Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([C:15]1[NH:16][O:17][C:18](=[O:20])[CH:19]=1)[CH2:13][CH3:14]>C(=O)(O)[O-].[Na+]>[CH2:12]([C:15]1[N:16]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[O:17][C:18](=[O:20])[CH:19]=1)[CH2:13][CH3:14]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCc1cc(=O)o[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1cc(=O)on1C(=O)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
20.9 gm of 2,4-dichlorobenzoyl chloride was added to 8 gm of 3-n-propyl-3-isoxazolin-5-one. The system was heated at 100° C. for 3 hours. Afterwards, the system was neutralized with 150 ml of saturated sodium bicarbonate solution. The product was extracted with methylene chloride. The organic solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. The organic solution was stripped to yield 28.8 gm of the crude product as a brown oil. The product was purified by HPLC using 1:3 tetrahydrofuran/hexane as the eluant to yield the title compound as a brown solid, m.p. 63°-65.5° C.
Reaction SMILES: C1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])OC1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH2:8][CH2:7][CH2:6][C:4](=[O:10])[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccccc1
Reactant: CC1(CCCCl)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CCCN(C)c1ccccc1
Reaction time: 8 h

Procedure:
To 49.4 g (0.30 mol) 5-chloro-2-pentanone ethylene ketal and 64.2 g (0.60 mol) N-methylaniline in 100 ml toluene, add 27.7 g (0.33 mol) NaHCO3 and 2.0 g KI. Reflux with a water separator overnight. Allow to cool, filter, and concentrate. Distill at 50°/0.1 mm to remove N-methylaniline. Stir the residual liquid with 175 ml 1.0 N HCl for 2 hrs. Neutralize with NaHCO3 and extract with ether. Dry, concentrate, and distill to collect a fraction of b.p. 103°-110° /0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1>[Cl:1][C:2]1[S:3][C:4]([C:15](=[O:17])[CH3:16])=[CH:5][N:6]=1
Reactant: Clc1nccs1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of 2-chlorothiazole (5.0 g, 42 mmol) in THF (10 mL) was added dropwise to a −78° C. solution of n-BuLi (2.5 M in hexanes; 18.4 mL, 46 mmol) in THF (140 mL). The solution was stirred for 1 hour, and then N-methoxy-N-methylacetamide (4.7 g, 46 mmol) was added. The mixture was stirred for another hour, and then it was warmed to approximately 25° C. The reaction was quenched by the addition of a saturated aqueous ammonium chloride solution and extracted with ether (3×75 mL). The organics were combined, washed with brine, filtered and then concentrated. The residue was purified by flash chromatography (20 percent ether/pentane on silica gel), yielding 5.9 grams of yellow semi-solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(=O)([O-])O.[K+]>CC(C)=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(I)cc1)OC

Procedure:
A solution of 4-iodobenzoyl chloride (100 g, 375.6 mmol) in 300 mL of acetone was added to a solution of aminoacetaldehyde dimethylacetal (41.4 g, 1.05 equiv.) and potassium hydrogen carbonate (39.5 g, 1.05 equiv.) in 270 mL of acetone and 450 mL of water. After completion of the reaction, acetone was removed under reduced pressure at no more than 35° C. to induce crystallization. The crystal slurry was filtered, washed and dried in vacuo at <50° C., to give 120 g (95 M %, HPLC area % 96) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C([BH3-])#N.[Na+]>CO.CS(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:24]5[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cc3cc(-c4ccccc4)ccc3o2)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(-c5ccccc5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
A mixture of 4-(5-phenylbenzofuran-2-yl)benzaldehyde (49 mg, 0.14 mmol) and azetidine-3-carboxylic acid (30 mg, 0.28 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred for 16 h. Concentration of the solvent under reduced pressure yielded a yellow solid that was dissolved in DMSO (3 mL) and filtered to give a yellow solution that was purified by HPLC to yield 3 mg of desired product [hS1P1 EC50=1200 nM]: 1H NMR (400 MHz, CD3OD) δ 8.03 (d, 2H), 7.84 (br s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 (s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z: Calculated: 383.15; Observed: 383.9 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:26][CH:27]=1.[H-].[Na+]>CN(C)C=O.O>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:26][CH:27]=1)[C:11]([CH3:16])=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cc1ccc2c(c1)cc(C)n2Cc1csc(-c2ccccc2)n1)C(=O)O
Yield: 90.4 %

