Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11]N(C)C)=[CH:5][NH:6]2.[OH-].[Na+].C(O)(=O)C.[N+:21]([CH:24]([CH3:26])[CH3:25])([O-:23])=[O:22]>C(OCC)(=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:24]([CH3:26])([N+:21]([O-:23])=[O:22])[CH3:25])=[CH:5][NH:6]2
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2cccc(F)c12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1c[nH]c2cccc(F)c12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A slurry of 4-fluoro-3-(dimethylaminomethyl)-1H-indole (4.3 g, 22.4 mmol) in 14.1 ml of 2-nitropropane is treated with solid NaOH (941 mg, 23.5 mmol), and the resulting mixture is heated at reflux overnight. After cooling to ambient temperature, the reaction mixture is acidified with 10% aqueous acetic acid (25 ml) and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate (50 ml) and brine (50 ml). The layers are separated, and the organic layer is washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give 3.71 g of 4-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (76%).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][C:14]1([OH:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:41])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>>[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH:41][C:1]([N:17]4[CH2:18][CH2:19][C:14]([OH:20])([CH3:13])[CH2:15][CH2:16]4)=[O:12])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(O)CCNCC1
Product: CC1(O)CCN(C(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-methyl-piperidin-4-ol and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=417.6 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CN(C=O)C>[CH2:19]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]=1)=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 750 mg (4.62 mmol) of 1H-Indazole-3-carboxylic acid (Snyder, H. R.; Thompson, C. B.; Hinman, R. L. J. Am. Chem. Soc. 1952, 74, 2009) in 20 mL of DMF is added 1.92 g (13.86 mmol, 3.0 equiv) of K2CO3, followed by 1.43 mL of benzyl bromide. The reaction mixture is stirred 15 min at RT then heated at 60° C. for 16 h. The reaction is cooled to RT, poured into 100 mL 1N HCl, and extracted with EtOAc (2×100 mL). The organic layers are washed with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 20/1 to 2/1 afforded 735 mg of the title compound as a yellow oil which later solidified: 1H NMR (CDCl3, 300 MHz) δ8.20 (d, 1H), 7.55 (d, 2H), 7.40-7.18 (m, 11H), 5.70 (s, 2H), 5.57 (s, 2H); Rf =0.15 in hexane/EtOAc 10/1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([CH2:18][CH2:19]Cl)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O>[CH2:21]([N:28]1[CH2:19][CH2:18][C:4]2([C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCC1(CCCl)c2ccccc2Sc2ccccc21
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: c1ccc(CN2CCC3(CC2)c2ccccc2Sc2ccccc23)cc1

Procedure:
A mixture of 9,9-bis(2'-chloroethyl)thioxanthene (3.4 g.) and benzylamine (10 ml.) is heated under reflux for 2 hours, cooled diluted with water (100 ml.) and acidified with concentrated hydrochloric acid. The liquid is decanted from the residual gum which is triturated with water (200 ml.) when it solidifies. The solid is crystallised from ethanol to give 1'-benzylthioxanthene-9-spiro-4'-piperidine, m.p. 248° C. Addition of ether to the ethanolic filtrate remaining after removal, by filtration, of the base, yields 1' -benzylthioxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 263°-266° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([N:33]([CH2:36]C)CC)C.C(#[N:40])C>>[C:1]([NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[N:33][CH3:36])#[N:40]
Reactant: CNC(=S)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: CCN(CC)CC
Reactant: CC#N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CN=C(NC#N)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
A mixture of 0.56 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.39 g of p-toluenesulfonyl chloride, 0.21 g of triethylamine, and 3 ml of acetonitrile was heated at reflux for 30 minutes. The solvent was removed by distillation, and to the residue were added 0.27 g of cyanamide, 0.17 g of sodium hydride, and 4 ml of ethanol, followed by heating under reflux for 30 minutes. Concentrated hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a 2N potassium carbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was removed by distillation, and the residue was subjected to silica gel column chromatography (developing solution: n-hexane:ethyl acetate=1:1) and then recrystallized from a mixture of ethyl acetate and diethyl ether to obtain 50 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14](Cl)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[OH2:2].[O:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][O:25][CH:26]2[CH2:30][CH2:29][N:28]([C:14](=[O:15])[CH2:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH2:27]2)[CH2:21][CH2:22]1.[O:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][O:25][CH:26]2[CH2:30][CH2:29][N:28]([C:14](=[O:15])[CH2:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH2:27]2)[CH2:21][CH2:22]1
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1OC
Reactant: C1CC(OCCN2CCOCC2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(CC(=O)N2CCC(OCCN3CCOCC3)C2)cc(OC)c1OC
Product: O
Reaction time: 1 h
Yield: 70 %

