Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC1CN(Cc2ccccc2)CC1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Reaction time: 1 h

Procedure:
c is-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While this solution was cooled on a dry ice/acetone bath, triethylamine (5.21 mL) was added. Methanesulfonyl chloride (2.89 mL) was then added dropwise and the mixture was further stirred for 1 hour. Following addition of water (50 mL), the temperature of the mixture was allowed to rise to room temperature and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (50 mL) and the extract was combined with the dichloromethane layer. The combined dichloromethane layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours while heated. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (300 mL). The solution was washed with water, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=1:1) to give 4.61 g of cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.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.O.C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3]([CH:4]=[O:5])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1c(O)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1c(O)cccc1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
2-Bromo-6-hydroxybenzaldehyde (2.0 g), 4-chlorophenylboronic acid (1.86 g) and tetrakis(triphenylphosphine)palladium(0) (0.575 g) were suspended in a mixed solvent of dimethoxyethane (7 mL), ethanol (2 mL) and 2N Na2CO3 aqueous solution (5 mL). The reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and poured into water. The organic layer was washed with water and with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was triturated with methanol and filtered to afford the title compound.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: OCCS
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CO2
Temperature: 25 °C

Procedure:
In 400 ml of methylene chloride was suspended 40.0 g of Compound b obtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, was added to the suspension followed by stirring at room temperature for an hour. Then, 10.7 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further 4 hours. After 100 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from toluene to give 37.6 g of methyl 11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate as white crystals.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.Cl.[NH2:24][OH:25]>C(O)(=O)C.O.COC(C)(C)C>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[N:24][OH:25])[CH2:17][CH:18]=[CH2:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NO
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: C=CC[C@H](COCc1ccccc1)OCC=NO
Reaction time: 1 h

Procedure:
({[(2R)-2-(2,2-Diethoxyethoxy)pent-4-en-1-yl]oxy}methyl)benzene (C2) (12.4 g, 40.2 mmol) was dissolved in acetic acid (28 mL) and water (12 mL). Hydroxylamine hydrochloride (2.84 g, 40.9 mmol) was added as a solid. After 1 hour, additional hydroxylamine hydrochloride (2.84 g, 40.9 mmol) was added. After 1 more hour, the reaction mixture was diluted with tert-butyl methyl ether (100 mL) and washed with water (3×50 mL), then washed with aqueous potassium carbonate solution (0.5 M, 100 mL). The organic layer was concentrated to provide the product as a pale yellow oil, which consisted of a roughly equimolar mixture of oxime isomers, as assessed by 1H NMR. Yield: 9.60 g, 38.5 mmol, 96%. 1H NMR (400 MHz, CDCl3) δ 7.98 and 7.67 (2 br s, total 1H), [7.50 (t, J=5.6 Hz) and 6.95 (t, J=3.6 Hz), total 1H], 7.28-7.39 (m, 5H), 5.74-5.87 (m, 1H), 5.04-5.14 (m, 2H), 4.55 and 4.56 (2 s, total 2H), 4.47-4.49 (m, 1H), 4.18-4.28 (m, 1H), 3.47-3.65 (m, 3H), 2.30-2.37 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:26]=[CH:25][C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:25][CH:26]=1)[N:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]2[OH:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(NCCOC(C)=O)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(NCCOC(C)=O)cc2c1O
Temperature: 25 °C
Yield: 25.4 %

