Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]([CH2:18]Cl)=[CH2:17]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([Cl:15])=[CH2:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc(F)cc1
Yield: 79 %

Procedure:
According to the procedure of W. K. Anderson et al., J. Chem. Soc., Perkin 1,1 (1976), a mixture of 4-fluorophenol (20.0 g, 0.178 mol) and K2CO3 (27.3 g, 0.196 mol) in acetone (250 mL) was heated at reflux for 1 hour. 2,3-Dichloro-1-propene was added, and the resulting mixture was refluxed for 2 days, cooled, and concentrated. The mixture was diluted with H2O, and extracted with ether (3×150 mL). The ethereal extracts were dried (MgSO4) and concentrated to give a brown oil. Distillation under high vacuum gave 26.4 g (79%) of product as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:4][CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[S:8].F[B-](F)(F)F.CN(C)[C:32](C1C=CC=CC=1)=[CH:33]C=[N+](C)C.CC[O-].[Na+].C(SCC(OCC)=O)CC1C=CC=CC=1>C(O)C>[CH3:24][N:2]([CH3:1])[C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:4][CH:5]=[C:6]([CH2:12][CH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[CH:33][CH:32]=1)[C:7]([O:9][CH2:10][CH3:11])=[S:8]
Reactant: CCOC(=S)C(=CC=C(c1ccccc1)N(C)C)c1ccccc1
Reactant: CN(C)C(=CC=[N+](C)C)c1ccccc1
Agent: CCOC(=O)CSCCc1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=S)C(=CC=C(c1ccccc1)N(C)C)CCc1ccccc1

Procedure:
The procedure is as in Example 24 for the preparation of ethyl 5-dimethylamino-5-phenyl-2-phenylthio-2,4-pentadienoate, starting with N-(3-dimethylamino-3-phenylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5.8 g), a 2M ethanolic solution of sodium ethylate (10 cc) and ethyl (phenethylthio)acetate (4.5 g) in ethanol (50 cc). After purification by chromatography on a silica column with dichloromethane as eluent, ethyl 5-dimethylamino-5-phenyl-2-phenethylthio-2,4-pentadienoate (4.5 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[C:31]=3[F:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1F
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1c(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1C(F)(F)F

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2-fluoro-3-trifluoromethylphenol according to the procedure of Example 69. MS (ESI) m/z 556.
Reaction SMILES: [Ag:1]=O.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+].[F:10][C:11]([F:26])([CH2:23][CH:24]=[CH2:25])[C:12]([O:14]C(=O)C(F)(F)CC=C)=[O:13]>O>[F:10][C:11]([F:26])([CH2:23][CH:24]=[CH2:25])[C:12]([O-:14])=[O:13].[Ag+:1]
Reactant: O=[Ag]
Reactant: C=CCC(F)(F)C(=O)OC(=O)C(F)(F)CC=C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCC(F)(F)C(=O)[O-]
Yield: 87 %

Procedure:
A suspension of silver oxide in water is prepared by adding a solution of NaOH (1.76 g, 0.044 mol) in water (100 ml) to an aqueous solution of silver nitrate (7.14 g, 0.042 mol in 100 ml), decanting the supernatant liquid, washing the residue with water (3×100 ml) and adding 100 ml of water. To this vigorously stirred suspension is added a solution of 2,2-difluoro-4-pentenoic acid (III) (5.44 g, 0.04 mol) in water (100 ml). After 10 minutes the mixture is filtered and the filtrate concentrated (20 Torr, 30° C.) to afford a solid residue which is dried over phosphorus pentoxide (0.05 Torr, 50° C., 24 hours) to give 8.4 g (87%) of silver 2,2-difluoro-4-pentenoate as a white amorphous powder. A suspension of 7.3 g (0.03 mol) of the silver salt in 50 ml of dichloromethane is stirred under nitrogen, cooled to 0° C. and then 1.9 g (1.3 ml, 0.015 mol) of oxalyl chloride is added slowly. The cooling bath is removed and the reaction mixture allowed to warm up to room temperature. Heating to 40° C. for 30 minutes completes the reaction. After cooling to room temperature, the supernatant liquid is decanted and the residue washed with dichloromethane (2×5 ml). The organic layers are combined and the solvents removed by distillation at atmospheric pressure. The so-obtained oily residue is then purified by distillation yo yield 2.85 g of very hydroscopic 2,2-difluoro-4-pentenoic acid anhydride III, bp 78-80° C./20 Torr.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:5]1(=[O:22])=[O:21].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.Cl>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH2:9][N:4]([CH2:3][CH2:2][NH:26][CH:23]2[CH2:25][CH2:24]2)[S:5]1(=[O:22])=[O:21]
