Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][N:21]([CH3:33])[CH:20]=3)=[O:18])=[C:11]([F:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:34][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]([CH3:33])[CH:20]=1)=[O:18]
Reactant: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Reactant: Cn1cc(B(O)O)cn1
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: O
Solvent: C1COCCO1
Product: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.125 g, 0.221 mmol) was combined with 1-methyl-pyrazole-4-boronic acid (0.058 g, 0.277 mmol) and K2CO3 (0.092 g, 0.664 mmol) in dioxane (2 mL) and H2O (0.333 mL), the mixture sparged with argon, treated with Pd(PPh3)4 (0.013 g, 0.011 mmol), sparged again with argon, and heated to 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with H2O, then brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (103 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.57 (dd, J=12.7, 7.2 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (dd, J=8.6, 5.6 Hz, 2H), 7.58 (dd, J=11.0, 7.4 Hz, 1H), 7.30-7.22 (m, 3H), 6.74 (dd, J=5.7, 2.5 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H); MS (ESI) m/z: 532.2 (M+H+).
Reaction SMILES: II.[C:3]([O:7][C:8](=[O:80])[CH2:9][CH2:10][C@H:11]1[NH:26][C:25](=[O:27])[CH2:24][C@@H:23](/[CH:28]=[CH:29]/[CH2:30][CH2:31][S:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:22][C:21](=[O:52])[CH2:20][NH:19][C:18](=[O:53])[C@@H:17]([CH:54]([CH3:56])[CH3:55])[NH:16][C:15](=[O:57])[C@@H:14]([CH2:58][S:59]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:13][C:12]1=[O:79])([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl.CO>[C:3]([O:7][C:8](=[O:80])[CH2:9][CH2:10][C@@H:11]1[C:12](=[O:79])[NH:13][C@@H:14]2[CH2:58][S:59][S:32][CH2:31][CH2:30][CH:29]=[CH:28][C@@H:23]([O:22][C:21](=[O:52])[CH2:20][NH:19][C:18](=[O:53])[C@@H:17]([CH:54]([CH3:56])[CH3:55])[NH:16][C:15]2=[O:57])[CH2:24][C:25](=[O:27])[NH:26]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O
Agent: II
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O

Procedure:
To a solution of I2 (117 mg, 0.46 mmol) in CH2Cl2/MeOH (9:1, 130 mL) was added dropwise a solution of bis-trityl 8F (50 mg, 0.046 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 50 mL) followed by brine (20 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×25 mL). The combined organic phase was dried (MgSO4) before concentration in vacuo gave a white solid. Purification by column chromatography on silica gel (1-3% MeOH/CH2Cl2) gave bicyclic depsipeptide 9F (19 mg, 0.032 mmol, 69%) as a white solid: [α]25D −76.7 (c 0.60, MeOH); 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=4.0 Hz, 1H), 7.35 (d, J=6.5 Hz, 1H), 7.23 (t, J=5.5 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.05 (ddt, J=15.5, 7.0, 2.0 Hz, 1H), 5.84-5.73 (m, 2H), δ 4.97 (td, J=8.0, 4.5 Hz, 1H), 4.18-4.01 (m, 3H), 3.61 (dd, J=15.1, 8.0 Hz, 1H), 3.24 (dd, J=10.5, 6.5 Hz, 1H), 2.95-2.75 (m, 5H), 2.73-2.62 (m, 3H), 2.51 (dd, J=13.6, 2.0 Hz, 1H), 2.42 (ddd, J=18.0, 9.0, 3.5 Hz, 1H), 2.19-2.04 (m, 2H), 1.83 (s, 9H), 0.98 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 175.7 (C), 171.8 (C), 171.7 (C), 170.9 (C), 169.9 (C), 168.2 (C), 130.2 (CH), 129.6 (CH), 82.6 (C), 69.4 (CH), 65.4 (CH), 57.6 (CH), 53.8 (CH), 42.4 (CH2), 40.0 (2×CH2), 38.6 (CH2), 34.1 (CH2), 33.1 (CH2), 28.2 (CH3), 27.4 (CH), 24.9 (CH2), 20.6 (CH3), 20.2 (CH3); LRMS (ES+) m/z 623 (90%, [M+Na]+), 601 (100%, [M+H]+).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][CH:5]=1
Reactant: Cc1ccc(OC(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1ccc(CBr)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
270 g of 4-difluoromethoxytoluene in 800 ml of CCl4 were initially introduced and 300 g N-bromo-succinimide were added. After adding a pinch of azobisisobutyronitrile, the mixture was heated to the reflux temperature. After 8 hours, it was cooled, the insoluble succinimide was filtered off and the residue on the filter was washed with CCl4. The carbon tetrachloride was distilled off from the reaction solution and the crude product was purified by fractional distillation. 250 g of 4-difluoromethoxy-benzyl bromide were obtained. Boiling point=82°-5° C./0.4 mm Hg; nD20 =1.5200.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][O:10][CH2:11][CH2:12][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:10]1[CH2:11][CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9]1
Reactant: Clc1nccnc1C1=CCCOC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2nccnc2C2=CCCOC2)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine (0.13 g, 0.68 mmol), 4-aminophenol (0.15 g, 1.35 mmol), and cesium carbonate (0.44 g, 1.35 mmol) were mixed in DMF (2 mL) in a microwave tube. The tube was sealed and placed under a nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 2.5 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was filtered and washed with water to give 4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 270.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](I)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[CH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]/[C:18](=[CH:26]\[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])/[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Reactant: O=S(=O)(I)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCCOC/C(=C\S(=O)(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 104.7 %

