Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:21])=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:40])=[CH:25][N:24]=1.Cl.O1CCOCC1>CC(O)C>[Br:21][C:3]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([NH:29][C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:40])=[CH:25][N:24]=2)=[CH:12][CH:11]=[C:10]2[C:4]=1[CH:5]1[CH2:14][CH2:13][CH:9]2[CH2:8][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:6]1
Reactant: Nc1ccc2c(c1Br)C1CCC2CN(C(=O)C(F)(F)F)C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2Br)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Temperature: 120 °C
Yield: 19.2 %

Procedure:
1-(4-Amino-3-bromo-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (76 mg, 0.209 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (68.4 mg, 0.230 mmol, 1.1 eq) were dissolved in IPA (2 mL). 4.0 M HCl in dioxane (57.5 μL, 0.230 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-{2-[3-bromo-10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-5-chloro-pyrimidin-4-ylamino}-N-methyl-benzamide as a pale yellow foam (24.99 mg, 19%). LCMS (m/e) 623 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.03 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 8.26 (s, 1H), 8.14 (s, 1H), 7.55-7.26 (m, 4H), 7.15-7.05 (m, 1H), 6.30-6.20 (m, 1H), 4.23 (dd, 1H, J=5.3 and 13.5 Hz), 3.95-3.83 (m, 1H), 3.47-3.38 (m, 1H), 3.30-3.20 (m, 1H), 3.20-3.09 (m, 1H), 3.04 (s, 3H), 3.06-2.97 (m, 1H), 2.10-1.97 (m, 2H), 1.87-1.70 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1.[CH3:17]I>>[CH3:17][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1
Reactant: CI
Reactant: O=C1Cc2c(cccc2C2CCCNC2)N1
Product: CN1CCCC(c2cccc3c2CC(=O)N3)C1

Procedure:
Using the procedure of Example 3, 1,3-dihydro-4-(piperidin-3-yl)-2H-indole-2-one and methyl iodide were reacted to obtain 1,3-dihydro-4-(1-methyl-piperidin-3-yl)-2H-indole-2-one which melted at 160° C. after crystallization from benzene.
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=[O:2].CN(C=O)C.[F:12][C:13]1[C:21]([C:22]#[N:23])=[C:20]2[C:16](C=[CH:18][NH:19]2)=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:21]([C:22]#[N:23])=[C:20]2[C:16]([C:3]([CH:1]=[O:2])=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: N#Cc1c(F)ccc2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (COCl)2 (2.47 g) in DCM (40 mL) at 0° C. was added a solution of DMF (3 mL) in DCM (20 mL) dropwise. Half an hour later, a solution of 6-fluoro-1H-indole-7-carbonitrile (D141) (2.6 g) in DCM (20 mL) was added. The reaction was allowed to warm to RT to form a yellow precipitate. After 5 hours the solvent was removed by evaporation, and then THF (30 mL) and 2 M aqueous NaOH (30 mL) solution were added to the residue obtained above. After stirring for about 1 h, the organic phase was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 6-fluoro-3-formyl-1H-indole-7-carbonitrile (D142) (3.0 g) as a yellow solid.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][OH:8].CN(C)C=O.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>O>[C:6]([O:10][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:9])[CH2:7][OH:8]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Sodium hydrogen carbonate (2.20 g, 26.3 mg) was added to a solution of glycolic acid (2.00 g, 26.3 mmol) in water (2.00 mL), and the mixture was stirred for one hour at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, and to a dimethylformamide (10.0 mL) solution of the resulting residue, p-methoxybenzyl chloride (4.10 g, 26.3 mmol) was added. The mixture was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer thus obtained was washed sequentially with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, a crude product of the title compound (4.24 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:20])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(-c2cccc3[nH]ccc23)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 4-(3,5-difluoro-phenyl)-1H-indole (13.52 g, 59 mmol) in t-BuOH: ethanol: acetic acid (375 mL: 225 mL: 115 mL) was added pyridinium tribromide (57 g, 177 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (286 mL). Zinc dust (19.25 g, 295 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 9.88 g (68%) of 4-(3,5-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([NH2:37])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+].O>O1CCOCC1>[NH2:37][C:32]1[C:28]2[C:29](=[O:31])[CH:30]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:12](=[O:13])[C:11]5=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]5[C:9]4=[O:18])=[CH:24][CH:23]=3)[O:26][C:27]=2[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)ccc3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(F)ccc2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Yield: 87 %