Reactant: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCNC2CC2)Cc2ccccc2N1c1ccccc1F

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.96 g, 0.25 mmol) was reacted with cyclopropylamine and then treated with HCl to afford N-{2-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]ethyl}cyclopropanamine as a white solid:
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([N:23]1C(=O)C2C(=CC=CC=2)C1=O)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[NH2:23][CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)C(c1nc2n(c(=O)c1Cc1ccccc1)CCCC2)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(C)C(N)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step 9 (19), 95 mg (0.22 mmol) was dissolved in 3 ml of dry ethanol then 50 μl (1.6 mmol) of hydrazine was added and the reaction was left to stir at room temperature for 1 h then heated to 40° C. for 2.5 h. The precipitate was removed by filtration and washed with ethyl acetate and the solvent evaporated off resulting in 75 mg of crude 2-(1-amino-2-methylpropyl)-3-benzyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (20). This was purified on a silica column yielding 42 mg (0.13 mmol 63%) as a clear oil.
Reaction SMILES: F[C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:13]([F:12])=[C:14]([C:15]2[N:17]=[C:4]([OH:5])[C:3]3[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=3[N:16]=2)[CH:18]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: O=C(Cl)c1ccc(F)nc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2nc(F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2,6-difluoronicotinic acid chloride (6.4 g), dissolved in acetonitrile (200 mL) was added 2-fluoro-5-chlorobenzamidine (6.73 g) and diisopropyl ethyl amine (24 mL). The mixture was heated to reflux for 2 h and cooled to room temperature. The mixture was concentrated under reduced pressure. The precipitate was filtered and washed with ether and dried under reduced pressure to afford the 2-(5-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[2,3-d]pyrimidin-4-ol that was used without further purification.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[C:15]2=[O:35])=[CH:11][CH:10]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O.C1COCC1>[F:32][C:31]([F:33])([F:34])[O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:37][CH:36]=3)[C:15]2=[O:35])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.4 mL, 5.0 mmol) was added to a suspension of the hydrochloride of 1-(4-aminobenzyl)-3-(4-trifluoromethoxybenzyl)-1,3-dihydrobenzimidazol-2-one (U) (806 mg, 1.79 mmol) in abs. THF (40 mL). The reaction mixture was stirred at RT for 30 min, methanesulphonyl chloride (0.16 mL, 2.1 mmol, dissolved in abs. THF (1 mL)) was added within a period of 20 min, and the reaction mixture was again stirred at RT over a period of 18 h. To the reaction mixture there were then added H2O (150 mL) and aqueous 2N hydrochloric acid solution (5 mL). After 2 hours, the precipitated solid matter was separated by a frit and then dried in vacuo and recrystallized from ethanol (20 mL). The desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (70) was obtained in a yield of 505 mg (57% of theory, mp: 182-187° C.).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5](C(O)=O)[C:4]=1[CH3:12])=[O:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCN.[OH-].[Na+]>CN(C)C=O.[Cl-].[Na+].O.O>[CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:12])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CN(C)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C=O)[nH]1
