Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=O)=O.[C:25]([C:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:8]2[C:7]([C:26]#[C:25][C:27]3([OH:35])[CH:32]4[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=2)=[CH:16][CH:17]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COc1ccc(Cc2nc(C)ccc2OS(=O)(=O)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: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cc2nc(C)ccc2C#CC2(O)CN3CCC2CC3)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyl trifluoromethane sulfonate, 116 mg of 3-ethynyl-3-quinuclidinol, 147 mg of tetrakis(triphenylphosphine)palladium(0), 24 mg of cuprous iodide, 266 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 3 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 192 mg of the target compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To 2.39 g (10 mmol) of 1-benzhydryl-3-hydroxyazetidine dissolved in 20 ml of pyridine were added 1.46 g (12 mmol) of dimethylaminopyridine. Thereto was added 12.10 g (11 mmol) of p-toluenesulfonyl chloride at -40° C., followed by gradual increase in the temperature and subsequent 1 day of stirring at room temperature. This was mixed with 150 ml of water, extracted with chloroform (100 ml×3) and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (250 ml, ethyl acetate:hexane 1:2) to yield 2.88 g (73%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:22].[Na+]>O1CCOCC1.O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: O=C1Cc2cccc(Oc3ccc4ccccc4c3)c2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccc2ccccc2c1
Reaction time: 72 h
Yield: 54.4 %

Procedure:
A mixture of 2-oxo-7-(β-naphthoxy)indoline (5 g) and sodium hydroxide (1.6 g) in dioxane (40 ml) and water (80 ml) was refluxed with stirring for 72 hrs. After cooling, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in hot ethanol and filtered. The filtrate was evaporated in vacuo, and ethyl acetate was added to the residue. The resultant ethyl acetate solution was heated. The precipitating crystals were collected by filtration and recrystallized from ethanol to give 2-[2-amino-3-(β-naphthoxy)phenyl]acetic acid (2.9 g). This substance was dissolved in an aqueous sodium bicarbonate, and the solution was filtered and lyophilized to give sodium 2-[2-amino-3-(β-naphtoxy)phenyl]acetate (2.8 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[Cl:16])[C:10]([NH2:12])=O>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[Cl:16])[C:10]#[N:12]
Reactant: NC(=O)c1cc(Br)c(Cl)c(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cc(Br)c(Cl)c(Br)c1
Yield: 98 %

Procedure:
(328B1): Phosphoryl trichloride (90 ml, 966 mmol) was added to a suspension of 3,5-dibromo-4-chlorobenzamide (148 g, crude, ˜380 mmol) in acetonitrile (1500 ml) at reflux. The reaction mixture was heated to reflux for additional 90 minutes. The reaction mixture was evaporated to dryness, then partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed one more time with aq. NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness to give 3,5-dibromo-4-chlorobenzonitrile (110 g). The material was used without further purification in the next reaction.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH:13]=[CH2:14]
Reactant: C=CCNCC=C
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCN(CC=C)CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
2-Bromo-1-(3-pyridyl)ethanone hydrobromide (10 g, 23.49 mmol) is added portion wise over 5 minutes to a stirred solution of diallylamine (5.2 mL, 42.29 mmol) and diisopropylethylamine (10.24 mL, 58.73 mmol) in tetrahydrofuran (150 mL) at 0° C. The resulting mixture is stirred at 0° C. for 1 hour. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (300 mL). The layers are separated and the aqueous phase is re-extracted with dichloromethane (300 mL). The combined organic layers are dried over magnesium sulfate and the solvents are removed under reduced pressure to give a crude product which is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (4.75 g, 93%). ES/MS (m/e): 217 (M+1).
Reaction SMILES: [Na].[CH:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.O>CN1CCCC1=O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=1
Reactant: OC1CCCCC1
Reactant: Brc1cncc(Br)c1
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1cncc(OC2CCCCC2)c1
Temperature: 90 °C

Procedure:
Under an argon atmosphere, sodium (750 mg, 31.75 mmol) was added to refluxing cyclohexanol (15 mL). The mixture was refluxed until complete consumption of sodium. The remaining cyclohexanol was removed by a stream of argon to give a white solid, which was dissolved in N-methyl-pyrrolidinone (16 mL). After addition of 3,5-dibromopyridine (3 g, 12.66 mmol), the mixture was stirred and heated at 90° C. for 1 h, then cooled to room temperature, poured into cold (5° C.) water (60 mL), and extracted with diethyl ether (3×50 mL). The combined organic phases were washed with water (25 mL) and then brine (25 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation to give 6.2 g of an orange oil, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate (95/5, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 1.6 g (50%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[Cl:1][C:2]1[C:10]2[C:9]([NH:13][NH2:14])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1csc2ncnc(Cl)c12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncnc2scc(Cl)c12
Reaction time: 24 h

