Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:51]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:52]
Reactant: O=C(Cl)C1CCCCC1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(piperidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (870 mg, 2 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(piperidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (365 mg, 44%) as a white solid: LC/MS m/e calcd for C24H29N3O3 (M+H)+: 408.52, observed: 408.2.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11]Br)=[O:7])=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:18]=[N+:19]=[N-:20])=[O:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
A mixture of 3-(4-chlorobenzoyl)benzyl bromide (4.2 g, 13.6 mmol) and sodium azide (1.32 g, 20.3 mmol) in ethanol (40 ml) was refluxed for 5 hours, cooled to ambient temperature, and kept 16 hours. The mixture was filtered and the solids were washed twice with ethanol. The combined filtrate and washes were evaporated to dryness under vacuum and the residue was treated with diethyl ether and filtered. The filtrate was evaporated to dryness under vacuum and dried to provide 3.7 g (100%) of 3-(4-chlorobenzoyl)-benzyl azide, m.p. 43°-45° C.
Reaction SMILES: S[CH2:2]CC[Si](OC)(OC)OC.C[O-].[Na+].[Na+].[Cl-].CSCCC[Si](OC)(OC)OC.[C:29]([S:32][CH2:33][CH2:34][CH2:35][Si:36]([O:41][CH3:42])([O:39][CH3:40])[O:37][CH3:38])(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[C:29]([S:32][CH2:33][CH2:34][CH2:35][Si:36]([O:37][CH3:38])([O:39][CH3:40])[O:41][CH3:42])(=[O:31])[CH2:30][CH3:2]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: CO[Si](CCCSC(C)=O)(OC)OC
Agent: CO[Si](CCCSC)(OC)OC
Agent: C[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCC(=O)SCCC[Si](OC)(OC)OC

Procedure:
816 grams of 3-mercapto-1-propyltrimethoxysilane, 871 grams of 25 weight percent methanolic solution of sodium methoxide, and 1,724 grams of toluene were charged to a 5-liter flask under an atmosphere of nitrogen. The stirred mixture developed a pinkish color. Methanol was removed from the flask by distilling off a methanol-toluene azeotrope, during which time the contents of the flask turned colorless. The appearance of a strong density current in the distillate which coincided with an increased in distillation head temperature from 63° C. to 108° C. signaled the point at which methanol removal from the flask was complete. With continued stirring, the contents of the flask were allowed to cool and were placed in an ice-water bath. 361 grams of propionyl chloride was added to the flask dropwise and/or in small portions with continued stirring in an ice-water bath until the reaction was complete. Aliquots of the stirred mixture were taken periodically and placed onto pH paper. An alkaline reading indicated the completion of the reaction. The final mixture was a white suspension of NaCl in a toluene solution of the product. This mixture was filtered and the solvent was removed from the filtrate to yield a light brown product. Gas chromatography indicated 5 percent 3-mercapto-1-propyltrimethoxysilane, 25 percent of 3-(methylthio)-1-propyltrimethoxysilane, and 70 percent of 3-(acetylthio)-1-propyltrimethoxysilane (product). Flash distillation from one to two grams of powdered sodium methoxide yielded a colorless product. The sodium methoxide was added to ensure that any remaining acidity was neutralized. Further optional fractional distillation yielded a product in excess of 98 percent purity by GC.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=1.[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:29]=[C:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[S:24][C:19]([C:17]2[N:18]=[C:13]([CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[CH:14]=[CH:15][CH:16]=2)=[N:20]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 78.8 %

