Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].BrC[CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1
Reactant: BrCCc1ccsn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
(a)(i) A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After stirring for 2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl(thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene/ethyl acetate as eluant gave N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8: H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][C:12]1[CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: Nc1ncccc1Oc1ccc(C(F)(F)F)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine (1.24 g, 4.88 mmol) and CHCl3 (150 mL), cooled to 0° C. and bromine (0.275 mL, 5.37 mmol) was added dropwise. The reaction was stirred for 60 minutes. The reaction was quenched into a saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (2×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel eluting with 20% EtOAc/hexanes. The combined fractions of product were treated with charcoal, filtered through GFF paper and concentrated to afford the title compound (0.850 g, 52.3% yield) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:32])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:26](=[O:29])([OH:28])[OH:27])S(C4C=CC=CC=4)=O)[C@@H:13]([F:30])[C@H:12]3[OH:31])[C:9]=2[N:10]=1.C(N(CCCC)CCCC)CCC.C[Si](Cl)(C)C>CN(C=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:32])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14](/[CH:16]=[CH:17]/[P:26](=[O:27])([OH:29])[OH:28])[C@@H:13]([F:30])[C@H:12]3[OH:31])[C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(S(=O)c3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](/C=C/P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Compound 35.18 (12 mg, 0.025 mmol) was dissolved in anhydrous DMF (4 mL), treated with tributylamine (0.12 mL, 0.5 mmol) and TMSCl (0.063 mL, 0.5 mmol). The mixture was heated to 130° C. for 4 h, cooled to r.t., and then quenched with 2 mL water. The mixture was stirred at r.t for another 2 h and then the solvent was removed under reduced pressure. The residue was washed with 3×20 mL acetonitrile to remove TBA and TMSOH. The acetonitrile washes were discarded and the solid was dissolved in water, subjected to a reverse phase HPLC to give compound 35.19 (6.6 mg, 73% yield). 1HNMR (D2O, 300 MHz) δ 8.40 (s, 1H), 6.57 (m, 1H), 6.13 (t, 1H), 5.92 (d, 1H), 4.90-5.20(m, 3H). 31PNMR (D2O, 300 MHz): 11.815 ppm. LRMS (ESI) MH+ C11H13FN5O6P requires 362.1. Found 362.0.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>O>[OH:10][CH:11]([NH:3][C:2]1[N:4]=[C:5]([NH:6][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])[N:7]=[C:8]([NH2:9])[N:1]=1)[C:12]([Cl:15])([Cl:14])[Cl:13]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1nc(N)nc(N)n1
Solvent: O
Product: Nc1nc(NC(O)C(Cl)(Cl)Cl)nc(NC(O)C(Cl)(Cl)Cl)n1
Reaction time: 3 h
Yield: 81 %

Procedure:
This compound has previously been prepared by Bump and Atkinson [J. Am Chem. Soc., 72, 629 (1950)]. Melamine (44.2 g, 0.3 mole) was added all at once to a stirred solution of chloral (221.2 g, 1.5 mole) dissolved in 375 ml. of water at 70°-80° C. The reaction mixture was stirred for 3 hours and the white precipitated product was filtered to give an 81% yield after drying. The product had a melting point >200° C. and decomposed on further heating.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([CH:17](OS(C(F)(F)F)(=O)=O)[CH3:18])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>ClCCl>[CH2:1]([O:8][C:9]([C:11]1([CH:17]=[CH2:18])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1(C(=O)OCc2ccccc2)CCCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC1(C(=O)OCc2ccccc2)CCCOC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.3 %

Procedure:
A solution of 3-(1-trifluoromethanesulfonyloxy-ethyl)-tetrahydro-pyran-3-carboxylic acid benzyl ester (8.368 mmol) in dichloromethane (100 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 mL, 33.472 mmol). After stirring at room temperature for 2.5 h, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (809.5 mg, 39% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.58-1.80 (m, 3H), 2.29-2.40 (m, 1H), 3.42-3.54 (m, 2H), 3.81 (app dt, J=10.5, 4.2 Hz, 1H), 4.27 (dd, J=11.4, 1.8 Hz, 1H), 5.13-5.27 (m, 4H), 5.77 (dd, J=17.4, 10.9 Hz, 1H), 7.31-7.42 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Br:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Br:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Br)c1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Br)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 74.2 %