Procedure:
5-Chloro-4-chlorothieno[2,3-d]pyrimidine (1.38 g, 6.73 mmol) and hydrazine monohydrate (5.0 ml, 103 mmol) in absolute ethanol (20 ml) were heated at 75° C. After stirring for 24 h, the solution was concentrated to yield 5-chloro-4-hydrazinylthieno[2,3-d]pyrimidine. Method [6] Retention time 0.35 min by HPLC (M+=201 and 203).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][C:22]=2[O:31][CH3:32])=[C:9]([CH3:33])[N:8]=1.[C:34]([O-])(O)=O.[Na+]>CO>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C@@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16])[C:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:34])=[O:29])=[CH:23][C:22]=2[O:31][CH3:32])=[C:9]([CH3:33])[N:8]=1
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a solution of the product from step (v) (0.09 g) in MeOH (1 mL). The solution was heated at 70° C. for 3 h and then poured into saturated aqueous NaHCO3 solution (10 mL). The aqueous was extracted with EtOAC and the combined organic phases were dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.007 g.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: CC(C)Br
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Br)ccc1OC(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
2-Bromopropane (3.39 mL, 36.2 mmol) was added to a suspension of 4-bromo-2-methoxy-phenol (5 g, 24.1 mmol), K2CO3 (6.67 g, 48.3 mmol) and DMSO (71 mL) at room temperature. The heterogeneous mixture was stirred at 55° C. for 2 hours, then cooled to room temperature and diluted with water. The reaction mixture was extracted with Et2O and the extract was washed successively with 10% aq. NaOH solution, water, then brine solution. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-1-isopropoxy-2-methoxy-benzene (5.83 g, 94%) as a pale yellow oil. ESI-MS m/z calc. 244.0. Found 245.0 (M+1)+; Retention time: 1.93 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03-6.95 (m, 2H), 6.76 (dd, J=7.7, 1.1 Hz, 1H), 4.47 (dt, J=12.2, 6.1 Hz, 1H), 3.84 (s, 3H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11](=[C:21](OC)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:30])(=O)C1C=CC=CC=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1.N>CN(C=O)C>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31]/[C:21](=[C:11]2\[C:10](=[O:30])[NH:9][C:17]3[C:12]\2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=C1C(=O)N(C(=O)c2ccccc2)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 77 from 1-benzoyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-aminobenzonitrile in DMF and subsequent treatment with methanolic ammonia.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH2:22][CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: CN(C)CCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCCC(c1ccncc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 3-dimethylamino-1-propanol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 3-dimethylamino-propan-1-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (44 mg, 48%) as a white solid. The resulting solid was washed with hexane-ether and then, collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15](=[O:31])[C:14]([CH3:17])([CH3:16])[CH2:13][NH:12][C:11]2[N:18]([CH3:22])[N:19]=[C:20]([CH3:21])[C:10]1=2
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)S(=O)C(C)(C)CN2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (0.1 g, 0.28 mmol), Example D.4) in DCM (5 mL) at 0° C., was added m-CPBA (48.5 mg, 0.28 mmol) dissolved in 3 mL DCM (dropwise in 10 min). The resulting mixture was stirred for about 10 min at rt. Subsequently, 5% aqueous sodium bicarbonate (10 mL) and DCM (20 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate followed by 10% MeOH in ethyl acetate) to afford 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine 5-oxide (65 mg, 0.175 mmol, 62%), as white solid: LC-MS (Table 1, Method a) Rt=2.72 (major) and 2.97 (minor), diastereomeric ratio (64:36); m/z 372 (M+H)+; Isomer A: 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (3 H, s) 1.35 (3 H, s) 1.74 (3 H, s) 3.05 (1 H, dd, J=14.7, 6.1 Hz) 3.55 (1 H, dd, J=14.7, 3.8 Hz) 3.66 (3H, s) 3.65-3.69 (1 H, m) 5.67 (1 H, s) 7.17-7.23 (2 H, m) 7.18-7.23 (1 H, m); Isomer B: 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (3 H, s) 1.38 (3 H, s) 1.39 (3 H, s) 3.02 (1 H, dd, J=14.6, 7.1 Hz) 3.51 (1 H, dd, J=14.6, 2.8 Hz) 3.61 (1 H, dd, J=2.8 Hz) 3.64 (3 H, s) 5.50 (1 H, s) 7.34 (1 H, dd, J=8.6, 2.2 Hz) 7.47 (1 H, d, J=2.2 Hz) 7.89 (1 H, d, J=8.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:4]=1.[C:22]1([N:28]2[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C=O)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[N:29][N:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 3-(aminomethyl)-7-fluoro-1-(2-fluorophenyl)quinolin-4(1H)-one (intermediate H) (50 mg, 0.175 mmol), 1-phenyl-1H-pyrazole-4-carboxylic acid (66 mg, 0.349 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (112 mg, 0.24 mmol), triethylamine (53 mg, 0.524 mmol), and DMF (3 mL) was stirred at room temperature overnight. The crude material was purified by flash chromatography (12 g silica gel eluting with 100% hexanes ramped to 70% ethyl acetate in hexanes). The product 1-phenyl-1H-pyrazole-4-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (46 mg, 58%) was obtained as an off-white solid. MS calcd. for C22H14ClF2N3O2 [(M+H)+] 426.1, obsd. 426.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH:27]=O)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:49]6[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:7][CH:6]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)o5)cc4c3C2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)o5)cc4c3C2)nc1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a 0° C. solution of methyl-2-{8-[5-(formyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.12 g, 0.29 mmol) in DCM (20 mL) was added Na(OAc)3BH (0.126 g, 0.59 mmol) and stirred for 10 min. To the reaction mixture was added N-methylpiperzine (0.149 g, 1.49 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was partitioned between DCM (50 mL) and water (25 mL) and the organic layer was separated, washed with water (2×25 mL), dried over sodium sulfate filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g, 69.4%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:18]2[CH2:19][CH:20]3[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]3)[CH2:17]2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C1CC2CCC1CNC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c2ccccc12)N1CC2CCC(CC2)C1

