Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[O:3]=[C:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:6]([C:7](=[O:31])[CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:5]1.Cl>O1CCCC1>[O:3]=[C:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([C:7](=[O:31])[CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
The 3,6-dioxo-5α sterol was prepared by acid-catalyzed isomerization of the 5β sterol. To methanol (250 ml) was added the 3,6-dioxo-5β sterol 1017 (9.6 g, 24 mmol) and tetrahydrofuran (25 ml) to dissolve the sterol completely. Concentrated hydrochloric acid (12.5 ml) was added, and the reaction was allowed to proceed overnight. The solvent was then removed under vacuum to yield 9.6 g (100% yield) of methyl 3,6-dioxo-5α-cholan-24-oate 1018 (see Organic Preparations and Procedures Int. 19(2-3), 1987, 197-208; authors used base-catalyzed isomerization using sodium methoxide rather than HCl).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: NCCc1ccccn1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-(2-aminoethyl)pyridine in DME. EI-MS m/e (%): 306 (M+, 80), 93 (100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=2[N:16]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCO)nc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of intermediate 11 (140 mg, 0.593 mmol), Et3N (240 mg, 2.37 mmol) and methylsulfonyl chloride (102 mg, 0.89 mmol) was dissolved in DCM and the solution was stirred for 6 h at rt. The solution was then washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo to give 4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate (intermediate 12) (180 mg, 96%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=1[C:11]([OH:13])=[O:12])=O.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=1>C(OC(=O)C)(=O)C>[CH3:31][N:30]([CH3:32])[C:26]1[CH:25]=[C:24]([N:23]([CH3:33])[CH3:22])[CH:29]=[CH:28][C:27]=1[C:7]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cn1cccc1C(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3cccn3C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
Employing the procedure of part B of Example 17 hereinabove, 3.70 g (0.01 mole) of 2-[(1-methyl-2-pyrrolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared as described in part A above, and 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine were interacted in the presence of 10 ml of acetic anhydride to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-methyl-2-pyrrolyl)-4,5,6,7-tetrachlorophthalide (Formula IV: R0 =R1 =R2 =R3 =Cl; R=R7 =CH3 ; R4 =N(CH3)2).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:53][S:54]([NH:57][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:56])=[O:55]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCI (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+584.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=C[CH:6]=[CH:5][C:4]=1O.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:30]=3[O:29][C:27](=[O:28])[C:22]=2[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(O)c1OC
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(Cc1ccccc1)CC3
Yield: 35 %

Procedure:
Prepared by the procedure of Example 1 from 2,3-dimethoxyphenol and methyl 1-benzyl-4-oxo-3-piperidine-carboxylate hydrochloride. Yield 35%; mp 138°-140° C.
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1>O>[N:22]1([C:8]2[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: c1ccc2[nH]cnc2c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1C(F)(F)F
Temperature: 25 °C
Yield: 287.7 %

Procedure:
A reaction vessel was charged with 150 ml dimethylacetamide, 13.0 g (50 mmol) ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and 11.8 g (100 mmol) benzimidazole. The reaction mixture was heated at a temperature of 115°-125° C. for 96 hours. The mixture was cooled to room temperature, diluted with water and extracted three times with ethyl ether. The combined ether extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide 49.1 g of a dark gold oil. This oil was subjected to Kugelrohr distillation (90° C. @0.5 mm Hg) to provide 31.7 g of a yellow oil product identified in Table I.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4](=[O:14])(=[O:13])[N:3]=[C:2]([NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)ccc21
Reactant: CC(N)C(C)(C)C
Product: CC(NC1=NS(=O)(=O)c2ccc(Cl)cc2N1)C(C)(C)C

