Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][C:9](=O)[N:8]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH2:7][C:6]=2[CH:36]=1.B.C1COCC1.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH2:7][C:6]=2[CH:36]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1cc(Cl)ccc1-3
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(Cl)ccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 6) in THF (0.02 M), BH3.THF (1 M solution in THF, 5 eq) was added and the solution allowed to stir at RT for 2 h. MeOH (0.02 M) and a 1.25 M solution HCl in MeOH (0.24 M) were added carefully and stirred overnight at RT before being heated at 60° C. for 3 h. The volatiles were then removed in vacuo. The volume of the solution was reduced in vacuo before diluting with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was then used in the next step without any further purification (quant); MS (ES+) 494 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[N:16][CH:17]=[C:12]2[CH2:11][NH:10][C:9]1=[O:32].CC(C)([O-])C.[K+]>O1CCCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:16][CH:17]=[C:12]2[CH:11]=[N:10][C:9]1=[O:32]
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CC5CCC3C5)C(=O)NC4)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc4cnc(=O)n(C5CC6CCC5C6)c4n3)cc2)CC1
Reaction time: 48 h
Yield: 70.5 %

Procedure:
Prepared from 200 mg (0.46 mmol) of 1-bicyclo[2.2.1]hept-2-yl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, exo and 207 mg (1.84 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours. After the workup, the semi-solid is triturated in diethyl ether/hexane, and the powder is collected and dried to give 140 mg (70%) of the title compound: mp>210° C. (dec).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([CH3:19])[N:9]=1)(C)(C)C.Cl>O1CCOCC1>[CH3:19][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:12][C:8]([NH2:7])=[N:9]1
Reactant: Cn1nc(NC(=O)OC(C)(C)C)cc1-c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(N)cc1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of (1-methyl-5-pyridin-2-yl-1H-pyrazole-3-yl)-carbamic acid tert-butyl ester (82 mg, 0.30 mmol) in dioxane (0.85 ml) was treated with 4M HCl in dioxane (0.85 ml) and the resulting suspension was stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium bicarbonate solution and brine. The ethyl acetate phase was dried and the solvent was evaporated to yield the product as light brown viscous oil (51 mg, 97%) which was used without any further purification. MS: M=175.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([NH:17][C:18]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:34]C(C)([O-])C.[Na+].IC>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[C:3]([C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[C:4]([C:8]([N:10]2[C@@H:14]3[CH2:15][CH2:16][C@H:11]2[C@H:12]([N:17]([CH3:34])[C:18]2[CH:23]=[N:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][N:19]=2)[CH2:13]3)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(c1cccc(F)c1-c1ncccn1)N1[C@@H]2CC[C@H]1[C@H](Nc1cnc(C(F)(F)F)cn1)C2
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(c1cnc(C(F)(F)F)cn1)[C@@H]1C[C@H]2CC[C@@H]1N2C(=O)c1cccc(F)c1-c1ncccn1
Yield: 60.5 %

