Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](Br)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)C.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:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2 g, 0.68 mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in dry toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.03 g, 0.03 mmol) and the mixture was heated at reflux temperature under a nitrogen atmosphere for about 48 hours. The mixture was cooled to room temperature and diluted with diethyl ether (40 mL). The mixture was poured into a 10% aqueous solution of potassium fluoride (20 mL) and the mixture was stirred for 1 hour. The biphasic mixture was filtered through a pad (1 cm) of diatomaceous earth and the Organic phase was separated. The aqueous phase was extracted with diethyl ether (10 mL) and the combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified using silica gel chromatography with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes, as eluent to give the title compound as an off white solid, 0.16 g (80%). 1H NMR (CDCl3) δ 8.58 (br s, 2H), 8.50 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27–7.20 (m, 3H), 7.06 (t, 2H, 8.7 Hz), 6.86 dt, 1H, J=7, 1 Hz). MS (+ve ion electrospray) 290 (100), (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 1-methyl-piperazine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H37N6O2Cl2 [(M+H)+] 595.2350, observed 595.2351.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br.Br[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: BrCc1ccnc2ccccc12
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (147 mg, 296 μmol) in DMF (740 μl) was added 4-(bromomethyl)quinoline hydrobromide (135 mg, 444 μmol) and cesium carbonate (289 mg, 888 μmol). The reaction was stirred at rt for 18 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (57 mg, 30%) as a white solid. MS m/z 638 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14].COC1C=CC(C[NH2:22])=CC=1>CN(C=O)C>[NH2:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(N)c2ccccc2[nH]c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (example 72) (0.66 g, 3.23 mmol) was suspended in DMF (7 mL), and 4-methoxybenzylamine (0.94 mL, 7.26 mmol) was added. The reaction was heated at 100° C. for 1 hour and the DMF was removed under vacuum. The residue was dissolved in TFA (6 mL) and stirred at room temperature for 30 minutes and dichloromethane (10 mL) was added. The solid product that formed was collected, suspended in water and the solution stirred overnight. The solid was collected by filtration to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.150 g, 25%) as a white solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ7.19 (m, 2H), 7.57 (m, 1H), 7.88 (bs, 2H), 8.12 (d, J=7.6 Hz, 1H), 11.23 (s, 1H). MS 186 (MH+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:25])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]1C=CC=C(C2N=C(C3NC(C4C=C(C)C=CC=4)=NN=3)C(N)=NC=2)[CH:27]=1.N1C=CC=C(C2N=C(C3NC(C4SC=CC=4)=NN=3)C(N)=NC=2)C=1>>[NH2:26][CH2:27][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:25])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:18]=3)=[N:11][N:12]=2)=[CH:3][CH:2]=1
Reactant: Nc1cccc(-c2nnc(-c3nc(-c4cccnc4)cnc3N)[nH]2)c1
Reactant: Cc1cccc(-c2nnc(-c3nc(-c4cccnc4)cnc3N)[nH]2)c1
Agent: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2cccs2)[nH]1
Product: NCc1ccc(-c2nnc(-c3nc(-c4cccnc4)cnc3N)[nH]2)cc1

Procedure:
