Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:4]([I:25])[C:3]=1[OH:26].[CH3:27]I>>[CH3:27][O:26][C:3]1[C:2]([I:1])=[CH:7][C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][C:4]=1[I:25]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1
Reactant: CI
Product: COc1c(I)cc(C(=O)NCCCCCCCCc2ccccc2)cc1I

Procedure:
The title compound was prepared as a solid (0.691 g, 94%) from 2,6-diiodo-4-(8-phenyl-octylcarbamoyl)phenol using methyl iodide and a procedure similar to step 4 of Example 93; 1H NMR (DMSO-d6) δ 1.19-1.34 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.59 (m, 2H), 3.21 (dd, J=6.4, 14.1 Hz, 2H), 3.78 (s, 3H), 7.10-7.21 (m, 3H), 7.21-7.31 (m 2H), 8.28 (s, 2H), 8.53 (t, J=5.6 Hz, 1H); mass spectrum [(+) ESI], m/z 592 (M+H)+, 614 (M+Na)+.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][Br:17])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1N(C(C)=O)C(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1N(C(C)=O)C(C)=O
Yield: 63.6 %

Procedure:
A mixture of N-acetyl-N-(2-methoxy-6-methylphenyl)acetamide (25.0 g, 0.11 mol), N-bromosuccinimide (20.1 g, 0.11 mol), and benzoyl peroxide (4.5 g, 0.019 mol) in carbon tetrachloride (300 mL) was stirred under reflux for 3 hours. The solution was cooled, filtered, and evaporated, and the residual solid was crystallized from ethyl acetate:hexane to give 21.0 g of N-acetyl-N-(2-(bromomethyl)-6-methoxyphenyl)acetamide, 95% pure by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16]O)=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:26])=O>ClCCl>[Cl:1][C:2]1[C:11]([C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][Cl:26])=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NC(C)(C)CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NC(C)(C)CCl)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 6.9 g (20 mmol) of methyl 2-chloro-3-(1-hydroxy-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoate and 5 ml of thionyl chloride was stirred at room temperature for 6 hours. The solution was diluted with 50 ml of dichloromethane and subsequently concentrated. The residue was dissolved in 20 ml of dichloromethane. Addition of cyclohexane resulted in the formation of a crystalline precipitate which was filtered off with suction and dried. 6.4 g (88% of theory) of methyl 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](O)[CH3:5].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([Cl:14])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1c(F)cccc1Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1c(F)cccc1Cl
Yield: 92.6 %

Procedure:
2-chloro-6-fluoro-alpha-methylbenzyl alcohol of (B) (45.1 g, 0.26 mol) is dissolved in chloroform (70 ml), and thionyl chloride (61.5 g, 0.52 mol) is added over a period of 30 minutes. The resultant mixture is refluxed for 16 hours. Excess thionyl chloroform are then removed on a rotary evaporator, resulting in pure title product (46.2 g, 92.6%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[C:19]1([CH2:29][CH2:30][C:31]([N:14]2[C@@H:13]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:17][O:16][C:15]2=[O:18])=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCc1cccc2ccccc12
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCc1cccc2ccccc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
14.8 mmole of butyllithium in hexane were added dropwise to a solution of 2.63 g (14.8 mmole) of (S)-(-)-4-benzyl-2-oxazolidinone dissolved in 50 ml of anhydrous tetrahydrofuran at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at this temperature, and then 2.95 g (13.5 mmole) of 1-naphthylpropionyl chloride in 15 ml of anhydrous tetrahydrofuran were slowly added dropwise at the same temperature=the mixture was then stirred for 3 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then freed from the solvent by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: a 1: 4 by volume mixture of ethyl acetate and hexane), to afford 4.65 g (96%) of the title compound as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Cl:26][C:4]1[O:5][C:6]([C:7]2[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: C=C(C)[C@H]1CC=C(c2ocnc2C)CC1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)[C@H]1CC=C(c2oc(Cl)nc2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of Example 32A (0.55 g, 2.7 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1 M in THF, 3.25 mL, 3.25 mmol) dropwise over a period of 6-8 min. After 30 min hexachloroethane (1.28 g, 5.41 mmol) was added at once as a solid and the mixture was left to stir overnight warming to ambient temperature. The mixture was diluted with Et2O and washed with aqueous NH4Cl solution and water. The organic layer was separated and concentrated in vacuo, and the residue chromatographed on silica gel with EtOAc/hexanes (0%-20%) to yield 0.47 g (73%) of the title compound as an oil. 1H NMR (300 MHz, DMSO-d6) δ 6.11 (m, 1H), 4.74 (m, 2H), 2.48-2.24 (m, 3H), 2.23-2.00 (m, 5H), 1.92-1.82 (m, 1H), 1.73 (s, 3H), 1.57-1.41 (m, 1H). MS (ESI+) m/z 238 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6].Cl[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6])=[O:17]
Reactant: COC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (2.0 g) was dissolved in water (34 ml). A solution (50 ml) of methyl chloroformate (0.858 ml) in toluene was added to the obtained solution. Further, an aqueous solution (15 ml) of sodium hydrogencarbonate (1.44 g) was added dropwise to the obtained mixture. They were stirred at room temperature for 1 hour to conduct the reaction. After the extraction with toluene twice and with ethyl acetate twice, the organic layers were combined together. The solvents were evaporated under reduced pressure. n-Hexane and 2-propanol were added to the residue. The obtained mixture was heated to 50° C. to obtain a homogeneous solution, which was cooled to 10° C. to form crystals. The crystals were taken by the filtration, washed with cold 2-propanol (6 ml) and then dried to obtain (3S)-3-methoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.70 g) in a yield of 78%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1
Reactant: Cc1sc2cc(CCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1sc2cc(CCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propan-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl ester as yellow oil, MS: 428 (M+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[K+]>CO.[Pd]>[C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccccc2c(O)nn1-c1ccc(-c2ccccc2)cc1
Yield: 74.2 %

