Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: Cc1ccccc1Nc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
From 2,6-dichloro-3-nitropyridine and o-toluidine, prepared in a similar manner as the one described in Example 1.127, Step A, the title compound was obtained. LCMS m/z=264.30 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(P(N(C)C)(N(C)C)=O)C.[H-].[Na+].[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[C:32]([NH2:38])=[N:33][CH:34]=[C:35](Br)[N:36]=1>CCOC(C)=O>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[C:32]([NH2:38])=[N:33][CH:34]=[C:35]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:36]=1
Reactant: Fc1cccc(S)c1
Reactant: Nc1ncc(Br)nc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ncc(Sc2cccc(F)c2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
3-Fluorobenzenethiol (70.49 mg, 46.47 μL, 0.55 mmol) was added to HMPA (1 mL) followed by the addition of sodium hydride (60% dispersion in mineral oil) (24 mg, 0.6 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes then 3-(1H-Benzimidazol-2-yl)-5-bromo-pyrazin-2-amine (80 mg, 0.27 mmol) was added and reaction heated at 110° C. under microwave conditions for 45 minutes. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water (×2), saturated aqueous NaHCO3 (×1) and brine. (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (10 mg, 11% Yield). 1H NMR (400.0 MHz, CDCl3) δ 76.95-7.0 (1H, m), 7.03-7.06 (1H, m), 7.1-7.13 (1H, m), 7.3-7.4 (2H, m), 7.50-7.55 (1H, m), 7.8-7.85 (1H, m), 8.22 (1H, s) and 10.2 (1H, br s) ppm; MS (ES+) 338.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[O:17][CH3:18].Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:24]3[N:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
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(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 95 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
A mixture of 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.637 g, 2.528 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.5 g, 1.873 mmol) and saturated aqueous NaHCO3 (10 ml) in 1,2-dimethoxyethane (25 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (0.169 g, 0.078 mmol) was added and the mixture was stirred under nitrogen at 95° C. for 17 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then filtered through glass fibre paper. The combined filtrates were partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane), to give 275 mg (47%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 4.00 (3H, s), 7.26 (1H, dd, J 10.9, 8.4 Hz), 7.61-7.64 (1H, m), 7.76 (1H, dd, J 2.1, 8.1 Hz), 8.58 (1H, s), 8.81 (1H, s).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution of the product of Example 2B (3.5 g, 5.5 mmol) in dichloromethane (40 mL) was treated with trifluoroacetic acid (20 mL), stirred at 25° C. for 1 hour, and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product (3.19 g).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[C:14]([NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNC(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
After dissolving 5 g of homoveratrylamine in 20 ml of pyridine, 5.6 g of acetic anhydride was added and reacted at 65°-70° C. with stirring for 2 hours. The reaction mixture was poured into 150 ml of ice water and then made weakly acidic by adding 50 ml of a 6N aqueous hydrochloric acid solution. The resultant solution was extracted three times with 50 ml of chloroform. The extracted solution was combined, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Ether was added to the residue and precipitated crystals were filtered. N-acetylhomoveratrylamine having a melting point of 101°-102° C. was obtained as colorless crystals. The yield was 5.7 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[C:4]([Cl:16])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:16][C:4]1[C:5]([S:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
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: C1COCCO1
Product: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine (200 mg, 0.71 mmol.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (172.0 mg, 0.781 mmol.), (PPh3)4Pd (437 mg, 0.07 mmol.), 2M Na2CO3 (1.0 ml, 2.13 mmol, 3.0 eq.) and dioxane (15.0 ml) was added to the reaction vessel which was flushed with argon. The reaction mixture was stirred at 90° C. for 12 hrs and then dried so that the solvent was evaporated. The reaction mixture was partitioned between EA and water. The organic layers were collected, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:2) to give a pale yellow solid of 102 mg (42.3%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OCc4ccccc4)c3)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(O)c3)nc2)cc1

Procedure:
8.00 g (23.40 mmol) of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine, 7.03 g (28.10 mmol) of 4-octyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid), 7.00 g (65.52 mmol) of sodiumcarbonate and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 200 ml of toluene, 100 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between water and ether, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane: ethyl acetate=98:2), giving 10.66 g of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR15## 10.66 g (22.84 mmol) of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine are hydrogenated together with 2.00 g of Pd (10%)/C in 100 ml of tetrahydrofuran until the calculated volume of hydrogen has been consumed, the catalyst is subsequently filtered off, and the filtrate is evaporated and dried, giving 8.43 g of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine.
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11].[C:14]([NH-:18])([CH3:17])([CH3:16])[CH3:15].[Li+]>O1CCCC1>[C:14]([NH:18][Si:2]([CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11])([CH3:13])[CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: CC(C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)NC(C)(C)C)C(C)=C1C
Reaction time: 2 h
Yield: 81 %

