Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](OCC)(OCC)([O:21][CH2:22][CH3:23])[CH2:19][CH3:20].C(OC(=O)C)(=O)C>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][CH3:20])[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(CC)(OCC)OCC
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2
Solvent: CC(=O)OC(C)=O
Product: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-5,6-dimethoxy-2-indolinone, triethyl orthopropionate and acetic anhydride
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([Cl:11])[CH:13]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1cc(Cl)cc(B(O)O)c1
Product: COc1cc(Cl)cc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 32.6 %

Procedure:
The title compound (41 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-chloro-5-methoxyphenylboronic acid (107 mg, 0.57 mmol) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)[N:3]=1.O.[NH2:28][NH2:29]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NC3CCc4ccccc43)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(NC2CCc3ccccc32)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
To 4-[2-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (500 mg, 1.45 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74.0 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by HPLC to afford the title compound (100 mg) as a brown solid. LC-MS (ES) m/z=358 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.81 (s, 1H), 1.90-1.92 (m, 1H), 2.84-3.051 (m, 2H), 5.43 (s, 2H), 5.71 (s, 1H), 6.12 (s, 2H), 6.40 (s, 1H), 7.23-7.48 (m, 6H), 7.75 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 11.58 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:31][OH:32]>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:32][CH2:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1nc(SC)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K), is treated with ethyl glycolate, a compound of formula (P), to yield 2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (U).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[N:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncc(-c3cnc(C4CCCNC4)[nH]3)cn2)cc1

Procedure:
Solid (±)-tert-butyl 3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (Example 21) was treated with 0.5 mL of trifluoroacetic acid at room temperature for 0.5 hour. Three times the reaction mixture was diluted with toluene and concentrated to give a dark semi-solid. The crude material was chromatographed on silica (4 g) eluted with 1:10:90 v/v acetic acid-methanol-dichloromethane. The clean fractions were collected, concentrated under reduced pressure, and the material was three times diluted with toluene and concentrated, then dried under high vacuum to afford the title compound as a pale yellow solid; Rf 0.17 with 1:10:90 v/v acetic acid-methanol-dichloromethane; melting point 140° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.22 (s, 2H), 8.5-9.2 (br s, 2H), 8.35-8.45 (m, 2H), 7.9 (d, 1H), 7.4-7.5 (m, 3H), 3.4-3.6 (m, 2H), 3.2-3.4 (m, 2H), 2.9-3.1 (m, 1H), 2.0-2.2 (m, 1H), 1.6-1.9 (m, 3H); MS (ESI+) m/z 306 (M+1); H-PGDS FPBA IC50: 1.25 μM.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])[N:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[N:3][C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])=[N:5]1
Reactant: COC1CCC(OC)O1
Reactant: CC(c1nc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(c1nc(-n2cccc2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Reaction time: 1 h
Yield: 67.7 %