Procedure:
6.0 g of Compound 14 was dissolved in 90 ml of dioxane, 60 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 5 hours. The reaction solution was cooled on ice and adjusted to pH 7.5 by addition of a 10N aqueous solution of sodium hydroxide thereto, water was further added, and the precipitated crystals were collected by filtration to give 4.78 g (87%) of Compound 15.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].CS(C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:6]2[C:5]3[S:9][CH:10]=[CH:11][C:4]=3[S:3](=[O:13])(=[O:12])[N:2]([CH3:1])[C:7]=2[OH:8])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2sccc2S1(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 G. of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide are dissolved in 31 ml. of absolute dimethylsulfoxide under an atmosphere of nitrogen. 1.44 G. of freshly distilled triethylamine and 2.83 g. of 4-bromophenyl isocyanate are added to the solution and the mixture is then stirred for 24 hours at room temperature. This mixture is then poured into 225 ml. of 3-N hydrochloric acid and the prepcipitate which separates out is filtered on a sinter filter, washed three times with 20 ml. of distilled water each time and dried as much as possible. The precipitate is dissolved in 250 ml. of methylene chloride, dried over sodium sulfate, stirred with activated charcoal and filtered. The organic phase is shaken out four times with 250 ml. of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride. The combined aqueous phases are rendered strongly acid with concentrated hydrochloric acid. The product which separates out is extracted three times with 250 ml. of methylene chloride each time. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and the solvent is removed by distillation. The crystalline residue is dissolved in 50 ml. of chloroform. While boiling, activated charcoal is added and the mixture is filtered hot. The product is made to crystallize by scratching. The crystals are removed by filtration, digested with a little cold chloroform, and 4'-bromo-3-hydroxy-2-methyl-2H-thieno[2,3-e]1,2-thiazine-4-carboxanilide 1,1-dioxide, melting point 178° C. to 179° C. (decomposition), is obtained.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([F:35])=[CH:29][C:28]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CS(OCCC1CCCCC1)(=O)=O>>[CH:20]1([CH2:19][CH2:18][N:39]2[CH2:38][CH2:37][N:36]([C:28]3[CH:29]=[C:30]([F:35])[C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[CH2:41][CH2:40]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OCCC1CCCCC1
Agent: Cl
Product: COc1cc(F)c(N2CCN(CCC3CCCCC3)CC2)cc1F

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (342 mg) and 2-cyclohexylethyl methylsulfonate (309 mg), respectively, to provide crude 1-(2-cyclohexylethyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (476 mg).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][NH2:21]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:21][CH3:20])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CN
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In an argon atmosphere, 5.24 g (22.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding 25.0 mL (48.8 mmol) of a tetrahydrofuran solution (concentration: 1.95 mol/L) of methylamine, the mixture was stirred at room temperature for 1 hour. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./3.8×102 Pa) to obtain 1,3-di-tert-butyl-2-methylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHMe) as a pale yellow liquid (yielded amount: 4.41 g, yield: 86%).
Reaction SMILES: [CH3:1][O:2][NH:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[CH3:16])(=[O:6])=[O:5].NN>[Pd].C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([CH3:16])=[C:7]([S:4]([NH:3][O:2][CH3:1])(=[O:5])=[O:6])[CH:12]=1
Reactant: CONS(=O)(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CONS(=O)(=O)c1cc(N)ccc1C

