Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].[N:19]1(C(N2C=CN=C2)=N)C=CN=[CH:20]1>O1CCCC1>[NH2:19][C:20]1[O:8][C:7]2[C:2](=[C:3]([C:17]#[N:18])[C:4]([CH3:16])=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[F:9])[N:1]=1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)c(F)c2oc(N)nc2c1C#N
Temperature: 25 °C
Yield: 87.3 %

Procedure:
4-Amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (1.66 g, 6.86 mmol) and di(imidazol-1-yl)methanimine (2.821 g) were suspended in tetrahydrofuran (33 ml), and stirred under reflux under nitrogen atmosphere for 120 hours. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was fractionated with 10% methanol-containing chloroform and water. The organic layer was separated, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the solvent was evaporated away under reduced pressure. The residue was recrystallized form methanol to obtain the entitled compound (1.60 g, 87%) as a pale brown solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]>CC(C)=O>[Cl:21][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]
Reactant: Cc1c(N)cc(C(N)=O)cc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: Cc1c(Cl)cc(C(N)=O)cc1Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Cyanuric chloride (65.0 mg, 0.35 mmol) was added to an acetone solution (5 mL) of 3-amino-5-chloro-4-methyl-benzamide (65.0 mg, 0.35 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. Ice was added to the mixture and subsequent filtration yielded of 3-chloro-5-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-4-methyl-benzamide (101.0 mg, 87%) as white solid. MS (m/z) calced for C11H8N5O (MH+), 331: found, 331.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:11][C:12]([N:16]2C(C)=CC=C2C)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.O.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:11][C:12]([NH2:16])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To stirred solution containing 502 mg (1.15 mmol) of 5-(benzyloxy)-4-decyl-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine in 10 mL of ethanol-water 9:1 were added 800 mg (11.50 mmol) of hydroxylamine hydrochloride. The reaction mixture was then stirred at reflux during 5 h. A second portion of 800 mg (11.50 mmol) of hydroxylamine hydrochloride was added and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was then poured into 70 mL of water and then basified to a pH 9-10 with a 1N NaOH aqueous solution. The mixture was extracted with two 70-mL portions of ethyl acetate. The combined organic layer was washed with a 70-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 3:2 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 305 mg (75%); silica gel TLC Rf 0.25 (3:2 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.85 (t, 3H, J=6.4 Hz), 1.26 (m, 14H), 1.61 (m, 2H), 2.27 (s, 3H), 2.56 (dd, 2H, J=8.0, 8.0 Hz), 4.71 (s, 2H), 5.24 (br s, 2H) and 7.35-7.40 (m, 5H); 13C NMR (CDCl3) δ 13.94, 18.86, 22.64, 28.41, 29.27, 29.39, 29.50, 29.55, 29.71, 31.87, 31.88, 75.88, 127, 88, 128.24, 128.24, 128.58, 128.58, 136.79, 142.8, 158.92, 161.09 and 162.82; mass spectrum (APCI), m/z 356.2704 (M+H)+ (C22H34N3O requires 356.2702).
Reaction SMILES: [Cl-].[NH4+].C([N:6](C(C)C)CC)(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[C:25]([OH:27])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C(=O)C.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[C:25](=[O:27])[NH2:6])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89%) as a white solid, MS (ISP): 229.0 (M+H)+..
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncccc2N)CC1

