized from acetonitrile/water (1/1) to afford 99.8 g of pure 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole a15.