Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:19][N:20]=[C:15]3[N:14]=[N:13]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].O>C1COCC1.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:10]4[CH:9]=[C:8]([C:5]5[N:4]=[CH:3][C:2]([OH:31])=[CH:7][N:6]=5)[CH:29]=[CH:28][CH:27]=4)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)[CH:22]=[N:23]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(Br)cn5)c4)c3n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(O)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
800 mg (1.66 mmol) of 1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazolo[4,5-b]pyrazine is suspended in 10 ml of THF and 1 ml of DMF, and 515 mg (1.99 mmol) of bis(pinacolato)diboron and 488 mg (4.97 mmol) of potassium acetate are added. The reaction mixture is evacuated and flushed with argon a number of times. 16.3 mg (0.023 mmol) of bis(triphenylphosphine)palladium(II) chloride is added, and the mixture is again evacuated and flushed with argon. The reaction mixture is stirred at 80° C. for 24 h. When the reaction of the starting material is complete, 255 mg (1.656 mmol) of sodium perborate trihydrate and 2 ml of water are added to the reaction mixture, which is then stirred at room temperature for 24 h. The reaction mixture is filtered off with suction and washed with ethyl acetate. The filtrate is subsequently adjusted to pH 12 using NaOH solution and extracted with ethyl acetate. The aqueous phase is neutralised using hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are then dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:36][CH2:37][CH3:38])=[CH:23][C:24]([Cl:35])=[C:25]([S:27]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])[CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:40](Cl)([Cl:42])=[O:41]>C(N(CC)CC)C>[C:31]([NH:30][S:27]([C:25]1[C:24]([Cl:35])=[CH:23][C:22]([O:36][CH2:37][CH3:38])=[C:21]([C:10]2[N:9]([C:40]([Cl:42])=[O:41])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:39])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)[CH:26]=1)(=[O:29])=[O:28])([CH3:32])([CH3:33])[CH3:34]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-5-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzene-sulfonamide (example 44) was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([NH:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][O:28][CH2:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([NH:23][CH:24]([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1NC(C)C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
A solution of 7-benzyloxy-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.67 g, 4.12 mmol) in 25 mL of toluene and 25 mL of methanol was treated with palladium on carbon (0.44 g, 0.42 mmol, 10% w/w). The mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa). After 16 h, the reaction was filtered through a pad of CELITE filter agent and rinsed with solvent until the filtrate ran clear. The filtrate was concentrated under reduced pressure to provide a white solid. Purification by chromatography (SiO2, 3:1 CHCl3:(80:18:2 CHCl3:MeOH:NH4OH) gradient to 1:1) gave 0.50 g of 4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-ol as a white solid. MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Cl[CH2:12][CH:13]=[C:14]([Cl:16])[CH3:15]>C(O)C>[C:2]([CH:3]([CH2:12][CH:13]=[C:14]([Cl:16])[CH3:15])[C:4](=[O:5])[CH3:6])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(Cl)=CCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)Cl)C(C)=O

Procedure:
To a solution of 46 g sodium (2 g atom) in 500 ml ethanol at reflux, in a 2-liter flask equipped with mechanical stirrer, and addition funnel, was added 325 g ethyl acetoacetate (2.5 mole) over 30 minutes. The resulting solution of enolate was refluxed for 15 minutes, and then 250 g (2.0 mole) 1,3-dichlorobut-2-ene was added dropwise at such a rate as to maintain reflux with gentle heating towards the end of the addition. After addition, refluxing and stirring were maintained for 4 hours, the condenser converted for distillation, and ethanol removed as 500 ml distillate. The residual product was cooled, water and 1.2 N hydrochloric acid were added and the organic layer separated. The aqueous portion was extracted with ether, the organic layers combined, washed with water and brine, filtered through sodium sulfate and evaporated in vacuo to give 485 g dark yellow oil (96%, based on dichlorobutene). Vpc showed 73% of trans plus cis product, together with other volatiles.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([NH:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([N@:35]2[CH2:37][CH:36]2[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].O>CN(C=O)C>[NH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][C@H:36]([NH:35][S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:37][N:16]([C:14]2[O:13][N:12]=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[CH:15]=2)[C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:40]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[N@]2CC2Cc2c[nH]c3ccccc23)cc1
Reactant: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)no1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N(C[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(-c2ccc3cnccc3c2)no1
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a 25 mL of round-bottom flask was added allyl 3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate (68 mg, 230 μmol) (prepared as shown for Example 11), 1,8-diazabicyclo(5.4.0)-7-undecene (6.8 μl, 46 μmol) and 2 mL of DMF at room temperature. (S)-3-((1-(4-Nitrophenylsulfonyl)aziridin-2-yl)methyl)-1H-indole (98 mg, 276 μmol) (prepared as described in US Patent Publication No. US 2007/0173506 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein) in 1 mL of DMF was added to the reaction mixture dropwise. After 3 hours, 10 mL of water was added, and then the reaction mixture was extracted twice with 20 mL of EtOAc. The extracts were combined, concentrated under reduced pressure, and purified by flash chromatography on silica gel (65% EtOAc/hexane) to give allyl(S)-3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(3-(isoquinolin-6-yl)isoxazol-5-yl)carbamate (130 mg, 86% yield). MS m/z: 653 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:17]=[CH2:18])[OH:16])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:3][C:1]1[CH2:2][CH2:18][CH2:17][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:4]=1
Reactant: C=CC1(O)CCCCCCCCCCC1C(=C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=CCCCCCCCCCCC(=O)CCC1

