Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:11]=[O:12])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(Cl)c(Cl)c1

Procedure:
A mixture of 3,4,5-trichloroaniline (400 mg; 2 mmol) in toluene (15 ml) and phosgene (6 ml 20% in toluene; 12 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trichlorophenylisocyanate. To the crude product was added 3-[4-(4-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) and refluxed for 16 h. The solvent was evaporated rated and the residue resuspended in ethyl acetate, filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1) graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 730 mg of the title compound. M.p. 211°-212° C. MS (70 eV): m/z 477 (4%, M+), 254 (56), 221 (59), 209 (100), 158 (35), 138 (25), 111 (20), 70 (45).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([NH2:7])=O.S(C)C.CCO.Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(Br)cc(C(N)=O)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CN)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a solution of 3-bromo-5-(methyloxy)benzamide (4.00 g, 17.4 mmol) in THF (60 mL), BH3.Me2S (2.64 g, 34.8 mol) was added at 0° C. After the end of the addition, the reaction mixture was kept refluxing overnight (monitored by TLC). After cooling to room temperature, EtOH was cautiously added to the reaction mixture. When there no more air bubbles appeared, the mixture was acidified with 1N HCl to pH=2. Then the mixture was stirred at 50° C. for 4 h, filtered and the filter rinsed with water (20 mL×2). The filtrate was washed with EtOAc (50 mL×3). After addition of 2N NaOH (pH=10), the filtrate was extracted with EtOAc (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a mixture of solid and oil. MeOH (10 mL) and conc. HCl (10 mL) were added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O gave the captioned product (3.10 g, 71%), {[3-bromo-5-(methyloxy)phenyl]methyl}amine, as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.12-7.09 (m, 2 H), 6.86 (s, 1 H), 3.98 (s, 2 H), 3.69 (s, 3 H); 13C NMR (100 MHz, D2O): δ160.2, 135.8, 124.2, 123.0, 117.8, 114.0, 55.8, 42.5; HPLC: retention time: 5.452 min; purity: 97.4% (HPLC).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8]CC2C(=O)C3C(=CC(Cl)=CC=3)N(C3C=CC=CC=3)C=2)=[O:7])=[CH:4][N:3]=1.O[C@H]1CCNC1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:28]=[CH:29][CH:2]=[N:3][CH:4]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Agent: O[C@H]1CCNC1
Product: NC(=O)c1cccnc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(S)-3-hydroxypyrrolidin-1-yl)-nicotinamide was prepared starting from intermediate E and (S)-3-hydroxypyrrolidine. MS calcd. for C26H23ClN4O3 [(M+H)+] 475.2, obsd. 475.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[O:6].Cl[C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:11]=[C:10]2[NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[O:6]
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc2[nH]nc(NC(=O)C(F)(F)F)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(F)cc(F)c1)c1ccc2c(c1)c(NC(=O)C(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (19.11 g, 51.76 mmol) in dry dichloromethane (300 mL) was treated with chlorotriphenylmethane (14.72 g, 52.8 mmol) and triethylamine (14.55 mL, 103.5 mmol). After stirring at room temperature for two days, the reaction was washed with a solution of NH4Cl, dried and evaporated. Purification of the crude by chromatography over silica gel (DCM/MeOH) afforded 27.32 g of the title compound (86% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl>O1CCOCC1.CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH:26]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (131 mg, 480 μmol), 5-bromo-2-morpholinobenzenamine (124 mg, 480 μmol) and 4.0N hydrochloric acid (0.12 mL, 480 μmol) solution in dioxane in MeOH (1.50 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-hexane solvent mixture. Mass Spectrum (ESI) m/e=493.0 & 495.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=1.O>C1COCC1>[Cl:8][C:9]1[N:14]=[C:13]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:10]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)COCc1cc(OCC2CC2)nc(Cl)n1
Reaction time: 0.08 h