Procedure:
To a solution of 4-chlorobenzenesulphonyl iodide (4.95 g, 16.4 mmol) in dichloromethane (12 mL) at room temperature was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (2.36 g, 10.9 mmol). The mixture was stirred at room temperature for 23 hours, cooled to 0° C. and triethylamine (2.9 mL, 21.8 mmol) added dropwise. The reaction was stirred at 0° C. for 1.25 hours, diluted with distilled water (25 mL) and dichloromethane (12 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (10 mL) and the combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (25 mL), 5% aqueous sodium thiosulphate solution (25 mL) and distilled water (10 mL). The dichloromethane phase was concentrated under reduced pressure to give a brown oil (4.46 g). The crude product was purifed by chromatography on silica by eluting with hexane/ethyl acetate (3:1) to give, after combination and evaporation of appropriate fractions, the title compound as a oil, (3.50 g, 82%), Rf =0.38 (silica, hexane/ethyl acetate, 2:1).
Reaction SMILES: [C:1]12([CH2:11][N:12]=[C:13]=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:15][C:16]1[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]12([CH2:11][NH:12][C:13]([N:20]3[CH:21]=[C:16]([F:15])[C:17](=[O:23])[NH:18][C:19]3=[O:22])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 1-adamantylmethyl isocyanate was added a solution of 5-fluorouracil (2.60 g) in N,N-dimethylacetamide (20 ml) at 80° C. and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[N-(1-adamantylmethyl)carbamoyl]-5-fluorouracil (1.85 g), as colorless crystalline powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:5]([C:16]([OH:18])=O)=[CH:4][N:3]=1.[CH:19]1[CH:20]=[CH:21][C:22]2[N:27]([OH:28])[N:26]=[N:25][C:23]=2[CH:24]=1.C(Cl)CCl.[NH3:33]>CN(C=O)C>[N:27]1([O:28][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=3)[C:5]([C:16]([NH2:33])=[O:18])=[CH:4][N:3]=2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=2[N:25]=[N:26]1
Reactant: N
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(CNc2nc(Cl)ncc2C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1cc(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of 2-chloro-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylic acid (1 g, 3.74 mmol) and HOBt*H2O (858 mg, 5.61 mmol) in DMF (10 mL), EDC (1.08 g, 5.61 mmol) was added. The mixture was stirred at room temperature for 30 min. Ammonia (0.5 M in dioxane, 15 mL, and 7.5 mmol) was added. It was stirred at room temperature overnight. Dioxane was removed under vacuum, the residue was added water to induce precipitation and the resulting solids were isolated by filtration to give 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (1.04 g). MS 366.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](=[O:22])[CH3:21].C(Cl)[Cl:24]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:22][CH:20]([Cl:24])[CH3:21])=[O:16])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: O=C(Cl)c1ccc(C(=O)OCc2ccccc2)cc1
Reactant: ClCCl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(Cl)OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc chloride (524 mg) was fused in vacuo and, after cooling, treated with 4-(benzyloxycarbonyl)benzoyl chloride (21.48 g, 78.2 mmole). After 30 min., acetaldehyde (3.44 g, 78 mmole) was added at 0° C. The reaction mixture was stirred at room temperature for 30 min. and then diluted with CH2Cl2. The mixture was stirred for another 30 min. and then washed with water (3×). After drying with MgSO4, filtration, and concentration in vacuo, a green/brown solid was obtained that was chromatographed (25:75-CH2Cl2 :hexane) to give 7.65 (31%) of 1-chloroethyl 4-(benzyloxycarbonyl)benzoate as a white solid: mp 79°-82° C.; Anal. calcd for C17H15CIO4 ; C, 64.06; H, 4.74. Found: C, 63.88; H, 4.44. This chloroethyl ester (4.00 g, 12.5 mmole) was combined with the sodium salt of 3-[hydroxy-(2-thienyl)methylene]-6-chloro-5-fluoro- 2,3-dihydro-2-oxo-1H-indole-1-carboxamide (4.51 g, 12.5 mmole) and sodium iodide (644 mg, 4.3 mmole) in acetone (40 ml) and refluxed for 12 hr. The reaction mixture was filtered and the filtrate concentrated in vacuo. The orange/brown gum was chromatographed (25:75-EtOAc: hexane, then 1:99-EtOAc:CH2Cl2) to give 1.947 g (25%) of an orange foam: Anal. calcd. for C31H22ClFN2O7S·2/3H2O: C, 58.81; H, 3.72; N, 4.43. Found: C, 58.74; H, 3.38; N, 4.38.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.O>C1COCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([CH2:9][O:10][CH2:1][O:2][CH3:3])[CH:7]=1
Reactant: COCCl
Reactant: OCc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, chloromethyl methyl ether (6.09 mL) was added to a solution of 3-bromobenzylalcohol (5.00 g) and diisopropylethylamine (18.9 mL) in THF (45 mL) at 0° C., and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (6.37 g) of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([CH3:29])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([CH3:29])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH2:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1c1cc(Cl)cc(Cl)c1
Yield: 57 %