Procedure:
The title compound of Example 238 (63 mg, 0.14 mmol) was dissolved in DMF (1.4 mL) and then sodium tert-butoxide (15 mg, 0.15 mmol) followed by iodomethane (9 μL, 0.14 mmol) were added. After 15 h at room temperature the reaction mixture was diluted with EtOAc and water was added. The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried over MgSO4, filtered and evaporated. Purification was performed using Agilent prep method X to give the title compound (40 mg, 62%). MS (ESI) mass calcd. for: C23H20F4N6O, 472.2. m/z found 473.2 [M+H]+. 1H NMR (500 MHz, Chloroform-d) 8.81 (d, J=4.9 Hz, 2H), 8.35 (s, 1H), 8.02 (s, 1H), 7.55-7.46 (m, 1H), 7.34-7.20 (m, 3H), 4.81-4.73 (m, 1H), 4.67 (d, J=4.3 Hz, 1H), 4.17-4.08 (m, 1H), 3.05 (s, 3H), 2.12 (dd, J=12.8, 8.3 Hz, 1H), 1.98-1.44 (m, 5H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.C([Mg]Cl)(C)C.[C:33]([Si:37]([CH3:50])([CH3:49])[N:38]1[C:42]2[N:43]=[CH:44][CH:45]=[C:46]([CH:47]=[O:48])[C:41]=2[CH:40]=[CH:39]1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([Si:37]([CH3:50])([CH3:49])[N:38]1[C:42]2=[N:43][CH:44]=[CH:45][C:46]([CH:47]([OH:48])[C:2]3[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=4)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=3)=[C:41]2[CH:40]=[CH:39]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(C=O)ccnc21
Reactant: COCN(c1cc(Cl)c(C)nc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)c(C)nc1C(O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 145 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (152.7 mg, 0.3 mmol) in 2 ml of THF under nitrogen atmosphere at 0° C. was added via syringe 2.0M isopropyl magnesium chloride (0.36 ml, 0.72 mmol). The reaction mixture was stirred for about 45 minutes and 1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (54 mg, 0.21 mmol) was added and the resultant mixture was stirred for 30 minutes at 0° C. and then 2 hours at room temperature. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated and washed with water twice and dried. Concentration of this mixture afforded the crude product (210 mg) which was used in the next step without any further purification. MS (ES) (M++H) expect 689. found 688.9
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13]P(=O)(OCC)OCC.[H-].[Na+].[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.O>O1CCCC1>[CH3:24][O:25][CH2:26][O:27][C:28]1[C:32](/[CH:33]=[CH:13]/[C:3]2[N:4]=[C:5]([N:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[S:6][C:2]=2[CH3:1])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1nc(N2CCOCC2)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCOCC2)sc1C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of diethyl {[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}phosphonate (1.56 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.22 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.14 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5, v/v) to give 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)morpholine as pale-yellow crystals (1.05 g, yield 54%). melting point: 162-164° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[N:9]([CH2:30][O:31][CH3:32])[C:8]1=[O:33])=[O:6].[CH2:34](Br)[CH:35]=[CH2:36].[H-]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1([CH2:36][CH:35]=[CH2:34])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[N:9]([CH2:30][O:31][CH3:32])[C:8]1=[O:33])=[O:6]
Reactant: COCN1C(=O)C(C(=O)OC)C(c2ccccc2OC)Cc2cc(C(F)(F)F)ccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)C(=O)N(COC)c2ccc(C(F)(F)F)cc2CC1c1ccccc1OC

Procedure:
To a suspension of sodium hydride (384 mg; 8 mmole; 50% oil dispersion) in dry dimethylformamide (35 ml), cooled in an ice water bath, was added a solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-1-(methoxymethyl)-4-(methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (917 mg; 21 mmole) in dimethylformamide (8 ml) with stirring. After stirring at 0°-5° C. for 30 minutes, allyl bromide (1.5 ml) was added in one portion, the mixture was allowed to stand at 0°-5° C. for three additional hours, whereupon excess hydride was destroyed by the addition of water. The mixture was diluted with ether and washed with water. The aqueous layer was extracted with ether (three times), and the combined ether extracts were dried (magnesium sulfate) and concentrated. The crude residue was flash chromatographed (silica gel/5-20% ethyl acetate:hexane) to obtain 905 mg of the title compound in crystalline form.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:33])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:33])[N:15]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cccnc32)cc1
Temperature: 140 °C
Yield: 79.8 %

