Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.COC(CCC/C=C1/C(=O)C2C(C/1)CCC2)=O.O.C(O)(=O)C>[Cl-].[Na+].O1CCCC1>[OH:8][CH:9]([CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20]
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)COc3ccccc3)CCC2C1=O
Yield: 28.2 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (4.1 mg), prepared as described in Reference Example 54, and in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (1.0 ml; 7:13:2 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The extract was washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue (3.0 mg) was subjected to preparative thin layer chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (3:2 v/v), to give 6-[(E)-3-hydroxy-4-phenoxybut-1-enyl] -3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (0.9 mg), in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-hydroxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-hydroxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CSC.B.O.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CN1CCOCC1)Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: O
Solvent: CO
Product: Clc1ccc(-n2ccc(NCCN3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To an ice cooled solution of N-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)-2-morpholinoacetamide (0.1 g, 0.28 mmol) in dry tetrahydrofurane (4 ml), in a dry nitrogen atmosphere, was dropwwise added a 2M solution of borane dimethylsulfide in THF (0.7 ml, 1.4 mmol). The solution was slowly warmed to reflux, refluxed 4 hrs and additionally stirred at room temperature for 16 hrs. The mixture was ice cooled while water (2 ml) and 6M HCl (0.5 ml) cautiously added and, then, refluxed for 2 hrs. Solvents were coevaporated with methanol to dryness in vacuo. The crude residue was partitioned between 10% NaOH aqueous solution and ethyle acetate. The combined organic phases were washed with water, dried over sodium sulphate, filtered and evaporated to dryness yielding 94 mg of crude compound which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate 50:50 to ethylacetate 100%). 1-(3,4-Dichlorophenyl)-N-(2-morpholinoethyl)-1H-pyrazol-3-amine (53 mg) was obtained as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:23].Br>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:23]
Reactant: CCCCCCCCc1cnc(-c2ccc(OC)c(F)c2)nc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Yield: 101.5 %

Procedure:
This 2-(p-methoxy-m-fluorophenyl)-5-octylpyrimidine (50 g) was heated for substitution together with glacial acetic acid (500 ml) and hydrobromic acid (47%) (170 g) for 72 hours, followed by distilling off acetic acid and hydrobromic acid under reduced pressure, adding aqueous NaOH and toluene, extracting the objective substance into the toluene layer and then distilling off toluene to obtain 2-(p-hydroxy-m-fluorophenyl)-5-octylpyrimidine ((i); Y=F, m=8) (48.5 g). This product was used in the next stage without its purification.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[C:32]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ncccc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 12-L, three-neck, round-bottom flask equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet gas adapter is charged with 2-methyl nicotinic acid (302 g, 2.2 mol), EDCI (464 g, 2.4 mol), HOBt (327.3 g, 2.4 mol, 1.1 equiv) and 4.5 L of anhydrous acetonitrile. The mixture is stirred for 45 minutes at room temperature to dissolve most of the solids and is then cooled to 5° C. using an ice-water bath. A mixture of t-butylamine (242 mL, 2.5 mol) and Hunig's base (402 mL, 2.5 mol) in 500 mL of anhydrous acetonitrile and 500 mL of anhydrous dichloromethane is added slowly over 45 minutes, maintaining the temperature below 10° C. The mixture is stirred for 15 hours at room temperature under nitrogen. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (3.0 L) then washed with saturated ammonium chloride solution (2.0 L). The organic-phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant crude residue by silica gel flash column chromatography followed by trituration with 5% ethyl acetate/heptane gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][S:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]=2[S:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)CSc1ccccc1C(=O)OC
Solvent: O
Product: CCOC(=O)Cc1csc2c(C(=O)OC)cccc12
Yield: 36.7 %

Procedure:
Under a nitrogen stream, to methyl 2-(3-ethoxycarbonyl-2-oxo-propylsulfanyl)-benzoate (8.02 g, 27.1 mmol) was added polyphosphoric acid (25 g) at room temperature, and the resultant solution was stirred for 1 hour at 80° C. Under ice-cooling, to the solution was added water, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. Solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:3)), to thereby obtain the titled compound (2.77 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:31][C:32]([NH2:34])=[O:33]>CN(C)C=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:31][C:32]([NH2:34])=[O:33])[C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: NC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(cn1CC(N)=O)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo-[3,4-d][2]benzazepine were added to an ice-cooled solution of 1.6 g (14.2 mmol) of potassium t-butoxide in 60 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 1.4 g (15.0 mmol) of 2-chloroacetamide were added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a red residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 50% ether in tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow solid. Recrystallization from ethyl acetate gave colorless needles, mp 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCNCC1
Reactant: Clc1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Temperature: 0 °C

