Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22].N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22]
Reactant: CC1(C)CC(c2cccc(S(=O)(=O)Cl)c2)Nc2ccc(Cl)cc21
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(S(=O)(=O)Nc3ccc(F)cc3)c2)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzenesulfonyl chloride (204 mg 0.55 mmol) was dissolved in dichloromethane (5 mL). Pyridine (5 mL) was added to the mixture and cooled to 0° C. 4-fluoro-phenylamine (61 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was removed and the residue was purified on thin layer chromatography using petroleum ether/ethyl acetate=3:1 as eluent to afford 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-(4-fluoro-phenyl)-benzenesulfonamide as white solid (89 mg, 37% yield). MS (ESI+APCI) M+1=445.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC(OC)=CC=3)=[CH:20][CH:19]=2)[C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(COc2ccc(Nc3c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c3C(=O)O)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: O=c1c2cc(O)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 5.0 g of 2-chloro-6-[[4-[(4-methoxyphenyl)methoxy]phenyl]amino]-3,5-dinitrobenzoic acid, 10 ml of phosphorus oxychloride, 0.2 ml of N,N-dimethylaniline and 50 ml of 1,2-dichloroethane was heated at reflux for 15 minutes and the reaction mixture was filtered hot. The filter cake was washed with 1,2-dichloroethane to provide the title compound, mp 278°-281° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCCC[Sn]([C:27]1[N:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][N:32]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Temperature: 25 °C

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-3-methyl-1,8-naphthyridine (540 mg, 2.53 mmol), 2-(1,1,1-tributylstannyl)pyridine (933 μL, 2.53 mmol), Pd(PPh3)4 in toluene (10 mL) and heating at reflux for 14 h. The reaction was allowed to cool to rt and evaporated in vacuo. The resulting residue was triturated with hexanes and the solid was dried under vacuum to give 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine. 1H NMR (400 MHz, CDCl3) δ ppm 9.14 (1H, dd, J=4.3, 2.0 Hz), 8.72 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.65 (1H, dd, J=8.3, 1.9 Hz), 8.09 (1H, dt, J=8.0, 1.1 Hz), 7.90 (1H, td, J=7.7, 1.8 Hz), 7.60 (1H, dd, J=8.3, 4.2 Hz), 7.40 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 2.75 (3H, s)
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: COc1ccc(I)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (7-3, 34 g, 162 mmol) in DMF (65 mL) was added sodium methoxide (37 mL, 162 mmol) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (7-4) as a white powder. ESI+ MS [M+H]+ C7H8INO2: 265.8 found, 266.0 required.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27].[S:39](O)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH:28][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1

Procedure:
Boc-Phe-OH (4 g, 15 mmole), H-Arg-OBzl.TosOH (8.9 g, 15 mmole) and HOBt (2.1 g, 15.75 mmole) were dissolved in DMF (25 ml), and WSCI (12.9 ml, 15.75 mmole) was added dropwise thereto while cooling, and the thus-obtained mixture (pH=4) was stirred overnight. To the reaction solution, AcOEt (300 ml) was added thereto, and the solution was washed with 1N HCl, water and 5% NaHCO3 and water, in order, and dried with Na2SO4 . AcOEt was distilled off under reduced pressure, and the thus-obtained residue was treated with ethyl acetate, ether, and n-hexane to give an oily substance. The substance was obtained by decantation and treated with ethyl acetate and hexane to give precipitates of the object product (6.89 g, 60%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1cccs1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OCc4cccs4)[C@@H](COC(C)=O)O3)c2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 0.30 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3'-O-(2-thienyl)methyluridine in 10 ml of dioxane were added 0.55 ml of triethylamine and 0.16 g of 4-methoxy-benzoyl chloride. The mixture was stirred at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over sodium anhydrous sulfate and concentrated. The residue was subjected to silica gel chromatography and purified by elution with chloroform, giving 0.37 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3-(4-methoxybenzoyl)-3'-O-(2-thienyl)me thyluridine in a yield of 91%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[C:11]#N.[OH2:21].[OH-:22].[Na+].OO>C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[C:11]([OH:22])=[O:21]
Reactant: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C#N
Reactant: O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 40 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Example 24A (12.0 g, 42 mmol) in ethanol (50 mL) was added 15 mL of water and then warmed to 40° C. Then 50% sodium hydroxide (7.8 mL, 148 mmol) was added to the above reaction mixture followed by 50% hydrogen peroxide (7.3 mL, 127 mmol), which was added in 4 portions, each portion one hour apart. The reaction mixture was heated at 40° C. for 4 more hours. The reaction was monitored by LC/MS. After almost all the nitrile was converted to the amide, sodium hydroxide (6.7 mL, 127 mmol) was added followed by 10 mL of water. After stirring at 80° C. for 12 h, the reaction mixture was concentrated under reduced pressure to remove ethanol and diluted with 100 mL of water. The resulting solution was washed (2×25 mL) with diethyl ether. The aqueous solution was neutralized to pH 7 with 6N HCl and concentrated under reduced pressure to dryness. The residue was suspended in dichloromethane (100 mL), the solution heated to 60° C. and filtered; this process was repeated 3 times. The combined filtrates were concentrated under reduced pressure and azeotroped with toluene to afford 10.2 g (80%) of the title compound. MS (ESI+) m/z 304 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:7][CH:6]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2ccc3ccccc32)cc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
Ethyl-4-fluorobenzoate (4 mL, 27.3 mmol) and indole (3.51 g, 30 mmol) were dissolved in 50 mL of dimethylsulfoxide (DMSO). Potassium fluoride (37% on basic alumina, 12.8 g) and 18-crown-6 (720 mg, 2.73 mmol) were added and the mixture was heated to 120° C. for 24 hours. The reaction was diluted with ethyl acetate and washed with hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The organic layer was dried over magnesium sulfate, filtered and the solvent removed. Purification by flash chromatography on silica gel eluted with 5% ethyl acetate, hexane provided 1.45 g (20%) of a white solid
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].N[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C[N:28](C)C=O>>[OH:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:3]([C:2]2[NH:28][C:26]3[C:21]([C:19]=2[CH3:18])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:4])=[CH:6][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Reactant: NCC(=O)c1ccccc1
Reactant: CN(C)C=O
Product: COc1cc(C(=O)c2[nH]c3ccccc3c2C)cc([N+](=O)[O-])c1O