Compound I-140 3-(5-(3-aminophenyl)-4H-1,2,4-triazol-3-yl)-5-(pyridin-3-yl)pyrazin-2-amine; 1H NMR (400.0 MHz, DMSO) d 6.98-7.03 (m, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.74 (s, 2H), 7.82 (dd, J=5.2, 8.1 Hz, 1H), 8.06 (s, 2H), 8.74 (dd, J=1.3, 5.2 Hz, 1H), 8.96 (d, J=7.9 Hz, 1H), 9.02 (s, 1H), 9.60 (s, 1H) and 15.03 (br s, 1H) ppm; MS (ES+) 331 Compound I-141 5-(pyridin-3-yl)-3-(5-m-tolyl-4H-1,2,4-triazol-3-yl)pyrazin-2-amine; MS (ES+) 330 Compound I-142 5-(pyridin-3-yl)-3-(5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine; 1H NMR (400.0 MHz, DMSO) d 7.22 (dd, J=3.8, 4.8 Hz, 1H), 7.68-7.73 (m, 2H), 7.81 (d, J=3.0 Hz, 1H), 7.95 (s, 2H), 8.69 (dd, J=1.2, 4.9 Hz, 1H), 8.84 (d, J=6.1 Hz, 1H), 8.99 (s, 1H), 9.55 (s, 1H) and 14.96 (s, 1H) ppm; MS (ES+) 322 Compound I-143 3-(5-(3-(aminomethyl)phenyl)-4H-1,2,4-triazol-3-yl)-5-(pyridin-3-yl)pyrazin-2-amine; MS (ES+) 345
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]1([CH:26]2[C:38]3[NH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]=3[CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.CCCCCC.O>[C:20]1([CH:26]2[C:38]3[NH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]=3[CH2:29][CH2:28][N:27]2[CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CN1CCc2c([nH]c3ccccc23)C1c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
147 mg (1.45 mmol) of triethylamine and 277 mg (1.21 mmol) of benzyl bromoacetate were added successively to a solution of 300 mg (1.21 mmol) of 1-phenyl-1,2,3,4-tetrahydro-β-carboline, as obtained in Example 70, in 10 ml of methylene chloride, with ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours. After this time, 277 mg of benzyl bromoacetate and 183 mg of triethylamine were added to the reaction mixture, and the resulting mixture was allowed to stand for 2 days. At the end of this time, first a saturated aqueous solution of sodium hydrogencarbonate and then water were added successively to the reaction mixture, which was then extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the ethyl acetate was removed by evaporation under reduced pressure to give 0.61 g of a crude mixture. The resulting residue was subjected to column chromatography using 13 g of silica gel with a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to yield 0.49 g of the title compound as yellow crystals in quantitative yield. The product was subsequently recrystallized from ethyl acetate to yield 0.37 g of the title compound as yellow crystals, melting at 130.8°-132.0° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]([O:47][CH3:48])=[O:46]>CC(C)=O>[CH3:48][O:47][C:45](=[O:46])[CH2:44][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:10]3[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenol (0.541 g, 1.163 mmol) was reacted with K2CO3 (0.225 g, 1.628 mmol) and methyl bromoacetate (0.249 g, 1.628 mmol) in acetone (10 ml) to give the product (0.525 g, 0.976 mmol, 84%) as a solid. 1H NMR (DMSO-d6) δ 3.66 (s, 3H), 4.03 (s, 2H), 4.77 (s, 2H), 5.30 (s, 2H), 6.84 (d, J=6.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.04-7.20 (m, 8H), 7.30 (dd, J=1.7, 8.5 Hz, 1H), 7.35-7.47 (m, 8H), 7.54 (d, J=1.2 Hz, 1H); [ESI(+)], m/z 538 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>>[CH3:1][NH:2][C:3]1[C:12]([C:13]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([C:17]([F:16])([F:26])[F:27])[CH:19]=2)=[O:15])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CNc1nc2ncccc2cc1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CNc1nc2ncccc2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 69 %

Procedure:
2-(Methylamino)-1,8-naphthyridine-3-carboxylic acid was coupled to 3-(trifluoromethyl)benzylamine using the general amide coupling procedure. The crude product was purified by flash chromatography, CH2Cl2/MeOH 95:5, yielding 62.4 mg (69%) of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][N:25]=[C:26]1[C:30]2[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=2[O:28][CH2:27]1>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:35][C:33]1[CH:32]=[CH:31][C:30]2[C:26](=[N:25][O:24][CH3:23])[CH2:27][O:28][C:29]=2[CH:34]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: CON=C1COc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc2c(c1)OCC2=NOC