Procedure:
2,3,4,5-tetramethylcyclopenta-2,4-diene (3.67 g, 30 mmol) was added into a flask containing tetrahydrofuran (100 mL), n-butyl lithium (12 mL) was added in droplets thereto at 0° C., and the reaction temperature was gradually increased to room temperature so that the reaction was carried out for 8 hours. This solution was cooled to −78° C., dichloromethylsilane (3.87g, 30 mmol) was slowly added in droplets thereto, and then the reaction was carried out for 12 hours. After the reaction, the volatile material was removed, and the resultant product was extracted with hexane (100 mL), after which the volatile material was removed, thereby obtaining as pale yellow oil 5.5 g of (chloro) (dimethyl) (2,3,4,5-tetramethylcyclopentadienyl)silane. The (chloro)(dimethyl)(2,3,4,5-tetramethylcyclopentadienyl)silane thus obtained was dissolved in tetrahydrofuran (100 mL) without additional purification, after which lithium tert-butylamide (2.02 g) was added in droplets thereto at 0° C. and the reaction was carried out at room temperature for 2 hours. After the reaction, the volatile material was removed, and the resultant product was extracted with hexane (100 mL), thus obtaining as pale yellow oil 6.09 g (yield 81%) of (tert-butylamino) (2,3,4,5-tetramethylcyclopenta-2,4-dienyl)dimethylsilane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)nc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 55 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (586 mg) described in Preparation Example 53, the title compound (530 mg) was obtained.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]1([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([NH:16][CH2:15][CH2:14][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NCCN1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C1CCC(NCCN2CCOCC2)CC1
Temperature: 25 °C

Procedure:
Cyclohexanone (2.00 g, 20.4 mmol) and 2-morpholin-4-yl-ethylamine (2.98 mL, 20.4 mmol) were dissolved in 10 mL methanol. The solution was stirred at room temperature for an hour. NaBH3CN (1.62 g, 24.4 mmol) was slowly added portionwise in the solution. After the addition, the mixture was stirred at room temperature for 4 hour then concentrated under reduced pressure. To the residue was added 50 mL water and the mixture was adjusted to PH=10 with dilute aqueous KOH and extracted with ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo to give an oil. MS: 213(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (440 mg, 70%).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2([CH3:63])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][C:57]([N:54]4[CH2:53][CH2:52][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:56][CH2:55]4)([CH3:63])[CH2:58][CH2:59]3)=[O:40])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CN1CCN(C2(C)CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2(C)CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.10 mL (0.72 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 140 mg (0.49 mmol) ethyl[4-(4-methyl-piperidin-4-yl)-piperazin-1-yl]-acetate (Example A8b) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac. and the residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 nach 30:1). The fractions containing the product were combined, evaporated down i. vac. and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[C:5]([F:12])[CH:4]=1.C(=O)([O-])O.[K+].O.Br[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:8]=2)=[C:5]([F:12])[CH:4]=1
Reactant: N=C(N)c1ccc(Br)cc1F
Reactant: CC(C)n1ncnc1C(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (9.84 g, 38.8 mmol), potassium hydrogen carbonate (15.6 g, 154.8 mmol), THF (98 mL) and water (16 mL) at reflux was added a solution of 2-bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.0 g, 38.8 mmol) in THF (19 mL) over 15 min. The resulting mixture was stirred for 18 h at reflux before concentrating in vacuo. The resultant residue was treated with water and the solid formed collected by filtration, washed (water, then 1:1 diethyl ether:cyclohexane then diethyl ether) to give 5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole as a brown solid (10.1 g, 74%). 1H NMR δ (ppm) (CDCl3): 8.21-8.14 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.47-7.38 (2H, m), 7.26 (1H, s), 5.91 (1H, br, s), 1.59 (6H, d, J=6.63 Hz).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(C=CN2)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[C:22]5[C:23]([CH:31]=[CH:30][NH:29]5)=[CH:24][CH:25]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2cc[nH]c2c1
Product: Fc1cnc(Nc2ccc3cc[nH]c3c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 6-aminoindole were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.80 min.; purity: 91%; MS (m/e): 378 (MH+).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([Cl:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[S:28][C:29]([CH3:32])=[CH:30][N:31]=1)[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1cnc(C(=O)c2cc(Cl)cc(Br)c2)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
To a suspension of NaH (60%, 1.77 g, 44.2 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (10.12 g, 44.2 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of 14 g (44.2 mmol) (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone in THF (10 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc mixtures to afford (Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acid ethyl ester as an gel (18 g, yield=106%) The material is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccsc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride (82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chlorothieno[3.2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled to room temperature, and concentrated in vacuo. The residue is treated with water for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant solid is purified by flash column chromatography eluting with a gradient of 1% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-[(2,4-dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 198–200° C.; 1H NMR (DMSO-d6) δ 7.47 (d, J=4 Hz, 1H), 7.54 (dd, J=6, 2 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 8.61 (s, 1H), 9.67 (s, 1H); MS 318.1, 320.2 (M+H)+.