Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][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].Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=[O:20].N1C=CC=CC=1>BrC1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:22][CH:23]=[CH:24][N:25]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: NC(=O)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: Brc1ccccc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3C(N)=O)cc12
Temperature: 156 °C
Yield: 36 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloronicotinamide were used. Pyridine was used as base, bromobenzene was used as solvent, and the reaction was heated at reflux (156° C.) for 18 hours. Chromatography followed by recrystallization (methanol/water) of the resulting solid in afforded the title compound (36%) as a yellow solid: mp, 127.0°-129.0° C.; 13C NMR (CD3OD) δ173.0, 157.9, 152.2, 139.0, 135.4, 132.4, 129.0, 123.9, 119.1, 113.7, 113.2, 113.0, 112.5, 111.3, 61.4, 45.4, 24.3; HRMS calculated for C18H21N5O 323.1748, found 323.1726. Anal. calcd. for C18H21N5O.H2O; C, 63.33; H, 6.79; N, 20.51. Found: C, 63.19; H, 6.50; N, 20.30.
Reaction SMILES: [OH-].[Na+].[N:3]1[C:16]2[C:7](=C3[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][C:10](=O)[C:9]3=[O:18])[CH:6]=[CH:5][CH:4]=1>>[CH:6]1[C:7]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[N:3]=[CH:4][CH:5]=1
Reactant: O=C1C=Cc2ccc3ncccc3c2C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ccccc2-c2ncccc21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
Subsequently, in a stream of argon, 1.5 L of a 10% aqueous solution of sodium hydroxide was added to 51.0 g (244 mmol) of 1-azaphenanthrene-5,6-dione, and heated and stirred at 85° C. for 90 minutes. After the mixture was cooled to room temperature, the precipitate was filtered out. The filtrate was extracted with chloroform and concentrated, and added to the precipitate, whereby a crude material was obtained. The crude material was purified by chromatography on silica gel with toluene/ethyl acetate=10:1 to give 16.8 g of 4-azafluorene-9-one (37.9% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23]
Reactant: C[C@H]1[C@@H](C/C=C/c2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1[C@@H](CCCc2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Reaction time: 30 h
Yield: 96.9 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-chlorophenyl)-2-propene-1-yl)-4-methylazetidin-2-one (0.37 g, 1.10 mmol) in 5 mL of methanol is treated with 30 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 30 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-1-propyl)-4-methylazetidin-2-one as an oil (360 mg, 97% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC(C)(C)C)=O)[CH2:13][C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:21])[C:7]=1[F:31])[CH3:2].Cl>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:21])[C:7]=1[F:31])[CH3:2]
Reactant: CCOC(=O)Cc1ccnc(N(CC(F)(F)c2cccc[n+]2[O-])C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Through a 0° C. solution of 0.221 g (0.485 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-fluoropyridin-4-yl)acetate 30-1, contaminated with ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-fluoropyridin-4-yl)acetate, in 3 mL EtOAc was passed a steady stream of HCl gas for 20 min. The reaction was stirred at 0° C. for 20 min. The mixture was then flushed with N2 and poured onto 200 mL EtOAc/50 mL 2.0M NaOH/7 mL conc NaOH. The layers were mixed and then separated. The aqueous layer was back extracted with 25 mL EtOAc. The combined organics were washed w/100 mL water and 100 mL brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by automated flash chromatography (40 g silica cartridge, linear gradient 0-5% MeOH/CH2Cl2 over 30 min, 30 mL/min flow rate) provided ethyl(2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-fluoropyridin-4-yl)acetate 30-2. 1H NMR (CDCl3, 400 MHz) δ8.288 (d, 1H, J=6.41 Hz, ArH); 7.727 (d, 1H, J=5.13 Hz, ArH); 7.622 (dd, 1H, J=2.20 Hz, 7.87 Hz, ArH); 7.363-7.323 (m, 1H, ArH); 7.297-7.257 (m, 1H, ArH); 6.455 (t, 1H, J=4.95 Hz, ArH); 4.751-4.663 (m, 2H, CH2); 4.164 (dd, 2H, J=7.14 Hz, 14.28 Hz, CH2); 3.560 (s, 2H, CH2); 1.254 (t, 3H, J=7.15 Hz, CH3); MS (Electrospray): m/z 356.1 (M+H).