Procedure:
0.28 g (1.0 mmol) rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) were reacted with 0.23 g (1.1 mmol) 4-chloromethyl-2-phenyl-thiazole in 5 ml N,N-dimethylformamide in the presence of 0.09 g (2.0 mmol) sodium hydride (55%) in mineral oil) at room temperature for 16 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of n-heptane and ethyl acetate) to give 0.38 g (90%) of rac-2-ethoxy-3-[2-methyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as light brown solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:31]=1[CH:32]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[CH2:5][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7][C@H:2]([NH:1][CH2:32][C:31]2[CH:34]=[C:35]([O:38][C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: COC(=O)[C@H]1C[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.3 %

Procedure:
To a stirred solution of (2S*,3S*,5S*)-3-amino-1-benzyloxycarbonyl-5-methoxycarbonyl-2-phenylpiperidine (0.79 g, 2.16 mmol) and 2-methoxy-5-trifluoromethoxybenzaldehyde (0.59 g, 2.70 mmol) in CH2Cl2 (25.0 ml) was added NaB(OAc)3H (0.69 g, 3.24 mmol) potionwise at room temperature. The turbid reaction mixture was stirred at room temperature for 3 hours; the NaB(OAc)3H added dissolved gradually with stirring, and the turbidity of the reaction mixture decreased. sat. Na2CO3 aq. solution was added, and from the mixture was separated the CH2C2 layer. The aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 layer and extracts were dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil (1.55 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 32.0 g). Elution with CH2Cl2 --MeOH (300:1/200:1) gave title compound (1.15 g, 93.1%) as a colorless syrup, which crystallized spontaneously on standing in a refrigerator. This was recrystallized from (i-Pr)2O to give analytically pure title compound (1.058 g, 85.3%). mp 93.5-95.0 C. (fine colorless needles); IRmax (nujol): 1730(s), 1700(s), 1610(w), 1498(s), 1220(s), 1147(s), 1110(s), 1080(s), 1055(s), 1028(s), 742(s), 730(s), 703(s), 695(s) cm-1 ; 1H-NMR δ: 7.43-7.23(m, 9H), 7.21(br.s, 1H), 7.09-7.00(m, 2H), 6.73(d, J=9.2 Hz, 1H), 5.39(br.d, J=5.3 Hz, 1H), 5.16(d, J=12.5 Hz, 1H), 5.02(d, J=12.5 Hz, 1H), 4.50(dd, J=13.7, 1.8 Hz, 1H), 3.79(d, J=13.9 Hz, 1H), 3.68(d, J=13.9 Hz, 1H), 3.63(s, 3H), 3.54(dd, J=13.7, 5.5 Hz, 1H), 3.28(ddd, J=10.2, 5.5 4.8 Hz, 1H), 2.89-2.28(m, 1H), 2.24-2.01(m, 1H), 1.54(br.s, 2H) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])=[CH:5][CH:4]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>>[O:23]=[C:11]1[NH:12][C:13]2[C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17][C:18]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])=[CH:4][CH:5]=2)[C:10]1=[O:24]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Agent: Cl
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c1=O
Yield: 45.2 %

Procedure:
4-(4-Aminophenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione hydrochloride (80 mg, 0.24 mmol) and 2-nitrobenzenesulfonyl chloride (78 mg, 0.35 mmol) were used in a process similar to Example 9 to give the titled compound (53 mg, yield 46%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=O)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[CH2:19][CH2:20][C:21]4[C:26]3=[C:25]([CH:24]=[CH:23][CH:22]=4)[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:8][C:6]=2[CH:7]=1
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A stirred mixture of 9.14 g (0.022 mole) of N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 3c in 250 ml of phosphorus oxychloride was refluxed for 7 hours under nitrogen then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, dried over Na2SO4 and concentrated in vacuo to 8.5 g (98%) of an oil. This material was adsorbed on a tall chromatography column containing 350 g of alumina made up in CH2Cl2. Elution with CH2Cl2 brought forth fractions of virtually pure tetracycle which were combined and concentrated to afford 4.6 g (53% overall yield) of product as a foam. This was crystallized from a small volume of methanol to furnish 2.6 g of 9-bromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 153°-155° C.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25](Br)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][CH:41]=1)CCC>CCOC(C)=O.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>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25]([C:37]4[O:38][CH:39]=[CH:40][CH:41]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 366 mg (0.76 mMol) 1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 17: a) in 7 ml degassed DMF under a N2-atmosphere are added 174 mg (0.15 mMol) of Pd[P(C6H5)3]4 and 0.6 ml (1.9 mMol) of 2-tributylstannyl-furan (Aldrich). After 4 h stirring at 100° C., the reaction mixture is diluted with EtOAc and washed with NaHCO3 solution. The aqueous layers are extracted twice with EtOAc, the organic phases washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2; CH2Cl2/Et2O 7:3) and crystallization from DIPE yields the title compound. mp: 180-182° C.; ES-MS: (M+H)+=465; HPLC(Grad20-100) tRet=15.0.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1([CH3:30])[CH3:29].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1([CH3:30])[CH3:29])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h

