Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10](=[O:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(=O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of [benzhydryl-(2-oxobutyl)amino]acetic acid tert-butyl ester (7.4 g, 20.1 mmol, 1 eq.) in dry MeOH:THF (100 mL, 1:1) at −23° C., was added CeCl3.7H2O (1.43 g, 3.83 mmol, 0.19 eq.). The reaction mixture was stirred until homogeneous, then NaBH4 (0.57 g, 15.1 mmol, 0.75 eq.) was added slowly (in small portions). The reaction was stirred for additional 20 min, then poured onto brine. This mixture was extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo to afford [benzhydryl-(2-hydroxybutyl)amino]acetic acid tert-butyl ester in quantative yield. This was used without further purification. ESMS: m/z 370.4 [M+H].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (0.020 g, 0.064 mmol) and ammonium acetate (49 mg, 0.64 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction was heated at 65° C. for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (20 mg, 100%). LCMS calculated for C17H14ClFN3 (M+H)+: m/z=314.1. found: 313.9.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]1[C@H:27]([CH3:28])[CH2:26][NH:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[NH2:22][C@H:23]1[C@H:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C[C@@H]1CNC[C@H]1N
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1N

Procedure:
In the same manner as described in Example 5, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino4-methylpyrrolidine, and xylene was refluxed for 3 hours to give 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline3-carboxylic acid, m.p. 255°-256° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:40](=O)(O)[O-:41].[Na+].C(Cl)(Cl)=O>C(Cl)Cl>[N:1]([C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5])=[C:40]=[O:41]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A 50 mL round bottomed flask was charged with 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (500 mg, 0.926 mmol), methylene chloride (10 mL) and saturated sodium bicarbonate solution (10 mL). The solution was cooled in an ice-water bath for 5 min. Phosgene (2.5 mL, 20% w/w solution in toluene) was added to the mixture. The solution was stirred rapidly for 30 minutes. The ice-bath was removed, and the reaction mixture was stirred for an additional 30 minutes. The layers were separated and the aqueous layer was extracted twice with methyllene chloride. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. The residue was triturated with anhydrous ether to give 457 mg (081 mmol, 87%) of 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide, which was used directly without any further purification or characterization in the subsequent step.
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[C:3]1[CH:20]=[N:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[N:4]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[Br:24][C:20]1[C:3]([N:2]([CH3:1])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Solvent: O
Product: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl 3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (1.0 g), N-bromosuccinimide (608 mg) and acetonitrile (20 mL) was stirred at room temperature for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 3→30% ethyl acetate/hexane) to give the title compound (915 mg, 74%) as a colorless oil.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16].O>ClCCl>[CH:1]([NH:14][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzhydrylamine (1.83 g) was dissolved in dichloromethane (3.0 ml). Carbonyldiimidazole (1.78 g) was added to the solution. The mixture was stirred at room temperature overnight. Water and dichloromethane were added thereto. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation to give imidazole-1-carboxylic acid benzhydrylamide.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1SC2C=CC=C(Cl)C=2N=1.[OH-].[Na+].O.[CH2:26]([OH:30])[CH:27]([CH3:29])[CH3:28]>>[CH2:26]([O:30][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: Clc1cccc2sc(Br)nc12
Reactant: CC(C)CO
Agent: Clc1nc2c(Cl)cccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COc1nc2c(Cl)cccc2s1
Yield: 96.8 %

Procedure:
A mixture (11.30 g, 0.05 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 94% sodium hydroxide (2.34 g, 0.055 mole) in isobutanol (100 c.c.) was heated under reflux for 1 hour. Water was added and the alcohol was distilled azeotropically together with water. The resulting oily substance was extracted with chloroform, and the chloroform layer was washed with water. The solvent was then removed under reduced pressure to obtain 11.70 g of 2-isobutoxy-4-chlorobenzothiazole as a yellow viscous liquid. Yield 96.8%, purity 97.2%, b.p. 103.5°-105° C./0.15 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:23](O)(=[O:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[S:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:8]2[N:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:25])[CH3:24])=[CH:3][CH:4]=3)[N:9]=2)=[CH:18][CH:17]=1)(=[O:21])(=[O:20])[NH2:22]
Reactant: CC(=O)O
Reactant: Nc1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(7-aminoquinazolin-2-ylamino]-benzenesulfonamide (1 eq) (For synthesis see example 43) in THF was added acetic acid (5 eq), HBTU (4 eq) and DIEA (10 eq). The reaction mixture was stirred at room temperature for 48 h. The reaction does not go to completion. Diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. Filtered, concentrated and purified by semi-prep HPLC to provide N-(2-(4-sulfamoylphenylamino) quinazolin-7-yl)acetamide ES/MS m/z 358.0 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([CH2:12][CH:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15](OC)=[N:14]3)[CH2:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:26].[NH4+:27]>>[ClH:26].[C:1]1([N:7]2[CH:11]([CH2:12][CH:13]3[NH:14][C:15](=[NH:27])[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CC2CC(C(F)(F)F)=NN2c2ccccc2)CCCC1
Product: Cl
Product: N=C1CCCCC(CC2CC(C(F)(F)F)=NN2c2ccccc2)N1

