Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.264 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (66 mg, 0.395 mmol). The product was collected as a white solid (33 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.64 (d, J=2.27 Hz, 1H) 8.60 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.02-8.06 (m, 2H) 7.84 (s, 1H) 6.77 (d, J=8.84 Hz, 1H) 5.89 (s, 1H) 5.13 (dt, J=13.14, 6.57 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.09 (s, 6H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H) LC-MS (ES) m/z=459.2 [M+H]+
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O.C1COCC1>O>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: NC(=O)Cc1nc(N2CCNC3(CC3)C2)cc2ccccc12
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Reaction time: 1.5 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide (4.95 g, 16.70 mmol) and (7-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (5.44 g, 25.05 mmol) are azeotroped twice with dry THF. Dry THF (100 ml) is then added, and under an atmosphere of argon KOtBu (1.0 M in THF, 50 ml, 50 mmol) is added dropwise during 20 min. After an additional 90 min, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with H2O and extracted twice with EtOAc. The combined organic layers are washed twice with saturated aq NH4Cl solution (back extracted), dried over Na2SO4 and concentrated. Purification by FCC(CH2Cl2/MeOH 100:0 to 98:2 to 96:4 to 94:6 to 92:8 to 90:10) yields the title compound, which is converted to its acetate salt by concentration of a EtOH/AcOH solution. 1H NMR (DMSO, 400 MHz) δ 0.26-053 (br, 4H), 1.89 (s, 3H, CH3COOH), 2.36 (s, 3H), 2.80 (br m, 2H), 3.15-3.48 (br m, 2H), 6.14 (d, J=8.2 HZ, 1H), 6.44 (dd, J=8.2/7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 7.00 (s, 1H), 7.02 (dd, J=8.2/8.2 Hz, 1H), 7.40 (dd, J=8.2/8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.97 (d, J=2.9 Hz, 1H), 11.04-11.21 (br, 1H), 11.86 (d, J=2.9 Hz, 1H); ES-MS: 464 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26](ON1C(=O)CCC1=O)=[O:27])=[O:22])([O-:17])=[O:16].Cl>O.O1CCCC1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26]([NH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:27])=[O:22])([O-:17])=[O:16]
Reactant: O=C(C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.65 g of (S)-3-amino-3-phenylpropionic acid were suspended in 70 ml of water, the pH of the suspension was adjusted to 10.5-11 by adding sodium hydroxide solution, and 70 ml of tetrahydrofuran were added. The mixture was cooled to 0-5° C. in an icebath and 13 g of 2,5-dioxopyrrolidin-1-yl(S)-3-(3,5-dinitrobenzamido)-3-phenylpropionate were added in portions with stirring over a period of 15 min. On completion of addition, the pH of the reaction mixture was kept between 9-9.5 by adding sodium hydroxide solution. On attainment of a constant pH with virtually full conversion (HPLC monitoring; <0.5 area % of reactant), the solution was diluted to a volume of about 800 ml with water, a pH of 1.5-2 was established by addling 4 N hydrochloric acid and the mixture was stirred for a further 30 min. The solid was filtered off with suction, washed with water and dried at 50° C. under reduced pressure. The dried solid was digested in 250 ml of tetrahydrofuran at 40° C. for 20 min, the suspension was cooled and the solid (product fraction 1) was filtered off with suction. The mother liquor was concentrated at a water bath temperature of 40° C. to a volume of about 70-80 ml, the resulting suspension was cooled to room temperature, and the solid (product fraction 2) filtered off with suction. The product fractions were combined and dried at 50° C. under reduced pressure. The yield was 11.1 g; HPLC purity >99.5 area %; 1H NMR (DMSO) δ (ppm): 2.64 (d, 2H), 2.77 (m, 2H), 5.15 (m, 1H), 5.52 (m, 1H), 7.10-7.20 (m, 5H), 7.25 (t, 1H), 7.31 (t, 2H), 7.39 (d, 2H), 8.44 (d, 1H), 8.95 (m, 1H), 9.01 (m, 2H), 9.53 (d, 1H), 12.17 (s, 1H, CO2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1>[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:2][OH:3])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 80.2 %

Procedure:
Hydroxylamine hydrochloride (6.55 g, 94.3 mmol) was added to a pyridine (30 mL) solution of 1-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone (10 g, 31.4 mmol). The solution was stirred a reflux (4 h). The pyridine was evaporated and 150 mL of an aqueous solution of citric acid (10%) and CH2Cl2 (100 mL) were added to the residue and the organic layer was extracted. The aqueous layer was washed 2 times with CH2Cl2 (2×100 mL). Finally, the organic layers were combined and concentrated in vacuum. The residue was purified by silica gel flash chromatography (MPLC) to obtain 8.4 g of a white solid. Rf=0.31 (1/9 EtOAc/hexanes); mp 63-65° C.; 1H NMR (CDCl3): δ 0.12 (s, (CH3)2Si), 0.96 (s, CH3)3C), 4.73 (s, CH2), 7.44 (d, J=8.2 Hz, C6H4), 7.50 (d, J=8.2 Hz, C6H4), 8.61 (s, OH); 13C NMR (CDCl3): δ −5.3 (CH3Si), 18.4 (C(CH3)3), 25.9 (C(CH3)3), 64.4 (CH2O), 120.6 (q, J=273.2 Hz, CF3), 124.4 (C6H2), 125.9 (C6H2), 128.6 (C6H2), 144.2, (C6H2), 147.9 (q, J=32.1 Hz, CN).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:13]Br>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)C1CCC(=O)C(Br)C1