Procedure:
6-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-pyridinecarbonitrile (1.25 g, 4.7 mmol) and methyl thiosalicylate (1.59 g, 9.4 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The reaction mixture was refluxed for 15 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-chloroform to give the titled compound (1.48 g, 78%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]2[N:14]=[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][C:29]([CH3:32])=[N:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:16]=[C:17]([NH:18][CH3:19])[C:12]=2[CH2:11][CH2:10]1.O.C(O)(C(F)(F)F)=O>C(=O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[C:13]2[N:14]=[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][C:29]([CH3:32])=[N:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:16]=[C:17]([NH:18][CH3:19])[C:12]=2[CH2:11][CH2:10]1
Reactant: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Agent: O=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
A racemic mixture of 7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 193) was purified using chiral supercritical fluid chromatography (SFC) to afford peak A (Example 193A) and peak B (Example 193B). SFC Method: Chiralpak OJ-H (30×150 mm), 30% methanol (0.1% diethylamine) in CO2, 100 bar, flow rate 50 mL/min for 12 min, absorbance 268 nm, injection 2.0 mL of 10 mg/mL solution in methanol, tR (peak A)=4.7 min, tR (peak B) 9.6 min. The absolute stereochemistry of individual enantiomers (Examples 193A and 193B) was not determined 193A: LC-MS (M+H)+=446.2. LC Rt 13.03 min (Waters Sunfire 4.6×150 mm 10 to 100% B in A over 15 min, 1.5 mL/min. (A is 90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.46 (1H, s), 8.04 (1H, s), 7.51 (1H, d, J=8.55 Hz), 7.04-7.13 (2H, m), 6.78-6.87 (3H, m), 4.42-4.50 (1H, m), 3.68 (3H, s), 3.13 (3H, s), 2.62-2.79 (3H, m), 2.49 (3H, s), 1.96-2.08 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Cyanophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea (0.1 g 0.26 mmol) was dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) was added and the reaction was heated at reflux under a nitrogen atmosphere. After 30 min the reaction was allowed to cool to ambient temperature, filtered and concentrated to give a viscous oil. The crude product was purified by flash chromatography on silica gel by eluting with methylene chloride:methanol 85:15 with 3% triethylamine. The product, N-(3-cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea, was concentrated to give an oil which crystallized from ethyl ether (0.05 g, 48%, mp 157-8° C.); LRMS (M+H)+ m/z 299; 1H NMR (CDCl3): 7.5-7.3(m, 4H), 4.05(m, 1H), 3.60(m, 2H), 3.32(m, 2H), 3.17(m, 2H), 2.72(m, 2H), 2.0-1.6(m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:4]2[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1
Reactant: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.80 g, 5.9 mmol), methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (0.30 g, 1.2 nunol) and triphenylphosphine (0.46 g, 1.8 mmol) in 1,2-dichloroethane (20 ml) was added at 10° C. a solution of 95% DEAD (0.54 ml) in 1,2-dichloroethane (5 ml) taking 30 minutes. The mixture was stirred for one hour at the same temperature range, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 0.15 g of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C(C)=CC(C)=CC=1C.CS(C)=[O:39]>>[CH:2]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:39]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CBr)c2-c2ccccc2)cc1
Reactant: CS(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C=O)c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of the compound prepared in Step 1 (362 mg, 0.79 mmol) in dimethyl sulfoxide (7 mL) was added collidine (0.14 mL, 1.0 mmol). The solution was heated at 120° C. for 3 hours and then kept at overnight at room temperature. The reaction solution was partitioned between ethyl acetate and water and the organic solution was washed with water, dried and concentrated. The residue was chromatographed (1:1 hexane:ethyl acetate) to give the desired product (205 mg, 66%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.4 %

Procedure:
Oxalyl chloride (0.07 ml, 0.800 mmol) was added to a stirred solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (WO 2008074820; 86 mg, 0.40 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated in vacuo to give a yellow gum (123 mg) which was used in the subsequent reaction (D53) without further purification
Reaction SMILES: [C-]#N.[Na+].[Br:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]Br)[CH:8]=[CH:9][CH:10]=1.[CH3:20][N:21](C)C=O>O>[Br:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][C:20]#[N:21])[CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1ccccc1Sc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccccc1Sc1cccc(Br)c1

