Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:30]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:31]/[C:32](/[CH3:43])=[CH:33]\[C:34]([O:36][CH2:37][CH2:38][S:39][CH:40]([CH3:42])[CH3:41])=[O:35].[CH2:44](O)[CH3:45]>>[CH3:44][C:45]1[NH:31][C:32]([CH3:43])=[C:33]([C:34]([O:36][CH2:37][CH2:38][S:39][CH:40]([CH3:41])[CH3:42])=[O:35])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:30]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=1)=[O:13]
Reactant: CCO
Reactant: CC(=O)Nc1ccc(OCCOC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: C/C(N)=C/C(=O)OCCSC(C)C
Product: CC(=O)Nc1ccc(OCCOC(=O)C2=C(C)NC(C)=C(C(=O)OCCSC(C)C)C2c2cccc([N+](=O)[O-])c2)cc1
Temperature: -5 °C
Yield: 42 %

Procedure:
12 g (0l03 moles) of 2-(4-acetylaminophenoxy)ethyl 2-(3-nitrobenylidene)acetylacetate and 5.92 g (0.03 moles) of 2-isopropylthioethyl 3-aminocrotonate are heated under reflux in 30 ml of ethanol for 8 hours. The solution is then cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl 2,6-dimethyl-5-(2-isopropylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as yellow crystals melting--after recrystallisation in aqueus ethanol--at 142°-144° C. The yield was 42% of the theoretical yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.O>O1CCOCC1.C(=O)([O-])O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:40])([F:39])[F:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 78.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzyl)oxy]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 152-1 and 4-(trifluoromethyl)phenylboric acid (621 mg) were dissolved in dioxane (10 mL) and sodium hydrogen carbonate aqueous solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (162 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (900 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:34]#CBr.O>CS(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[N:9]=[C:8]2[N:5]1[CH2:4][CH2:3][N:2]([C:1]#[N:34])[CH2:7][CH2:6]1
Reactant: N#CBr
Reactant: COc1ccc2c(c1)c(N1CCN(C)CC1)nn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(N1CCN(C#N)CC1)nn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-5-methoxy-1-phenylsulfonyl-1H-indazole (55.0 g, 0.14 mol) of Example 5d, potassium carbonate (22.0 g, 0.16 mol) and dimethylsulfoxide (DMSO) [500 ml] under N2 was added dropwise, cyanogen bromide (16.0 g, 0.15 mol) dissolved in DMSO (125 ml). The reaction was stirred at room temperature for 4 hours and was then poured into H2O (2.5 l). The solid which formed was collected and washed well with H2O. The solid was dried and weighed to yield 41.0 g. A 5.0 sample was recrystallized twice from ethanol (utilizing decolorizing carbon) to afford 3.5 g (50%) of 4-(5-methoxy-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile. m.p. 171°-173° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:29].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:29]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Nc1cccc2c1CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc4c3CCC4=O)c2cc1OC
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 4-amino-1-indanone (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.6 ml) was heated at 100° C. for 1 h 45 min. After cooling, the mixture was diluted with water and made alkaline with saturated NaHCO3. The precipitate was collected by filtration, washed with water and dried to give title compound (59 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.CN(C)C.Cl[S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1ccc(CCOCCN)s1
Agent: CN(C)C
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step c) as the hydrochloride salt (1.50 g) was stirred under nitrogen in dichloromethane (25 ml). Trimethylamine (2.21 ml) was added followed by methyl 3-(chlorosulphonyl)propanoate (1.18 g). The mixture was stirred at room temperature overnight. The solution was diluted with a further amount of dichloromethane and the organics washed with dilute hydrochloric acid then water, then dried (MgSO4). The mixture was filtered and the volatiles removed in vacuo to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=O)C.CO.O>C1(C)C=CC=CC=1>[CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:13]
Reactant: CCOC(=O)CCCCCn1ccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=CCCCCCn1ccnc1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Under an atmosphere of nitrogen, 8.8 ml of a 25% (W/V) solution of diisobutylaluminum hydride in toluene was added dropwise to a solution of 2.50 g of 1-(5-ethoxycarbonylpentyl)imidazole in 120 ml of toluene at -70° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added one ml of methanol at -70° C.; and one ml of water at 0° C., then the mixture was stirred at 30° C. for one hour. The reaction mixture was filtered, the filtrate was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (25:1) as eluent to give 1.15 g of the title compound having the following physical characteristics:
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Product: CC(=O)OCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 100 °C

