Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(O)C.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:9][NH:8][C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NNc1ccc(Cl)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NNc2ccc(Cl)nn2)cc1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 14.5 g (0.1 moles) of 6-chloro-3-pyridazinylhydrazine, 145 ml of ethanol and 15.1 g (0.1 moles) of 4-nitrobenzaldehyde is refluxed with stirring for 2 hours, cooled and 75 ml of water are added. The precipitate is filtered, washed with water, triturated with hot ethanol, filtered again and dried to give 25.4 g (91.5%) of the named compound; m.p. 290° C. (with decomposition).
Reaction SMILES: Br.[O:2]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[NH:9])[CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)ns1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of morpholinoformamidine hydrobromide (2.00 g, 9.52 mmol) and perchloromethyl mercaptan (1.02 ml, 9.52 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.52 g, 38.1 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1.07 g (54.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46]O)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.P([N:97]=[N+:98]=[N-:99])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:97]([CH2:46][C@@H:45]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:34]([C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:13]=[CH:12][C:11]=1[C:14]1[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:35])=[N+:98]=[N-:99]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol) in THF (2 mL) was added triphenylphosphine (55.8 mg, 0.213 mmol) followed by DIAD (0.041 mL, 0.213 mmol) and diphenyl phosphorazidate (58 mg, 0.21 mmol). After stirring at room temperature overnight, a second addition of all three reagents was added (1.2 eq each) and stirring was continued for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (Isco 40 g column eluting with 0-50% EtOAc/hexanes) to give the title compound (86 mg, 73%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.25 (s, 0.5H), 8.15-8.10 (m, 1H), 7.97 (s, 0.5H), 7.51-7.34 (m, 5H), 7.25-6.90 (m, 5H), 5.04-4.97 (m, 1.5H), 4.41-3.97 (m, 3.5H), 3.50-3.01 (m, 3.5H), 2.88-2.46 (m, 3.5H), 1.66-1.62 (m, 3H), 1.61 (s, 4.5H), 1.60 (s, 4.5H), 1.18-0.94 (m, 4H), 0.64-0.56 (m, 3H); MS(ESI) m/z 663.5 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.O>CC(O)=O>[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Sodium cyanoborohydride (6.4 g) was added in several portions to a solution of 6.0 g 2-(2-aminophenyl)-1H-indole in 200 ml HOAc at 5° C. The resulting solution was stirred at room temperature overnight. Water was added and the reaction mixture was concentrated. The residue was diluted with ice water and made basic with 50% NaOH. This mixture was extracted with Et2O and the extracts were washed with water and saturated NaCl solution, and dried (MgSO4). Concentration gave 6.1 g crude product which was chromatographed by HPLC to give 3.05 g solid, m.p. 115°-117° C.
Reaction SMILES: N1C[CH2:4][C@@H:3]([OH:6])C1.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:35]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:19][CH:18]=3)[C:9]=12>>[C:3]([OH:6])(=[O:25])[CH3:4].[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@H:35]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:21][CH:22]=3)[C:9]=12
Reactant: O[C@@H]1CCNC1
Reactant: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Product: CC(=O)O
Product: COCCN1CC[C@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
N2-(4-{4-Amino-1-[(3S)-1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine monoacetate was prepared from (R)-(+)-3-pyrrolidinol in a manner analogous to that used for the preparation of rac-N2-(4-{4-amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as a pink solid (0.103 g, 53%). 1H NMR (DMSO-d6, 400 MHz) 1.89 (s, 3H), 2.28-2.31 (m, 2H), 2.35 (s, 3H), 2.40 (s, 3H), 2.65 (t, 2H), 2.73-2.87 (m, 2H), 3.17 (t, 2H), 3.24 (s, 3H), 3.45 (t, 2H), 5.37 (m, 1H), 6.79 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.59 (s, 2H); RP-HPLC Rt 11.607 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 499 (MH+).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BrH:19].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[Br-:19].[CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][P+:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: CCCCCCCCCOc1ccccc1CO