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I>[I:1][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(I)c1
Temperature: 110 °C
Reaction time: 23 h

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), sodium iodide (fine powder, dried, 300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 5-bromo-m-xylene (136 μL, 1.10 mmol), and solvent (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was allowed to reach room temperature. Ethyl acetate (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL, sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC. The results are tabulated below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.CN([CH:20]=[O:21])C>O=P(Cl)(Cl)Cl>[CH:20]([N:14]1[C:15]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cccc2c1[nH]c1ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2c3ccccc3n(C=O)c12
Temperature: 0 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask was dissolved POCl3 (0.6 mL, 15.23 mM) in 20 mL of dry DMF. The reaction mixture was stirred at 0° C. in an ice bath. To this was added slowly, 1-methoxy-9H-carbazole (1 g, 5.07 mM) dissolved in 30 mL of dry DMF. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture and the precipitated product was filtered off. The residue was dissolved in EtOAc and was washed with brine and dried over anh. Na2SO4. Ethyl acetate was then evaporated to obtain the desired product as a white fluffy solid with a yield of 96% (1.1 g); mp 161-163° C.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][C:15]1[N:16]=[C:17]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[S:18][CH:19]=1>CCN(CC)CC.O=S(Cl)Cl.C(Cl)Cl>[CH:22]([N:21]([CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH3:14])[N:16]=1)[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7])([CH3:24])[CH3:23]
Reactant: Cc1csc(CNC(C)C)n1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(Cc2nc(C)cs2)C(C)C)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Et3N (1 drop, catalytic) was added to a stirred suspension of mono-Methyl isophthalate (0.294 mmol, 1.0 eq) in 2 ml SOCl2 under Ar. The mixture was heated to reflux at 90° C. for 2 h. The reaction was cooled to RT, and the solvent was removed in vacuo. The residue was placed under an Ar atmosphere and dissolved in 2 ml anh CH2Cl2. The resulting solution was treated with a solution of N-((4-methylthiazol-2-yl)methyl)propan-2-amine (0.294 mmol, 1.0 eq made from reductive amination of 4-methylthiazole-2-carbaldehyde with isopropylamine) dissolved in 1 ml anh CH2Cl2 under Ar. After stirring at RT for 30 min, the reaction was treated with ET3N (0.294 mmol, 1 eq). After stirring at RT for 30 min, the reaction is poured into a seperatory funnel, washed with sat. NaHCO3 (×1), water (×3), brine (×1), and dried over Na2SO4. The inorganics were removed via filtration, and the solvent was removed in vacuo yielding the crude product in 93% yield.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([OH:16])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[N:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1)#[N:24].ClCCl>C(#N)C>[C:23]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][O:9][CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=2)[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)=[O:16])=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: N#Cc1ccc(COC(C(=O)c2ccccn2)c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To 2.14 g (0.01 mole) of α-pyridoin in 50 ml of acetonitrile was added 0.80 g (0.01 mole) of pyridine and then 1.65 g (0.01 mole) of p-cyanobenzoyl chloride portionwise with stirring. Stirring was continued for 1/2 hour. Then 150 ml of dichloromethane was added, the organic phase washed thoroughly with water, dried and evaporated to an oily solid residue. The residue was stirred with 80% hexane and 20% acetone to obtain a solid, 1.7 g (50%). After recrystallization from hexane-acetone, 0.9 g (53%), m.p., 152°-154° C., of NA-VI was recovered.