Procedure:
Sodium hydride (19.0 mg, 0.46 mmol) was added to a solution of cyclopropylmethanol (0.037 mL, 0.46 mmol) in dry THF (1 mL) at room temperature. The mixture was stirred for 5 minutes and then a solution of 2,4-dichloro-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (120 mg, 0.46 mmol) in dry THF (1 mL) was added. The reaction was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water, brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with mixtures of 0% to 10% ethyl acetate in heptanes to afford the title compound as a solid, 40 mg, (29%) as yellow solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20](/[CH:30]=[CH:31]\[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].CO>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20]([CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(/C=C\c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1-c1cc(CCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A mixture of 20 mg (0.034 mmol) (Z)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-styryl-4-o-tolyl-pyridin-3-yl)-isobutyramide (Example 73) and 2 mg 10% palladium on carbon in 1 ml methanol was stirred at room temperature under an atmosphere of hydrogen gas for 2 h. The reaction mixture was filtered and concentrated. Column chromatography afforded 14 mg (72%) of the title compound as an orange waxy solid.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[Cl:5][C:6]1[CH:7]=[C:8](I)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C1COCC1.[Cl-].[Na+].O.[Br-].[Zn+2].[Br-]>[Cl:5][C:6]1[CH:7]=[C:8]([C:1]#[CH:2])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C#C[Mg]Br
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of zinc bromide (5.0 g, 22.2 mmol) in anhydrous THF (100 mL) at room temperature under a nitrogen atmosphere was added a solution of ethynyl magnesium bromide (0.5 M in THF, 44.4 mL, 44.4 mmol). After 5 minutes 3,5-dichloro-iodobenzene was added (4.03 g, 14.8 mmol) followed by tetrakis-triphenyl phosphine palladium (0) (855 mg, 0.74 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into brine and extracted with ether (4×100 mL). The ether layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 7.4 (d, J=1.6 Hz, 2H), 7.3 (d, J=1.6 Hz, 1H), 3.19 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCCOCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)ethanol (1 eq.) in DCM (0.2 M) was added p-toluenesulfonyl chloride (1.3 eq.) and triethylamine (1.5 eq.). The reaction was stirred at rt for 18 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 30% ether in hexane) to afford the title compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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:31]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 45.1 %

Procedure:
A solution of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 1.99 mmol) in dimethylformamide (20 mL) was treated with phenylboronic acid (0.485 g, 3.8 mmol), tetrakis(triphenylphosphine)palladium (0.138 g, 0.119 mmol), and a solution of sodium carbonate (0.506 g, 4.78 mmol) in water (10 mL). The reaction mixture was stirred at 80° C. for 18.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (15 mL) was added. The precipitate was filtered and was washed with water. The crude solid was triturated with diethyl ether (30 mL). The resulting solid was dried over night on the lyophilizer to give 0.407 g (45%) of 3-phenyl-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.9416 (s, 1H), 7.6190-7.6011 (m, 2H), 7.5369-7.4493 (m, 3H), 7.3995-7.2248 (m, 15H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1M ammonium acetate over 15 min, 0.5 mL/min) Rt=11.813 min (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14](C(O)=O)[NH:15]2)=[C:11]([CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([CH3:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc2[nH]c(C(=O)O)cc12
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(OCc2ccccc2)cc2[nH]ccc12
Temperature: 230 °C
Yield: 33.7 %

Procedure:
A suspension of 6-benzyloxy-4-methyl-1H-indole-2-carboxylic acid (28 mg, 0.95 mmol) and copper chromite (19 mg, 0.06 mmol) in quinoline (1.4 ml) was heated at 230° C. (bath temp.) for 1.5 h. The mixture was poured onto 2 N HCl/ice water 1/1 and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous NaHCO3 solution and brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure left a black oil which was purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 90 mg (0.32 mmol, 34%) of the title compound as brown oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].C1COCC1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>CCOC(C)=O>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (50.2 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc and Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 71% (100 mg, 0.181 mmol) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClCCl.CCCC(C)C>[C:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:33]4[CH2:34][CH2:35][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32]4)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:29])[CH2:8][C@@H:9]1[CH3:28])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCC(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
1-methylethyl[(cis)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 7) (95 mg, 0.241 mmol) was dissolved in Dichloromethane (DCM) (2 mL) and to this was added tert-butyl 1 piperazinecarboxylate (67.3 mg, 0.361 mmol) as a solid and the resulting solution stirred under nitrogen for 40 min. sodium triacetoxyborohydride (66.4 mg, 0.313 mmol) was added and stirred as a suspension over the weekend. The reaction was quenched with ammonium chloride (2 ml). The organics were separated and the aqueous reextracted with DCM (5 ml). The combined organics were washed with water (5 ml) and reduced in vacuo to give a colourless solid. (135 mg). The solid was dissolved in DCM and loaded onto a 12+M silica cartridge for automated flash chromatography. A gradient of 20 to 100% ethyl acetate in iso-hexane over 10 CV was used and the appropriate fractions reduced in vacuo to give a colourless oil which was dried on high vac overnight (98 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: OCCNc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nccc(NCCO)n2)ccc1-n1cnc(C)c1
Yield: 23 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-(2-chloro-pyrimidin-4-ylamino)-ethanol, using potassium carbonate as a base. The title compound was isolated as a slightly orange solid in a yield of 23%. MS ISP (m/e): 341.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.14 (s, 1H), 7.91 (s broad, 1H), 7.82 (d broad, 1H), 7.63 (s, 1H), 7.33 (d broad, 1H), 7.25 (s broad, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.00 (d, 1H), 4.74 (t, 1H), 3.78 (s, 3H), 3.55 (qa, 2H), 3.50-3.35 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: C(N(CCC)CCC)CC.Cl[C:12]1[N:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=2)[N:13]=1.[CH2:26]([N:28]1[CH:43]=[CH:42][C:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:34]=[CH:35][C:30]=2[C:29]1=[O:44])[CH3:27]>C(O)CC(C)C>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:24][CH3:25])[N:13]=[C:12]([N:39]1[CH2:38][CH2:37][N:36]([C:33]3[N:34]=[CH:35][C:30]4[C:29](=[O:44])[N:28]([CH2:26][CH3:27])[CH:43]=[CH:42][C:31]=4[N:32]=3)[CH2:41][CH2:40]1)[N:21]=[CH:20]2
Reactant: COc1cc2cnc(Cl)nc2cc1OC
Reactant: CCn1ccc2nc(N3CCNCC3)ncc2c1=O
Agent: CCCN(CCC)CCC
Solvent: CC(C)CCO
Product: CCn1ccc2nc(N3CCN(c4ncc5cc(OC)c(OC)cc5n4)CC3)ncc2c1=O
Yield: 92.9 %