Solvent: CC#N
Product: CCCCCCCCCOc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compound with 1-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80° C. for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to yield the 2-nonyloxybenzaldehyde (210 g), bp 121° C. (0.3 mm Hg). A solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10° C. was reduced by treating with an excess of sodium borohydride (6 g) and after stirring the mixture for a further 15-20 min. at room temperature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 mL) and the resultant solution was heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from a tetrahydrofuran/ethyl ether mixture gave the pure [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.C[Si](C)(C)N[Si](C)(C)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.CO.C(N(CC)CC)C>[C:22]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then trimethylsilyl chloride (61.92 g) and hexamethyldisilazane (107.5 ml) were added to the suspension in 10-15 minutes at ambient temperature. The reaction mixture was refluxed at 35° C. to 40° C. for 3 hours and then it was cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25° C. to 30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for overnight under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40° C. to 45° C. Hexane (400 ml) and 5% citric acid solution (750 ml) was added to the recovered solid and filtered. The solid product obtained was washed with water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with hexanes (200 ml) and dried to obtain the titled product. Yield=125 gm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#CC(C)(O)CC
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 102.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 3-methyl-1-pentyn-3-ol (0.56 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid methyl ester (673 mg, 98%) as an orange oil: EI-HRMS m/e calcd for C21H28O3 (M+) 328.2038, found 328.2040.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]([Li])(C)(C)[CH3:18].FC(F)(F)S(O[C:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=1[C:34]([O-:36])=[O:35])(=O)=O>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[CH2:17]([O:36][C:34]([C:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=1[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1)=[O:35])[CH3:18]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C([O-])C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: [Li]C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2cc3c(cc2C)C(C)(C)CCC3(C)C)CCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred (-78° C.) solution of 4.2 g of 2-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene in 40 ml of tetrahydrofuran is added 18 ml of tert-butyllithium (1.7N in pentane). The reaction mixture is stirred at -78° C. for 1 hour, warmed to room temperature and stirred for 1 hour. Thirty ml of 0.5M zinc chloride solution in tetrahydrofuran is added and the stirring continued for 1 hour. Three grams of 2-trifluoromethanesulfonyloxycyclohexen-1-ylcarboxylate and 0.8 g of tetrakis(triphenylphosphine palladium(O) in tetrahydrofuran is added and the reaction mixture is heated at reflux temperature for 3 hours. Following the reaction work-up of Example 1, 2.75 g of 2-(3,5,5,8,8-pentamethyl-5,6,7,8,-tetrahydro-2-naphthalenyl)-1-cyclohexene-1-carboxylic acid ethyl ester is obtained. The above isolated ester is reduced to the corresponding alcohol with lithium aluminum hydride in diethyl ether, and this is then converted to the triphenylphosphonium bromide as in Example 1. Reaction of the bromide with ethyl 3-methyl-4-oxocrotonate and sodium ethoxide in methylene chloride, as in Example 1, gives the title compound as a mixture of E,E- and Z,E- esters in a 8:1 ratio. The esters are separated into the individual isomers by chromatography.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=O.N[C:17]1[C:21]([C:22]#[N:23])=C[NH:19][N:18]=1>C(O)(=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:19]3[N:18]=[CH:17][C:21]([C:22]#[N:23])=[C:15]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 6.15 g. of 3-dimethylamino-3'-methoxyacrylophenone and 3.16 g. of 3-aminopyrazole-4-carbonitrile in 50 ml. of glacial acetic acid is refluxed for 15 hours and then cooled. The precipitate is recovered by filtration giving the desired product, m.p. 165°-166° C.