Procedure:
The title product of Example 133 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [S:1]([Cl:3])Cl.N1C=C[CH:7]=[CH:6][CH:5]=1.[NH:10]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([O-:14])=[O:13]>C(Cl)(Cl)(Cl)Cl>[CH:19]([O:18][C:16]([CH2:15][N:10]([CH2:11][C:12]([O:14][CH:6]([CH3:7])[CH3:5])=[O:13])[S:1][Cl:3])=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)OC(=O)CNCC(=O)[O-]
Reactant: ClSCl
Reactant: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)CN(CC(=O)OC(C)C)SCl
Reaction time: 1 h

Procedure:
2.1 g (0.02 mole) of sulfur dichloride was dissolved in 35 ml of carbon tetrachloride, and 1.6 g (0.02 mole) of pyridine was dropwise added to the resulting solution at 0° to 5° C. After completion of the dropwise addition, 4.3 g (0.02 mole) of isopropyl iminodiacetate was further dropwise added thereto at 10° to 20° C., and the resulting mixture was stirred for one hour at the same temperature. After completion of the reaction, crystals were filtered off, and the mother liquor was concentrated under reduced pressure to obtain an oily product. Yield: 5.5 g (97%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1.[C:35]([O:39][C:40](=[O:54])[CH2:41][CH2:42][S:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[NH:28][C:48]([C:47]2[CH:46]=[C:45]([CH:53]=[CH:52][CH:51]=2)[CH2:44][S:43][CH2:42][CH2:41][C:40]([O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:54])=[O:49])[CH:10]=1)=[O:29]
Reactant: Nc1ccc(OC2CCOCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(tetrahydro-2H-pyran-4-yloxy)phenyl)isonicotinamide (270 mg, 0.52 mmol, 1.00 equiv, 90%) in dichloromethane (10 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (339 mg, 0.92 mmol, 2.00 equiv, 80%), EDC HCl (220 mg, 1.15 mmol, 2.00 equiv), and 4-dimethylaminopyridine (140 mg, 1.15 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 150 mL of dichloromethane and was washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1)˜dichloromethane:methanol (20:1). The product was obtained as 190 mg (42%) of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Reactant: C1CCNCC1
Product: COC(=O)[C@H](CCN1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97 %

Procedure:
(S)-4-Bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (0.10 g, 0.34 mmol) (prepared as in Example 120, Steps A-D) and piperidine (1 mL) were heated to 50° C. for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3×10 mL) and then chromatographed eluting with MeOH/dichloromethane (1:9) to provide 93 mg of colorless oil (97% yield).
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Reactant: NNc1cccc(Cl)c1
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1cccc(Cl)c1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 3-chlorophenylhydrazine.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>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>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=1
Reactant: C#Cc1cccc(O)c1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.7 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 986 mg (8.4 mmol) 3-ethynyl-phenol using 106 mg (0.56 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 8 mL (55 mmol) triethylamine in 12 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel (DCM/MeOH gradient) and subsequently RP-HPLC (ACN/H2O gradient). Yield: 419 mg (29%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH2:15].C1COCC1>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: CN
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromoisatoic anhydride (4.84 g, 20.0 mmol) in THF (20 mL) was added 2M MeNH2/THF (15 mL, 30 mmol). The resulting mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the crude material was used in next step without further purification. MS (ESI): m/z=229.03/231.06 [M+H]+. HPLC: tR=3.14 min (ZQ3: polar—5 min).
Reaction SMILES: F[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:25])[CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][CH2:23][CH3:24])[CH2:17][CH2:16]1)[CH3:11].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH2:23]([N:22]([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:25])[CH2:16][CH2:17]1)[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: O=Cc1ncccc1F
Reactant: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2C=O)CC1