Procedure:
Under anhydrous conditions 5.3 g. crude 3,4,5-trimethoxyphenylacetic acid chloride [equivalent to 4.5 g. (0.0184 mole) by nuclear resonance spectrum analysis] in 20 ml. dry benzene was added dropwise to a stirring mixture of 3.7 g. (0.0184 mole) of 3-(2-morpholinoethoxy)pyrrolidine and 30 g. (0.0217 mole) of potassium carbonate in 50 ml. dry benzene. The product formed rapidly and separated out as a gummy mass. After stirring 1 hr. at room temperature, chloroform was stirred into the reaction mixture to dissolve the product. The inorganic materials were removed by filtration and the filtrate concentrated at reduced pressure to give 5.3 g. crude product (70% yield). A portion (2.6 g.) of the crude product was chromatographed on magnesium silicate to give 1.6 g. of pure product.
Reaction SMILES: C(OC[O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)C.Cl>CO.O>[F:22][C:19]([F:20])([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([OH:5])=[CH:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CCOCOc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Ether 110 (379 mg, 1.21 mmol) was treated with 1.25M HCl in MeOH (11 mL) and the mixture was stirred at room temperature for 12 h, and then at 53° C. for 2 h. The resulting cooled solution was diluted with water (50 mL) and extracted with CH2Cl2 (5×50 mL). The combined extracts were evaporated to dryness and the residue was triturated in pentane to give 2-[4-(trifluoromethoxy)phenyl]-5-pyrimidinol (112) (305 mg, 99%) as a white solid: mp (pentane) 156-157° C.; 1H NMR (CDCl3) δ 8.45 (s, 2H), 8.38 (dt, J=8.9, 2.4 Hz, 2H), 7.29 (br dd, J=8.9, 0.7 Hz, 2H), 5.60 (br s, 1H); HRESIMS calcd for C11H8F3N2O2 m/z [M+H]+ 257.0532. found 257.0526.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18].Cl[CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])=[CH:11][C:10]=1[CH3:18]
Reactant: ClCSc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCSc2ccccc2)cc1C
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
Cesium carbonate (13.00 g, 40.0 mmol) is added to a solution of 4-methoxy-3-methyl benzoic acid (6.65 g, 40.0 mmol) in dry DMF (50 ml) at ambient temperature. The mixture is stirred at 65° C. for 20 minutes and cooled to 0° C., before chloromethyl phenylsulfide (5.76 g, 36 mmol) in dry DMF (10 ml) is added dropwise. Stirring is continued at 0° C. for 30 minutes, then at ambient temperature for 2 hours and finally at 70° C. for 1 hour, before water is added and the product extracted into diethyl ether. The ether solution is washed with 1M sodium hydroxide and 4 times with brine, dried (MgSO4) and evaporated. The crude product is used in Intermediate 8 without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Cl.[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (2.8 cc) and 4,4-diphenylpiperidine hydrochloride (2.7 in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (10 cc), 2-[3-(4,4-diphenylpiperidino)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[O:11])=[CH:5][N:4]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]=[O:11])[Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][N:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(NC=O)cn1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(N(C=O)[Si](C)(C)C)cn1
Temperature: 10 °C
Yield: 87 %

Procedure:
N-(2-Methoxy-5-pyridyl)formamide (30.4 g, 0.2 mol) was added to 200 ml benzene. This was stirred with a mechanical stirrer under argon at 10° C. Trimethylsilyl chloride (25 g, 0.23 mol) was added. While stirring at 10° C., triethylamine (21 g, 0.21 mol) dissolved in 50 ml benzene was added dropwise over 0.5 hour. The slurry was warmed to room temperature and after 0.5 hour filtered. The salt cake was washed with 100 ml benzene and the combined filtrates concentrated on a rotary evaporator at 30° C. under aspirator vacuum. The dark liquid product was distilled under reduced pressure. A clear liquid, 39 g, 87% yield, (b.p. 87° C./0.25 mmHg). The product was stored under argon.
Reaction SMILES: C(O)(=O)C(C)=C.[C:7]([O:12][CH3:13])(=[O:11])[C:8](C)=[CH2:9].[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCCCCCCCCC)(=[O:18])[C:15](C)=[CH2:16].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(OCCCC)(=O)C>[CH3:20][CH2:21][CH2:22][CH2:23][CH:24]([CH2:13][O:12][C:7]([CH:8]=[CH2:9])=[O:11])[CH2:25][CH3:26].[CH3:23][CH2:22][CH2:21][CH2:20][O:19][C:14]([CH:15]=[CH2:16])=[O:18]
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Agent: C=C(C)C(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCOC(C)=O
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC
Temperature: 105 °C
Reaction time: 2 h

Procedure:
Into a four-neck flask equipped with a stirrer, a cooling tube, and a nitrogen gas inlet tube was charged 350 parts of butyl acetate and the whole was heated to 105° C. Under introduction of nitrogen gas, a mixture of 31 parts of methacrylic acid, 129 parts of methyl methacrylate, 40 parts of stearyl methacrylate, and 5 parts of benzoyl peroxide as an initiator was added dropwise over a period of 2 hours. After the copolymerization was continued for 2 hours with maintaining the same temperature, butyl acetate was removed by distillation to obtain an acrylic copolymer resin having a weight-average molecular weight of 11,000 and an acid value of 100 mgKOH/g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.065 g, 0.16 mmol) and triethylamine (0.046 ml, 0.33 mmol) in dichloromethane (5 ml) was added methanesulphonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.043 g, 60%) as white solid. MS m/e: 457 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH3:17])[N:5]([C:13](=[O:16])[CH2:14][OH:15])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].[H-].[Na+].[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>C(COC)OC>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH3:17])[N:5]([C:13](=[O:16])[CH2:14][O:15][S:23]([N:22]([CH3:27])[CH3:21])(=[O:25])=[O:24])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)[C@H](C)N(C(=O)CO)c1c(C)csc1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](C)N(C(=O)COS(=O)(=O)N(C)C)c1c(C)csc1C
Temperature: 25 °C

