Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:12]=2[N:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49]>>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:18]=2)=[O:21])[CH:52]=[CH:51][CH:50]=1)#[N:49]
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reactant: N#Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: N#Cc1cccc(NC(=O)c2ccc3[nH]c(Nc4c(Cl)cccc4Cl)nc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid (32 mg, 0.1 mmol) in DMF TEA (50 μL, 0.36 mmol) and TBTU (32.1 mg, 0.1 mmol) were added, followed by 3-amino-benzonitrile (11.8 mg, 0.1 mmol). After shaking overnight at room temperature, the solvent was removed i.vac. and the residue purified by preparative reverse phase chromatography (gradient H2O/AcCN=90:10 to 35:65; both solvents containing 0.1% TFA).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.B>C1COCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Product: c1cncc(CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
1-Boc-4-[(3-pyridinyl)acetyl]piperazine (8.0 g, 26.2 mmol) was added to a solution of borane.ThF (2.0 M in THF, 39.5 mL, 78.6 mmol) in THF (200 mL) at 0° C. The mixture was heated to reflux for 8 h and cooled to room temperature. The excess borane was quenched with methanol and 3 N HCl. The mixture stirred for 3 h at room temperature, and the solvents were removed under vacuum. The crude product was purified by chromatography (SiO2, 4:1 CH2Cl2:CMA) to provide 1-[2-(3-pyridinyl)ethyl]piperazine (2.82 g, 36%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C@H:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C@@H:9]([CH3:10])[O:11][C:21]2=[O:22])=[CH:12][CH:13]=1
Reactant: C[C@@H](O)CNCc1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
(R)-1-(4-bromobenzylamino)propan-2-ol (5F2) (0.034 mol, 8.2 g) was dissolved in THF (150 ml) and triethylamine (0.051 mol, 5.12 g) was added, followed by carbonyldiimidazole (0.037 mol, 6.0 g). The mixture was stirred at room temperature for 2 hours then heated to reflux for 20 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organics were washed with water and brine before drying over sodium sulphate. The crude mixture was purified on silica eluting with 35% EtOAc/Petroleum Ether to give (R)-3-(4-bromobenzyl)-5-methyloxazolidin-2-one (5F3) 6.7 g (74%); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H) 7.16 (d, 2H) 4.62 (m, 1H) 4.41-4.32 (m, 2H) 3.49 (m, 1H) 2.95 (m, 1H) 1.39 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([F:26])[CH:5]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([F:26])[CH:5]=1
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)c(F)c1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A mixture of 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-3-fluoro-benzoic acid methyl ester (160 mg, 0.44 mmol) and 10% palladium on activated carbon (75 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-3-fluoro-benzoic acid methyl ester (140 mg, 87%) as a solid which was used in the next step without further purification: LC/MS m/e calcd for C22H23FN2O2 [M+H]+ 367.4, observed 367.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:33]=1[C:34](Cl)=[O:35]>C1COCC1>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:33]=1[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:35]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine (92 mg, 0.23 mmol) in 2 mL of THF, added 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.27 mmol). The reaction was stirred for 30 min at rt and quenched by addition of polystyrene-trisamine resin (20 mg). The reaction was allowed to stir overnight. The reaction was treated with excess Et3N, filtered, and washed with THF. The filtrate was collected, reduced in vacuo, and upon treatment with DCM, a white solid formed. Filtration and washing with the solid with Et2O yielded the desired product as a white solid, 96 mg, 65% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.89 (s, 1H); 9.78 (s, 1H); 8.84 (d, J=6 Hz, 1H); 8.30 (d, J=5 Hz, 1H); 8.00 (s, 1H); 7.77-7.23 (m, 2H); 7.55-7.33 (m, 7H); 7.22 (q, J=8 Hz, 1H); 7.11 (t, J=7 Hz, 1H); 6.69 (td, J=2, 8 Hz, 1H); 6.60 (d, J=5 Hz, 1H). HRMS calculated C30H20ClF2N6O [M+H]+ 553.1355, found 553.1360.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].N1C=CC=CC=1.O1CCOCC1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:25]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: O=C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 25 °C