Procedure:
Starting from 3,6-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and 1,2,2-trimethylpropylamine (500 mg; 5.62 mmol) with the use of same procedure as in example 21 250 mg (39.8%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.3 (s, 1H, NH), 7.70 (d, 1H, H-8), 7.31 (dd, 1H, H-7), 7.25 (br d, 1H, H-5), 7.15 (br, 1H, NH), 3.75 (q, 1H, CH), 1.10 (d, 3H, CH3), 0.9 (s, 9H, 3×CH3). Analysis: C13H18ClN3O2S requires C, 49.44; H, 5.74; N, 13.3; (found C, 49.37; H, 6.04; N, 13.11).
Reaction SMILES: CC(C)(OC([NH:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]1)=O)C.[ClH:33]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[ClH:33].[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([N:12]3[CH2:13][CH2:14][CH:9]([NH:8][NH2:7])[CH2:10][CH2:11]3)=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.8 g (0.0498 mol) of N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine were dissolved in 100 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The excess trifluoroacetic acid was removed in vacuo, the residue was dissolved in 50 ml of water and made alkaline with 10% aqueous sodium carbonate solution. The solution was extracted thoroughly with dichloromethane, the combined extracts were dried over magnesium sulphate and evaporated down in vacuo. The residue thus obtained was taken up in ethyl acetate and converted into the hydrochloride by the addition of ethereal hydrogen chloride solution. After recrystallisation from anhydrous ethanol 6.2 g (33.3% of theory) of colourless crystals of melting point 160-162° C. were obtained.
Reaction SMILES: [C:1](O)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[C:22]1([C@H:28]2[CH2:32][O:31][C:30](=[O:33])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>O1CCCC1>[C:1]([N:29]1[C@@H:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:32][O:31][C:30]1=[O:33])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5]
Reactant: CCC=CC(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2-pentenoic acid (5.44 g, 54 mmol) and triethylamine (6 g, 60 mmol) in anhydrous tetrahydrofuran (120 mL) under nitrogen at −78° C. was added trimethylacetyl chloride (7.36 mL, 60 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, 0° C. for 1 hour, then re-cooled to −78° C. At the same time, in a seperate flask charged with a solution of (S)-(+)-4-phenyl-2-oxazolidinone (8.86 g, 54 mmol) in anhydrous tetrahydrofuran (130 mL) under nitrogen at −78° C. was added dropwise a solution of n-butyl lithium (22 mL, 54 mmol, 2.5 M in hexanes). The mixture was stirred at −78° C. for 20 minutes and then transferred via a cannula into the reaction flask containing the mixed anhydride at −78° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2×250 mL). The organic layer was separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (S)-3-((E)-pent-2-enoyl)-4-phenyl-oxazolidin-2-one as a white foam (9.9 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[N:5]2.FC1[C:15]([CH:24]([CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])CC)=NC2C(N=1)=CC=CC=2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:15][C:24]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:6]=[N:5]2
Reactant: CCC(C[Si](C)(C)C)c1nc2ccccc2nc1F
Reactant: Cc1cnc2cc(F)ccc2n1
Product: C[Si](C)(C)C#CCCc1cnc2cc(F)ccc2n1

Procedure:
The title compound was prepared in accordance with the general method of Example 118(A), from 6-fluoro-2-methyl-quinoxaline (100 mg, 0.62 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 66 mg (0.24 mmol, 39%) of 6 fluoro-2-(4-trimethylsilanyl-but-3-yl)-quinoxaline as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Yield: 90 %

Procedure:
This step was carried out using the procedure described in Tetrahedron Letters 30 (39), 1989, 5193-5196. A 0.5 M solution of A1 in acetone was treated with K2CO3 (1.3 eq.) and Me2SO4 (1.2 eq.) and the mixture was refluxed 6 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed with sat. aq. NaHCO3 solution, and brine, then dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 90% yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.35 (5H, m), 5.17 (2H, m), 4.77-4.50 (2H, m), 4.10-3.85 (1H, m), 3.74 (1.5H, s), 3.64 (1.5H, s), 3.30 (1H, m), 3.10 (1H, dd, J 13.6, 4.4), 2.86 (1H, m), 1.45 (9H, s). MS (ES+) C19H26N2O6 requires 378, found: 401 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH2:11][S:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[ClH:14]>>[ClH:14].[O:13]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:12]=2[CH2:11][S:10]1
Reactant: O=C1SCc2c1cccc2[N+](=O)[O-]
Agent: Cl
Product: Nc1cccc2c1CSC2=O
Temperature: 25 °C

