Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[C:30]1([S:36][CH2:11][CH2:12][C:13]2([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:14][CH2:15]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(OC3CCCCO3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(SCCC2(OC3CCCCO3)CC2)cc1

Procedure:
2-[1-(2-p-Toluenesulphonyloxyethyl)cyclopropyloxy]tetrahydro-4H-pyran (Compound 4) (1.30 g) was dissolved in a premixed, stirred solution of potassium tert-butoxide (0.45 g) and thiophenol (0.50 g) in N,N-dimethylformamide (10 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ether (50 ml) and water. The organic layer was washed consecutively with 2N sodium hydroxide solution, water, and brine. Drying and concentration in vacuo gave a residue which was purified by chromatography (50 g silica gel; 10% ether in petroleum ether as eluant) to give 2-[1-(2-phenylthioethyl)cyclopropyloxy]tetrahydro-4H-pyran. Distillation of a portion gave an analytical sample, b.p. 121°-122° C./0.1 mmHg. (Found: C, 69.07; H, 8.01; S, 11.31. C16H22O2S requires C, 69.03; H, 7.97; S, 11.52%).
Reaction SMILES: C(C1C=C(C(C)(C)C)C=C(CNC2C(Br)=CC=CC=2Br)C=1O)(C)(C)C.[BH4-].[Na+].[C:28]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([CH:42]=[N:43][C:44]2[C:49]([F:50])=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=2[F:54])[C:33]=1[OH:55])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([CH2:42][NH:43][C:44]2[C:49]([F:50])=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=2[F:54])[C:33]=1[OH:55])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(C=Nc2c(F)c(F)c(F)c(F)c2F)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(CNc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1cc(CNc2c(F)c(F)c(F)c(F)c2F)c(O)c(C(C)(C)C)c1

Procedure:
Using an analogous procedure to the synthesis of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)amino]methyl]phenol described above, NaBH4 (1.2 g) was added to a solution of 2,4-bis(tert-butyl)-6-[[(2,3,4,5,6-pentafluorophenyl)imino]methyl]phenol (0.5 g, 1.25 mmol). The product was isolated as an air sensitive white solid, and stored under nitrogen. Yield 0.48 g, 95%.
Reaction SMILES: [C:1]([C:9]1[S:13][CH:12]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>>[C:1]([C:9]1[S:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1csc(C(=O)c2ccccc2)c1
Reactant: CO
Product: COC(=O)Cc1csc(C(=O)c2ccccc2)c1

Procedure:
9.8 gm of raw 5-benzoyl-thiophene-3-acetic acid were dissolved in 150 cc of methanol. A stream of gaseous hydrochloric acid was bubbled through this solution until the same was saturated. The methanol was evaporated and the residue was taken up in ether. The ethereal phase was washed with an aqueous 10% potassium carbonate solution, then with water until the wash waters were neutral. Thereafter, the ethereal phase was dried over magnesium sulfate, treated with carbon black, filtered and the ether was evaporated. After distillation, 5.45 gm of methyl 5-benzoyl-thiophene-3-acetate were obtained in the form of a colorless liquid, soluble in ether and insoluble in water, boiling at 170° -172° C. under 0.2 mm of Hg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.O>ClCCl>[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([NH:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH:19]=[N:20][CH:21]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cncc(C#Cc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Add methanesulfonyl chloride (0.035 mL, 0.45 mmol) to a solution of 5-phenylethynyl-pyridin-3-ylamine dihydrochloride, (prepared as described in EXAMPLE 155), (0.120 g, 0.45 mmol) and pyridine (0.075 mL, 0.90 mmol) in dichloromethane (2.5 mL) at 0° C. Warm to room temperature and stir overnight. Add pyridine (0.020 mL, 0.24 mmol) and methanesulfonyl chloride (0.010 mL, 0.11 mmol), stir for 20 h and add water. Separate the layers and concentrate the organic phase. Purify by silica gel chromatography, eluting with 1.1 hexanes:ethyl acetate, to give the title compound (0.091 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:19][CH2:20][CH2:21][O:22][C:23]1[C:30]([CH3:31])=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[CH3:32]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:17]([Cl:18])[CH:16]=[CH:15][CH:14]=3)[N:1]=[C:27]2[C:26]2[CH:29]=[C:30]([CH3:31])[C:23]([O:22][CH2:21][CH2:20][OH:19])=[C:24]([CH3:32])[CH:25]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1c(Cl)cccc1C(=O)Nc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3c(Cl)cccc3c(=O)n2-c2ccc(Br)cc2)cc(C)c1OCCO