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.67 g, 10 mmol) in dimethylforamide (10 mL) was added benzotriazol-1-yloxytris (dimethylamino)- phosphonium hexafluorophosphate (BOP reagent, 6 g, 13.5 mmol) followed by 3 mL diisopropylethylamine. After stirring for 5 minutes, 1 mL of N,N-dimethylethylendiamine was added and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 25 mL of 1N sodium hydroxide and 25 mL of brine. After stirring for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted (3×200 mL) with 10% of methanol in dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated using a rotary evaporator. The residue which remained was purified by chromatography (silica gel column, 5%-10% methanol in dichioromethane) to give 1 g (42%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-(carboxylic acid (2-dimethylamino-ethyl)-amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24]OCC[Si](C)(C)C)[CH:20]=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]1([C@@H:46]([N:48]2[CH:52]=[C:51]([C:53](Cl)=[O:54])[CH:50]=[N:49]2)[CH3:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH3:24])[CH:20]=[C:21]([NH:23][C:53]([C:51]2[CH:50]=[N:49][N:48]([C@H:46]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH3:47])[CH:52]=2)=[O:54])[CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Nc2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(=O)n(C)c2)cn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Intermediate (6c), 2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) was stirred in dichloromethane (5 mL) at RT with triethylamine (0.092 mL, 0.66 mmol). The reaction mixture was cooled to 5° C. and then a solution of intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, (54 mg, 0.231 mmol) in dichloromethane (1 mL) was added drop wise. After addition the reaction was stirred at RT for 1 hour and then the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (10 mL) and aqueous saturated sodium hydrogen carbonate solution (10 mL). The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate (10 mL). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired intermediate, 2-(1-Methyl-2-oxo-5-{[1-((S)-1-phenyl-ethyl)-1H-pyrazole-4-carbonyl]-amino}-1,2-dihydro-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester, 0.108 g, 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11](=[O:12])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: COc1cccc(CCC(=O)Cl)c1
Reactant: Nc1ccc(F)cc1
Product: COc1cccc(CCC(=O)Nc2ccc(F)cc2)c1
Yield: 97.2 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylpropionylchloride (6.62 g, 33.3 mmol) and 4-fluoroaniline (3.70 g, 33.3 mmol) to afford N-(4-fluorophenyl)-3-(3-methoxyphenyl)propanamide (8.85 g, 97% yield): ES−MS (m/z) 273.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:46](Cl)Cl>COCOC>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:46])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: COCOC
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione in 35 ml of anhydrous methylene chloride and 22.5 ml of methylal is combined in incremental portions at room temperature with a mixture of 1.0 g of phosphorus pentoxide and 7.5 g of silica gel. The mixture is agitated for 3 days at room temperature and then another 11 ml of methylal, 500 mg of phosphorus pentoxide, and 3.75 g of silica gel are added. After another 2 days, the reaction mixture is vacuum-filtered, the residue is washed thoroughly with methylene chloride, and evaporated to dryness under vacuum. The crude product is purified on 350 g of silica gel with a hexane/ethyl acetate gradient (0-50% ethyl acetate), thus obtaining 3.6 g of 17α,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C. [α]D25 =+165° (chloroform).