Procedure:
In a 3-L flask equipped with a stirrer and thermometer, 100 g (613 mmol) of N-hydroxyphthalimide, 53.3 g (674 mmol) of pyridine and 1100 g of 1,4-dioxane were placed and were stirred at room temperature. To the resulting mixture, 94.8 g (674 mmol) of benzoyl chloride was added dropwise over 1 hour, and the resulting mixture was stirred at room temperature for further 2 hours. Subsequently, 1100 g of pure water was added dropwise over 30 minutes to dissolve by-produced salts and thereby yielded a crystal of the target N-benzoyloxyphthalimide. The mixture was stirred and aged for further 1 hour, the crystal was filtrated using a Nutsche, was rinsed with an appropriate amount of water, was dried at 60° C. under a reduced pressure and thereby yielded 162 g (604 mmol) of N-benzoyloxyphthalimide in a yield of 98.6% on the basis of N-hydroxyphthalimide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.OB(O)[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37].C(=O)([O-])[O-].[K+].[K+].COCCOC>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:41]=[CH:40][CH:39]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(-c5cccc(C(=O)O)c5)c4)n3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 64.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (25 mg, 0.05 mmol), 3-(dihydroxyboryl)benzoic acid (10.6 mg, 0.06 mmol), tetrakis(triphenylphosphine) palladium (0) (3.1 mg, 0.003 mmol) and potassium carbonate (11.0 mg, 0.08 mmol) was added DME (0.9 mL) and distilled water (0.3 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 110° C. for 20 minutes. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in dichloromethane and methanol, and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using dichloromethane:methanol (100:0) to (80:20) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give a solid that was suspended in dichloromethane and vacuum filtered to give 3′-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}-1,1′-biphenyl-3-carboxylic acid (0.0164 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.57-8.53 (m, 2H), 8.21 (s, 1H), 7.95-7.92 (m, 2H), 7.78 (d, J=6.2 Hz, 1H), 7.62-7.55 (m, 2H), 7.07 (s, 2H), 3.63 (s, 6H), 3.58 (s, 3H), 2.55 (s, 3H). MS m/z 512 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccncc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(4-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (867 mg, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH:14]1[C:19]([C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21])=[CH:18][CH:17]=[C:16]([F:26])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)C.O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:24][CH2:23][CH2:22][C:20](=[O:21])[C:19]2[CH:14]=[CH:15][C:16]([F:26])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2CCCN2)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Yield: 27.2 %

Procedure:
Boil 4 g of 2-(4-chlorobenzyl)pyrrolidine, 6.8 g of ω-chloro-4-fluorobutyrophenone, 4.2 g of potassium carbonate and 20 ml of methyl ethyl ketone under reflux for 68 hours. After cooling the resulting reaction mixture to ambient temperature, add 50 ml of water and 50 ml of diethyl ether. Collect the ether phase and dry it over sodium sulfate. Concentrate the dried ether phase to a brown oil before distilling it under a high vacuum to obtain 2.0 g of the title compound as viscous light-brown oil of b.p. 188° to 192° at 0.02 mm of Hg.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]12([NH2:14])[CH2:13][CH:11]([CH2:12]1)[CH2:10]2.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>CN(C=O)C>[C:9]12([NH:14][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[O:16])[CH2:13][CH:11]([CH2:12]1)[CH2:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC12CC(C1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC12CC(C1)C2)n1ccnc1

Procedure:
Triethylamine (0.1 mL, 0.5 mmol) was added to a solution of bicyclo[1.1.1]-pentan-1-amine hydrogen chloride (19 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole (32 mg, 0.192 mmol) in DMF (2 mL) (clear solution turned into suspension). The suspension was used for the synthesis of compound 1 without further isolation of compound 1b.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([CH3:10])=[N:8][CH:9]=1.CCN(CC)CC.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>CCOC(C)=O.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.[Cu]I>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A 12 L reactor equipped with an overhead stirrer and N2 bubbler was charged with a solution of 5-bromo-2-methyl-3-nitropyridine (945 g, 4.35 mol) in EtOAc (5.7 L, 6 vol). To the reaction mixture, Pd(PPh3)2Cl2 (15.4 g, 0.022 mol, 0.005 equiv), CuI (8.28 g, 0.0435 mol, 0.01 equiv) and Et3N (3 L, 21.75 mol, 5 equiv) were added. Nitrogen was bubbled through the solution for 15 min and 3-dimethylamino-1-propyne (556 mL, 5.22 mol, 1.2 equiv) was added. The reaction-temperature setting was increased to 60° C. stepwise. The maximum temperature attained was 66° C. The reaction was continued for 3 h at this temperature (60° C.) and was judged complete by HPLC analysis. The reaction was cooled to ambient temperature and the inorganic salts were filtered off by passing the reaction mixture through a pad of celite. The filter cake was washed with EtOAc (2 L, 2 vol). The filtrate was transferred into a 20 L separatory funnel. The EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol). The layers were separated. The EtOAc layer was then washed with 10% brine in water (5 L, 5 vol). The layers were separated and the EtOAc layer was pumped down to a low volume (ca. 2 L, 2 vol) under reduced pressure. IPA (5 L, 5 vol) was added to the solution and the solvent was again evaporated to a low volume (ca. 2 L, 2 vol). The solution of N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl-1-amine was subjected to hydrogenation in two batches using the procedure described in step 2, below,
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH:27]=O)=[CH:24][CH:23]=[CH:22][CH:21]=2>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH3:17])(=[O:5])=[O:4]
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: Cc1[nH]c2ccccc2c1C=C1C(=O)Nc2ccc(S(=O)(=O)N(C)C)cc21