Reaction SMILES: NC1[C:3]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])=[C:4]([C:10]2[C:11]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:12]=3[C:13](=[O:17])[N:14]([CH3:16])[CH:15]=2)[CH:5]=[CH:6]C=1NC.C1N=CN([C:45]([N:47]2[CH:51]=[N:50][CH:49]=[CH:48]2)=O)C=1.[O:52]1CCCC1>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][C:3]1[C:49]2[NH:50][C:51](=[O:52])[N:47]([CH3:45])[C:48]=2[CH:6]=[CH:5][C:4]=1[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[CH:15]=1
Reactant: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(Oc2ccc(F)cc2F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c([nH]c(=O)n5C)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 4-[3-amino-2-(2,4-difluorophenoxy)-4-(methylamino)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (98.0 mg, 0.178 mmol) in tetrahydrofuran (1.0 mL) was treated with N,N-carbonyldiimidazole (57.7 mg, 0.356 mmol) and stirred at 50° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (77 mg, 75%). LCMS calculated for C29H23F2N4O5S (M+H)+: m/z=577.1. found: 577.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:52])([CH3:51])[C:29]([F:50])([F:49])[C@:30]([C:33]3[CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[CH:36]=[CH:35][C:34]=3[F:48])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[C:54]1[S:55][C:56]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:57]=2[N:58]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:52])([CH3:51])[C:29]([F:49])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:54]4[S:55][C:56]5[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:57]=5[N:58]=4)[CH:36]=[CH:35][C:34]=3[F:48])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5s4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 75.6 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-6,6-difluoro-5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.2) (35 mg, 49 μmol) with 2,6-dichlorobenzo[d]thiazole (13.4 mg, 63.7 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (28 mg, 76% yield) as a light yellow solid. MS (ISP): m/z=756.4 [M+H]+ and 758.3 [M+2+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:13][CH:12]=1)[CH3:2].[CH2:31]([I:33])[CH3:32].[CH2:34](O)[CH3:35]>>[I-:33].[I-:33].[CH2:27]([N+:24]([CH2:31][CH3:32])([CH2:25][CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N+:3]([CH2:34][CH3:35])([CH2:1][CH3:2])[CH2:29][CH3:30])=[CH:16][CH:15]=1)[CH3:28]
Reactant: CCO
Reactant: CCN(CC)CCCCCCCc1ccc(CCCCCCCN(CC)CC)cc1
Reactant: CCI
Product: CC[N+](CC)(CC)CCCCCCCc1ccc(CCCCCCC[N+](CC)(CC)CC)cc1
Product: [I-]

Procedure:
To solution of 97 mg of 1,4-bis(7-diethylaminoheptyl)benzene in 1 ml of absolute ethanol, was added 187 μl of ethyl iodide, and the mixture was refluxed for 3 hours and evaporated under a reduced pressure. After adding acetone, the mixture was concentrated and allowed to stand in a freezer for a week to obtain 152 mg of the title compound as a pale brown crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1)#[N:2].C([O-])=O.[NH4+:15].C(O)(=O)C>[Ir].CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: [NH4+]
Agent: [Ir]
Agent: O=C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1ccc(C#N)cc1
Temperature: 60 °C

Procedure:
726 mg (5.0 mmol) of 4′-cyanoacetophenone (MW: 145.16), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06) and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol and 286 μL (5.0 mmol) of acetic acid were added and stirred while heating at 60° C. for 3 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-(4′-cyanophenyl)ethylamine. Its conversion rate was 100% based on NMR measurement, with 95% of DL-1-(4′-cyanophenyl)ethylamine, 1% of 1-(4′-cyanophenyl)ethanol, and 4% of other by-products. Since no compound in which reduction of cyano groups occurred was generated, we confirmed that reductive amination reaction was carried out in a functional-group-selective manner.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@H:35]([CH:44]([CH3:46])[CH3:45])[C:36]([NH:38][C@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][CH:44]([CH3:46])[C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:29]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:36](=[O:37])[NH:38][C@@H:39]([CH3:43])[C:40](=[O:41])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C)C(=O)O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Aminophenylboronic acid pinacol ester was added (146.9 mg, 0.67 mmol) was added to a solution of HO-Ala-Val-Fmoc 20b (330 mg, 0.8 mmol), DCC (166 mg, 0.8 mmol) and DMAP (5 mg, cat.) in dry DCM (8 mL) previously stirred for 30 minutes at room temperature in a flask flushed with argon. The reaction mixture was then allowed to stir at room temperature overnight. The reaction was followed by LCMS and TLC. The reaction mixture was diluted with CH2Cl2 and the organics were washed with H2O and brine before being dried with MgSO4, filtered and the solvent removed by rotary evaporation under reduced pressure. The crude product was dryloaded on a silicagel chromatography column (Hexane/EtOAc, 6:4) and pure product 20 was isolated as a white solid in 88% yield (360 mg).