Procedure:
8.13 g (0.03 mol) N-(hydroxyacetyl)-N-(2,4-dimethylthien-3-yl)-alanine-methylester is added in portions to a slurry of 1.05 g (0.035 mol) sodium hydride (80% in mineral oil) in 50 ml dry dimethoxyethane with stirring at 10°-15° under a blanket of nitrogen. The mixture is stirred at room temperature for half an hour, and then are added 4.3 g (0.03 mol) dimethylsulphamic acid chloride. The mixture is stirred for 18 hours at 50°, then cooled to room temperature, filtered, concentrated in vacuo, the residue taken up in CHCl3, washed thoroughly with water, dried over MgSO4 and evaporated in vacuo to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O1CCCC1.O>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 in 2 ml tetrahydrofuran were added 30 μl of triethylamine and 15 μl of methanesulfonyl chloride, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate-diethyl ether, to give 26 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH:6]([CH3:10])[CH2:7][CH2:8][OH:9])#[N:2].[CH2:11](O)[CH2:12][CH:13]([OH:15])C.C(#N)C=C>>[C:13]([O:9][CH2:8][CH2:7][CH:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:10])(=[O:15])[CH:12]=[CH2:11]
Reactant: CC(CCO)OCCC#N
Reactant: CC(O)CCO
Solvent: C=CC#N
Product: C=CC(=O)OCCC(C)OCCC#N

Procedure:
Following the procedures described in Example 1, 3-(2-cyanoethoxy)-1-butanol (bp 145°-150° C./2.5 mm Hg) is prepared from 1,3-butanediol and acrylonitrile, acrylation of which gives the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])[CH3:27]>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1/[C:26](/[CH3:27])=[CH:25]/[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: CC(=CBr)c1ccc(F)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-Bromo-1-methyl-vinyl)-2,4-difluoro-benzene (279 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-2% MeOH-DCM. The product was further purified by HPLC. Yield: 14 mg. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (m, 1H), 7.22 (s, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.90 (m, 2H), 6.70 (s, 1H), 3.70 (s, 2H), 2.85 (m, 4H), 2.60 (s, 3H), 2.45 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCCO
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: OCCOCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in diethylene glycol(10 ml) and 4-amino-1-butanol(4 ml) was added. The reaction mixture was reacted at the same condition of Step 3 in the Example 42 to obtain 550 mg of desired compound as solid in 86% of yield.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])=[CH:4][C:3]=1[CH3:30].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([CH3:51])[C:49]=1[F:50])[CH2:45]Br>C1COCC1>[F:50][C:49]1[C:48]([CH3:51])=[CH:47][C:44]([CH2:45][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]2[CH:28]=[CH:29][C:2]([F:1])=[C:3]([CH3:30])[CH:4]=2)[C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])=[CH:43][C:42]=1[CH3:41]
Reactant: Cc1cc(CBr)cc(C)c1F
Reactant: Cc1cc(COCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(COCCCC[C@@H](Cc2cc(C)c(F)c(C)c2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a cooled (−78° C.) solution of (R)-3-(6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one (0.220 g, 0.532 mmol) in 5 mL of THF, was added LiHMDS (0.80 mL, 0.80 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (0.346 g, 1.596 mmol) in 3 mL of THF was added. After stirring at −78° C. for 1 h the reaction mixture was warmed to room temperature for 2 h, and then quenched with 20 mL of NH4Cl solution and extracted with dichloromethane (20 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.106 g, 36% yield). GC-MS: tR=15.6 min; m/z 549 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.[C:15]([C:22]1[NH:23][CH:24]=[CH:25]N=1)(C1NC=CN=1)=O.N1CCCC1.O>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]([C:12]([N:23]2[CH2:22][CH2:15][CH2:25][CH2:24]2)=[O:14])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1c(C(=O)O)ccc2c1CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNC1
Product: COc1c(C(=O)N2CCCC2)ccc2c1CCC2
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a clear solution of 4-Methoxy-indan-5-carboxylic acid (12.0 gm, 0.0625 mole) in Tetrahydrofuran (60 ml), Carbonyl-diimidazole (13.24 gm, 0.0812 mole) was added at 25-28° C. The reaction mixture was heated to 65-70° C. and stirred for 2 hours to the reaction mixture, a solution of Pyrrolidine (5.74 ml, 0.0687 mole) in Tetrahydrofuran (20 ml) was added at 10-15° C. The reaction mixture was poured into water (200 ml) and extracted with Ethylacetate (2×100 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum and purified by column chromatography using Ethyl acetate:Hexane (20:80) as mobile phase. The fractions were distilled under vacuum to give 6.0 gm of desired product as a viscous oil.