Procedure:
A suspension of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (1.57 gm, 5.5 mmol) in acetic acid (25 mL) was heated at 100° C. for 3-4 hours. The solvent was evaporated. Traces of solvent were removed by chasing with toluene. The residue was dissolved in acetonitrile and diluted with chloroform. Upon standing, product crystallized (0.77 gm), m.p. 173°-175° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:18][CH2:19][C:20]1(O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1(O)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D), 4-(aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (Step A of Example 19) and triethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:45]=1[O:52][CH3:53]>>[CH3:53][O:52][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]([O:50][CH3:51])[C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: COc1cccc(OC)c1OCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4c(OC)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.067 g of 2-(3-bromopropoxy)-1,3-dimethoxybenzene are used to prepare the title compound. Rf=0.20 (2:1 EtOAc-heptane); Rt=5.83.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH3:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=1[CH3:10])=[O:9]
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(O)c1sccc1Br
Product: COc1ccc(NC(=O)c2sccc2Br)c(C)c1
Yield: 75.2 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (6.7 g, 49 mol) was reacted with 2-methyl-4-methoxyaniline (12 g, 53 mmol) to afford the desired product (13 g, 80%) as an orange solid: ESI MS m/z 331 [C12H10FNO2S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[I:21][Si](C)(C)C.II.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O1CCCC1>[I:21][CH:9]1[CH2:8][CH2:7][C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1CCCc2cc(F)ccc2N1
Reactant: C[Si](C)(C)I
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(F)cc2CCC1I
Temperature: -15 °C
Yield: 73 %

Procedure:
7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (411 mg, 2.3 mmol) (Step A) dissolved in a mixture of 7.9 mL of dry methylene chloride and 1.0 mL of dry tetrahydrofuran was treated with 1.62 mL (1.18 g, 11.6 mmol, 5 eq) of triethylamine and the resulting solution cooled to -15° C. Iodotrimethylsilane (0.66 mL, 932 mg, 4.7 mmol, 2 eq) was added followed by 1.183 g of iodine (4.7 mmol, 2 eq) added in small portions over 5 minutes. The mixture was warmed to room temperature over 5 minutes at which time 15 mL of methylene chloride was added followed by 20 mL of 10% aqueous sodium sulfite. The layers were separated and the organic layer washed with 10% sodium sulfite (3×20 mL). The aqueous layer was further extracted with 20 mL of methylene chloride. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The crude product was chromatographed on silica gel, eluting with methylene chloride/methanol (99:1) to afford 511 mg (1.68 mmol, 73%) of the product. 1H NMR (300 MHz, CDCl3): 2.70 (m,3H), 2.93 (m,1H), 4.62 (t,9 Hz,1H), 6.95 (m,3H), 7.86 (br s,1H). FAB-MS: calculated for C10H9FINO 305; found 306 (M+H,100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:25][C@@H:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Agent: BrB(Br)Br
Product: CC[C@@H](N)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 165.8 %

Procedure:
Following General Procedure F, (R)-tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (30 mg, 0.063 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) to afford the desired product (22 mg, 87%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.63-7.56 (m, 2H), 7.53 (d, J=5.4 Hz, 1H), 7.40 (t, J=6.6 Hz, 3H), 7.08 (s, 1H), 6.04 (d, J=5.4 Hz, 1H), 4.31 (dd, J=9.2, 5.9 Hz, 1H), 2.57 (s, 3H), 2.21-2.01 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); ESI MS m/z 383 [C20H17ClN2O2S−H]−; HPLC 96.9%, tR=8.69 min.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N-:35]=[N+]=[N-].[Na+]>CS(C)=O.O.[Cu]I.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>[NH2:35][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Temperature: 110 °C
Yield: 92.3 %

Procedure:
Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (306 mg, 0.56 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane (24 mg, 0.17 mmol), sodium azide (73 mg, 1.12 mmol) and sodium ascorbate (6 mg, 0.028 mmol) were stirred in DMSO-water 1:1 (3 ml) which had been degassed with N2. CuI (1.1 mg, 0.0056 mmol) was added and the tube purged with N2, sealed and heated to 110° C. for 2 h. The mixture turned black and evolution of gas was observed. LCMS after this time indicated 34% conversion to the desired amine and starting material remaining. Additional equivalents of all reagents were added and the reaction was heated to 110° C. for a further 2 h. LCMS after this time indicated 75% conversion to the desired material. The solvents were removed under reduced pressure and the resulting residue was triturated with water. The resulting solid was isolated by filtration and dried to afford the crude product (250 mg, 73% purity by LCMS) (92%). This material was used directly in the next step without further purification.
Reaction SMILES: O=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH2:3][C:4]#[N:5].Cl.[CH3:17][NH2:18].C([O-])(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH3:17][NH:18][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH:3][C:4]#[N:5]
Reactant: CN
Reactant: N#CCC(=O)c1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CNC(=CC#N)c1ccc2ccccc2c1
Yield: 58 %