Procedure:
To a stirred suspension of 3.15 g (19.4 mmoles) of 2-chloronaphthalene and 4.46 g (24.2 mmoles) of 4-piperidinecarbonyl chloride hydrochloride in 60 ml nitrobenzene is added gradually 9.7 g (73 mmoles) of aluminum chloride. The mixture is heated to 65°-70° C. for 2 hours and cooled. Ice water and concentrated HCl are added to the reaction mixture. The solid precipitate is partitioned between aqueous sodium hydroxide solution and ether and the organic phase washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue is recrystallized from cyclohexane to yield 6-chloro-2-naphthyl 4-piperidyl ketone. M.P. 98°-100°-5°.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
A solution of Compound 140 (0.100 g, 0.28 mmol) in dichloroethane was added with acetic acid (0.48 mL, 0.84 mmol) and 1-methyl-4-piperidone (0.84 mL, 0.68 mmol). After 20 minutes, the mixture was added with sodium triacetoxyborohydride (0.0827 g, 0.39 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethanol to obtain Compound 141 (0.0767 g, 0.17 mmol, 59%).
Reaction SMILES: CO[C:3]([NH:5][C@@H:6]([CH2:10][OH:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C1(C)C=CC=CC=1>[CH3:9][CH:7]([C@@H:6]1[CH2:10][O:11][C:3](=[O:4])[NH:5]1)[CH3:8]
Reactant: COC(=O)N[C@@H](CO)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1COC(=O)N1
Temperature: 150 °C

Procedure:
27.2 g (168.7 mmol) of the compound from Example V are dissolved in 400 ml of toluene and stirred under reflux in an oil bath at 150° C. while passing in nitrogen.
Reaction SMILES: [BH4-].[Li+].O1CCCC1.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C@@H:22]([C:23]4[CH:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[C:25]([Cl:33])[CH:24]=4)[C@H:21]([C:34]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@@H:40]([CH2:43][OH:44])[O:39][CH2:38]4)=[O:35])[NH:20][C:19]43[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][CH2:45]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C@@H:22]([C:23]4[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=[C:25]([Cl:33])[CH:24]=4)[C@H:21]([C:34]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@@H:40]([CH2:43][OH:44])[O:39][CH2:38]4)=[O:35])[NH:20][C:19]43[CH2:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][CH2:45]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc([C@H]2[C@H](C(=O)N[C@@H]3CC[C@@H](CO)OC3)NC3(CCC(C)(C)CC3)[C@@]23C(=O)Nc2cc(Cl)ccc23)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@@H]1CC[C@@H](CO)OC1)[C@H](c1cc(Cl)cc(CO)c1)[C@]21C(=O)Nc2cc(Cl)ccc21
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Lithium borohydride (26 mg, 1.25 mmol) was gradually added to a tetrahydrofuran (4 ml) solution of the compound (107 mg, 0.17 mmol) obtained in Step 2 of Example 22 at room temperature and the resulting mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography [methanol:ethyl acetate=1:9 (v/v)] to give 69 mg (68%) of the title compound as a colorless solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:25]>C(O)(=O)C.[Cu](Cl)Cl>[Br:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1Br
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) suspended in 48% hydrobromic acid (50 mL) and acetic acid (50 mL), an aqueous solution (20 mL) of sodium nitrite (0.69 g, 10 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to copper bromide (I) (1.44 g, 10 mmol) in 48% hydrobromic acid (50 mL) at −10° C., and the resulting reaction mixture was stirred at room temperature for 1 hour. After addition of ethyl acetate, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to give 1.70 g of the desired product as a colorless solid (yield 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[O:30]1[CH2:31][CH:29]1[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C(c1ccc(Cn2nccc2-c2ccc(O)cc2)cc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(Cn2nccc2-c2ccc(OCC3CO3)cc2)cc1)N1CCCC1
Yield: 99.6 %