Procedure:
To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (0.35 g, 1.2 mmol) in DMF (10 ml) was added 2-bromomethyl-3-bromo-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (0.45 g, 1.1 mmol) and triethyl amine (0.5 ml, 3.3 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (450 mg, 74%): mp, 219-221° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, c-CH2), 1.08-1.14 (m, 2H, c-CH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65-1.70 (m, 1H, c-CH), 2.98 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87 (s, 3H, OCH3), 4.06-4.14 (m, 3H, NCHH+OCH2CH3), 4.19 (dd, J=10, 15 Hz, 1H, CHH), 4.55 (d, J=17 Hz, 1H, CH), 5.75-5.81 (m, 1H, CHN), 6.86-6.96 (m, 3H, Ar), 7.53 (d, J=9 Hz, 1H, Ar), 8.40 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO). 13CNMR (CDCl3): 9.1, 9.2, 15.4, 16.9, 42.2, 49.1, 52.0, 56.1, 56.7, 65.3, 110.1, 112.3, 112.8, 119.5, 119.9, 120.7, 129.7, 136.8, 138.1, 142.0, 149.6, 150.5, 170.0, 173.3; Anal Calcd for C24H27BrN2O6S: C, 52.27; H, 4.94; N, 5.08. Found: C, 52.57; H, 4.68; N, 4.95.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23]([NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2ccccc2n(CC(=O)O)c1=O
Solvent: c1ccncc1
Product: O=C(O)Cn1c(=O)c(NS(=O)(=O)c2ccccc2)cc2ccccc21

Procedure:
2-[3-Amino-2-oxo-2H-quinolin-1-yl]acetic acid, (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removing the pyridine, the residue was recrystallized in acetone to yield a white crystal solid as the product, 2-[3-benzenesulfonylamino-2-oxo-2H-quinolin-1-yl]acetic acid, (EX-4A)(0.117 g, y=41%). HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50° C.): retention time 2.85 min, M+H+=359.2 for formula C17H15N2O2S. 1H NMR (400 MHz, Acetone-d6): d 5.12 (s, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.48-7.63 (m, 4H), 7.75 (dd, J=8, 1.6 Hz, 1H), 7.74 (s, 1H), 8.00-8.03 (m, 2H). 13C NMR (101 MHz, Acetone-d6): d (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129.4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.5 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (15.0 g, 89.8 mmol) in ethanol (300 mL) were added 3-amino-1-propanol (8.23 mL, 107.8 mmol) and sodium carbonate (47.6 g, 449 mmol). The reaction mixture was vigorously stirred at rt for 72 h. Then the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (100% EtOAc) to give the title compound as a white solid (9.5 g, 51%). LC/MS m/z 206.3 (M+H)+; 1H NMR (300 MHz, CD2Cl2) δ 1.85 (quintet, 2H), 3.55 (t, 2H), 3.65 (t, 2H), 4.85-4.98 (br, 2H), 7.85 (d, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:3]([C:2]([NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-tert-butylbenzoyl chloride, the title compound was isolated as a white solid (80 mg). MS (ES): M/Z [M+H]=430. NMR: (400 MHz, DMSO-d6): 1.30 (s, 9H), 1.75 (s, 3H), 5.47 (q, J=17.8 Hz, 2H), 5.51 (d, J=8.3 Hz, 2H), 7.70-7.76 (m, 3H), 8.18 (d, J=1.5 Hz, 1H) and 8.70 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].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>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(CN1CCN(c2ccc(-c3ccccc3)nn2)CC1)N1CCN(C2CCC2)CC1
Temperature: 85 °C