Procedure:
A mixture of 2-isopropenyl-1-vinylcyclododecan-1-ol (0.100 g; 0.4.10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.007 g; 0.018.10-3 mol) in tetrahydrofuran (5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 6 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying over magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 5-methylcyclohexadec-5-en-1-one (0.065 g) is obtained, which has the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:32]([N+:33]([O-])=O)=[CH:31][CH:30]=[C:29]([Cl:36])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1.NN>CO.[Ni]>[NH2:33][C:32]1[C:2]([Cl:1])=[C:3]([C:29]([Cl:36])=[CH:30][CH:31]=1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)c3ccccc23)nc1Nc1ccncc1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(N)c3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C

Procedure:
52 mg of 2-[1-(2,6-dichloro-3-nitrobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-44-1, 0.10 mmol, 1.0 eq.) were dissolved in 5.2 ml of dry methanol. 23.4 mg raney nickel (50%, 0.199 mmol, 2.0 eq.) and 0.045 ml hydrazine (35%, 0.498 mmol, 5.0 eq) were added. The reaction mixture was stirred at room temperature vigorously over night. The slurry was filtered over celite and washed with methanol twice. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to yield 19.2 mg (0.04 mmol, 38%) of the analytically pure target compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([O:14][CH2:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a stirred suspension solution of LiAlH4 (28.5 g, 0.75 mol) in anhydrous THF (1 L) at 0° C. under N2 was added dropwise over 30 min a solution of (S)-2-(benzyloxymethyl)-3-methylbutanoic acid (66 g, 0.30 mol) in anhydrous THF (500 mL). The reaction mixture was warmed to rt and stirred overnight. After the mixture was cooled to 0° C., water (29 mL) was added dropwise, followed by 10% aq NaOH (29 mL). The mixture was filtered and the filtrate was evaporated. The residue was partitioned between EtOAc and water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 86%). 1H NMR (400 MHz, CDCl3): 0.92 (m, 6H), 1.66 (m, 1H), 1.77 (m, 1H), 2.70 (brs, 1H), 3.59 (m, 4H), 4.51 (m, 2H), 7.30 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 68.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.18 g, 0.39 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.07 g, 0.39 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a light yellow solid (0.14 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]2[C:15]([CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[C:25]([CH2:24][CH3:23])[CH:26]=[CH:27][CH:22]=2)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(C2C=CCC2)c1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of lithiumfluorene in 50 cm3 of tetrahydrofuran is added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated during this procedure was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1H-NMR spectra).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][CH2:44][NH2:45]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH2:44][CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CN(C)CCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 84.8 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (10 mg, 0.018 mmol) in THF (3 mL) was added N,N-dimethyl-1,3-propanediamine (0.012 mL, 0.096 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (9 mg, 84%). LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) δ 1.58 (m, 2H), 2.19 (s, 6H), 2.24 (m, 2H), 2.34 (s, 3H), 3.10 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Product: CN1CCN(c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)CC1