Procedure:
3.9 g (0.01 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-trifluoromethylethyl)-1H-1,2,4-triazole and 1.3 g (0.01 mol) of 2,5-dimethoxytetrahydrofuran were dissolved in 15 ml of acetic acid, and the solution was refluxed under stirring for one hour. After cooling, the reaction solution was poured into water and neutralized with sodium hydrogencarbonate. Then, precipitates were extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 3 g (yield: 68%) of the desired compound having a melting point of from 73.5° to 75° C. as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(B(CC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)C>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CCB(CC)c1cccnc1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccnc4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was reacted with diethyl(3-pyridyl)borane by the method of Example 35 to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-3-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine as a white solid: δH (400 MHz, CDCl3) 0.73 (6H, q, J 8.1), 1.01 (9H, t, J 8.0), 1.72 (6H, s), 7.46-7.53 (2H, m), 7.61 (1H, d, J 5.5), 7.67 (1H, d, J 7.0), 8.52 (1H, s), 8.72-8.79 (2H, m), 9.71 (1H, m), 10.24 (1H, d, J 7.0); m/z (ES+) 447 (M++H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)CC(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CC(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Yield: 41 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-Amino-5-methyl-hexanoic acid (175 mg, 1.2 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 2.4 mL, 1.2 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 4.5 hours. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The crude product was purified by MPLC (methylene chloride-methanol) to provide the title compound as an off-white solid in 41% yield. MS ESI(−) m/e: 432.1062 (M−1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([CH2:21][CH:22]=[CH2:23])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]([CH2:21][CH:22]=[CH2:23])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:26][CH:25]=[CH2:24])[CH:18]=[CH:17]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=CCN(Cc1cccc2cc[nH]c12)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN(Cc1cccc2ccn(CC=C)c12)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Slowly add sodium hydride (60% dispersion in mineral oil, 1.75 g, 43.7 mmol) to a 0° C. solution of N-[tert-butoxycarbonyl]N-allyl N-[(1H-indol-7-yl)methyl]amine (6.6 g, 23 mmol) in anhydrous dimethylformamide. Warm the mixture to 20-24° C., stir for 30 minutes, add allyl bromide (4.0 mL, 46 mmol), and stir the mixture at 20-24° C. overnight. Dilute the reaction mixture with ethyl acetate (450 mL), wash sequentially with water (2×100 mL) and saturated aqueous sodium chloride (150 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 10% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a light brown oil (6.8 g, 91%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:27][CH3:28])[C:23]=1[O:24][CH2:25][CH3:26])[CH:19]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][C:18]2[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:24][CH2:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOc1c(OC)cc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1c(OC)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2.2 g (11.8 mmol) of N-Boc-piperazine and 2.5 g (11.8 mmol) of 3,5-dimethoxy-4-ethoxybenzaldehyde are mixed in 50 ml of dry of dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.25 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (4.1 g of oil) is used on the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.Cl.Cl.[NH2:13][C:14]1([CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:13][C:14]1([CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH2:18][CH2:17][N:16]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([NH2:1])[N:3]=[CH:4][N:5]=2)[CH2:15]1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: NC1(CNC(=O)c2ccc(F)cc2F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (72.0 mg; 0.47 mmol; 1.02 eq.), N-[(3-aminopyrrolidin-3-yl)methyl]-2,4-difluorobenzamide dihydrochloride (150.0 mg; 0.46 mmol; 1.0 eq.), potassium carbonate (126.3 mg; 0.91 mmol; 2.0 eq.) in DMSO (2.00 ml) was stirred at 60° C. for 2 h. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, acetonitrile/0.1% NH4OH in water) to afford the title compound in 70% yield. LC-MS: (M+1=374, obsd.=374).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[CH:66][CH:65]=1>>[CH2:74]([O:73][C:71](=[O:72])[CH2:70][C:67]1[CH:66]=[CH:65][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:69][CH:68]=1)[CH3:75]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 35.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (120 mg, 0.257 mmol), was reacted with diisopropylethylamine (207 mg, 1.60 mmol), diphenylphosphinic chloride (146 mg, 0.618 mmol), then reacted with ethyl 2-(4-aminophenyl)acetate (56 mg, 0.315 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (57 mg, 47%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:26]=3[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.048 g, 0.21 mmol) and 1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.21 mmol) in DMF (1 mL) were added Hunig's base (0.055 g, 0.42 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (0.090 g, 0.23 mmol). The mixture was stirred at room temperature for 1 hour, and then partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (0.028 g, 0.063 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.43 (s, 4H), 5.60 (q, J=7.1 Hz, 1H), 3.77 (ddd, J=12.6, 7.5, 3.0 Hz, 1H), 3.52 (ddd, J=12.3, 8.3, 3.0 Hz, 1H), 2.84 (tt, J=6.9, 3.3 Hz, 2H), 2.52 (s, 3H), 2.09-1.81 (m, 5H); MS: (ES) m/z calculated for C19H18ClF3N6O [M+H]+ 439.1, found 438.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][C:31](Cl)=[O:32])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOc1cccc(OCC(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46a (9.57 g, 52.6 mmol) and CH2Cl2 (200 mL). The resultant solution was cooled in an ice bath and iPr2NEt (20.4 g, 27.5 mL, 158 mmol) was added followed by acid chloride 47a (14.1 g, 65.7 mmol) in CH2Cl2 (120 mL) over 30 min. The mixture stirred at rt overnight. The red solution was diluted with CH2Cl2 (250 mL) and was washed with saturated aqueous NH4Cl (200 mL), saturated NaHCO3 (200 mL), and brine (200 mL). The organic phase was filtered through phase separation paper and concentrated in vacuo to an orange solid. The solid was triturated with EtOH (75 mL), filtered, pressed with a rubber dam, and rinsed with EtOH (3×20 mL). The solid dried to give 14.3 g of 48a as a yellow solid (80%). 1H NMR (300 MHz, CDCl3): δ 11.36 (s, 1H), 8.78 (d, 1H), 7.72 (d, 1H), 7.30-7.20 (m, 2H), 6.67-6.59 (m, 3H), 4.66 (s, 2H), 4.09 (qt, 2H), 4.07 (qt, 2H), 1.44 (t, 3H), 1.42 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.8 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].S(Cl)([Cl:22])=O>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([Cl:22])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A mixture of 2,2',4'-trifluoro-4-biphenylylacetic acid (3.6 g.) and thionyl chloride (15 ml.) was refluxed for 1 hour; excess thionyl chloride was removed and the residual acid chloride distilled at 141°-143° C./1.0 mm as a yellow oil, solidifying on cooling, (3.11 g.). Recrystallisation from 62-68 petroleum ether gave colourless needles of 2,2',4'-trifluoro-4-biphenylylacetyl chloride, m.p. 70°-73° C. 1 g. of this was dissolved in ether (10 ml.) and the solution added slowly to a stirred mixture of ammonia (SG=0.880; 5 ml.) and ether (25 ml.) at room temperature. After stirring for 15 minutes, the product was isolated in ether, washed, dried and evaporated. Recrystallization of the residue from methylene chloride/40-60 petroleum ether followed by a further crystallization from 100-120 petroleum ether gave colourless plates of 2,2',4'-trifluoro-4-biphenylylacetamide, m.p. 137°-140° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]2=[O:7])[CH:21]=1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 402.99 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([OH:34])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:15]([O:14][C@H:10]1[C@H:11]([O:13][C:15](=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@@H]1CN(Cc2ccccc2)C[C@H]1OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-9 (1.85 g, 98.8%) was obtained in the same manner as that in Reference Example 2, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 500 mg, 2.59 mmol) and oleic acid (Tokyo Chemical Industry Co., Ltd.; 1.61 g, 5.69 mmol).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow oil. MS: 531.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CCO>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A 25 mL round bottom flask was charged with (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.352 g, 1.50 mmol) and EtOH (5 mL). Hydrazine Hydrate (0.326 mL, 10.5 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Pyrrolidin-1-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.219 g, 1.07 mmol, 71% yield).