Procedure:
To a solution of 3βhydroxy-4,4-dimethylcholesta-5,16-diene (220 mg, 0.5 mmol) in pyridine (1.5 mL) at ice bath temperature was added benzoyl chloride (0.1 mL) and the whole stirred for 1.5 hours. Concentration under reduced pressure and purification of the residue by flash chromatography gave 3β-benzoyloxy-4,4-dimethylcholesta-5,16-diene (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]=O)([O-:18])=[O:17].N1CCCCC1>CN(C)C=O>[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2/[CH:28]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])([O-:18])=[O:17]
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 72 h
Yield: 5.3 %

Procedure:
3',4',5'-Trimethoxyacetophenone (1.31 g) and 5-nitroindole-3-carboxaldehyde (1.18 g) were dissolved in N,N-dimethylformamide (20 ml), and piperidine (528.7 mg) was added thereto, followed by stirring at 100° C. for 72 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from methanol to give Compound 21 (125 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([O:14]CC)=[O:13])=[O:10])=[O:5])[CH3:2].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([OH:14])=[O:13])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)CS(=O)CCNC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCCS(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
There was added 30 g (0.12 mol) of ethyl 2-[2-(ethoxycarbonylamino)ethylsulfinyl]acetate to a solution of 9.56 g of sodium hydroxide dissolved in 120 ml of water, and the mixture was stirred for 2 hours at room temperature and washed with ethyl acetate. The alkaline phase was separated and acidified with conc. HCl under cooling with ice, and the solvent was removed under reduced pressure. The residue was dissolved in ethanol and the insoluble substance was removed by filtration. The filtrate was removed under reduced pressure, and the residue was dissolved in chloroform and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give 18.36 g of white solid. The solid was recrystallized from ethanol-n-hexane (1:1) to give 15.0 g of the titled compound.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]([O:11][CH2:10][C:6]2[C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: OCc1cccc2c1OCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1cccc2c1OCO2)n1ccnc1
Yield: 86.8 %

Procedure:
A solution of (benzo[d][1,3]dioxol-7-yl)methanol (2.0 g, 13.1 mmol) and di(1H-imidazol-1-yl)methanone (4.26 g, 26.2 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water and extracted with CH2Cl2, and the combined layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (2.8 g, 86%). 1H NMR (400 MHz, CDCl3) δ 8.15 (t, J=0.9 Hz, 1H), 7.44 (t, J=1.4 Hz, 1H), 7.07 (dd, J=1.6, 0.8 Hz, 1H), 6.95 (m, 2H), 6.84 (m, 1H), 6.01 (s, 2H), 5.33 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH:20]1([C:25](=O)[CH2:26][C:27]#[N:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]2[C:26]([C:27]#[N:28])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[N:1]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 367.4 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:10]3=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[CH3:24][N:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:10]2[CH2:16]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CNCCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate 64A (0.91 g, 3.17 mmol) in 20 mL THF was added formaldehyde (37% in water, 2.36 mL) followed by sodium triacetoxyborohydride (1.34 g, 6.34 mmol) and acetic acid (0.27 mL, 4.76 mmol). The resulting mixture was stirred at room temperature overnight and then quenched with NaHCO3 saturated solution and stirred for 10 minutes. The reaction mixture was concentrated under vacuum and extracted with 10% iPrOH/DCM.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:36]=2)[N:31]=[CH:30][N:29]=1>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:45][CH3:46])=[C:35]([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCS(C)(=O)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (92 mg, 0.32 mmol) was treated with cesium carbonate (113 mg, 0.35 mmol) in anhydrous tetrahydrofuran (2 mL) and the suspension stirred at 40° C. for 20 minutes. 4-Chloro-7-methoxy-6-(2-(methylsulfonyl)ethoxy) quinazoline from the previous step (100 mg, 0.32 mmol) was carefully added in portions and the resulting mixture heated at 40° C. for 2h. Cesium carbonate was filtered off, the filtrate concentrated under reduced pressure and the residue purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazolin-4-ylthio)phenyl)urea (36.88 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.53-7.40 (m, 4H), 7.30-7.28 (d, 1H), 6.49 (s, 1H), 4.59-4.56 (m, 2H), 4.00 (s, 3H), 3.78-3.74 (m, 2H), 3.20 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 572 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.Cl.[NH2:29][OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14](/[C:17](=[N:29]/[OH:30])/[CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(S(=O)(=O)c3ccc(C(C)=O)cc3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(S(=O)(=O)c3ccc(/C(C)=N/O)cc3)c2)CCOCC1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 50, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]acetophenone oxime in 83% yield, m.p. 180°-181° C.;