Procedure:
A solution of β-oxo-2-naphthalenepropionitrile (5.0 g, 0.0256 mol) in toluene is treated with methylamine hydrochloride ()2.6 g, 0.0384 mol), sodium acetate (3.15 g, 0.0386 mol) and a catalytic amount of acetic acid, heated at reflux temperature (fitted with a Dean Stark trap) for 6 hours, cooled, diluted with ethyl acetate and dilute hydrochloric acid. The organic phase is dried over Na2SO4 and concentrated in vacuo to give a residue which is triturated under hexanes to give the title compound as a yellow solid, 3.1 g (58% yield) mp 138° C., identified by IR, 1NHMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6]Br)[CH3:2].[Mg].[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23](=[O:24])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1.II>[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23]([OH:24])([CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOCCCBr
Reactant: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOCCCC1(O)SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Yield: 100.5 %

Procedure:
To a Grignard reagent solution prepared from 3-ethoxypropyl bromide (41.7 g), magnesium metal (shoot, 11.2 g) and iodine (0.2 g) in 110 ml of anhydrous ether and 30 ml of anhydrous benzene, a solution of cis-1,3-dibenzyl-hexahydrothieno[3,4-d]imidazole-2,4-dione ([α]D20 + 91°, 60.0 g) in 700 ml of anhydrous benzene is added with stirring for two and half hours at 25° to 40°C. The mixture is stirred and refluxed at 68° to 73° C for 5 hours. The reaction mixture is decomposed by the addition of 3N sulfuric acid (280 g) below 20°C. The organic layer is washed with water and concentrated in vacuo to give the residual oil of 76 g of cis-1,3-dibenzyl-4-hydroxy-4-(3-ethoxypropyl)-hexahydrothieno[3,4-d]imidazol-2-one. [α]D20 + 17° (C = 1 in CHCl3). IR (Nujol) 3350 cm-1 (OH); 1690 cm-1 (C = O).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:22](Cl)(=[O:26])[C:23](Cl)=[O:24].CO.[C:30](=O)(O)[O-:31].[Na+]>C1COCC1>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:22](=[O:26])[C:23]([O:31][CH3:30])=[O:24])=[CH:15][N:16]3[CH3:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(=O)c1cn(C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-trifluoromethoxyphenyl)-1-methyl-1H-indole (0.304 g, 1.04 mmol) in dry THF (5 mL) under nitrogen at 0° C. was added oxalyl chloride (0.11 ml, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hour. The mixture was cooled in an ice bath. Methanol (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour then poured into excess sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 20-50% ethyl acetate in hexane as an eluant. The title compound was obtained as a cream-colored solid (0.196 g, 50%), mp: 152-153° C. Mass spectrum (+APCI, [M+H]+) m/z 378; 1HNMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 7.95 (t, 1H, J=0.77 Hz), 7.90-7.95 (m, 2H,), 7.65 (dd, 1H, J=8.3 Hz and 1.5 Hz), 7.45 (d, 2H, J=8.6 Hz), 4.0 (s, 3H), and 3.9 ppm (m, 3H).
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])=[CH:44][CH:43]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 60%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:15])[CH2:7][C:8]([CH3:14])([CH3:13])[O:9]2)=[CH:4][CH:3]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-:25].[K+].[K+].[I-].[K+]>CC(C)=O>[C:16]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:15])[CH2:7][C:8]([CH3:13])([CH3:14])[O:9]2)=[CH:4][CH:3]=1)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(O)ccc2c1OC(C)(C)CC2=O
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(OC(=O)c2ccccc2)ccc2c1OC(C)(C)CC2=O
Yield: 82.4 %

Procedure:
The mixture of 10.3 g. of the compound obtained in (1), 8.2 g. of benzyl chloride, 10.2 g. of potassium carbonate, 0.5 g. of potassium iodide, and 100 ml of acetone was refluxed for 2 hours. The mixture was then filtered, and the filtrate was concentrated. Ether was added to the concentrate. The ether layer was washed successively with water, 1 N aqueous sodium hydroxide, and again with water. The solution was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane, to obtain 12.2 g. (yield: 82.4%) of the subject compound.