Procedure:
(4-((5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone (173 mg, 0.5 mmol), 2-(bromomethyl)oxirane (544 mg, 3 mmol) and K2CO3 (552 mg, 4 mmol) were charged to a 100-mL flask containing 2-butanone (20 mL) and heated at reflux temperature for 17 h. The mixture was cooled, filtered and evaporated in vacuuo to give crude product as an oil (201 mg, 98%). This crude material was used without further purification. LCMS (m/z): 404.2 [M+H]+
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl[C:68]1[C:73]([O:74][CH2:75][O:76][CH3:77])=[CH:72][C:71]([F:78])=[CH:70][N:69]=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].C(OCC)C.C1(C)C=CC=CC=1>[F:78][C:71]1[CH:72]=[C:73]([O:74][CH2:75][O:76][CH3:77])[C:68]([NH2:14])=[N:69][CH:70]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COCOc1cc(F)cnc1Cl
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCOc1cc(F)cnc1N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Benzophenoneimine (55.3 ul), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (29.3 mg), sodium tert-butoxide (22.6 mg) and Pd2DBA3 (15.3 mg) were added to a toluene (0.5 ml) solution of the compound 319-1 (30 mg). The reaction solution was heated to 100° C. and stirred for 3 hours. Diethyl ether was added to the reaction solution, and the obtained mixture was filtered with Celite. The filtrate was concentrated under reduced pressure. 2 M hydrochloric acid (78.5 ul) was added to a THF (1 ml) solution of the residue, and the obtained mixture was stirred at room temperature for 12 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to ethyl acetate), so as to obtain the title compound (17 mg).
Reaction SMILES: ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:10]([CH:12]1[O:17][C:16]2[CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13]1)[CH3:11].Br[C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:42][CH2:41][CH:40]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2)=[N:36][CH:37]=1>O.O1CCOCC1>[CH2:10]([CH:12]1[O:17][C:16]2[CH:18]=[C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:42][CH2:41][CH:40]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]4)=[N:36][CH:37]=3)[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13]1)[CH3:11]
Reactant: CC(C)(C)OC(=O)CC1CCN(c2ncc(Br)cn2)C1
Reactant: CCC1CNc2ccc(B3OC(C)(C)C(C)(C)O3)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1CNc2ccc(-c3cnc(N4CCC(CC(=O)OC(C)(C)C)C4)nc3)cc2O1
Reaction time: 12 h
Yield: 60 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.4 mg, 0.025 mmol), potassium carbonate (174.7 mg, 1.258 mmol), 2-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure indicated in Scheme A1, 160.0 mg, 0.553 mmol) and tert-butyl 2-(1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)acetate B-6 (172.1 mg, 0.503 mmol) were mixed in a 4:1 dioxane:water mixture (5.55 mL) at room temperature. The reaction mixture was degassed several times under reduced pressure and stirred for 12 h under an atmosphere of argon. The mixture was then filtered through a celite pad, washed with ethyl acetate (30 mL) and concentrated to dryness under reduced pressure. The residue was adsorbed on silica (1.0 g) and purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give tert-butyl 2-(1-(5-(2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetate B-7 as a light yellow oil (140.0 mg; Yield=60%). MS (ESI) [M+1]+ 425.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4C)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4C)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.61 g) in methylene chloride (18.3 ml) was added dropwise a solution of m-chloroperbenzoic acid (243 g) in methylene chloride (4.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 272) (277 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]2[CH:45]=[C:46]([C:48]([OH:50])=O)[N:47]=[C:41]2[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[N:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[CH2:59][CH2:58]2)=[CH:53][CH:52]=1>C(Cl)Cl>[N:51]1[CH:52]=[CH:53][C:54]([N:57]2[CH2:62][CH2:61][C:60]3([CH2:63][CH2:64][N:65]([C:48]([C:46]4[N:47]=[C:41]5[CH2:40][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:44][CH2:43][N:42]5[CH:45]=4)=[O:50])[CH2:66][CH2:67]3)[CH2:59][CH2:58]2)=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
DIPEA (5.96 mmol, 4.0 equiv.), EDCl (2.24 mmol, 1.5 equiv.) and HOBt (2.24 mmol, 1.5 equiv.) were added at 0° C. to a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (1.49 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (F-19) (1.49 mmol, 1.0 equiv.) in DCM (5 ml) was added at 0° C., and then the reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with DCM (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 63%