Procedure:
4-Methylpiperazine was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 9.80(1H,s), 8.82(1H,s), 8.47(1H,s), 8.23(1H,s), 8.15(1H,s), 7.75(1H,d), 7.67(1H,d), 7.54 (1H,s), 7.28(5H,m), 5.68(2H,s) 3.64(4H,m), 2.27(3H,s); m/z (M+) 451.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27]([C:23]5[CH:22]=[C:21]6[C:26](=[CH:25][CH:24]=5)[NH:18][CH:19]=[CH:20]6)=[O:29])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5[nH]ccc5c4)ccc32)cc1)c1ccc2[nH]ccc2c1

Procedure:
Compound 527 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 1H-indole-5-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.18; found: 511.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([CH:34]=1)[NH2:33].C[Al](C)C>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([NH:33][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:25][CH3:26])[CH:34]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(Cl)ccc1C
Yield: 45 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-chloro-2-methyl aniline (0.057 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.057 g of desired product. 1HNMR (DMSO-d6): δ 2.32 (s, 3H), 4.05 (s, 3H), 7.13 (d, J=9.9 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.49 (t, 1H), 7.59 (d, 1H), 7.61-7.75 (m, 2H), 7.84 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.19 (s, 1H), 9.94 (br s, 1H), 12.83 (br s, 1H); MS (m/z): 487.11 [M]+.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].Cl.[NH:6]1[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:8]=[CH:7]1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:14][C:12]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: OP(O)O
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1c[nH]cn1)P(=O)(O)O
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
3 g. Phosphorous acid are added to 3.5 g. imidazol4-ylacetic acid hydrochloride (m.p. 198-200° C.) in 40 ml. chlorobenzene. The reaction mixture is stirred for 10 minutes at 110° C., cooled and 9 g. phosphorus trichloride slowly added dropwise thereto. The reaction mixture is heated for 16 hours to 110° C., cooled, the chlorobenzene is decanted off from an orange-coloured syrup and the residue is mixed with 50 ml. 6N hydrochloric acid. The suspension is heated under reflux for 5 hours, cooled, mixed with charcoal and filtered off with suction. The filtrate is evaporated, dried and boiled up with acetone for 2 hours. The residue (4.3 g.) is dissolved in water, the solution is adjusted with 2N aqueous sodium hydroxide solution to a pH of 5, mixed with methanol and the precipitate obtained is filtered off with suction. There are obtained 1.2 g. (about 16.9% of theory) of the desired product; m.p.>290° C. The compound is obtained as the monosodium salt containing 2 moles of water of crystallisation (Mrel =0.37).
Reaction SMILES: C([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:26])=[S:25])=[CH:14][CH:13]=2)(C)(C)C.Cl.C(N(CC)CC)C.[CH:41]1[C:53]2[CH:52]([CH2:54]OC(Cl)=O)[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>C(OCC)(=O)C.O>[NH2:26][C:24]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:27])[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]([CH2:8][NH:7][C:6](=[O:32])[O:5][CH2:54][CH:52]1[C:53]3[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=3[C:46]3[C:51]1=[CH:50][CH:49]=[CH:48][CH:47]=3)=[C:18]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[S:25]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 189 (1)) (1.38 g, 3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in tetrahydrofuran (20 ml). To the obtained mixture were added triethylamine (0.84 ml, 6 mmol) and 9-fluorenylmethylchloroformate (1.16 g, 4.5 mmol) and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl [6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (1.52 g, 86.9%) as an amorphous.
Reaction SMILES: ICC.ClCC1CC1.[CH3:9][N:10]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]1=[O:29].[Br:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:41][CH2:42][CH3:43]>>[Br:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:41][CH2:42][CH3:43].[CH2:42]([O:41][C:32]1[CH:33]=[CH:34][C:35]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:36][C:31]=1[C:18]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](=[O:29])[N:10]([CH3:9])[CH:19]=1)[CH3:43]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Agent: CCOc1ccc(S(C)(=O)=O)cc1Br
Agent: ClCC1CC1
Solvent: CCI
Product: CCOc1ccc(S(C)(=O)=O)cc1-c1cn(C)c(=O)c2c1CCCC2

Procedure:
2-bromo-1-ethoxy-4-methanesulfonylbenzene was prepared in a similar manner as Example 46, step 1 except that iodoethane was substituted for (chloromethyl)cyclopropane. The title compound of Example 163, step 3 and 2-bromo-1-ethoxy-4-methanesulfonylbenzene were reacted in a similar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 7.92 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.59 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.18 (m, 2H), 1.65-1.61 (m, 4H), 1.45-1.02 (t, J=7.2 Hz, 3H). LCMS: 362.0 (M+H)+