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[C:29]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCCC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (728 mg, 2.76 mmol), benzoic acid (338 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.45 ml, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for two hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-benzoyloxyoctane as a colorless liquid substance (503 mg, yield: 93%/(S)-2-octanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:104]1[CH2:109][CH2:108][O:107][CH2:106][CH2:105]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)=[N:6][CH:7]=[CH:2][C:3]=1[N:104]1[CH2:109][CH2:108][O:107][CH2:106][CH2:105]1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
Reactant: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nccc(N3CCOCC3)c2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
A mixture of N-(5-bromo-6′-methoxy-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (142.1 mg, 0.27 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (25.8 mg, 0.054 mmol), tris(dibenzylideneacetone)dipalladium (0) (25.1 mg, 0.027 mmol), morpholine (0.05 mL, 0.57 mmol), and sodium tert-butoxide (74.9 mg, 0.78 mmol) in dry toluene (5 mL) was degassed by nitrogen. The mixture was heated to 100° C. After 23 h, the reaction was cooled to rt then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (5-20% EtOAc in hexanes) to afford an impure orange residue that was further purified with SFC chromatography to afford a yellow solid as 5,7-difluoro-N-(6′-methoxymorpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (2H, m), 8.10 (2H, m), 7.95 (2H, m), 7.61 (1H, d, J=9.6 Hz), 7.39 (1H, ddd, J=6.7, 4.8, 2.0 Hz), 7.01 (3H, m), 6.53 (1H, d, J=2.3 Hz), 4.07 (3H, m), 3.91 (4H, m), 3.24 (4H, m), 2.23 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16][C:15]=2[N+:28]([O-])=O)=[O:12])=[CH:6][CH:5]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH:17]=[CH:16][C:15]=2[NH2:28])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)CC(C)C)ccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)CC(C)C)ccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethoxy-N-[5-[methyl(3-methyl-1-oxobutyl)amino]-2-nitrophenyl]-benzeneacetamide (1.05 g, 2.53 mmol) was dissolved in EtOAc (50 mL) containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (35 psi) at rt overnight. The solution was filtered through celite and the solvent concentrated. LC/MS analysis showed that title compound was pure (>95%) and could directly be used for next step. Yield: 965 mg (99%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.8 Hz, 2H), 7.12 (s, 1H), 7.00 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.78 (m, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.69 (s, 2H), 3.13 (s, 3H), 2.05 (m, 1H), 1.93 (d, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 0.78 (d, J=6.8 Hz, 6H).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>CC#N>[Cl:10][C:11]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([NH:5][CH3:3])=[O:14]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cnc1Cl
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Methanamine (0.355 mL, 2.85 mmol) and triethylamine (0.662 mL, 4.75 mmol) were dissolved in CH3CN (14.2 mL) at 23° C. 2,5-Dichloronicotinoyl chloride (500 mg, 2.376 mmol) was added and the reaction was stirred for 16 h. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc (20 mL) and 5% aq. NaHCO3 soln. (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated. The resulting solid was triturated in 5% EtOAc-Hexane to provide the desired product as a cream powder (456.7 mg, 94%). 1H NMR (CD3OD) δ 8.46 (d, 1H, J=2.54 Hz), 7.96 (d, 1H, J=2.54 Hz), 2.90 (s, 3H); MS(ESI+) m/z 205.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2].CO.C([O-])=O.[NH4+]>[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCN1CCOC(c2ccc(N)cc2)C1
Reaction time: 8 h

Procedure:
Combined 4-Ethyl-2-(4-nitro-phenyl)-morpholine (3.00 g, 0.0127 mol) with Methanol (300 mL, 6 mol) and add Ammonium formate (5.6 g, 0.089 mol) then 10% Pd/C, 50% wet (0.88 g, 0.00041 mol). Stir under N2 overnight. Filtered through Celite and concentrated. Partitioned between aq. Na2CO3 and EtOAc, the organics were dried (MgSO4), filtered. To give 4-(4-Ethyl-morpholin-2-yl)-phenylamine as yellowish oil which solidified upon standing (2.45 grams). 1H-NMR (CDCl3) δ 7.17 (d, J=8.4 Hz, 2H), 6.68-6.65 (m, 2H), 4.47 (dd, J=10.4, 2.3 Hz, 1H), 4.05-4.01 (m, 1H), 3.90-3.84 (m, 1H), 3.84 (dt, J=11.6, 2.4 Hz, 1H), 3.66 (broad s, 2H), 2.94-2.90 (m, 1H), 2.84-2.81 (m, 1H), 2.46 (q, J=7.2, 2H), 2.2 (dt, J=8.1, 11.5 Hz, 1H), 2.05 (t, J=11.0 Hz, 1H), 1.12 (t, J=7.2 Hz, 1H); LC/MS (ESI+): 207 (M+H).