Procedure:
A solution of ethyl benzoylacetate (0.192 g, 1.00 mmol), 3,5-dichlorophenylhydrazine hydrochloride (0.235 g, 1.10 mmol), and p-toluenesulfonic acid monohydrate (0.019 g, 0.10 mmol) in ethanol (10 mL) was heated at reflux for 24 hours. The reaction solution was concentrated and the resulting residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid solution. The organic layer was further washed with water and brine, dried (sodium sulfate) and concentrated to afford a yellow solid. The crude product was triturated with hexanes and collected by suction filtration. Air drying afforded 0.174 g (57%) of product as a bright yellow solid: 1H NMR (DMSO-d6) δ12.60-12.40 (br s, 1H), 7.92 (s, 2H), 7.87-7.83 (d, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.36-7.31 (m, 1H), 6.02 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Solvent: C1CCOC1
Solvent: CO
Product: OCC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
To a solution of 1 g 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid in 15 ml THF were added dropwise at 0° C. 9.5 ml BH3*THF in THF (1M). Then the reaction mixture was heated at reflux for 2 h and then cooled again to 0° C. followed by cautious addition of 30 ml methanol. After evaporation of the solvents the residue was codestilled twice with toluene. The crude product was subjected to the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[Na+].[I-:11]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][I:11]
Reactant: [I-]
Reactant: Clc1ccccc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccccc1CI
Yield: 95 %

Procedure:
A mixture of 2-chlorophenylmethylbromide (4 g, 19.47 mmol) and NaI (14 g, 97.33 mmol) in acetone (40 ml) was stirred under reflux for 1 hour. The reaction mixture was cooled, filtered and concentrated in vacuo. The residue was triturated with hexane and filtered. The solution was concentrated in vacuo, and the resulting oil purified by flash chromatography (silica, hexane) to afford the title compound (4.67g, 63%) as an oil: 1H NMR (CDCl3) δ 7.34 (4H, m), 4.54 (2H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:17]=3[C:16]=2[NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[O:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
4-chlorobutanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 119 as a white solid (45 mg).). LCMS showed MH+=448, TRET=2.77 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:1]2[CH:5]=[N:4][C:3]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:2]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1-c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1-c1ncn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
3-(1H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (20 mg) described in Manufacturing Example 14-3, 4-benzyloxybenzyl chloride (32 mg), potassium carbonate (86 mg, and DMF (3.0 mL) were stirred for 0.5 hour at 60° C. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, then 1:1) to obtain the titled compound (27 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:30])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(F)c(Cl)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 14%) as a white solid. MS (ESI+) for C18H18ClFN2O3S m/z 397 (M+H)+.
Reaction SMILES: [Si](Cl)(Cl)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH:23]([CH3:25])[CH3:24])[CH-:18]3)[CH:10]=[C:11]([CH3:13])[CH:12]=1.[Li+]>C1COCC1>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH:23]([CH3:25])[CH3:24])[CH2:18]3)[CH:8]=[C:7]([CH3:6])[CH:12]=1
Reactant: Cc1cc(C)cc(-c2cccc3[cH-]c(C(C)C)cc23)c1
Agent: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1
Yield: 72.8 %

Procedure:
SiMe2Cl2 (0.69 g, 5.4 mmol) was dissolved in 80 mL of THF. While stirring, lithium 4-(3′,5′-dimethylphenyl)-2-iso-propylindenide (2.9 g, 11 mmol) was added as a dry powder and the contents allowed to stir overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in pentane and filtered to removed LiCl salts. The pentane was removed in vacuo to yield a flaky white solid (2.1 g, 67%)
Reaction SMILES: CS(OCCC1C=CC([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=CC=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:36][CH2:35][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:17]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cl
Product: Clc1ccc([C@@H]2Cc3cnc(Nc4cccc(CCN5CCCCC5)c4)nc3-c3ccccc32)cc1Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 6 to afford the desired product as hydrochloride salt. M.p.=165-169° C. 1H NMR (DMSO) 400 MHz δ 10.32 (bs, 1H), 9.66 (s, 1H), 8.35-8.30 (m, 2H), 7.77 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.57-7.46 (m, 3H), 7.44-7.42 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.04-7.00 (m, 1H), 6.86 (d, J=7.2 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 3.53-3.48 (m, 2H), 3.28-3.13 (m, 4H), 3.09-3.01 (m, 2H), 2.94-2.84 (m, 2H), 1.81-1.65 (m, 5H), 1.42-1.32 (m, 1H). LCMS m/e 529 [M+H]. Calc. for C31H30Cl2N4.2.08 Hydrochloric acid.0.04 Water.0.33 Ethyl Acetate: C, 61.12; H, 5.52; N, 8.82. Found C, 61.12; H, 5.52; N, 8.82.