Procedure:
12.4 G. sodium cyanide (0.25 mole) is added to a solution of 58.6 g. 2-(3-bromophenylthio)benzyl bromide (0.164 mole) in 200 cc. dimethylformamide (DMF). The reaction is slightly exothermic. The resulting solution is allowed to stir for an hour without cooling, then is diluted with a large volume of water and extracted with ether three times. Ether extracts are washed several times with water, dried over sodium sulfate and the ether evaporated off. The crude yield of 2-(3-bromophenylthio)benzyl cyanide is 49.6 g.; the product is an oil which is hydrolyzed as such.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]3[CH3:34])=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: CC1CCCCN1CCCC(=O)O
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3C)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)butyric acid hydrochloride and dicyclohexylcarbodiimide in methylene chloride are stirred at room temperature for 16 hours. The reaction mixture is cooled and the solid removed by suction filtration. The methylene chloride is evaporated to give a residue which is dissolved in methylene chloride and diethyl ether. After removing the resulting crude product, the solvents are evaporated and the gummy resin is dried, triturated with diethyl ether, and dried to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (320 mg) in N,N-dimethylformamide (2.0 mL), was added potassium carbonate (452 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodomethane (444 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (325 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:77][NH:78][CH3:79]>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]>[CH3:77][N:78]([CH3:79])[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(F)c21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CN(C)c1cc(F)c2c(c1)Sc1cc(Br)ccc1N2C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 3,7-dibromo-1-fluoro-10-Boc-phenothiazine (8) (475 mg, 1 mmol) in touene (10 mL) Pd(dba)2 (28.9 mg, 0.05 mmol), BINAP (22.5 mg, 0.035 mmol), Cs2CO3 (652 mg, 2 mmol) and dimethylamine (0.6 mL, 1.2 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([O:15][C:16]1[C:21](=[O:22])[NH:20][CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[C:25]([F:33])[CH:24]=2)[CH:17]=1)[CH3:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[CH:17]=[C:16]([O:15][CH2:13][CH3:14])[C:21](=[O:22])[NH:20][CH:19]=3)=[CH:24][C:25]=2[F:33])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A suspension of 4-chloro-3-(trifluoromethyl)aniline (20.14 mg, 0.103 mmol) in DMF (8 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.103 mmol) in DMF (8 mL). HOBt (23.66 mg, 0.154 mmol), EDC (29.6 mg, 0.154 mmol) and Et3N (0.043 mL, 0.309 mmol) were added and the mixture was stirred at 50° C. for 8 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a white solid of N-(4-chloro-3-(trifluoro methyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (11.39 mg, 0.024 mmol, 23.6% yield). TLC (DCM/MeOH=10:1, Rf=0.6): 1H NMR (400 MHz, CD3OD) δ: 8.10 (s, 1H), 7.79 (d, J=8.82 Hz, 1H), 7.53 (d, J=8.82 Hz, 1H), 7.37-7.44 (m, 1H), 7.26-7.37 (m, 3H), 7.23 (d, J=1.98 Hz, 1H), 4.12 (q, J=7.06 Hz, 2H), 3.80 (s, 2H), 1.46 (t, J=6.95 Hz, 3H); ES-LCMS m/z 469.1 (M+H).
Reaction SMILES: C(OC(=O)C)C.Cl.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:48])[C:12]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)=[O:25]>C(O)C>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:48])[C:12]([C:40]1[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1)=[CH:13][N:14]2[CH2:23][C:24]([NH:26][CH:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:25]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)NC3CCNCC3)c12
Temperature: 25 °C
Reaction time: 28 h
Yield: 27.5 %

Procedure:
A 4N hydrochloric acid ethyl acetate solution (25 ml) was added to an ethanol solution (12 ml) of tert-butyl 4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate (820 mg, 1.44 mmol), followed by stirring at room temperature for 28 hours. The resulting mixture was concentrated under reduced pressure. After adding an aqueous sodium bicarbonate solution to the residue to adjust the pH to 8, the residue was washed with ethyl acetate. A 2N aqueous sodium hydroxide solution was added to the water layer to adjust its pH to 11, followed by extraction using dichloromethane. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-piperidin-4-ylacetamide (185 mg, yield: 27%).