Procedure:
ac) A solution of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 13.5 g of 2-aminoacetophenone in 250 ml of dry N,N-dimethylformamide is stirred at 90° for 16 hours. The reaction mixture is then evaporated to about two thirds and poured on to ice. The separated crystals are filtered under suction and dissolved in methylene chloride. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole of m.p. 195°-197° (from methylene chloride/methanol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](O)[CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CNC1C=CN=CC=1>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]\[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC(CCc1cccnc1)c1ccc2ccccc2c1
Agent: CNc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C(=C/c1ccc2ccccc2c1)\Cc1cccnc1
Product: C(=C\c1ccc2ccccc2c1)\Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 1-(2-naphthyl)-3-(3-pyridyl)propan-1-ol (1.14 g) in CH2Cl2 (30 ml) were added triethylamine (2.5 ml), methanesulfonyl chloride (0.70 ml) and catalytic amount of 4-methylaminopyridine. The mixture was stirred at room temperature for 8 hours. The mixture was washed with water and brine, dried and concentrated. The residue was dissolved in 1,8-diazabicyclo[5.4.0]undec-7-ene (20 ml) and stirred at 90° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=3:1) to give 3-[(E)-3-(2-naphthyl)-2-propen-1-yl]pyridine (123 mg) and 3-[(Z)-3-(2-naphthyl)-2-propen-1-yl]pyridine (67 mg). 3-[(E)-3-(2-naphthyl)-2-propen-1-yl]pyridine.
Reaction SMILES: I[CH2:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:19](=[O:20])[C:18]2[C@@H:17]3[C:21]([CH3:23])([CH3:22])[C@@:14]([CH3:24])([CH2:15][CH2:16]3)[C:13]=2[NH:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:19]([O:20][CH2:2][CH3:3])=[C:18]2[C:13]([C:14]3([CH3:24])[C:21]([CH3:23])([CH3:22])[CH:17]2[CH2:16][CH2:15]3)=[N:12]1.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:19](=[O:20])[C:18]2[C@@H:17]3[C:21]([CH3:23])([CH3:22])[C@@:14]([CH3:24])([CH2:15][CH2:16]3)[C:13]=2[N:12]1[CH2:2][CH3:3]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c2c(nn1-c1ccccc1Cl)C1(C)CCC2C1(C)C
Product: CCn1c2c(c(=O)n1-c1ccccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Yield: 9 %
Yield: 16 %