Temperature: 0 °C

Procedure:
3.4 g of (E) methyl methoxyimino-(2-bromomethylphenyl)acetate was added to 9.0 g of potassium carbonate and 1.8 g of 3-methoxyimino-6-hydroxy-2,3-dihydrobenzofuran in 30 ml of N,N-dimethylformamide, and they were reacted at room temperature for 6 hours. After the completion of the reaction, the reaction liquid was poured in ice/water. After the extraction with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 3.0 g of the title compound. (having a m.p. of 108-110° C. and 1H-NMR data shown in the following table).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.[BrH:24]>C(O)(=O)C>[BrH:24].[Br:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]1[CH:22]=[CH:21][C:12]2[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=2[CH:10]=1
Reactant: COC(=O)Nc1nc2cc(C(O)c3ccc(F)cc3)ccc2[nH]1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C(Br)c3ccc(F)cc3)ccc2[nH]1
Yield: 99.9 %

Procedure:
A solution of 6.3 parts of methyl [5-[(4-fluorophenyl)hydroxymethyl]-1H-benzimidazol-2-yl]carbamate in 60 parts of acetic acid, saturated with hydrogen bromide was stirred for 3 hours at room temperature. The reaction mixture was evaporated, yielding 9.18 parts (99.9%) of methyl [5-[bromo(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbamate monohydrobromide as a residue (int. 2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10](Cl)[N:9]=1>C(O)C>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(N4CCOCC4)nc(Cl)nc32)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Morpholine (0.8 ml) and ethanol (10 ml) were added to tert-butyl (3S)-3-(2,6-dichloro-9H-purin-9-yl)pyrrolidine-1-carboxylate (1.55 g, 4.3 mmol) and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.76 g, 100%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)(=O)C.[NH4+].[OH-]>CO>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-acetoxy-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazoline (1.54 g, 4.26 mmol) (from Example 18, Step A, supra) in MeOH (30 mL) was added an aqueous solution of NH4OH (29%, 0.86 mL, 12.7 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated at 100° C. for 1.5 hours. The mixture was then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as a gray solid. (Yield 1.21 g, 89%).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Si:15]([O:32][C@@H:33]1[CH2:38][CH2:37][C:36](=[O:39])[C@@H:35]([F:40])[CH2:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.OO.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.C(OC)(C)(C)C>[Si:15]([O:32][C@@H:33]1[CH2:38][CH2:37][C@@H:36]([OH:39])[C@@H:35]([F:40])[CH2:34]1)([C:28]([CH3:31])([CH3:29])[CH3:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CCC(=O)[C@@H](F)C1)(c1ccccc1)c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](O)[C@@H](F)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
L-Selectride® (1M in THF; 69.0 mL; 69.0 mm01) is dropped into a stirred solution of (2S*,4R*)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-fluorocyclohexanone (example C14; 23.3 g; 62.8 mmol) in dry THF (230 mL) at −15° C. The reaction mixture is stirred over night and cooled to 0° C. before careful addition of ice cold water (100 mL), followed by dropwise addition of H2O2 (30% solution in water; 39.0 mL). After 30 min. saturated Na2SO3-solution (80 mL) is dropwise added at 0° C. tert-BuOMe (300 mL) is added, the organic layer is separated and concentrated under reduced pressure. The aqueous layer is extracted with tert-BuOMe. All combined organic phases are washed with brine and dried over MgSO4. The solvent is removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt—10:0 to 9:1) to yield 15.5 g of the title compound as colourless liquid.