Procedure:
In a sealed vial, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}pyridazine (15.1 mg, 0.04 mmol), phenyl boronic acid (9.8 mg, 0.08 mmol), and Pd(PPh3)4 (2.3 mg, 0.002 mmol) in dioxane (0.7 mL) and 2N K2CO3 (0.1 mL). Degas with N2 and seal the vial. Heat the mixture at 85° C. overnight. Cool and partition between EtOAc (0.5 mL) and 1N NaOH (0.5 mL). Extract the organic phase and place directly on an SCX ion exchange resin cartridge. Wash the resin with EtOAc/MeOH (9:1). Discard this wash. Wash the resin with EtOAc/MeOH/TEA(9:1:1) and collect. Remove the solvent to yield the title compound. 1H NMR (CDCl3) δ 8.00 (dd, 2H) 7.66 (d, 1H), 7.49-7.40 (m, 3H) 6.99 (d, 1H), 3.73 (t, 4H), 3.66-3.63 (m, 4H), 3.26 (s, 2H), 2.75-2.66 (m, 5H), 2.35-2.29 (m, 4H), 1.88-1.84 (m, 2H), 1.74-1.71 (m, 2H) 1.35-1.2 (m, 2H); LC-MS (M+1) 421.05.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Pyridine (40 mL, 492 mmol) was added in a single portion to a chilled solution (0° C.) solution of indole (48 g, 410 mmol) in diethyl ether (820 mL). Ethyl chlorooxoacetate (50 mL, 451 mmol) was added dropwise. The resulting suspension was allowed to warm to ambient temperature over a period of 20 hours. The solid was isolated by filtration and washed with diethyl ether. The solid was combined with water (1 L), stirred for 1 hour, and then isolated by filtration to provide 75 g of ethyl (1H-indol-3-yl)(oxo)acetate.
Reaction SMILES: [C:1]([C:4]1[C:9]([F:10])=[C:8](O)[C:7]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:6]([C:18]#[N:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:4]1[C:9]([F:10])=[C:8]2[O:14][C:13]([CH:15]3[CH2:17][CH2:16]3)=[N:12][C:7]2=[C:6]([C:18]#[N:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(C#N)c(NC(=O)C2CC2)c(O)c1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Temperature: 25 °C
Yield: 71.5 %

Procedure:
N-(4-Acetyl-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)cyclopropanecarboxamide (I-81) (200 mg, 0.72 mmol) was dissolved in toluene (4 ml), pyridinium p-toluenesulfonate (40 mg, 0.14 mmol) was, added, followed by heating under reflux for 21 hours. After cooling to room temperature, this was diluted with ethyl acetate, washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/V) to obtain the entitled compound (133 mg, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])/[C:23]1=[O:41])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:41])=[O:21])[CH3:18]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cc(F)ccc1C)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Yield: 82 %

Procedure:
To a toluene (15 ml) solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (30 ml) was added E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.16 g, 0.45 mmol) prepared in example 145b. The reaction tube was sealed and heated by microwave irradiation at 135° C. for 35 min. After the solution was cooled to room temperature, methanol (25 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 200 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12.[O-:23]Cl=O.[Na+].Cl>O.CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([OH:23])=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C(=O)O)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a stirred solution of NaH2PO4.2H2O (513 mg, 3.3 mmol) in water (3 ml), was added a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.50 mmol) in acetone (6 ml) at 0° C. A solution of NaClO2 (541 mg, 5.98 mmol) in water (3 ml) was added to the reaction mixture at 0° C. and the reaction mixture was warmed to room temperature spontaneously. After 2 hours, 1N HCl solution was added to reach pH=5. The produced solid was filtered and dried with nitrogen gas flow. The title product (440 mg, 84% yield) was used next reaction without further purification. MS m/z: 351 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][O:22]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)([OH:22])[CH3:23])[C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: CC1(c2cccnc2)CO1
Reactant: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)(Cn1c2c(c3cc(Cl)ccc31)C1CCCN1CC2)c1cccnc1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (1.0 g, 4.06 mmol) in DMF (50 mL) was added sodium hydride (60%, 406 mg, 10.15 mmol). After stirring for 10 min., 3-(2-methyloxiran-2-yl)pyridine (823 mg, 6.09 mmol) was added to the reaction mixture, which was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc (2×100 mL). The organic layer was washed with water (5×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue that was crystallized with ethanol-hexane to yield the 1.2 g of 1-(10-chloro-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3,freebase) δ (ppm): 8.70 (s, 1H), 8.49 (d, 1H), 7.62 (d, 1H), 7.36 (s, 1H), 7.12 (m, 2H), 7.02 (d, 1H), 4.17 (q, 2H), 3.86 (t, 1H), 3.19 (m, 1H), 2.86 (m, 1H), 2.74 (m, 3H), 2.41 (m, 2H), 1.85 (m, 3H), 1.7 (s, 3H). Separation by chiral HPLC provides diastereomers II-130a-d.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of 2.42 g of 2,6-dimethylaniline, 7.35 g of hexafluoroacetone hydrate, and 0.04 g of p-toluenesulfonic acid monohydrate was stirred under heating at 100° C. for 5 hours. After the temperature was returned to room temperature, the mixture was diluted with ethyl acetate and washed with a 1N sodium hydroxide aqueous solution. Then, the solvent was distilled off under reduced pressure, and the precipitated crude crystals were washed with a n-hexane-ethyl acetate mixed solvent to obtain 4.47 g (yield 78%) of the title compound as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][N:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][N:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1noc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2noc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-benzisoxazolyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-benzisoxazolyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.