Procedure:
The title compound was prepared by reacting 4-chloro-1-naphthalenesulfonyl chloride (0.27 g) with 3-azabicyclo[3.2.2]nonane (0.13 g) in the presence of DIEA using a procedure similar to that used in Example 5. Yield: 0.33 g, mp: 133.9°-137.3° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)OCCO2
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Temperature: 0 °C

Procedure:
To a stirred solution of 12 g of 1,4-benzodioxane in 40 mL of chloroform cooled to -10° C. under calcium sulfate drying tube was added dropwise over 15 min, 6 mL of chlorosulfonic acid. The mixture was allowed to warm to 20C over 15 min, poured onto 400 mL of ice and extracted into 1 L of chloroform. Drying over MgSO4 and concentration under reduced pressure gave 21.5 g of 1,4-benzodioxane-6-sulfonylchloride as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:5][CH:4]=1.Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:32][CH:33]=1
Reactant: BrCc1ccccn1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cccc(OC(F)(F)F)c4)n3Cc3ccccn3)n(C)c2=O)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (136 mg, 0.295 mmol) in DMF (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (112 mg, 0.442 mmol) followed by potassium carbonate (102 mg, 0.738 mmol). The reaction was stirred at 65° C. for 2 h. The mixture partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (45:1) to give 1-(4-methoxybenzyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (96 mg, 59% yield) as a white solid. LCMS retention time 1.791 min; LCMS MH+ 552.
Reaction SMILES: [C:1](Cl)(=[O:29])[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:13][O:12][C:11]2=[O:26])=[CH:5][C:4]=1[O:27][CH3:28].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[NH4+].[Cl-]>C(Cl)Cl>[N:31]1([C:1]([O:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]3[C@@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH2:13][O:12][C:11]3=[O:26])=[CH:5][C:4]=2[O:27][CH3:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)Cl)c(OC)c2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CCCC3)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
To the above solution 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl carbonochloridate (124 mg, 0.33 mmol, 1.0 eq) in DCM (15 mL) was added TEA (67 mg, 0.66 mmol, 2.0 eq), followed by pyrrolidine (65 mg, 0.60 mmol, 1.5 eq) at 0° C. The mixture was stirred at rt over 2 days, basified with sat. aq. NH4Cl (30 mL), and extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl pyrrolidine-1-carboxylate (71.0 mg, 45.4% from two steps). LRMS (M+H+) m/z calculated 470.2, found 469.9. 1H NMR (CDCl3, 400 MHz) δ 7.00 (d, 1H), 6.74-6.78 (m, 2H), 6.64-6.70 (m, 1H), 6.50-6.56 (m, 2H), 4.12-4.17 (m, 1H), 3.82-3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.56-3.60 (m, 2H), 3.44-3.48 (m, 2H), 2.97 (d, 2H), 2.48-2.68 (m, 4H), 1.90-1.98 (m, 4H).