Reaction SMILES: C1[CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C([Li])CCC.C([C:22]1[C:30]2[C:29]([NH:31][NH2:32])=[N:28][CH:27]=[N:26][C:25]=2[N:24]([C@@H:33]2[O:39][C@H:38]([CH2:40][OH:41])[C@@H:36]([OH:37])[C@@:34]2([CH3:42])[OH:35])[CH:23]=1)=O>C(Cl)(Cl)Cl.O>[NH:31]([C:29]1[C:30]2[C:22]([CH:2]=[CH:3][O:4][CH3:5])=[CH:23][N:24]([C@@H:33]3[O:39][C@H:38]([CH2:40][OH:41])[C@@H:36]([OH:37])[C@@:34]3([CH3:42])[OH:35])[C:25]=2[N:26]=[CH:27][N:28]=1)[NH2:32]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(NN)ncnc21
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC=Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(NN)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of THF at 0° C., diisopropyl ethyl amine (10 eq.), and n-butyl-lithium (10 eq.), is (Ph3P)ClCH2OCH3 (10 eq.). After stirring this mixture at room temperature for 1.5 hours, one cools to −78° C. and adds the compound from Step 2. After stirring at −78 C overnight one warms to room temperature, separates the reaction mixture between water and chloroform, extracts the aqueous layer two more times with chloroform, and combines the organic layers. They are dried over sodium sulfate, evaporated and purified via column chromatography to give the target compound.
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])[CH2:18]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[O:27]1[CH2:28][CH2:29][CH:24]([C:22]([N:19]2[CH2:20][CH2:21][C@H:17]([O:16][C:15]3[C:10]4[CH2:9][NH:8][CH2:31][CH2:30][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:18]2)=[O:23])[CH2:25][CH2:26]1
Reactant: O=C(C1CCOCC1)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(C1CCOCC1)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (10.9 g, 25.8 mmol) was dissolved in methanol (300 mL) and Pd(OH)2 on Carbon (2 g, 14.24 mmol) and ammonium formate (3.35 g, 51.6 mmol) were added. The reaction mixture was refluxed for 2 h. The reaction was cooled down to rt, the reaction mixture was filtered and evaporated under high vacuum for 2 h to yield (tetrahydro-pyran-4-yl)-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-methanone (8.45 g, 95% yield) as a light yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.44-1.67 (m, 4H) 2.08-2.32 (m, 2H) 2.55-2.83 (m, 3H) 2.96 (t, 2H) 3.22-3.96 (m, 11H) 5.53-5.68 (m, 1H) 8.49-8.59 (m, 1H). LCMS: [M+H]+=333.5, Rt(6)=1.24 min.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(F)cc2F)CC1
Yield: 40.1 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 6-bromo-1-(2,4-difluorophenyl)-1-hexanone (0.9 g) were reacted and treated in the same manner as in Example 172 to give 0.55 g of 4-amino-5-chloro-N-((1-(6-(2,4-difluorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20]CO.O>>[CH3:20][CH2:16][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: CCO
Reactant: COC(=O)C(C)(C)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C(=O)O)c1ccc(C(C)(C)C)cc1
Yield: 73.2 %

Procedure:
A solution of methyl 4-tert-butylphenylacetate (30.00 g, 0.145 mol) and iodomethane (45.41 g, 0.320 mol) in 125 mL of dry THF was added to a slurry of NaH (8.72 g, 0.363 mol) in 200 mL of THF dropwise over 30 minutes. After completion of the addition, the reaction mixture was heated at reflux for 1.5 hr. The reaction was allowed to cool to room temperature, filtered through Celite and concentrated. The residue was diluted in ether, washed with H2O, and dried over MgSO4. Evaporation of the solvent afforded the desired product as an oil. A mixture of the crude methyl 4-tert-butylphenylisobutyrate and 4:1 EtOH/H2O containing KOH (10.07 g, 0.179 mol) were heated to reflux for 4 hr. The EtOH was evaporated in vacuo, the residual solution was acidified to pH 2 with 2N HCl, and the precipitated solid filtered. The white solid was the dried (60° C., 1 mm Hg, 24 hr) to give the desired product (23.45 g, 73.2% from methyl 4-tert-butylphenylacetate). 1H NMR (CDCl3) 1.34 (s, 9H), 1.62 (s, 6H), 7.37 (s, 4H), 11.4-12.4 (brs, 1H). 13C NMR (CDCl3) 26.16, 31.30, 34.35, 45.81, 125.31, 125.48, 140.64, 149.66, 183.57.