Procedure:
4-Nitrobenzo[c]thiophene-1(3H)-one (38.1 g) was added portionwise to a solution of 146.0 g of stannous chloride dihydrate in 325 ml concentrated hydrochloric acid. A slow exotherm from 18° to 42° occurred and the reaction mixture was maintained at 40°-45° by cooling. When the exotherm subsided, the suspension was stirred while cooling to ambient temperature (3.5 hours). The solid was collected, washed with a small volume of cold concentrated hydrochloric acid, then dried under nitrogen to give 57.7 g of crude 1,3-dihydro-1-oxobenzo[c]thiophene-4-amine hydrochloride, m.p. 205° (d).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: CCCc1cc(C(=O)OCC)c(NC=O)s1
Temperature: 137.5 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A mixture of compound 2c [Formula 2 wherein R1=COOEt, R2=H and R3=Pr] (5.0 g, 0.023 mol), ammonium acetate (1.80 g, 0.023 mol) and formic acid (17.70 mL, 0.469 mol) was stirred at 135-140° C. for 7 h, cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3×150 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3c); 5.27 g; Yield: 95%; 1H NMR (200 MHz, CDCl3): δ 0.96 (t, J=7 Hz, 3H), 1.38 (t, J=7 Hz, 3H), 1.59-1.76 (m, 2H), 2.69 (t, J=8 Hz, 2H), 4.33 (q, J=7 Hz, 2H), 6.88 (s, 1H), 8.49 (s, 1H) 10.93 (bs, 1H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=2[N:6]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]2[NH:6][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Cl

Procedure:
The benzoimidazole from step (c) above (255 mg, 1.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (231 mg, 1.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. M.p. 206.4-208.1° C. MS (ESI, pos. ion) m/z: 450.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C(OC([N:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[C@H:35]1[C:40](O)=[O:41])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:40]([C@@H:35]5[C@@H:36]([OH:39])[CH2:37][CH2:38][NH:34]5)=[O:41])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 244 mg (0.50 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine and 116 mg (0.50 mmol) of (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. The protecting group was cleaved off analogously using HCl in dioxane. The product was purified by means of flash chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: On1nnc2ccccc21
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The 4,8-dichloro compound from Example 250 (0.8 grams) was added to a solution of HOBT (1.2 grams) and sodium hydride (0.14 grams, 60% in mineral oil) in anhydrous dimethyl-formamide (60 mL). The resulting solution was irradiated with a 200 W lamp while stirring at 25° C. for 60 hours. The solution was poured into 1N aqueous NaOH while stirring and an additional 400 mL of water was added to the resulting mixture. Filtration provided a solid which was washed with water several times. The solid was dissolved in CH2Cl2 -acetone, dried over anhydrous MgSO4, and concentrated in vacuo to proved the title compound (0.87 grams, 90%, mp=120°-122° C., MH+ 563).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:25]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:3]=3)[S:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3nc(-c4ccc(Cl)cc4)cs3)c2c1
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 36.2 %

Procedure:
(The method G13 is representative of method G12 also. This method can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (645.2 mg, 2.375 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1050 mg, 4.98 mmol) in DMA (40 mL) was added Cs2CO3 (2430 mg, 7.46 mmol) at room temperature. The mixture was stirred at 80° C. for 9.5 h. Water was added and a precipitate formed which was collected by filtration and washed with H2O. Recrystallization from acetone/DMF/methanol gave 383.6 mg of the product in a 36% yield as yellow solid, >98% purity by 1H NMR). 1H NMR (400 MHz DMSO-d6) δ 12.52 (s, 1H), 9.78 (d, J=1.56 Hz, 1H), 8.91-8.88 (m, 1H), 8.74 (dd, J=4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J=8.56 Hz, 2H), 7.93 (d, J=9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J=8.56 Hz, 2H), 4.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])[CH3:2].[O-:28][C:29]#[N:30].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH:23]([CH3:24])[CH3:25])[C:29]([NH2:30])=[O:28])[CH:17]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)C)c1)N2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C(N)=O)C(C)C)c1)N2
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-isopropylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (310 mg, 0.85 mmol) in acetic acid (2 mL) and water (2 mL) was added a solution of sodium cyanate (110 mg, 1.7 mmol) in water (2 mL) dropwise at 40° C. The reaction mixture was stirred at 40° C. for 4 h. Then the reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (347 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]1([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:27]1[C:26]2[C:30](=[CH:31][C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:24][CH:25]=2)[NH:29][C:28]1=[O:32])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-phenyl-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow-orange solid.