Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].[CH:17]1(C(O)=O)[CH2:22]CCC[CH2:18]1>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9]([CH:10]1[CH2:11][CH2:22][CH2:17][CH2:18][CH2:12]1)=[O:13])[CH:5]([CH3:7])[CH3:6]
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Reactant: O=C(O)C1CCCCC1
Product: CSC(=O)OOC(OC(=O)C1CCCCC1)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with cyclohexanecarboxylic acid affords O-(1-cyclohexanoyloxyisobutoxy) S-methyl thiocarbonate (16) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20](=O)[CH3:21])[CH:15]=[N:16][CH:17]=1.Cl.CCOCC>C(O)(C)(C)C.C(O)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[C:6]3[C:5](=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[NH:9][C:20]=2[CH3:21])[CH:15]=[N:16][CH:17]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1cncc(Br)c1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cncc(Br)c1
Temperature: 80 °C

Procedure:
(3-Chloro-phenyl)-hydrazine hydrochloride (0.828 g, 4.63 mmol) and 1-(5-bromo-pyridin-3-ylsulfanyl)-propan-2-one (1.1 g, 4.63 mmol) were dissolved in tert-butanol (50 mL) and heated to 80° C. After heating overnight the reaction was cooled and concentrated. Purification on silica gel (0-50% EtOAc in hexanes) revealed the existence of hydrazone intermediates. The material was therefore resubmitted to the reaction conditions, with the addition of HCl in ether (13.9 mmol). After 2 hours acetic acid (2 mL) was added and the reaction continued to stir at 80° C. After stirring for 1 hour the reaction was cooled, concentrated and submitted to silica gel chromatography (10% MeOH in CH2Cl2) to afford a separable mixture of isomers, of which the first to elute from the column was the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([N:19]=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(N=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](/[N:33]=[CH:34]/[C:35]2[S:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:39]=2)=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:60](=O)[CH2:61][CH3:62].C(=O)([O-])O.[Na+]>ClCCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:34][C:35]2[S:36][CH:37]=[C:38]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:39]=2)[CH2:60][CH2:61][CH3:62])=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: CCC=O
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(/N=C/c3nc(-c4ccccc4)cs3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(Cc1nc(-c2ccccc2)cs1)c1ccc(CN(c2ccc(CCC(=O)OC)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
The yellow oil obtained in Example 50 was dissolved in 1,2-dichloroethane (20 mL), sodium triacetoxyborohydride (1.26 g, 6.0 mmol) was added at room temperature by small portions, and the mixture was stirred at room temperature for 60 hr. Propionaldehyde (200 mg, 3.0 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (5%-70% ethyl acetate/hexane) to give the title compound (549 mg, yield 80%, 2 steps) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2].[O:19]1CCOC[CH2:20]1>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[NH:14][C:20]1=[O:19])=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)CCCNc1ccccc1C(N)=O
Solvent: CCO
Product: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g) and N,N'-carbonyldiimidazole (2.52 g) in dioxane (20 ml) was heated to 150° C. After 30 minutes, the mixture was cooled below 80° C., and diluted with ethanol to give crude crystals. Collected crystals were recrystallized from ethanol to give 1-(3-ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (1.53 g) as a crystal.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[Na+].[I-]>C(#N)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:11]2[CH:12]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]2=[O:13])=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(Oc2ccc(F)cc2)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc(Oc2ccc(F)cc2)cn1Cc1ccc(Cl)cc1
Yield: 27 %

Procedure:
According to Scheme 32 Step 1: 5-(4-Fluorophenoxy)-2-methoxypyridine (2.37 mmol, 520 mg), 4-chlorobenzylchloride (3.55 mmol, 603 mg), NaI (2.37 mmol, 356 mg) in acetonitrile (15 mL) was heated at 150° C. for 20 minutes under microwave conditions. The cooled crude reaction washed with water, extracted with AcOEt. The organic layer was collected, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (heptane/AcOEt, 90:10 to CH2Cl2) and then CH2Cl2/acetone 90:10), following HPLC purification yielding 1-(4-chlorobenzyl)-5-(4-fluorophenoxy)pyridin-2(1H)-one (211 mg, 27%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:27][CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[OH:35][CH:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:29][CH2:28][NH:27][C:10]([C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][C:8]=1[CH3:13])=[O:12]
Reactant: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)O
Reactant: CC(C)(C)C(O)CCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCCC(O)C(C)(C)C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example X1) (1.86 g, 7.05 mmol) in tetrahydrofuran (60 ml) are added triethylamine (2.9 ml, 21.1 mol) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.69 g, 7.05 mmol). The mixture is stirred for 15 min at RT, before 1-amino-4,4-dimethylpentan-3-ol (1.02 g, 7.76 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield N-(3-hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X5) (1.30 g, 3.44 mmol, 49%). [M+H]+378.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4C)c3O2)cc1
Yield: 84.1 %

