Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:20])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.053 g, 0.194 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.110 g, 0.386 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 31 mg of yellow solid (42%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.91 (br s, 2H), 4.05-4.00 (m, 2H), 2.89-2.85 (m, 2H), 2.70-2.64 (m, 8H), 2.02-1.97 (m, 2H), 1.90-1.82 (m, 4H). MS (ESI): 383.2 (M+1). ESI-HRMS calculated for C21H27N4SO2 (MH+): 383.1900, Observed: 383.1895.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:10]([CH2:9][CH:8]([C:3]1([CH2:2][NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)[N:12]1[CH:16]=[C:15]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:14]=[N:13]1)#[N:11]
Reactant: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(CN)CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(CNC(=O)c2ccccc2)CCCC1
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of 3-[1-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 μL, 0.060 mol) in DCM (1.0 mL), was added TEA (17 μL, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H2O and ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H2O and ACN containing 0.15% NH4OH) to afford the product (7 mg, 27%).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19]2)=[CH:14][CH:13]=1.[NH2:26][CH2:27][CH2:28][OH:29].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:29][CH2:28][CH2:27][NH:26][C:23]([C:21]1[CH:20]=[N:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[CH3:2])=[CH:17][CH:16]=2)[CH:22]=1)=[O:24]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)O)cn2)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid hydrochloride prepared in Example 2-(1) (1.00 g), 2-aminoethanol (0.400 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.580 g), 1-hydroxybenzotriazole monohydrate (0.460 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=18:1) to give the titled compound (0.920 g) as a colorless solid.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC#Cc1ccc(F)cc1

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 4-(4-fluorophenyl)-3-butyn-1-ol and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated with N-bromosuccinimide (0.852 g, 4.79 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (200 mL), washed with saturated aqueous sodium bisulfite (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.55 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.55 (m, 1.3H), 3.37 (m, 0.7H), 3.2-2.9 (bm, 4H), 1.30 (m, 3H). MS calculated for C14H15BrF3NO2+H: 366, observed: 366.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[OH:33][CH2:34][C:35](O)=[O:36]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:34](=[O:33])[CH2:35][OH:36])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)CO
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: O=C(CO)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 48, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and hydroxyacetic acid, the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:15])=[CH:8][CH:7]=2)=[C:10]([CH3:14])[N:11]=1
Reactant: Cc1ncoc1-c1ccc(C(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
To a solution of Example 38D (4.39 g, 21.0 mmol) in THF (100 mL) at −78° C. was added LiHMDS (1.0 M in THF, 23 ml, 23 mmol) slowly via syringe. The solution was stirred 45 min, and then solid hexachloroethane (5.46 g, 23.1 mmol) was added in one portion. The reaction was allowed to proceed for 24 hr, gradually warming to ambient temperature. The reaction was quenched with half-saturated aq NH4Cl solution, and the product was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 20% EtOAc/hexanes eluant; SF40-240 g column) yielded 3.91 g (76%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (m, 4H), 7.10 (t, J=55.7, 1H), 2.39 (s, 3H). MS (DCI+) m/z 244 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH:19]=4)[CH2:16][N:15]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])=[CH:11][CH:12]=2)=[CH:32][CH:33]=1
Reactant: Brc1ccccn1
Reactant: CS(=O)(=O)CCN1CC(c2cccc(O)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Product: CS(=O)(=O)CCN1CC(c2cccc(Oc3ccccn3)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O

Procedure:
The title compound is prepared as described in Example 269 from Example 290 and 2-bromopyridine. HPLC-MS calculated for C29H26ClN3O5S (M+H+): 564.0, found 564.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[O:7][C:6]2=[O:19].C1O[C:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)([CH:24](Cl)[CH2:25][CH3:26])[O:22]C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][N:11]([CH2:26][CH2:25][CH2:24][C:23](=[O:22])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:10][CH2:9]1)[O:7][C:6]2=[O:19]
Reactant: COc1cc2c(cc1OC)C1(CCNCC1)OC2=O
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Product: COc1cc2c(cc1OC)C1(CCN(CCCC(=O)c3ccc(F)cc3)CC1)OC2=O

Procedure:
Reaction of 1,3-dihydro-5,6-dimethoxyspiro[isobenzofuran-1,4'-piperidine]-3-one and α-chloro-p-fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-5,6-dimethoxy-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine]-3-one.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:21]O>>[Cl:6][C:7]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:21])=[O:10]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl

Procedure:
Concentrated sulphuric acid (20 ml) was added to a suspension of 2-chloro-4-(N-methylsulphonylamino)benzoic acid (10.3 g) in methanol and the mixture was stirred and heated at reflux for 22 hours. It was cooled, evaporated to dryness and diluted with water, extracted with ethyl acetate, washed with aqueous sodium bicarbonate solution, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 2-chloro-4(N-methylsulphonylamino)benzoate(10.0 g) as an off-white solid, NMR (DMSO-d6) 3.15(s,3H) 3.85(s,3H) 7.2(d,1H) 7.3(s,1H) 7.85(d,1H) 10.5(s,1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][OH:14].[H-].[Na+].Br[CH2:18][CH2:19][OH:20].C[O-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:18][CH2:19][OH:20]
Reactant: OCCBr
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
4.49 g (0.0234 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime (VIII-1) are dissolved in 25 ml of dimethylformamide. 1 g (0.025 mol) of 60% strength sodium hydride is added to this solution which is then stirred at room temperature for one hour. 3.1 g (0.0248 mol) of 2-bromoethanol are added and the mixture is stirred at 25° C. for 12 hours. After the addition of 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol, the mixture is stirred at room temperature for 2 hours. A further 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol are added and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate and the organic phase is washed 3 times with 20 ml of 2 N aqueous sodium hydroxide solution. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using diethyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 2.26 g (39.6% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxyethyl)-oxime] 3-(O-methyl-oxime) (II-1) which, according to HPLC, comprises 84.29% of stereoisomer A and 12.58% of stereoisomer B.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: OCCCCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, 4-phenyl-1-butanol and DBU in DME. ES-MS ni/e (%): 355 (M+H+, 100).
Reaction SMILES: C(O)C.[O:4]=[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]=2[CH2:8][CH2:7][CH2:6]1.[BH4-].[Na+]>CC(C)=O>[OH:4][CH:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cccc2c1CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cccc2c1CCCC2O
Reaction time: 4 h

Procedure:
To 200 ml. of ethanol is added 10.9 g. of ethyl 1,2,3,4-tetrahydro-1-oxo-5-naphthoate and while the solution is stirred at room temperature, 950 mg. of sodium borohydride is added. The mixture is stirred for 4 hours, after which 2 ml. of acetone is added. The mixture is further stirred for 30 minutes and, then, the solvent is distilled off under reduced pressure. Following the addition of 30 ml. of 2N hydrochloric acid, the residue is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel(100 g. silica gel; eluted with chloroform). The described procedure gives ethyl 1-hydroxy-1,2,3,4-tetrahydro-5-naphthoate as an oily product.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CS(Cl)(=O)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:24][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCSc1ccncc1
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: c1ccc(CNCCCSc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
In 150 ml of methylene chloride were dissolved 5.22 g (30.8 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.16 ml (37.0 mmol) of triiethylamine, methanesulfonyl chloride [2.86 ml (37.0 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. 2.62 ml (24.0 mmol) of benzylamine was added to the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 10 g of the desired compound (yield: 16.1%, yellow oil).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:33]([CH:30]2[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added cyclopropanesulfonyl chloride (0.096 mmol, 13.55 mg) and the whole stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give the desired product as a clear film (12.0 mg, 0.029 mmol, 30%). MS (ESI): m/z [M+H]− 417.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: CC[Mg]Br
Reactant: COc1cc2nccc(Oc3c(F)cccc3C=O)c2cc1OC
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorobenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added thereto at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:11][C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH:12]2[C:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][C:18]=3[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)[C:10](=[O:32])[N:11]2[C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:37])=[C:21]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=1)#[N:25]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C

Procedure:
A microwave vessel is charged with a mixture of 4-(1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18, 50 mg, 0.10 mmol), 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) and a tip of a spatula of 4-dimethylaminopyridine in toluene (3 mL). Triethylamine (0.1 mL) is added, and the mixture is heated in a microwave at 150° C. for 10 min. Another portion of 4-nitrophenyl chloroformate (31 mg, 0.15 mmol) is added and the mixture is heated again at 150° C. for 20 min. All volatiles are evaporated and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 32 mg; ESI mass spectrum M+H]+=655, Retention time HPLC: 1.10 min (Z017_S04).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].Cl>ClCCl>[C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:25])([CH3:26])[C@@H:20]2[C:27]([OH:29])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Through a solution of 0.250 g (0.503 mmol) of tert-butyl(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was then stoppered and let sit overnight at room temperature. The solvent was evaporated to give 0.192 g of (3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylic acid as a colorless oil. Electrospray Mass Spec 440.1 (M−H)−.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22](OCC)=[O:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:30]>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[NH:21][N:20]=[C:19]([C:22]([NH2:30])=[O:23])[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Product: NC(=O)c1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of ethyl 5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-1H-1,2,4-triazole-3-carboxylate (867 mg) in 0.88 ammonia (25 ml) was stirred at room temperature for 18 h. The mixture was evaporated and the residual solid was washed with boiling methanol to leave the title compound as a white solid (255 mg) m.p. 212°-4° dec.