Procedure:
Cyclohexylamine (1.18 mL, 10.35 mmol) was added to a stirred solution of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) (1.80 g, 5.17 mmol) in xylene and heated at 140 ° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase washed by water and brine, then dried over Na2SO4 and evaporated to yield 1.68 g (82%) of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (29) as white solids. MP: 149° C.; 1H-NMR (DMSO-d6): δ 1.2-1.4 (m, 5H), 1.55 (m, 1H), 1.70 (m, 2H), 1.90 (m, 2H), 3.69 (s, 3H), 3.86 (m, 1H), 5.54 (s, 2H), 6.81 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.43 (m, 1H), 8.47 (dd, J=2.0, 8.0 Hz, 1H), 8.79 (dd, J=1.6, 4.8 Hz, 1H), 10.22 (d, J=7.2 Hz, 1H); EIMS m/z 408 (M+1).
Reaction SMILES: [CH:1]1([CH:5]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([N:29]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]3)=[C:24]([CH3:38])[CH:23]=2)[C:6]2[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH:13]=[CH:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH:39]1([CH:43]([O:58][C:59]2[CH:64]=[C:63]([CH3:65])[C:62]([N:66]3[CH:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[CH:68]=[N:67]3)=[C:61]([CH3:75])[CH:60]=2)[C:44]2[CH:57]=[CH:56][C:47]([C:48]([NH:50][CH2:51][CH2:52][C:53]([OH:55])=[O:54])=[O:49])=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH2:40]1.[OH-].[Li+]>C1COCC1>[CH:1]1([CH:5]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([N:29]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]3)=[C:24]([CH3:38])[CH:23]=2)[C:6]2[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH:39]1([CH:43]([O:58][C:59]2[CH:64]=[C:63]([CH3:65])[C:62]([N:66]3[CH:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[CH:68]=[N:67]3)=[C:61]([CH3:75])[CH:60]=2)[C:44]2[CH:57]=[CH:56][C:47]([C:48]([NH:50][CH2:51][CH2:52][C:53]([OH:55])=[O:54])=[O:49])=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: COC(=O)C=CNC(=O)c1ccc(C(Oc2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCC2)cc1
Agent: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)cc2)C2CCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(c2ccc(C(=O)NC=CC(=O)O)cc2)C2CCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)methyl)benzamido)propenoate, Isomer 1 (450 mg, 0.85 mmol) in THF (4 mL) was added 2N aqueous lithium hydroxide (4 mL, 8.0 mmol). The resulting mixture was stirred at 20° C. for 1 h. THF was removed under reduced pressure. The residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (20 mL*2). The organic layer was concentrated to give 3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)methyl)benzamido)propenoic acid, Isomer 1 (330 mg) as a colorless solid. 1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.88 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.61 (s, 2H), 5.15 (d, J=7.2 Hz, 1H), 3.50 (t, J=6.8 Hz, 2H), 2.70-2.67 (m, 1H), 2.52 (t, J=6.8 Hz, 2H), 2.04-1.94 (m, 3H), 1.82-1.72 (m, 9H). MS (M+1)=516.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](P(OCC)(OCC)=O)[O:5][CH3:6].[Li+].C[O-].[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32][O:33][C:34]1[C:42]2[CH:41]=[CH:40][S:39][C:38]=2[C:37]([CH:43]=O)=[CH:36][CH:35]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])/[C:4](/[O:5][CH3:6])=[CH:43]/[C:37]1[C:38]2[S:39][CH:40]=[CH:41][C:42]=2[C:34]([O:33][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH3:19])=[CH:35][CH:36]=1
Reactant: CCOP(=O)(OCC)C(OC)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Temperature: 75 °C
Yield: 56.9 %