Procedure:
To a solution of 2-amino-N-(4-bromophenyl)-3-chlorobenzamide (0.52 g, 1.60 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.31 g, 1.60 mmol) in anhydrous ethanol (20 mL), anhydrous copper (II) chloride (0.86 g, 6.40 mmol) was added and the reaction mixture was refluxed for 16 hours. The solvent was evaporated in vacuo, water (100 mL) was then added, and the product was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with water (2×100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude compound was purified by the Simpliflash system (20-40% ethyl acetate in hexanes as eluent), to give the title compound as a white solid. Yield 0.37 g (46%). MP 185-186° C. 1H-NMR (400 MHz, CDCl3) 8.25 (d, J=8.20 Hz, 1H) 7.89 (d, J=7.42 Hz, 1H) 7.56-7.34 (m, 3H) 7.03 (t, J=4.29 Hz, 4H), 4.06-3.87 (m, 2H) 3.87-3.74 (m, 2H) 2.18 (s, 6H) 2.11-1.95 (m, 1H). MS (ES+) m/z: 499.36, 501.38 (100%), 503.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.[C:43](=[NH:56])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23]([N:56]=[C:43]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C

Procedure:
To a solution of (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A8A) (1.2 mmol) in toluene (15 ml) was added subsequently at 22° C. and under a argon atmosphere benzophenone imine (2.4 mmol), sodium tert-butoxide (3.6 mmol) and 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.12 mmol). To the mixture was added tris(dibenzylideneacetone) dipalladium chloroform adduct (0.036 mmol), the tube was sealed and heated to 105° C. for 3 h. The mixture was cooled to 22° C., partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer was dried and evaporated to give the crude (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (A9A) as a yellow oil. MS (ISN): m/z=738.5 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28]CCCCC.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Reactant: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane washed 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Brown semi-solid. Yield: 150 mg (36%); 407 (M+H); 1H NMR: δ 7.91(1H, m), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 3.77(3H,s), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[CH:29]1([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:39]3[CH2:40][CH2:41][CH:36]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:37][CH2:38]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(C2CCCCC2)CC1
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Product: CC(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C4CCCCC4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide (as prepared in Example 90, Step A) and bicyclohexyl-4-one using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:23])([C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])=O)[NH:3]1.C[S:25]P1(=S)SP(=S)(SC)S1>C(COC)OC>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:23])([C:8](=[S:25])[NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])[NH:3]1
Reactant: CC1=CC(C)(C(=O)Nc2cccc3c2C(C)CC3(C)C)NN1C
Reactant: CSP1(=S)SP(=S)(SC)S1
Solvent: COCCOC
Product: CC1=CC(C)(C(=S)Nc2cccc3c2C(C)CC3(C)C)NN1C
Yield: 84.7 %

Procedure:
To a solution of 1.0 g of 1,3,5-trimethyl-N-(1,1,3-trimethyl-4-indanyl)pyrazolecarboxamide in 20 ml of dimethoxyethane was added 914 mg of 2,4-bis(methylthio)-1,3,2,4-dithiadiphosphetan-2,4-disulfide with stirring, followed by stirring for 10 hours at room temperature and for 1 hour at 50° C. After cooling, the reaction mixture was chromatographed on silica gel to obtain 0.89 g of 1,3,5-trimethyl-N-(1,1,3-trimethylindane-4-yl)pyrazole carbothioamide (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OCCCl)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:12]([O:11][CH2:15][CH2:14][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])[CH3:13]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: CCOCCn1c(Cl)nc2ccccc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Combine 2-chloro-1H-benzimidazole (15.3 g, 100 mmol) and tetrahydrofuran (300 mL). Cool to −70° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (200 mL, 0.5 M in toluene, 100 mmol). After 30 minutes, add 2-chloroethyl ethyl ether (22.2 g, 200 mmol) and tetrabutylammonium bromide (0.5 g). Warm to ambient temperature and heat to reflux. After 12 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[N:8][C:7]=1[C:19]([OH:21])=[O:20].[CH2:22](O)[CH3:23]>>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[N:8][C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCO
Reactant: O=C(O)c1nnc2ccc([N+](=O)[O-])cc2c1O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc2ccc([N+](=O)[O-])cc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethanol (200 ml.) was stirred at -40° C. and thionyl chloride (15 ml.) was added dropwise during 5 minutes. After a further 10 minutes at -40° C., 4-hydroxy-6-nitrocinnolin-3-yl carboxylic acid (10 g.) was added. The mixture was stirred overnight and allowed to warm to room temperature. The suspension was heated under reflux on a steam bath for 1 hour, and then kept at 0° C. for several hours. The solid was filtered off, and washed successively with ethanol (2 × 30 ml.) and ether (100 ml.) to give ethyl 4-hydroxy-6-nitrocinnolin-3-yl carboxylate, m.p. 294°-296° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].C(O)(=O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CCOCC.O>[CH:13]1([NH:16][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: C=Cc1ccncc1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: c1cc(CCNC2CC2)ccn1