Procedure:
Iodoethane (14 μL, 0.18 mmol) was added to (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 10; 47 mg, 0.16 mmol) and potassium carbonate (43 mg, 0.31 mmol) in dimethylformamide (1 mL). The mixture was heated at 60 degrees for 4 h, and then stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with NaOH. The solvent was evaporated from the ethyl acetate layer and the residue was purified by flash chromatography, eluting with 0-70% ethyl acetate/hexanes, to give 2-(2-chloro-phenyl)-3-ethoxy-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (12.3 mg, 16%) and (4S,7R)-2-(2-chloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (4.4 mg, 9%). APCI-MS (M+H) 331.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 4.73 g (0.0150 mole) of 9-bromo-1,2-dihydro-benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1000 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 14.9 g (0.150 mole) of 4-methylpiperidine, followed by 8.54 g (0.045 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to an oil which solidified. The solid was triturated twice with hexane to afford 4.9 g (83%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 177°-179° C.
Reaction SMILES: [C:1]([NH2:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[C:13]([N:20]([CH2:22][C:23]([OH:25])=[O:24])C)(OC(C)(C)C)=O.C([Cl:29])(=O)C>CO>[ClH:29].[C:1]([NH2:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[NH:20]([CH2:22][C:23]([OH:25])=[O:24])[CH3:13]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: NC(=O)c1ccc2c(c1)OCO2
Solvent: CO
Product: CNCC(=O)O
Product: Cl
Reaction time: 0.75 h

Procedure:
N-Boc sarcosine piperonylamide (500 mg, 1.54 mmol) in methanol (10 mL) was treated with acetyl chloride (1 mL). After 45 minutes, all volatiles were removed under reduced pressure to yield sarcosine piperonyl amide hydrochloride (395 mg, quant.) as a sticky solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:43])[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[NH:23][C:24]2([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[C:32]3[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:34])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:43])=[C:17]([NH:23][C:24]2([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[C:32]3[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:34])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of rac-4-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.044 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred for 3 h, concentrated. The residue was dissolved in DCM, the resulting solution was washed with Na2CO3 solution, dried with Na2SO4, concentrated to give 22 mg rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-piperidin-4-yl-benzamide. MS: [M+H]+=587
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)(=O)C>ClCCCl>[C:24]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(C)=O)cc3Cl)c2n1
Yield: 82.2 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) was dissolved in 1,2-dichloroethane (1.5 ml), and acetic anhydride (148 mg) and acetic acid (87 mg) were added at room temperature. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure, and ice water, a saturated aqueous sodium hydrogencarbonate solution were successively added to the residue. The precipitated white crystals were collected by filtration, washed with water, and dried under reduced pressure to give the objective compound (139 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.O=[C:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][CH2:14]1.C(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:20]([N:16]1[CH2:15][CH2:14][CH2:13][CH:19]([NH:11][C:6]2[C:5]3[CH:4]=[CH:3][N:2]=[CH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:18][CH2:17]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Product: c1ccc(CN2CCCC(Nc3cccc4cnccc34)CC2)cc1

Procedure:
The title compound was prepared by reaction of isoquinolin-5-amine with tert-butyl 4-oxoazepane-1-carboxylate using the method of Example 3, followed by deprotection using the method of Example 4 and reaction with benzaldehyde following the method of Example 8.
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[S:14](Cl)(Cl)(=[O:16])=[O:15].Cl.[Cl:20][C:21]1[N:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Cl:20][C:21]1[N:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([S:14]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)(=[O:16])=[O:15])[CH2:26]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1nccc2c1CCNC2
Reactant: Nc1ncns1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ncns1)N1CCc2c(ccnc2Cl)C1
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A solution of 1,2,4-thiadiazol-5-amine (0.740 g, 7.31 mmol) and triethylamine (3.06 ml, 21.94 mmol) in 20 mL DCM was cooled to −78° C. and was treated with sulfuryl chloride (0.595 ml, 7.31 mmol). The cooling bath was removed, and the reaction mixture was allowed to stir for 20 minutes. LC/MS showed mostly desired intermediate, so 5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (Anichem, North Brunswick, N.J., 0.750 g, 3.66 mmol) was added and the reaction mixture was allowed to stir for one hour. The reaction mixture was then poured into 1N citric acid and was extracted with EtOAc. The organics were concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-chloro-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-sulfonamide (1.064 g, 3.21 mmol). [M+H]+=332.1
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].C1C(=O)N([I:17])C(=O)C1>>[CH2:1]([C:3]1[C:8]([I:17])=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1I
Product: CCc1cc(N)ncc1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 5.0 g (41 mmol) 4-ethyl-pyridin-2-ylamine and 9.2 g (41 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography using silica gel: 10.3 g (100%).