Procedure:
To a flask containing diethyl 2-[(4-{[2-(acetyloxy)ethyl]amino}anilino)-methylene]-malonate (0.18 g) is added diphenyl ether (2 mL). The reaction mixture is heated from room temperature to 250° C. over 30 minutes under a flow of argon gas. The reaction is cooled to room temperature and filtered. The collected precipitate is washed repeatedly with methanol:dichloromethane and the filtrate is concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 5% to 50% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.04 g of ethyl 6-{[2-(acetyloxy)ethyl]amino}-4-hydroxy-3-quinolinecarboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C>[CH3:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH:4]=2)[N:9]=1
Reactant: Cc1ccc2cc(CBr)ccc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
The compound (421.7 mg) obtained in Example 119-1 was dissolved in anhydrous DMF (12.6 ml) and added with potassium phthalimide (663.1 mg), followed by stirring at room temperature for 2 hours. After the reaction, the solvent was distilled off and the residue was then added with water. The mixture was extracted with chloroform and the extract was dried with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (536.0 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)[NH2:5].[ClH:12].[H][H]>[Rh].O>[ClH:12].[ClH:12].[CH3:1][CH:2]1[CH2:3][CH:4]([NH2:5])[CH2:6][CH:7]([NH2:9])[CH2:8]1
Reactant: [H][H]
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1
Agent: [Rh]
Agent: Cl
Solvent: O
Product: CC1CC(N)CC(N)C1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
The 3-methyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146 ml) and treated with 6N HCl (22.5 ml, 135.0 mmol) and 5% Rhodium on Alumina (1.9 g, 0.9 mmol). The mixture was charged to 105 atm of Hydrogen and heated to 100° C. for 19 hours. The reaction was cooled and filtered through celite and concentrated to dryness to give 5-methylcyclohexane-1,3-diamine dihydrochloride (12.9 g, 64.5 mmol) as a racemic mixture. The salt (6.5 g, 32.5 mmol) was dissolved in isopropyl alcohol (100 ml) and acetonitrile (100 ml) and treated with potassium carbonate (25.2 g, 182.0 mmol). The mixture was stirred at room temperature overnight, filtered thru celite, and concentrated in vacuo to afford 2.2 g of 5-methylcyclohexane-1,3-diamine as a racemic brown oil: LCMS RT=0.41 (M+1) 128.9.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([S:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[NH2:31][C:32]1[N:33]=[N:34][C:35]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([F:48])[CH:39]=2)=[CH:36][N:37]=1>C(Cl)(Cl)Cl>[F:48][C:40]1[CH:39]=[C:38]([C:35]2[CH:36]=[N:37][C:32]3[N:33]([C:12]([S:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)=[CH:13][N:31]=3)[N:34]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]
Reactant: O=CCSc1ccc2ncccc2c1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1F
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cnc3ncc(Sc4ccc5ncccc5c4)n3n2)cc1F
Temperature: 25 °C

Procedure:
To a cooled (0° C.) mixture of (quinolin-6-ylthio)acetaldehyde (40.6 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) was added N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixture was stirred at 0° C. for 30 min, then gradually warmed to ambient temperature for 2 h. To the mixture was added methyl 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzoate (24.8 mg, 0.1 mmol). The reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated to 100° C. overnight. After cooling, the mixture was filtered and the filtrate was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=432.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.C([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)(OC(C)(C)C)=O>>[NH2:31][CH2:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:36]=[N:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(CN)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(N-boc-aminomethyl)pyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as an off-white solid. (HPLC: tR 1.87 min (Method A); M+H=400 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.51 (m, 2H), 8.17-8.11 (m, 2H), 7.99-7.95 (m, 1H), 7.86-7.83 (m, 1H), 7.61-7.58 (m, 1H), 3.92 (s, 3H), 3.79 (s, 2H), 3.58 (s, 3H), 2.06-1.97 (br, 2H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[C:14]1[CH:15]=[C:16]([CH:20]([NH:22][CH3:23])[CH3:21])[CH:17]=[N:18][CH:19]=1.[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:19]=[N:18][CH:17]=[C:16]([CH:20]([NH:22][CH3:23])[CH3:21])[CH:15]=1)[CH2:6][CH2:5]2
Reactant: CNC(C)c1cncc(Br)c1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(C)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Yield: 23.7 %