Procedure:
4-Vinyl pyridine (50 mmol), glacial acetic acid (3 ml), cyclopropylamine (4.28 g, 75 mmol) and water (12.8 ml) were heated at 50° C. for 22 hours. The crude reaction products were added to a vigorously stirred mixture of ether and saturated aqueous NaHCO3. After partitioning, the organic phase was washed with water, brine and dried. Filtered and solvents removed under vacuum. The residue was further distilled under vacuum (Kugelrohr) and the product amine collected. NMR (CDCl3) 8.45 (m, 2H), 7.05 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.07 (m, 1H), 1.37 (m, 2H), 1.25 (m, 2H); m/z 163.17.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:23]=[N:24][C:25]([N:29]([CH3:31])[CH3:30])=[CH:26][C:27]=4[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:32]([OH:35])[CH2:33][CH3:34])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:35][CH:32]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[N:24][C:25]([N:29]([CH3:30])[CH3:31])=[CH:26][C:27]=4[CH3:28])[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:33][CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
Acetic anhydride (142 μL, 1.50 mmol) was added to a stirred solution of 1-{9-chloro-1-[6-(dimethylamino)-4-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (200 mg, 0.500 mmol) in pyridine (1.6 mL) at room temperature, and the mixture was stirred at room temperature for 19 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (168 mg, 0.380 mmol, 76%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH:14][CH:15]=[O:16])=[CH:9][CH:8]=1.[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][NH:14][CH:15]=[O:16])=[CH:11][CH:12]=2)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=CNNc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Temperature: -5 °C

Procedure:
200 ml of acetonitrile and 200 ml of N,N-dimethylformamide were added to 60.4 g of 2-(4-aminophenyl)-1-formylhydrazine to be dissolved, followed by cooling to -5° C. 65.6 g of metanitrophenyl isocyanate dissolved in 200 ml of acetonitrile was added dropwise thereto. During this dropwise addition, the solution was cooled with stirring so that the temperature thereof would not exceed -5° C. A further 300 ml of acetonitrile was added at 0° C., and after stirring for 3 hours, formed crystals were filtered and washed with acetonitrile and then with methanol. The thus-obtained crystals were dissolved in 1 liter of N,N-dimethylformamide, the undissolved portion was filtered off, and 3 liters of methanol was added to the filtrate, followed by cooling to form crystals. The thus-formed crystals were then filtered and washed with acetonitrile and then methanol. The yield was 98.5 g.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[Cl:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3c(-c4ccccc4)c[nH]c3c2)ccc1Cl
Temperature: 130 °C

Procedure:
To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.039 g of phenylboronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried (magnesium sulfate) and concentrated to 0.094 g of crude product. Purification via flash chromatography on silica gel (98:2 methylene chloride/methanol) afforded 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide as a tan powder. MS (m/z): 409 (M−1); Rf 0.22 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[NH4+].[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[NH:23][C:22]2=[O:29])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]>C(O)(=O)C>[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[C:25]([S:3][C:4]#[N:5])=[C:24]([CH3:28])[NH:23][C:22]2=[O:29])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1SC#N
Temperature: 25 °C

Procedure:
1.86 g of bromine in 10 ml of acetic acid are added dropwise with stirring to 2.1 g of ammonium thiocyanate in 80 ml of acetic acid at 10°-15° C. during 15 minutes. Then 1.5 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 15 ml of acetic acid are added dropwise at 10°-15° C. during 5 minutes, and the reaction mixture is stirred for a further hour at room temperature and thereafter substantially evaporated under reduced pressure. The residue is dissolved in ethyl acetate, the solid material filtered off under suction and the filtrate washed with aqueous sodium bicarbonate solution and thereafter with water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (3:1) as eluent. The product is recrystallized from methylene chloride/diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-5-thiocyanato-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 159°-161° C., is obtained.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH:13]=[N:14][OH:15].[C:20]([C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:20]([C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15][N:14]=[C:13]([C:12]2[CH:11]=[C:10]([F:9])[CH:18]=[C:17]([F:19])[CH:16]=2)[CH2:28]1)#[N:21]
Reactant: C=C(C#N)C(=O)OCC
Reactant: ON=Cc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CC(c2cc(F)cc(F)c2)=NO1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
NCS (850 mg, 6.37 mmol) was added to a solution of 3,5-difluorobenzaldehyde oxime (1.00 g, 6.37 mmol) in DMF (60 ml), and the mixture was stirred at 40° C. for 1 h. Heating was then switched off, and ethyl 2-cyanoacrylate (1.20 g, 9.55 mmol) and NaHCO3 (561 mg, 6.68 mmol) were added. The mixture was stirred at RT for 2 h, and water (400 ml) was then added. The mixture was extracted with MTBE (3×50 ml), and the combined organic phases were washed with dilute sulfuric acid (0.5 M, ml), dried over Na2SO4 and concentrated. Chromatography of the residue on silica gel using the mobile phase heptane/EtOAc gave 810 mg of slightly contaminated ethyl 5-cyano-3-(3,5-difluorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate, which was used without further purification.