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][N:10]=[C:11]=[S:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([O-])=O>ClCCl>[NH2:15][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11]([NH:10][CH2:9][C:8]2[CH:13]=[CH:14][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)=[S:12])=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccc(N)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in dichloromethane (3 ml) and then cooled to 0° C. To the solution was added 4-nitrobenzylamine (75 mg), followed by stirring at room temperature for 6 hours. After the completion of the reaction, dichloromethane was evaporated therefrom under reduced pressure and the residue was dissolved in methanol (3 ml). To the solution was added catalytic amount of 5% platinum/carbon and the mixture was subjected to hydrogenation reaction under atmospheric pressure. After the completion of the reaction, the methanol was evaporated under reduced pressure and the obtained residue was column-chromatographed (hexane/ethyl acetate=1/1) to yield the compound 9a (137 mg, 85%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:17][C:18]([O:20]C)=[O:19])[C:3]=12.[OH-].[Na+]>O>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:17][C:18]([OH:20])=[O:19])[C:3]=12
Reactant: COC(=O)Cc1n[nH]c2nc(NC(=O)C(C)C)nc(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)Nc1nc(O)c2c(CC(=O)O)n[nH]c2n1

Procedure:
Compound 17 (4.41 g; 15 mmole) is suspended in 25 ml water, and a 2N aqueous solution of sodium hydroxide is added drop-wise at 0° C., while maintaining the pH at 11, until the methyl ester is completely hydrolyzed. The reaction solution is then filtered, and the filtrate is brought to pH 3 using 2 M KHSO4 solution, then extracted with ethyl acetate. The aqueous phase is evaporated and the product (18) is purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[OH:15])=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 66.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.99 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.18 g).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 100 °C

Procedure:
A solution of ethyl 2,3-dibromopropionate (6 mL) in anhydrous toluene (50 mL) was added to a solution of N,N′-dibenzylethylenediamine (5 g) and DIPEA (12 mL) in anhydrous toluene (50 mL) under a Nitrogen atmosphere. The resulting mixture was heated to 100° C. for 21 hours, then allowed to cool to r.t., diluted with AcOEt (100 mL) and washed with brine (3×100 mL). The organic extract was dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 9:1) to give ethyl 1,4-dibenzyl-piperazine-2-carboxylate (5.65 g) as a yellow oil, which was used without any purification in the next step. Diisobutylaluminium hydride (1M in toluene-29 mL) was dropped into a solution of ethyl 1,4-dibenzyl-piperazine-2-carboxylate (5.47 g) in anhydrous toluene (110 mL) previously cooled to −78° C. under a Nitrogen atmosphere. The solution was stirred at −78° C. for 1 hour, then a 20% sodium hydroxide solution (20 mL) was added and the mixture was allowed to warm to r.t. Further 20% sodium hydroxide solution (50 mL) was added and the solution was extracted with Et2O (2×150 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (5.33 g) as a crude, which was used without any further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN([CH:19]=[O:20])C>C(OCC)C>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at −78° C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=[CH:16][C:11]3=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:27][N:28](C=O)C.ClS(N=C=O)(=O)=O.CCOC(C)=O>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[C:16]([C:27]#[N:28])[C:11]3=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCN(C)CC3)nc21
Reactant: CN(C)C=O
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc3c(C#N)c[nH]c3n2)CC1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
