Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:7]=1.C[C:35]1[C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1.[C:53](=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:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[N:21]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[N:7]=[C:2]([C:38]3[CH:39]=[C:40]([CH:35]=[CH:36][C:37]=3[CH3:53])[C:41]([OH:43])=[O:42])[C:3]=2[CH:24]=[CH:23][C:22]1=[O:25]
Reactant: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 150 °C
Yield: 68 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (47.5 mg, 0.1 mmol) in dioxane (3 mL) and water (1 mL) were added 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.6 mL, 0.005 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was concentrated, & then added was DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (39 mg, 68%). LC-MS m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH2:5][CH2:4]1.CCN([CH2:34][CH3:35])CC.C[O:37]C(=O)OC>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH2:5][CH2:4]1)[C:34](=[O:37])[CH3:35]
Reactant: CCN(CC)CC
Reactant: COC(=O)OC
Reactant: CNC1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccccc2)CC1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(N(C)C(C)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(4-(methylamino)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (76 mg, 0.20 mmol, 1.00 equiv) in dichloromethane (15 mL). Then Et3N (1.25 mL) was added. To the above dimethylcarbonate (0.75 mL) was added at 0° C. The resulting solution was stirred for 3 hr at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 0.077 g (91%) of methyl 3-(4-(N-methylacetamido)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([O:9]C)=[O:8])([O-:3])=[O:2].[ClH:22]>C1(C)C=CC=CC=1.CCO>[ClH:22].[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(OCCN2CCCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(OCCN2CCCC2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Methyl 3-nitro-4-[2-(1-pyrrolidinyl)ethoxy]benzoate (5.9 g, 20 mmol) was mixed with 60 mL of 5 N aqueous HCl and refluxed 16 h. It was mixed with toluene/EtOH and concentrated under reduced pressure to dryness. The resulting solid was tritrated with hot EtOAc to afford 5.7 g (18 mmol, 90%) of the benzoic acid hydrochloride.
Reaction SMILES: C(N=[CH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2Cl)CCC.[O-:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+].C([OH:28])CCC>Cl>[CH2:19]([O:18][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:6]=[O:28])[CH:8]=2)[N:13]=[CH:12][CH:11]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[O-]
Reactant: CCCCN=Cc1ccc2nccc(Cl)c2c1
Reactant: CCCCO
Agent: Cl
Agent: [Na+]
Product: CCCCOc1ccnc2ccc(C=O)cc12
Temperature: 120 °C
Yield: 48.5 %

Procedure:
A mixture of butyl (4-chloro-quinolin-6-ylmethylene)-amine (322 mg, 1.3 mmol) and a solution of sodium butoxide in butanol (3 mL, 6.0 mmol, 2.0M) were placed in a microwave tube and the mixture was heated to 120° C. for 30 min in a closed microwave. Then, the suspension was diluted with 3.0N hydrochloric acid (3 mL) and the solvent was removed under the vacuum. The residue was diluted with water and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with saturated sodium bicarbonate solution, brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to obtain 145 mg (48.5% yield) of 4-butoxy-quinoline-6-carbaldehyde as a white solid: EI-LRMS m/e calcd for C14H15NO2 (M+) 230.1, found 230.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:22]1([CH:28]2[C:32]3[S:33][CH:34]=[CH:35][C:31]=3[C:30](=O)[O:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:30]1[O:29][CH:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:32]2[S:33][CH:34]=[CH:35][C:31]1=2
Reactant: O=C1OC(c2ccccc2)c2sccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OC(c2ccccc2)c2sccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 2.9 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (340 mg, 2.25 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (4.5 mL of a 1 M solution in THF, 4.5 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and then warmed to room temperature. A solution of 6-phenyl-6H-thieno[2,3-c]furan-4-one, (320 mg, 1.5 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. and then poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a yellow solid (15 mg, 3%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:4]=1.[H-].[Na+].[CH3:39]I.Cl>CN(C=O)C.O>[CH3:39][O:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1