Procedure:
4-Hydroxy-2-(4-iodophenyl)-2H-phthalazin-1-one (0.1 g, 0.3 mmol), phenyl boronic acid (0.04 g, 3 mmol), palladium black (0.02 g, 0.2 mmol) and KF (0.1 g, 18 mmol) were dissolved in MeOH (2 ml) and heated at reflux for 7 h. Removal of supernatant palladium by filtration, extraction with H2O and subsequent filtration of the precipitated solid yielded the desired title compound (0.07 g, 78% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.88 (1H, s), 8.33 (1H, d), 7.89–8.03 (3H, m), 7.78–7.86 (6H, m), 7.50 (2H, t), 7.39 (1H, t),; MS (ESI+)=315.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[O:23]1[CH2:26][CH:25]([CH2:27][NH2:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:28][CH2:27][CH:25]4[CH2:26][O:23][CH2:24]4)=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Reactant: NCC1COC1
Product: NC(=O)c1nc2n(c1C(=O)NCC1COC1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (55 mg) was reacted with oxetan-3-ylmethanamine similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-(oxetan-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 13 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(oxetan-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 443 (M)+. 1H NMR (400 MHz, DMSO) δ 11.37 (t, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 5.05-4.93 (m, 2H), 4.68-4.61 (m, 2H), 4.58-4.50 (m, 2H), 4.35 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.1 Hz, 2H), 3.21-3.13 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([NH:29][C:30](=[O:40])[C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)=[O:32])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:1][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][C:31](=[O:32])[C:30]([NH:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:40]
Reactant: CCCCNC(=O)C(=O)NCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCNC(=O)C(=O)NCCCCCBr
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of carbon tetrabromide (51 mg, 0.15 mmol) in CH2Cl2 (5 mL) was stirred into a 0° C. solution of triphenylphosphine (48 mg, 0.18 mmol) and N1-n-butyl-N2-(5-hydroxypentyl)oxalamide (30 mg, 0.130 mmol) in dry CH2Cl2 (5 mL) under an argon atmosphere. After 2 h, the reaction mixture was washed with water (5 mL), brine (10 mL), dried over anhydrous Na2SO4, and all volatiles were removed under reduced pressure. The residue was purified by SiO2 column chromatography using EtOAc/hexane (1:4) to give compound the title compound (32 mg, 84%) as a colorless solid, mp 109-110° C. TLC: 50% EtOAc/hexanes, Rf˜0.50; 1H NMR (300 MHz) δ 7.55 (br s, NH, 1H), 7.50 (br s, —NH, 1H), 3.40 (t, J=6.0 Hz, 2H), 3.25-3.35 (m, 4H), 1.80-1.85 (m, 2H), 1.40-1.60 (m, 6H), 1.25-1.35 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 160.30, 160.15, 39.65, 33.65, 32.45, 31.40, 28.60, 25.60, 20.20, 13.90. HRMS calcd for C11H22BrN2O2[M+1]+ 293.0865. found 293.0870.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([N:19]1[C:20]2=[CH:26][S:25][CH:24]=[C:21]2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCn2c(=O)c3cscc3n(C(C)=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (1.0 g, 2.6 mmol) in methylene chloride (50 ml) was cooled by an external ice bath and triethylamine (0.393 g, 3.88 mmol) and acetyl chloride (0.305 g, 3.88 mmol) were added. After stirring for 1 hour, the mixture was warmed to room temperature and quenched with water (10 ml). The separated organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solution was concentrated in vacuo, treated with toluene (10 ml) and reconcentrated to give the product (0.93 g, 83.5% yield) which was recrystallized from methylene chloride-hexanes to give the analytical sample as light brown crystals, mp 128°-129° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:29]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Product: COc1ccc(Oc2ccc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3c2)cc1