Procedure:
To a 1 l. three-necked flask provided with a stirrer, condenser and dropping funnel and containing a solution of 25.5 g. of 4-ketocyclohexanecarboxylic acid ethyl ester in 450 ml. of anhydrous ether cooled to -10° was added dropwise over 45 minutes 24 g. of bromine. The resulting colorless solution was washed with 3×100 ml. of water, then with 2×50 ml. of 5% sodium bicarbonate solution and finally with 2×100 ml. of water. The ether solution was dried over anhydrous magnesium sulfate and then the solvent was removed on a steam bath. The yield of crude 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester was 37 g.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:31]2[CH2:32][CH2:33][N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[C:30]2=[O:34])=[CH:12][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-fluorobenzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 364.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCCCCCBr
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCCBr)c(Cl)c1Cl

Procedure:
The title compound is prepared following substantially the same procedure described in Example 13, Step A, using the following substances: 2,3-dichloroanisole (89 g., 0.5 mole), 7-bromoheptanoyl chloride (127 g., 0.56 mole), aluminum chloride (74 g., 0.56 mole) and methylene chloride (500 ml.). This procedure affords 107 g. (58%) of 2,3-dichloro-4-(7-bromoheptanoyl)anisole which after recrystallization from the cyclohexane melts at 57°C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=359.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH:18]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH2:19]([NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([F:40])[CH:26]=1)=[O:23])[CH3:20]>>[CH2:19]([NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)=[C:27]([F:40])[CH:26]=1)=[O:23])[CH3:20]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)c(F)c1
Yield: 4 %

Procedure:
Method as described for example 147 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) as starting materials. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic fit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at low pH to afford a yellow solid (8.4 mg, 0.02 mmol, 4%).
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26][C:27]([NH:29]C(=O)C3C=CC=CC=3)=[S:28])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH2:1]([N:6]1[CH2:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26][C:27]([NH2:29])=[S:28])[CH2:12]2)[CH2:10][CH2:11]1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(=S)NC(=O)c1ccccc1)c1ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(N)=S)c1ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A mixture of 20g (138 mg, 0.27 mmol) and 1 N LiOH (0.5 mL) in THF/MeOH (2:1, 3 mL) was stirred at 50° C. for 2 h. The reaction was concentrated and the residue was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, concentrated and purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give 20h as yellow solid (83 mg). LC-MS m/z 409.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1c(F)cccc1F
Yield: 44.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 2,6-difluorobenzenesulfonyl chloride (170 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (100 mg, 45%) after purification by column chromatography with DCM as the eluent followed by trituration from EtOAc/n-hexane.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Reactant: Nc1n[nH]c2c(F)cccc12
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4cnccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; 1H NMR (DMSO, 500 MHz): δ12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.70-7.35 (5H, m), 7.25(1H, m), 6.95 (1H, m),; MS (m/z), MH+ 391.08.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(Oc3ccc(C#N)cc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromobenzonitrile, whereby the product was isolated as free base, 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-benzonitrile as a white solid. ISP mass spectrum, m/e 330.5 (M+1 calculated for C21H19N3O: 330).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.Cl.[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:15]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc(CNCc3ccccc3)cc2)cc1Br
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(Cc3ccccc3)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in step 1 of Example 9, in 60 mL of methylene chloride was added under nitrogen dropwise over 15 minutes to a solution of the HCl salt of N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]amine (5.0 g, 11.9 mmol), prepared in step 2 of Example 11, and triethylamine (4.6 mL, 33 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 16 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (6.1 g, 95%) as a white solid, MS (ESI) m/z 539 [M+H]+. Elemental Analysis for C31H27BrN2O2: Calc'd: C, 69.02; H, 5.04; N, 5.19; Found: C, 68.55; H, 5.32; N, 4.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 25.2 %

Procedure:
The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (44 mg; 0.204 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 15.2 mg (0.026 mmol; 25.2% yield) of the desired compound were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8])(=[O:18])=[O:17]
Reactant: O=Cc1scnc1Cl
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: O=Cc1scnc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 42a using 4-chlorothiazole-5-carbaldehyde and pyridine-2-sulfinate sodium salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[CH2:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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>[O:20]1[C:16]2[CH:15]=[C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)[CH:22]=[CH:21][C:17]=2[CH2:18][CH2:19]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)ccc2C)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
A mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide (50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.26 mg, 0.15 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0076 mmol) in 1,2-dimethoxyethane (1.5 mL) and 2 M Na2CO3 (0.3 mL) was stirred at 80° C. for 16 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 30 mg (49%) of 1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.2. found 402.0 (M+1)+. Retention time 1.83 minutes.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].F[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[CH2:7]([O:14][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:28])[F:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (20.7 g) in N,N-dimethylformamide (120 ml) was added n-heptanol (15.6 ml), and the mixture was stirred at room temperature for 30 min. A solution of 4-fluoro-3-trifluoromethylbenzoic acid (16.7 g) in N,N-dimethylformamide (60 ml) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was ice-cooled, water (320 ml) was added, and 6M-hydrochloric acid (40 ml) was added at room temperature. The mixture was stirred at room temperature for 30 min and precipitated crystals were collected by filtration. The crystals were dissolved in ethanol (60 ml) at 70° C., water (96 ml) was added dropwise at the same temperature and the mixture was stirred for 30 min. The mixture was allowed to cool to room temperature, and stirred for 30 min under ice-cooling. The precipitated crystals were collected by filtration to give the object product (24.1 g) as pale-brown crystals.