Reactant: CCOC(=O)CCCCCCn1cc(CO)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cn(CCCCCCC(=O)O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Example 3) (50 mg, 0.103 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (60% in mineral oil) (4.53 mg, 0.113 mmol) and the resulting mixture was stirred at RT for 15 minutes. Methyl iodide (7.08 μl, 0.113 mmol) was added and stirring continued at RT overnight. The mixture was added to water (30 ml) and the pH was adjusted to pH1 by addition of 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic portions were passed through a phase separating column and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc/iso-hexane. Further purification was carried out by dissolving the product in DCM (minimal) and loading onto a 20 cm×20 cm preparative TLC plate. The plate was run using a solvent system of 67% EtOAc in iso-hexane (300 ml) and the appropriate strip of silica was scrapped off the plate. The Si was suspended in 10% MeOH/DCM and sonicated. The suspension was filtered, rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 26.5 mg (0.06 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) in 3.0 ml EtOH and 4.0 ml of THF was added 240.1 mg NaOH (6.00 mmol, 3.0 ml of a 2M aqueous solution). After stirring at room temperature for 72 hours, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 10.4 (1H, s), 7.91-7.81 (5H, m), 7.54 (1H, d, J=8.1 Hz), 7.45 (1H, d, J=1.7 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz) 2.35 (5H, s), 1.33 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:15]2[NH:14][N:13]=[C:12]([CH:9]3[CH2:11][CH2:10]3)[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A dried 5-L, three-neck round bottom flask fitted with an overhead stirrer and reflux condenser was charged with a solution of 2,4-dichloropyrimidine (250 g, 1.678 mol) in anhydrous DMSO (2300 mL). 3-Cyclopropyl-1H-pyrazol-5-amine (227.4 g, 1.8458 mol) and DIPEA (438 mL, 2.517 mol) were added sequentially at RT. The resulting solution was stirred at 60° C. for 16 h, cooled to RT, and poured into ice water. The precipitated yellow solid was collected by vacuum filtration, and washed well with water, 1.5 N HCl (3×1 L), and finally rinsed of water (4×500 mL). The precipitate was dried by air suction overnight to give 320 g (81%) of 53 as yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.29 (s, 1H), 8.15 (s, 1H), 7.0 (br s, 1H), 6.0 (br s, 1H), 1.85-1.92 (m, 1H), 0.91-0.95 (m, 2H), 0.7 (m, 2H); MS (ESI+) m/z=236 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1.[OH-].[Na+].[ClH:16]>O>[Cl:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([Cl:16])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(Cl)c1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)Cl)cc1Cl

Procedure:
A mixture of 10.4 g. (0.052 mol.) of 3-chloro-4-methoxybenzoic acid methyl ester and 3.5 g. (0.09 mol.) of sodium hydroxide in 150 ml. of water was refluxed for two hours. The reaction mixture was cooled and acidified with 10% aqueous hydrochloric acid to precipitate 3-chloro-4-methoxybenzoic acid, m.p. 199°-202°. The acid was refluxed with thionyl chloride as described in the procedure of Example 9 to give 3-chloro-4-methoxybenzoic acid chloride, m.p. 55°-57°.
Reaction SMILES: C([O:4][C:5](=[O:77])[CH2:6][C@H:7]([OH:76])[C@H:8]([NH:16][C:17](=[O:75])[C@H:18]([NH:40][C:41](=[O:74])[C@H:42]([NH:44][C:45](=[O:73])[CH2:46][C@H:47]([OH:72])/[CH:48]=[CH:49]/[CH2:50][CH2:51][S:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:43])[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1.CC(O)=O>CO.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>[OH:76][C@H:7]([C@H:8]([NH:16][C:17](=[O:75])[C@H:18]([NH:40][C:41](=[O:74])[C@H:42]([NH:44][C:45](=[O:73])[CH2:46][C@H:47]([OH:72])/[CH:48]=[CH:49]/[CH2:50][CH2:51][S:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH3:43])[CH2:19][S:20][C:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:5]([OH:77])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCN1
Product: C[C@@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](Cc1ccccc1)[C@@H](O)CC(=O)O
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of 4D (170 mg, 0.159 mmol), Pd(PPh3)4 (9 mg, 0.008 mmol) in dry methanol (6 mL) under argon was added morpholine (28 μL, 0.32 mmol) which was allowed to stir for 3 h. The reaction mixture was concentrated in vacuo, CH2Cl2 (20 mL) was then added before washing with 1M HCl (15 mL), sat. sodium hydrogen carbonate (15 mL), sat. brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification was then carried out by column chromatography on silica gel (5-8% MeOH/CH2Cl2 then +0.2% AcOH) to give 5D (130 mg, 0.13 mmol, 61%).