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=391.9.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[N:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[BH4-].[Na+].O>C(O)C>[C@@H:1]1([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC1=NC(=O)N([C@H]2C[C@H](O)[C@@H](CO)O2)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
Method A (Reduction of 2). To a suspension of 2′-deoxy-5-azacytidine (2) (0.045 g, 0.2 mmol) in 96% ethanol (2.9 mL) was added NaBH4 (40 mg, 1.06 mmol), and the mixture was stirred for 10 min at RT. Water (4 mL) was added to the mixture giving a clear solution that was directly used for RP HPLC purification using a gradient of MeCN in 0.1 M triethylammonium bicarbonate buffer. The main fraction after evaporation provided 0.04 g of 9 as a solid. MS ES+ 231 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C=C(c2ccccc2)c2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc21
Yield: 78.2 %

Procedure:
Methyl 4-[[(1,1-dimethyl-3-phenyl-1H-inden-5-yl)amino]carbonyl]benzoate (325 mg, 0.82 mmol), 4.1 mL of 2N NaOH in 10 mL of tetrahydrofuran and 10 mL of methanol were stirred for 2 hours. The mixture was concentrated and acidified with 1N HCl (20 mL), extracted with ethyl acetate (35 mL×2). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in ether-hexane to give 246 mg (78% yield) of the title compound as white solids; NMR (DMSO-d6) δ1.35 (s, 6H), 6.58 (s, 1H), 7.38-7.70 (m, 7H), 7.73 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 8.04 (s, 4H), 10.38 (bs, 1H), 13.25 (bs, 1H); MS m/e 384 (MH+).
Reaction SMILES: [Sn](Cl)Cl.[N+](=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N-].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[C:17]([C:18](=[O:19])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
To a suspension of anhydrous tin (II) chloride (2.5 g, 13.2 mmol) in 150 mL of methylene chloride was added ethyl diazoacetate (8.3 g, 72.8 mmol). Then 3-nitrobenzaldehyde (10.0 g, 66.2 mmol) was added as a solid in small portions over 30 min. The resulting suspension was stirred at room temperature for 24 h. Additional tin (II) chloride (2.5 g) was added and the reaction was stirred an additional 24 h. The reaction was concentrated in vacuo, diluted with ethyl acetate, washed with water (2 times) and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 4:1 hexanes/ethyl acetate) to afford 5 g (32%) of the title compound. 1H NMR (CDCl3) (approximately 12:1 mixture of enol and keto tautomers, data for enol only) δ: 12.6 (s, 1H); 8.60 (t, 1H, J=1.8 Hz); 8.3 (m, 1H); 8.1 (m, 1H); 7.62 (t, 1H, J=7.9 Hz) 5.77 (s, 1H); 4.30 (q, 2H, J=7.2 Hz); 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1)#[N:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C(O)(C)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:5]=1)#[N:2]
Reactant: Clc1ccncc1
Reactant: N#CCc1cn(N)c2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: N#CCc1cn(Nc2ccncc2)c2ccccc12

Procedure:
The title compound was prepared from 3-cyanomethyl-1H-indol-1-amine and 4-chloropyridine hydrochloride in isopropanol at 90° C. for 6 hours in substantially the same manner as in Example 1, m.p. 80°-83° C.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:32][C:29]2[S:30][CH:31]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:28]=2)=[O:12])=[CH:13][CH:14]=1)(=[O:4])=[O:5]
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-methyl-N-phenylsulfamoyl)benzoic acid (16) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-methyl-N-phenylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an orange solid. Yield: 31 mg (24%). 1H-NMR: 8.63-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.40-7.30 (m, 4H), 7.13 (d, J=7.0 Hz, 2H), 3.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:33][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CC(C)(C)CN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NCC(C)(C)C)c(=O)n12
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
A mixture containing 8.16 g (0.04 mole) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.25 ml (0.04 mol) of methyl chloroformate in 20 ml of chloroform is dropped to the above solution at -16° C. during 10 minutes. After stirring for 5 minutes, 3.83 g (0.044 mol) of neopentylamine dissolved in 10 ml of chloroform are dropped to the above solution at -10° C. during 5 minutes. After stirring at -10° C. for 1 hour, the reaction mixture is washed 3 times with 80 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 80 ml of water each. The organic phase is dried over anhydrous sodium sulfate and then evaporated to give 6.8 g (62.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 191°-194° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)=[CH:10][C:5]2=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[C:3]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:4]=2[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[S:8][C:9]=1[C:11]1[CH:15]=[N:14][NH:13][CH:12]=1
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirred solution of ethyl 6-methyl-4-[(phenylsulfonyl)amino]-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 68) (5.8 g, 13.11 mmol) in CHCl3 (160 mL) at 60° C. was added bromine (0.81 mL, 15.73 mmol), pre-diluted in CHCl3 (36 mL), dropwise. The resulting mixture was stirred at 60° C. for ca. 1 h and then cooled to RT. The reaction mixture was then concentrated and the residue triturated with water (50 mL 3) and dried, to give the title compound (6.1 g). LCMS (A) m/z: 521/523 [M+1]+, Rt 1.11 min (acidic).