Procedure:
Treatment of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) with 2-methylphenyl boronic acid (0.732 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) generally according to the procedure described for Intermediate 118 afforded 1.3 g (84%) of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.72 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.67 (d, 2H); 7.38 (d, 2H); 7.20 (m, 3H); 7.05 (m, 2H); 5.05 (m, 1H); 4.22 (dd, 2H); 4.13 (dd, 1H); 3.40 (dd, 1H); 3.02 (dd, 1H); 2.05 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[CH:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][SH:21]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH:8]2[C:9]3([CH2:14][C:15](=[O:17])[NH:18][CH2:19][CH2:20][S:21]3)[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCS
Reactant: O=C(O)C=C1CCCCC1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)SCCN1
Temperature: 0 °C
Yield: 52.5 %

Procedure:
A mixture of 2-phenylmethyl-1-carboxymethylenecyclohexane (10 g) and 2-aminoethanethiol (10 g) in N,N-dimethylformamide (10 ml) was refluxed for 20 hours under nitrogen atmosphere. The mixture was cooled to 0° C. and diluted with ethyl acetate (100 ml), and the mixture was washed with 1N hydrochloric acid (100 ml), water (100 ml), a saturated aqueous solution of sodium bicarbonte (100 ml) and brine (100 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane (6.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][P:7](=[O:14])([O:11]CC)[O:8]CC.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][P:7](=[O:8])([OH:11])[OH:14]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Agent: Cl
Product: COc1cc(CP(=O)(O)O)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A suspension of diethyl (3-methoxy-4-nitrobenzyl)phosphonate (Compound 114E, 5.04 g, 16.6 mmol) in concentrated HCl (50.0 mL, 1630 mmol) was heated at 120° C. for a total of 16 h. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. After drying under vacuum for several hours, a solid had precipitated upon standing, giving the title material as a yellow solid, 4.1398 g (96%, 15.913 mmol). 1H NMR (DMSO-d6) δ ppm 7.81 (dd, J=8.3, 0.8 Hz, 1H), 7.23 (t, J=1.9 Hz, 1H), 6.99 (dt, J=8.3, 1.9 Hz, 1H), 5.75 (br s, 3H), 3.89 (s, 5H), 3.10 (d, J=22.0 Hz, 2H). MS (ES+): m/z 248.02 (100) [MH+]; HPLC: tR=1.68 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:18]([O:25][CH3:26])[CH:17]=[C:16]([O:27][CH3:28])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:19]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[C:18]([O:25][CH3:26])[CH:17]=[C:16]([O:27][CH3:28])[C:3]=1[C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Then, 13.05 g of the so-obtained 2'-hydroxy4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone was catalytically reduced by using 410 ml of ethyl acetate and 4.0 g of 5% palladium/carbon according to customary procedures, and after the reaction was conducted for 3 hours, the reaction liquid mixture was filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from methanol to obtain 12.45 g (yield=94.11%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a light-yellow needle.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([OH:17])=O)(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([N:37]([O:38][CH3:39])[CH3:36])=[O:17])(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)Nc1c(C(=O)O)[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1[nH]c2cc(Cl)ccc2c1NC(C)=O
Reaction time: 1 h
Yield: 20 %