Procedure:
Tri-n-propylamine (0.43 g) was added to 0.67 g of the 2-chloro-6,7-dimethoxyquinazoline synthesized in Referential Example 91 and 0.78 g of the 6-ethyl-2-piperazinopyrido[4,3-d]pyrimidine-5(6H)-one synthesized in Referential Example 14. Using 5 g of isoamyl alcohol as a solvent, they were heated and reacted for 10 hours under reflux. The resultant crystals were collected by filtration and then washed first with ethyl acetate and then with hexane. They were dried to obtain 1.24 g of the above-identified compound as white crystals (yield: 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Nc1ccc(OCCCCl)cc1
Yield: 83 %

Procedure:
A mixture of 6.6 g (0.036 mole) of (4-hydroxyphenyl)carbamic acid ethyl ester, 11.5 g (0.072 mole) of 1-bromo-3-chloropropane, 13.8 g (0.10 mole) of anhydrous potassium carbonate and 150 ml of acetone was heated at reflux for 21 hr. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.) collected by filtration and recrystallized from isopropanol to yield 7.7 g (83%) of white solid, m.p., 91°-93° C.
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([Cl:17])(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[ClH:17].[C:8]12([C:2]3[CH:3]=[CH:4][C:5]([C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=3)[CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2
Reactant: CC(=O)Cl
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C23CNCC2C3)cc1
Reaction time: 8 h

Procedure:
A 3 g. portion of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride is added to a cold (0° C.) mixture of 2.8 g. of acetyl chloride and 6.9 g. of aluminum chloride in 30 ml. of dichloromethane, and the reaction is stirred for 15 minutes. The mixture is then brought to room temperature, stirred overnight and carefully poured onto ice. This mixture is extracted twice with dichloromethane, and the extracts are combined, dried, filtered and concentrated to an oil. This oil is dissolved in a minimum of dichloromethane and treated with an excess of ether to give a solid which is collected, washed with ether and dried. Recrystallization from acetonitrile gives 500 mg. of the desired product, m.p. 195°-197° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([S:29][CH3:28])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (450 mg) in DMF (6 mL) was added sodium thiomethoxide (183 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water and the resulting precipitate filtered and air dried to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:12])([CH3:11])[CH3:10].[CH3:16][O-].[Na+].CI>CO>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([S:12][CH3:16])([CH3:10])[CH3:11]
Reactant: C[O-]
Reactant: COC(CC(C)CCCC(C)(C)S)OC
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(CC(C)CCCC(C)(C)SC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 10 g. of 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane, one equiv. of sodium methoxide and 100 ml. of methanol is added 1.5 equivalents of methyl iodide. The mixture is stirred for 2 hours at room temperature and then refluxed for 2 hours. After cooling to room temperature, solvent is removed by evaporation and the residue taken up in ether. The ether solution is washed with water, dried and evaporated under reduced pressure to give 1,1-dimethoxy-7-methylthio-3,7-dimethyloctane which can be purified by chromatography or distillation.