Reaction SMILES: Br[C:2]([CH3:14])([CH:4]([Br:13])[C:5](=[O:12])[CH:6]([Br:11])[C:7](Br)([CH3:9])[CH3:8])[CH3:3].C(Cl)Cl.S(=O)(=O)(O)O>N1C=CC=CC=1>[Br:11][C:6]([C:5](=[O:12])[C:4]([Br:13])=[C:2]([CH3:14])[CH3:3])=[C:7]([CH3:9])[CH3:8]
Reactant: CC(C)(Br)C(Br)C(=O)C(Br)C(C)(C)Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)=C(Br)C(=O)C(Br)=C(C)C
Temperature: 0 °C

Procedure:
The above crude, 2,3,5,6-tetrabromo-2,6-dimethyl-4-heptanone was dissolved in 200 ml. of methylene chloride and the solution was cooled to about -10° C. with an ice-methanol bath. To this solution, 250 ml of pyridine was added under a nitrogen atmosphere. The mixture was stirred about fifteen hours while the temperature was maintained at less than 25° C. The reaction mixture was poured into 800 ml of 15% solution of sulfuric acid in ice water (prepared by the addition of ice to 400 ml of 30% of sulfuric acid solution until the total volume reached 800 ml). The aqueous layer was extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extracts were washed with two 250 ml portions of 30% aqueous sulfuric acid and then with three 300 ml portions of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure (pot temperature less than 50° C.). 3,5-Dibromo-2,6-dimethyl-2,5-heptadiene-4-one (wt. 157.75 g) was obtained as a light brown oil containing about 8% solvent.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([O:40][C@@H:41](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.C(N1C2C(=CC(OC)=CC=2)CC1=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:40][CH3:41])=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Agent: COc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Yield: 52 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (3.35 g, 7.90 mmol) and 1-benzyl-5-methoxyindolin-2-one (2.00 g, 7.90 mmol). The crude product was purified by silica gel chromatography (15-40% EtOAc in hexane) followed by trituration (EtOAc) to give the title compound as a white solid (1.97 g, 52%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.36-7.23 (m, 10H), 7.14 (d, J=7.2 Hz, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 5.61 (d, J=15.1 Hz, 1H), 5.54 (d, J=15.4 Hz, 1H), 5.37 (s, 1H), 5.07 (d, J=15.4 Hz, 1H), 4.95 (d, J=15.7 Hz, 1H), 3.51 (t, J=8.1 Hz, 1H), 3.18 (s, 3H), 2.32-2.29 (m, 1H), 2.09-2.00 (m, 1H). MS ESI 486.3 [M+H]+, calcd for [C32H27N3O2+H]+ 486.2.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[C@H:27]1([NH:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:47])[CH:43]=3)[N:38]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:1]([NH:47][C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[N:38]=[C:37]([NH:36][C@H:27]2[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]2)[CH:46]=[CH:45]3)=[O:12])[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-amino-1-tert-butyloxycarbonyl-piperidine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=502.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:32])[C:14]2[CH:19]=[N:18][C:17](S(C)(=O)=O)=[N:16][C:15]=2[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)=[O:11])[CH3:8]>>[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:32])[C:14]2[CH:19]=[N:18][C:17]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:16][C:15]=2[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)=[O:11])[CH3:8]
Reactant: COCCCN
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-methoxy-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 35 (Step E) above, 30 mg, 0.08 mmol). 8-Cyclohexyl-2-(3-methoxy-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (24 mg, 80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (br, 1H), 8.48 (s, 1H), 6.21 (br, 1H), 5.11 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.70-3.46 (m, 4H), 3.37 (s, 3H), 2.06-1.24 (m, 15H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H28N4O4: 389.21 (M+H). Found: 389.2.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](=O)([O:12]C)[NH2:11].C1(C)C=CC=CC=1>C([Sn](=O)CCCC)CCC.CO>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10]([NH2:11])=[O:12])[CH3:2]
Reactant: COC(N)=O
Reactant: CCCCC(CC)CN
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC(CC)CNC(N)=O
Temperature: 110 °C
Yield: 91.7 %

Procedure:
Into a 300 ml reaction vessel equipped with a distillation apparatus, 50 g of 2-ethylhexylamine, 29 g of methyl carbamate and 100 ml of toluene were placed, and to the mixture was added 0.1 g of dibutyl tin oxide as a catalyst and heated with stirring. Methanol formed during the reaction was removed, when the reflux temperature was raised to 110° C., i.e.,the boiling point of toluene, the distillation apparatus was taken off and instead a reflux condenser was attached and the mixture was refluxed by heating for 30 minutes with stirring, then allowed to cool. The toluene was distilled off under reduced pressure, and the residue was washed with n-hexane and collected by filtration to obtain 61 g of N-(2-ethylhexyl)urea.