Procedure:
A mixture of 3-fluoropyridine-2-carbaldehyde (122.7 mg, 0.981 mmol), ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate (202.7 mg, 0.892 mmol), potassium carbonate (369.7 mg, 2.67 mmol) and dry toluene (13 mL) was heated at reflux under N2 overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-50% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[ethyl(2-formylpyridin-3-yl)amino]methyl}cyclohexyl)acetate as a yellow oil. Rf=0.79 (50% EtOAc/hexanes). LCMS calc.=333.2; found=333.3 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 10.13 (s, 1 H); 8.29 (d, J=4.1 Hz, 1 H); 7.41 (d, J=8.5 Hz, 1 H); 7.29 (dd, J=4.1, 8.4 Hz, 1 H); 4.08 (q, J=7.1 Hz, 2 H); 3.26 (q, J=7.0 Hz, 2 H); 3.05 (d, J=7.1 Hz, 2 H); 2.12 (d, J=6.9 Hz, 2 H); 1.71 (m, 4 H); 1.66 (m, 1 H); 1.41 (m, 1 H); 1.22-1.20 (t, J=7.1 Hz, 3 H); 1.06 (t, J=7.1 Hz, 3 H); 0.91-0.82 (m, 4 H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH3:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Temperature: 120 °C

Procedure:
Prepared according to procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.173 mmol), 3,5-dimethylbenzeneboronic acid (326 mg, 2.173 mmol), sodium carbonate (1.15 g, 10.87 mmol) and Pd(PPh3)4 (251 mg, 0.217 mmol) in toluene/water (4 mL:1 mL) and heating in the microwave for 90 min at 120° C. After purification 4-chloro-2-(3,5-dimethylphenyl)-7-fluoro-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=300 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC.C(=O)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][C:7]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:8])=[O:5]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)N=C=O
Reactant: CC(C)N
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)NC(=O)NC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) was dissolved in 40 mL toluene and isopropyl amine (1 g) added over a period of 30 seconds. After stirring 30 min, the solvent was removed to yield an oil. The oil was dissolved in hexane and cooled in dry ice to yield 1.2 g of crystals of the title compound. m.p. 113°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[NH2:12].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:20][CH2:19][N:17]([CH3:18])[CH2:16][CH2:15]1
Reactant: CN(CCCl)CCCl
Reactant: Cn1nc(N)c2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2nn(C)c3ccc(Br)cc23)CC1
Temperature: 100 °C

Procedure:
A vessel was charged with 5-bromo-1-methyl-1H-indazol-3-amine (250 mg, 1.10 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (230 mg, 1.21 mmol), H2O (250 μL), K2CO3 (500 mg, 3.63 mmol), and DMF (2.5 mL). The vessel was sealed and heated to 100° C. for 18 h. The reaction was poured into EtOAc and washed with 5% w/v aq LiCl (3×), dried (Na2SO4), filtered, and concentrated. The residue was treated with DCM and purification by flash column chromatography on silica gel (hexanes/ethyl acetate to remove side products; then DCM/MeOH eluent to elute product) provided 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole. LCMS-ESI+: calc'd for C13H17BrN4: 309.1, 311.1 (M+H+); Found: 309.2, 311.2 (M+H+).
Reaction SMILES: C1C2[C:10]3=[CH:12]C4C=CC(C(O)=O)=[CH:17][C:18]=4[N:9]3[CH2:8]C=CC=2C=CC=1.C1(C2C3C(=CC(C([O-])=O)=CC=3)[NH:30]C=2C2C=CC(OC)=CC=2C=O)CCCCC1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:68]([S:70]([O:73]C1C=CC=CC=1)(=O)=[O:71])=[CH2:69]>O1CCOCC1>[CH3:8][N:9]1[CH2:10][CH2:12][N:30]([S:70]([CH:68]=[CH2:69])(=[O:73])=[O:71])[CH2:17][CH2:18]1
Reactant: COc1ccc(-c2[nH]c3cc(C(=O)[O-])ccc3c2C2CCCCC2)c(C=O)c1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: C=CS(=O)(=O)Oc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1COCCO1
Product: C=CS(=O)(=O)N1CCN(C)CC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-(phenoxysulfonyl)-,1,1-dimethylethyl ester. To a solution of tbutyl 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (4.40 g, 11.2 mmol) in dioxane (30.0 mL) and BEMP (4.88 mL, 16.9 mmol) was added phenyl vinylsulfonate (4.14 g, 22.5 mmol). The resulting mixture was stirred at 22° C. for 1 hr and then at 110° C. in a sealed tube in a microwave for 15 min. The resulting mixture was concentrated under reduced pressure. Silica gel chromatography (1:1 EtOAc:hexanes) of the concentrate afforded the title compound (3.49 g, 52%) as a yellow oil. MS m/z 600 (MH+), ret time 3.11 min, column B, 4 minute gradient, flow rate 4 mL/min.