Procedure:
A suspension of 6.07 g (20.2 mmol) of (diethoxyphosphoryl)-methoxy acetic acid methyl ester (H. Gross, Justus Liebigs Ann. Chem. 1967, 707, 35-43), 0.86 g of lithium methylat (21.6 mmol) and 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.5 mmol) in 50 ml of DMF was heated for 21 h at 75° C. The suspension was cooled to 0° C., the solid filtered off and washed with 30 ml of cold (−15° C.) ethanol. The filter cake was dissolved in a mixture of 100 ml dichloromethane and 60 ml of water, the organic layer separated, dried over sodium sulfate and evaporated to dryness. Thereby, 3.45 g (55%) of the title compound with a purity of 91% (GC area) were obtained as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
A mixture of [2-(6-nitro-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (5 g, 16.4 mmol) and Raney Ni (1 g) in EtOH (100 mL) was stirred at room temperature under H2 (1 atm) for 5 h. Raney Ni was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give [2-(6-amino-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (B-10) (3 g, 67%). 1H NMR (DMSO-d6) δ 10.1 (br s, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.77-6.73 (m, 2H), 6.46 (d, J=1.5 Hz, 1H), 6.32 (dd, J=8.4, 2.1 Hz, 1H), 4.62 (s, 2H), 3.14-3.08 (m, 2H), 2.67-2.62 (m, 2H), 1.35 (s, 9H); ESI-MS 275.8 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.C(O)(=O)CC.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C:24]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])(=[O:27])[CH:25]=[CH2:26].[OH-].[Na+].C(OC(CC)CCCCC)(=O)C=C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(N)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:26]=[CH:25][C:24]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Pd]
Agent: C=CC(=O)OC(CC)CCCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCC(=O)O
Solvent: CC(C)(C)N
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
p-Anisidine (123 g), propionic acid (200 ml) and water (250 ml) were mixed in a 5 liter reaction flask and cooled to 0° C. Sulfuric acid 98% (202 g) was added gradually with cooling followed by the addition of sodium nitrite (69 g) dissolved in 200 ml water over a 50 minute period. The stirring was continued for a further one hour at 0°-2° C., t-Butylamine (0.5 g) was then added. After an additional 15 minutes of stirring Pd(dba)2 (1.0 g) and propionic acid (250 ml) were added. 2-Ethylhexyl acrylate (276 g) was then added over a period of 10 minutes while maintaining the temperature at 0° C. The reaction was then allowed to warm to room temperature and stirred for 24 hours. Sodium hydroxide (333 g of 30% solution) was added and after 10 minutes the lower aqueous layer was separated and extracted twice with ether (200 ml). The ether layers were combined and evaporated. The residue was combined with the organic layer and distilled to give separate fractions of propionic acid, excess ethylhexyl acrylate and 273 g of 2-ethylhexyl p-methoxycinnamate (94.0% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6]>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:5](=[O:6])[CH3:4])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:1])[CH3:10]
Reactant: O=C(O)c1cc(O)cc(O)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1

Procedure:
3,5-Dihydroxybenzoic acid (77grams, 0.5 mole) and 200 milliliters of acetic anhydride were mixed in a five hundred milliliter round-bottomed flask, which was fitted with a reflux condenser. As the mixture was heated to reflux the dihydroxyacid went into solution. Refluxing was continued for a total of 5 hours. A brown solution was obtained. Excess acetic anhydride was removed by rotary evaporation and the remaining solid was dried under vacuum at 40° C. The solid was dissolved in about 200 milliliters of refluxing chloroform, filtered hot and then diluted with 70 milliliters of petroleum ether (bp 60°-80° C.). The compound crystallized overnight and was isolated by filtration and washed with a 1:1 mixture of petroleum ether and chloroform. The compound was then recrystallized by the same procedure. Yield was 59 grams (50%) of white crystals. Melting point was 157°-159° C. NMR conducted as in the preceeding preparation, but using (DMSO-d6) gave as peaks, in ppm: 2.1 (s,6H), 7.23 (s, 1H), 7.55 (s, 2H), 13.3 (b, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.45 g, 1.32 mmol) (from Example 16, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.6 mmol) and methyl iodide (0.75 g, 5.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.3 g, 84%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C@@H:8]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:7][C@@H:8]([CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH2:15][CH2:16]1)=[O:10])=[O:4]
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NC(=O)CCl)CC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of chloroacetyl chloride (120 microL, 1.49 mmol) in dichloromethane (5 mL) was slowly added a mixture of (S)-1-(1-(2-amino-4-phenylbutanoyl)piperidin-4-yl)-3,3-dimethylindolin-2-one hydrochloride (600 mg, 1.36 mmol, EXAMPLE 1, Step 4) and triethylamine (420 microL, 2.99 mmol) in dichloromethane (4 mL) at 0° C. After 5 min, the reaction was quenched with water and the mixture was diluted with ethyl acetate to separate. The organic layer was washed with water (×2) and brine, dried over sodium sulfate and concentrated to give the title compound. The product was diluted with 6.0 mL of tetrahydrofuran to give 0.226 mol/L tetrahydrofuran solution assuming 100% conversion. The stock solution was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:35][CH2:34][CH2:32][OH:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: NCCO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12

Procedure:
Prepared according to the method of example 33(b), using N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 35(a)) (0.2 g) and ethanolamine (0.8 mL) to afford the title compound (0.068 g).