Procedure:
6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), [1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amine (85.6 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was subject to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (15 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 316.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:22])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]1=2.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[O:46]=[C:41]1[CH2:42][CH2:43][C:44](=[O:45])[N:40]1[O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:38])[C:7]4[CH:37]=[CH:36][CH:35]=[CH:34][C:8]=4[CH2:9][CH2:10][C:11]=3[CH:16]=2)=[CH:33][CH:32]=1
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)O)cc3)ccc21
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)ON4C(=O)CCC4=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
A solution of 87 mg (0.169 mmol) of the acid (15) in 10 ml of CH2Cl2 was treated with 40 mg (0.348 mmol) of N-hydroxysuccinimide and 87 mg (0.454 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl and stirred at room temperature overnight. The reaction was washed with H2O, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 10% ether in CH2Cl2 as eluent to give 34 mg (33%) of 16 as a white amorphous solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][CH2:12][CH2:13][CH2:14][C@:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([NH2:20])[CH2:16][C:17]([CH3:19])=[CH2:18])[CH3:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([N:11]2[CH2:12][CH2:13][CH2:14][C@:15]([CH2:16][C:17]([CH3:19])=[CH2:18])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:20][C:37]2=[O:39])[CH3:10])=[CH:7][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)C[C@@](N)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 157.3 %

Procedure:
A solution of (S)—N1—((S)-1-(4-bromophenyl)ethyl)-6-methyl-4-phenylhept-6-ene-1,4-diamine HCl salt (0.88 g, 2.2 mmol) in CH2Cl2 (120 mL) was cooled to 0° C. and i-Pr2NEt (1.15 mL, 3 equiv) was added. A solution of triphosgene (215 mg, 0.33 equiv) in CH2Cl2 (15 mL) was added dropwise over 10 min The mixture was stirred for 3 h at 0° C. LC-MS found the reaction completed. The mixture was concentrated, redissolved in 6:1 Ether/EtOAc (70 mL), washed with 1% aq HCl (2×15 mL), satd aq NaHCO3 (10 mL) and brine (10 mL), and dried over over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 40-g silica gel cartridge, eluted with a 5˜40% EtOAc in Hexanes gradient, to afford (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (487 mg, 52%) as a clear oil. LC-MS Method 1 tR=2.25 min, m/z 427, 429 (M+1); 1H NMR (CDCl3) δ 7.42 (d, 2H), 7.35 (t, 2H), 7.28-7.20 (m, 3H), 6.76 (d, 2H), 5.37 (q, 1H), 5.21 (s, 1h), 4.98 (s, 1H), 4.85 (s, 1H), 2.78 (m, 2H), 2.44 (m, 3H), 1.89 (td, 1H), 1.43 (d, 3H), 1.24 (m, 1H), 1.11 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: NCl
Reactant: c1cnc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of pyrrolo[2,3-b]pyridine (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (169.2 mL) is added drop-wise at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 5% Na2S2O3 aqueous solution (100 mL), and extracted with ether for three times. The combined organic layer is washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60-80% EtOAc in heptane to afford pyrrolo[2,3-b]pyridin-1-ylamine (703 mg, 31%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 5.04 (br, 2N—H), 6.35 (d, H), 7.09 (m, H), 7.35 (m, H), 7.91 (m, H), 8.34 (d, H).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1)(=O)C.[ClH:14]>>[ClH:14].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1
Reactant: CC(=O)NCCCn1nnnc1S
Agent: Cl
Product: NCCCn1nnnc1S

Procedure:
A mixture of 1-(3-acetamidopropyl)-1H-tetrazole-5-thiol (85 g) and 6N hydrochloric acid (1 l) was refluxed for 75 minutes under stirring. The reaction mixture was concentrated in vacuo and precipitates were collected by filtration and washed with hexane and diethyl ether to give 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (67.15 g).
Reaction SMILES: C1COCC1.[N:6]1[C:15]2[C:10](=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31](B(O)O)=[C:32]2[CH2:37][CH2:36][CH2:35][N:33]2[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>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].CN(C=O)C.C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[CH:8][CH:7]=[N:6]3)=[C:32]2[CH2:37][CH2:36][CH2:35][N:33]2[N:34]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: O=S(=O)(Oc1cccc2nccnc12)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2cccc4nccnc24)CCC3)nc1
Yield: 4 %