In a 25 mL round-bottomed flask, 6-(4-methylpiperazin-1-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (320 mg, 859 μmol, Eq: 1.00) was combined with DMF (11.8 ml) to give a colorless solution. The reaction mixture was cooled to −20° C. and stirred for 5 min. Chlorosulfonyl isocyanate (365 mg, 224 μl, 2.58 mmol, Eq: 3) in acetonitrile (11.8 ml) was added dropwise and the resultant cooled reaction was stirred at −20° C. and stirred for 3 hrs The reaction mixture was poured into 25 mL EtOAc and extracted with sat NaCl (3×20 mL). The crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% MeOH in DCM) to give 6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (113 mg, 55%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:12]([C:16]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:33])[C:23]2[C:18](=[CH:19][C:20]([Cl:34])=[CH:21][CH:22]=2)[N:17]=1)[CH:13]([CH3:15])[CH3:14])[C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7]Cl.C(OC(=O)N)(C)(C)C>>[CH2:26]([N:25]1[C:24](=[O:33])[C:23]2[C:18](=[CH:19][C:20]([Cl:34])=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH:12]([N:4]1[C:5](=[O:11])[C:6]([CH3:7])([CH3:9])[CH2:10][NH:1][CH2:2][CH2:3]1)[CH:13]([CH3:15])[CH3:14])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCN)C(=O)C(C)(C)CCl
Agent: CC(C)(C)OC(N)=O
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCC(C)(C)C1=O

Procedure:
Preparation of N-(2-amino-ethyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-3-chloro-2,2-dimethyl-propionamide: Following the procedure of Example 1d, 2-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(3-chloro-2,2-dimethyl-propanoyl)-amino]-ethyl}carbamic acid tert-butyl ester was converted to the title compound as a white solid: MS (ES) m/e 503.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:20][CH:8]([N:9]=[C:10]2[NH:13][CH2:14][CH:15](OC)OC)[CH2:7]3)=[CH:4][C:3]=1[F:21]>Cl>[Br:1][C:2]1[CH:12]=[C:11]2[C:5](=[CH:4][C:3]=1[F:21])[CH:6]1[CH2:20][CH:8]([CH2:7]1)[N:9]1[C:10]2=[N:13][CH:14]=[CH:15]1
Reactant: COC(CNC1=NC2CC(C2)c2cc(F)c(Br)cc21)OC
Agent: Cl
Product: Fc1cc2c(cc1Br)-c1nccn1C1CC2C1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 52.2 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed a solution of 5-bromo-N-(2,2-dimethoxyethyl)-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine (350 g, 979.79 mmol, 1.00 equiv) in hydrogen chloride (3M) (1500 mL). The resulting solution was stirred at 90° C. for 90 min and extracted with 1×1000 mL of ethyl acetate. The pH value of the aqueous layer was adjusted to 10 with sodium hydroxide (3 mol/L). The resulting solution was extracted with 3×500 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate: petroleum ether (1:2) to afford 150 g (52%) of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]3[O:18][CH2:17][CH2:16][C:15]4[CH:14]=[C:13]([C:19]5[N:20]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=6[F:31])[N:21]=[CH:22][N:23]=5)[S:12][C:11]=4[C:10]=3[N:32]=2)[CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C.O>C1COCC1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:20]1[C:19]([C:13]2[S:12][C:11]3[C:10]4[N:32]=[C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:2]5)[CH:7]=[CH:8][C:9]=4[O:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)=[N:23][CH:22]=[N:21]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4CNC4)ccc2OCC3)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
Azetidin-3-yl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine (452 mg, 1.0 mmol), Methanesulfonyl chloride (136 mg, 1.2 mmol), DIPEA (260 mg, 2.0 mmol) was dissolved in THF (10 mL). The reaction mixture was stirred at room temperature (r.t.) for 1 hour. LC-MS indicated the reaction was completed. To the reaction mixture was added 20 mL of water, the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness. The crude was purified by pre-HPLC to afford 363 (57.2 mg, yield: 11%). 1HNMR (DMSO-d6, 400 MHz): δ 9.50 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 7.97-7.91 (m, 2H), 7.77-7.72 (m, 2H), 7.48-7.43 (m, 2H), 7.15 (s, 1H), 6.99 (s, 1H), 6.72 (d, J=4.4 Hz, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.33 (s, 2H), 3.15 (s, 2H), 2.75 (s, 6H). ESI-MS: m/z=531 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)C1CCc2cc(OC)ccc2N1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)cc2CCC1C(=O)OC
Yield: 67.3 %

Procedure:
To a solution of 69.3 g (0,313 mol) of (±)-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline and 39 ml (0.407 mol) of ethyl chloroformate in 1400 ml of dichloromethane are added 85 g (0.63 mol) of potassium carbonate, and the mixture is heated at reflux for 18 h. The mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is chromatographed on a column of silica, with a 3/7 mixture of ethyl acetate and cyclohexane. 80.4 g of product are obtained in the form of an oil.