Procedure:
N-Methoxy-2-methyl-5-nitrobenzenesulfonamide (0.5 g, 2 mmol) was combined with 10% palladium on carbon (0.05 g), ethanol (10 mL), and hydrazine (1 mL) and heated at reflux for 18 h. The solution was filtered through celite, concentrated, and purified on silica gel with methanol in dichloromethane. Product was an off white solid (0.28 g, 1.3 mmoL). 1H NMR (300 MHz, d6-DMSO) δ10.3 (s, 1H), 7.11 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.7 (d, J=8.2 Hz, 1H), 5.37 (s, 2H), 3.57 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:29])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (72.42 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (77.3 mg, 59%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45Cl2N5O2S+H [(M+H)+]: 654.2793. found: 654.2790.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:6](Cl)=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: N
Reactant: Fc1nc(OC(F)(F)F)c(Cl)c(C(F)(F)F)n1
Solvent: CCOCC
Product: Nc1nc(OC(F)(F)F)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.7 g (0.278 mol) of gaseous ammonia were passed into a mixture of 38.0 g (0.147 mol) of 2-fluoro(chloro)-4-trifluoromethoxy-6-trifluoromethylpyrimidine in 150 ml of diethyl ether in the course of 1 hour at from -75° to -70° C. while stirring. Stirring was continued for 2 hours at -75° C. and for 2 hours after warming up to 25° C. The precipitate which had separated out was filtered off under suction, after which the organic phase was extracted with water, dried and partially evaporated down. Chromatography over silica gel using methyl tert-butyl ether gave 20.4 g (56.1% of theory) of the title compound of melting point 47°-49° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH:11]([OH:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:27]([NH:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])=[S:28])[C:3]=1[NH:9][CH2:10][CH:11]([OH:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(O)CNc1c(N)cccc1N
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)CC(O)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Yield: 33.7 %

Procedure:
To a solution of methyl 4-[(2,6-diaminophenyl)amino]-3-hydroxybutanoate (Reference Example 80; 100 mg, 0.418 mmol) in tetrahydrofuran (2 mL) was added a solution of 2,4-dichlorophenyl isothiocyanate (93.8 mg, 0.460 mmol) in tetrahydrofuran (2 mL) at 0° C. The resultant mixture was stirred at 0° C. for 1 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-70% ethyl acetate/n-hexane gradient to give the title compound as an oil (62.5 mg, 0.141 mmol, 34%).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([N+:45]([O-:47])=[O:46])=[C:31]([CH:44]=1)[NH:32][CH:33]=[C:34]1[C:42](=[O:43])OC(C)(C)OC1=O>CCCCCC>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([N+:45]([O-:47])=[O:46])=[C:31]2[C:44]=1[C:42](=[O:43])[CH:34]=[CH:33][NH:32]2
Reactant: Cc1ccc([N+](=O)[O-])c(NC=C2C(=O)OC(C)(C)OC2=O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc([N+](=O)[O-])c2[nH]ccc(=O)c12
Temperature: 100 °C
Yield: 90.4 %

Procedure:
To a stirred mixture of diphenyl ether (37 g) and biphenyl (13 g) was added isopropylidene (5-methyl-2-nitroanilino)methylenemalonate (14.6 g) at 220° C., and the mixture was heated at the same temperature for half an hour. The reaction mixture was allowed to cool to 100° C. and then n-hexane (100 ml) was added dropwise to the mixture. After cooling to ambient temperature, the precipitate was collected by filtration. The solid was washed with hot ethanol (70 ml) and allowed to cool to ambient temperature. The solid was collected by filtration and air-dried to give 1,4-dihydro-5-methyl-8-nitro-4-oxoquinoline (8.8 g) as a dark brown solid.
Reaction SMILES: [K].Cl.O.[NH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1>CO>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH:8]=3)=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxyde (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g) in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml) was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 ato. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent: ethyl acetate/dichloromethane/ethanol/triethyla-mine 40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:28]4[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=4)=[CH:34][C:35]3=[O:39])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cc1ccc(COc2cc[nH]c(=O)c2)cn1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(COc2ccn(-c3ccc4c5c(n(C)c4c3)CCCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one (90 mg, 0.46 mmol) and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (0.11 g, 0.60 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (20 mL) and washed with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 20 column volumes) gave the title compound (0.12 g, 57%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.0, 2.5 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.93-6.91 (m, 1H), 6.07-6.06 (m, 1H), 5.99 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H), 2.99-2.97 (m, 2H), 2.50 (s, 3H), 1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).