Procedure:
Add THF (2.2 mL) to trifluoro-methanesulfonic acid quinoxalin-5-yl ester (292 mg, 1.05 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) and bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol), purge the reaction with nitrogen for 2 min, and stir the reaction at room temperture for 20 min. Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL) and stir for 10 min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) and heat the reaction to 65° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 h and 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite® with methanol/chloroform, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Concentrate the pure fractions from the preparative HPLC in vacuo, take up in methanol, treat with MP-carbonate beads, filter, and concentrate in vacuo to provide the title compound (11 mg, 7%) as a clear, colorless oil. MS APCI+ m/e 314 (M+1). 1H NMR (DMSO-d6) δ 8.78 (m, 1H), 8.68 (m, 1H), 8.54 (m, 1H), 8.08 (m, 1H), 7.72 (m, 3H), 7.53 (m, 1H), 7.22 (m, 1H), 4.37 (m, 2H), 2.95 (m, 2H), 2.64 (m, 2H). HPLC: 98.6%, Rt=13.5 min. TLC (SiO2): Rf0.2 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][O:19]C)[CH:15]=3)[N:10]([C:21]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:22])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.C(=O)([O-])O.[Na+].O>CC(C)=O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]=[O:19])[CH:15]=3)[N:10]([C:21]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:22])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC=Cc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CC=O)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
1′-Acetyl-N-(5-chlorothiazol-2-yl)-5-(2-methoxyvinyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (83 mg, 0.192 mmol) was dissolved in acetone (3 mL). Thereafter, 6 N hydrochloric acid (1.5 mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at 50° C. for 2 hours. Thereafter, saturated sodium hydrogen carbonate and water were added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, to obtain 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-(2-oxoethyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (66.1 mg, 82%) in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([Li])(C)(C)C.CN([CH:24]=[O:25])C>CCOCC>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:24]=[O:25])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Temperature: -75 °C
Reaction time: 0.83 h

Procedure:
To a solution of [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (15 g, 56.1 mmol) in ether (450 mL), at −75° C. a solution of tert-butyl lithium (99 ml of 1.7 N solution in hexanes, 168 mmol) is added. The mixture is stirred for 50 minutes at −75° C., and then for 30 minutes at −30° C. To the obtained beige suspension, DMF (22.5 ml) is added during 15 minutes, and then the mixture is allowed to warm to ambient temperature. The mixture is poured on water and extracted with diethyl ether (500 mL). After washing the organic layer with brine (3 times 500 mL), and drying (sodium sulfate), removal of the solvent leaves the crude aldehyde, which is recrystallized, from toluene/hexane. Yield of the title compound: 9.9 g (81.8%) yellowish plates, mp=103° C. 1H-NMR (CDCl3, 300 MHz) δ 2.36 (s, 6H, N(CH3)2); 2.65-2.75 (m, 2H, CH2); 2.96-3.03 (m, 2H, CH2NMe2); 7.08 (d, 1H, 3J=2.7 Hz, H-2); 7.33 (d, 1H, 3J=8.4 Hz, H-7); 7.70 (dd, 1H, 4J=1.7 Hz, H-6); 8.13 (d, 1H, H-4); 8.74 (br s, 1H, NH); 10.02 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 23.91 (CH2); 45.76 (CH3); 60.40 (CH2N); 111.85 (C-7); 116.68 (C-3); 122.87 (C-6); 123.61 (C-2); 124.04 (C-4); 127.68 (C-9); 129.35 (C-5); 140.06 (C-8); 192.56 (CHO).