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Yield: 92.8 %

Procedure:
The synthetic intermediate of Example 1, namely 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (105 mg, 0.25 mmol) and potassium carbonate (103 mg, 0.75 mmol) were suspended in acetone (3 mL). Ethyl bromoacetate (0.08 mL, 0.75 mmol) was added to the suspension while cooling with ice. The suspension was allowed to room temperature, and refluxed while heating for 6 hours. Insolubles were filtered, and washed with acetone. Subsequently, the solvent was distilled off. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (7/1-4/1) to give the subject compound (117 mg) as colorless oil (yield 92%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)=[O:25].[ClH:38].O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:1].[ClH:38].[NH2:29][CH2:28][CH2:27][NH:26][C:24]([NH:23][C:15]1[CH:16]=[CH:17][C:18]2[NH:19][C:20]3[N:21]=[C:5]([NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]([CH:37]=4)[CH2:12][CH2:13][C:14]=1[CH:22]=2)[N:4]=[CH:3][C:2]=3[Cl:1])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: NCCNC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}carbamate (326 mg, 0.622 mmol) in DCM (12 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.544 mL, 2.18 mmol). After stirring overnight, the reaction solution was diluted with ether. The resulting precipitate was filtered and dried under vacuum to give the desired product (245 mg, 79%). LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][C:16]([CH3:21])([C:19]#[N:20])[C:17]#[N:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:14][CH2:15][C:16]([CH3:21])([CH2:19][NH2:20])[CH2:17][NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C#N)(C#N)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CN)(CN)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
LiAlH4 (3.22 g; 84.84 mmol; 3.0 equiv.) was suspended in 30 mL dry diethylether and cooled with an ice bath. A solution of 2-Benzyloxymethyl-2-methyl-malononitrile (5.72 g; 28.28 mmol; 1.0 equiv.) in 20 mL dry diethylether was added dropwise. The suspension was stirred at room temperature for 4 hours, and subsequently cooled with an ice bath. To this was added 3.22 mL H2O, 6.44 mL 2 M NaOH and 3.22 mL H2O. The precipitate was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to yield 5.47 g (84%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.84 (s, 3H), 2.59-2.69 (m, 4H) 3.29 (s, 2H), 4.49 (s, 2H), 7.24-7.39 (m, 5H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[C:13](Cl)[N:12]=1>O=P(Cl)(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[N:17]=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][C:15]=2[N:16]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: O=C(O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc2nc(-c3ccccc3)oc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.82 g (64.0 mmol) benzoic acid and 20 mL POCl3 are stirred together at 100° C. for 30 min. Within 45 min 7.00 g (42.7 mmol) 2,6-dichloro-5-aminopyrimidine are added by several portions. The reaction mixture is stirred for additional 2 h at the same temperature. After that the mixture is carefully added to an ice cold aq. NaOH solution. The resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1)[OH:32])[CH3:26].Cl>C1COCC1>[CH2:25]([N:27]([C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=1)[OH:32])[CH3:26]
Reactant: O=C(O)CC1CCCC1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CC1CCCC1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A stirred solution of cyclopentylacetic acid (2 ml, 0.0159 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (120 ml) was cooled to -8° C. and treated, dropwise with isobutyl chloroformate (2.12 ml, 0.0163 mol). The mixture was kept at -8° C. for 1.5 hour and then treated with a mixture of the product from Example 7, Step II, (4.0 g, 0.014 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (160 ml). It was kept at -8° C. for 1.5 hour and then treated slowly with 1N HCl (158 ml). The product was extracted with EtOAc. The extract was washed successively with water, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5% MeOH--CH2Cl2 to give 3.0 g of N-(4-(4-(ethyl(cyclopentylacetyl)amino)-1-hydroxybutyl)phenyl)methanesulfonamide. The mass spectrum had m/z 396 (M+).