Procedure:
To a mixture of (3-acetylamino-6-chloroindole)-2-carboxylic acid (step 3; 280 mg, 1.11 mmol), diphenyl phosphoryl azide (365 mg, 1.33 mmol) and N,O-dimethylhydroxylamine hydrochloride (162 mg, 1.66 mmol) in dimethylformamide (5 ml) was added triethylamine (0.58 ml, 4.16 mmol). After stirring for 1 h, the mixture was poured into water (10 ml) and extracted with diethyl ether (30 ml×2). The combined organic extracts were washed consecutively with water (20 ml×2), saturated sodium bicarbonate (20 ml), brine (20 ml), then dried (MgSO4). Removal of solvent gave the title compound as a brown solid (ca. 20%) which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1
Reactant: CC1(C)OB(CBr)OC1(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OB(CI)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To the mixture of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 8.3 mmol) synthesized in Production Example 2 and acetone (17 ml), sodium iodide (1.9 g, 13 mmol) was added at room temperature, and the obtained reaction mixture was stirred at room temperature for 2 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Hexane was added to the obtained residue, and insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, thereby obtaining the entitled compound (2.2 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 61.3 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(4-((dimethylamino)methyl)phenylamino)quinolin-3-yl)-2-methylpropan-1-one (80 mg, 0.186 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (84 mg, 0.291 mmol) to afford the desired product (58 mg, 61%) as a yellow-green solid: 1H NMR (300 MHz, CD3OD) δ 9.09 (s, 1H), 7.90 (s, 2H), 7.74 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.10 (s, 2H), 3.81 (m, 3H), 2.41 (s, 6H), 1.24 (d, J=6.6, 6H), ESI MS m/z 508, [C28H27Cl2N3O2+H]+; HPLC 99.7% (AUC), tR=11.16 min.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(-c2ccccc2)cc(=O)[nH]1
Product: Cc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
A mixture of 2-methyl-6-phenylpyrimidin-4(3H)-one (15 g) and POCl3 (150 ml) was refluxed under nitrogen for 20 h. The excess POCl3 was distilled off and the residue was diluted with ethyl acetate (500 ml) and washed with 10% solution of sodium bicarbonate (100 ml), water, brine and dried. The solvent was removed under reduced pressure and the residue was purified by chromatography (silica, 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 11 g (67%) of the titled as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:29][CH:30]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1.C(N(C(C)C)CC)(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:35]3[C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH:30]3[CH3:29])=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1COc2ccccc2N1
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1c2ccccc2OCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50 mg, 0.11 mmol), 3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (60 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2CL2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro -N[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=O)[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH:30][C:10]([C:7]3[N:6]=[CH:5][C:4]4[CH:3]=[CH:2][S:1][C:9]=4[CH:8]=3)=[O:12])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=C(O)c1cc2sccc2cn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2sccc2cn1
Yield: 5 %

Procedure:
5.0 mg (2.9%) of thieno[3,2-c]pyridine-6-carboxylicacid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to general procedure A using 54 mg (0.3 mmol) thieno[3,2-c]pyridine-6-carboxylic acid (synthesized in above example), 61 mg (0.25 mmol) intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 1 mL of DMF stirring at 85° C. for 1 h. LCMS: 404 (M+1)+.
Reaction SMILES: ClCCC1C=C([N+]([O-])=O)C=[CH:6][C:5]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1CCCl)(=[O:15])=[O:14]>C(N)(C)C>[CH3:18][CH:19]([NH:22][CH2:6][CH2:5][S:13]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2CCCl)c(CCCl)c1
Solvent: CC(C)N
Product: CC(C)NCCS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 2-chloroethyl-4-nitrophenylsulfone in isopropylamine is stirred at room temperature for about 72 hr. The isopropylamine is removed by evaporation, and the residue is dissolved with agitation in a mixture of methylene chloride and dilute sodium hydroxide. The methylene chloride layer is extracted with dilute sodium hydroxide, and dried over magnesium sulfate. The solvent is removed by evaporation to give 1-methyl-N-[2-[(4-nitrophenyl)sulfonyl]ethyl]ethanamine as an oil.
Reaction SMILES: C([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[CH:11]=[CH:10][CH:9]=2)(=O)C.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]=[C:25]=[O:26])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:24][C:25]([NH:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:5]([OH:4])[N:6]=[CH:7]3)=[O:26])=[CH:21][CH:22]=1
Reactant: CC(=O)Oc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2cnc(O)cc12
Reaction time: 1 h

Procedure:
5-Amino-3-isoquinolinyl acetate in toluene:THF (5:1, 5 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (105 mg). After stirring for 1 hour, the mixture was concentrated under reduced pressure and the residue dissolved in MeOH (20 mL) and treated with K2CO3 (4 eq) and stirred for 16 hours. The mixture was concentrated under reduced pressure and partitioned between CH2Cl2 and water. The aqueous phase was separated and the pH was adjusted to approximately 6 with HCl. The acidified solution was filtered, and the filter cake was dried. The solid was purified by reverse-phase chromatography (using TFA as eluent) to provide the title compound. MS (ESI+) m/z 374, 372 (M+H)+; MS (ESI−) m/z 372, 370 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.33 (d, J 5.8, 2H), 7.06 (m, 1H), 7.29 (m, 3H), 7.57 (m, 3H), 8.07 (d, J 7.8, 1H), 8.48 (s, 1H), 8.80 (s, 1H), 8.87 (s, 1H); Anal. Calcd for C17H14BrN3O2+0.2 TFA: C, 53.08; H, 3.42; N, 10.43. Found: C, 52.91; H, 3.62; N, 10.43.