Procedure:
A mixture of 7.8 g [4-(3-nitro-pyridin-2-yloxy)cyclohexyl]-carbamic acid tert-butyl ester and 0.8 g raney nickel in 100 ml methanol was hydrogenated at rt under 50 psi overnight. The reaction mixture was filtered and the filtrate concentrated.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([C@@H:17]4[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CO>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([C@H:17]4[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN([C@@H]1CCCC[C@@H]1c1ccccc1)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: O=C1NCN(c2ccccc2)C12CCN([C@H]1CCCC[C@H]1c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Elucidation of absolute stereochemistry: To a solution of 24 mg (cis)-1-phenyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 2) in methanol were added 14 mg 1R-(−)-camphorsulfonic acid and the solution stirred for 10 min. at ambient temperature. The resulting salt slurry was evaporated and the residue crystallized from ethyl acetate. With the single crystal X-ray structural analysis of the 1R-(−)-camphorsulfonic acid salt the absolute configuration at the cyclohexane ring was established as 1S and 2S.
Reaction SMILES: B(Br)(Br)Br.C[C:6]1[C:7]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([CH:29]([CH3:31])[CH3:30])[CH:22]=2)=[C:8]2[C:12](=[CH:13][C:14]=1[CH3:15])[NH:11][C:10]([P:16]([OH:19])(=[O:18])[OH:17])=[CH:9]2.Cl[CH2:33]Cl>>[CH3:33][C:7]1([O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:29]([CH3:30])[CH3:31])[CH:22]=2)[CH:6]=[C:14]([CH3:15])[CH:13]=[C:12]2[C:8]1=[CH:9][C:10]([P:16]([OH:19])(=[O:18])[OH:17])=[N:11]2
Reactant: COc1ccc(Oc2c(C)c(C)cc3[nH]c(P(=O)(O)O)cc23)cc1C(C)C
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CC1=CC(C)(Oc2ccc(O)c(C(C)C)c2)C2=CC(P(=O)(O)O)=NC2=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of boron tribromide (1 M in dichloromethane, 1.3 mL, 1.3 mmol) was added to a solution of 5,6-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)indolephosphonic acid (100 mg, 0.26 mmol) in dichloromethane (10 mL) at −78° C. The ice bath was removed and the reaction mixture was warmed to rt. After stirring at rt overnight, the reaction mixture was quenched with ice, diluted with ethyl acetate and washed with water then brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (86.3 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 6.97 (d, J=3.0 Hz, 1H), 6.60 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 6.26 (dd, J=9.0, 3.0 Hz, 1H), 3.22 (heptuplet, J=6.9 Hz, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 1.12 (d, J=6.9 Hz, 6H); Anal. Calcd for (C19H22NO5P+1.5H2O+0.1 C3H6O): C, 56.79; H, 6.32; N, 3.43. Found: C, 56.61; H, 5.92; N, 3.22.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:36]([C:28]2[NH:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure G: A mixture of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-butane-1,4-diamine (121 mg, 0.35 mmol), 1H-benzimidazole-2-carboxylic acid (70%, 97 mg, 0.42 mmol) (Eur. J. Med. Chem. 1993, 28, 71), HOBT (61 mg, 0.46 mmol), EDCI (91 mg, 0.46 mmol), and DIPEA (90 μL, 0.53 mmol) in DMF (5 mL) was stirred at room temperature overnight. Workup and purification gave the product as a pale yellow oil. (71 mg, 41%). 1H NMR (CDCl3) δ 1.40-1.47 (m, 2H), 1.56-1.63 (m, 2H), 2.06 (s, 3H), 2.25 (s, 3H), 2.62 (t, 2H, J=7.5 Hz), 3.30 (q, 2H, J=6.0 Hz), 3.81 (s, 2H), 4.18 (s, 2H), 7.21 (s, 1H), 7.30-7.33 (m, 2H), 7.49-7.55 (m, 3H), 7.70-7.75 (m, 3H), 7.99 (d, 1H, J=6.0 Hz), 8.21 (s, 1H), 8.40 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.32, 23.96, 27.56, 39.69, 53.84, 54.24, 59.72, 59.87, 112.7, 120.80, 120.88, 123.66, 125.22, 126.83, 127.24, 128.12, 130.18, 132.31, 133.15, 134.62, 136.64, 139.13, 141.77, 143.22, 145.43, 146.90, 154.28, 159.30, 159.68. ES-MS m/z 515 [M+H]+. Anal. Calcd. for C30H32N6O.1.6CH2Cl2: C, 60.39; H, 5.64; N, 13.37. Found: C, 60.20; H, 5.52; N, 13.54.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([NH2:12])[N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>>[Cl:15][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([NH2:12])[N:3]=1
Reactant: Nc1nc(O)cc(C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C(F)(F)F)n1
Temperature: 0 °C
Yield: 22 %

Procedure:
33.4 g (0.186 mol) of 4-hydroxy-6-trifluoromethylpyrimidin-2-ylamine are added in portions (in each case ca. 5 g) to a mixture of 85 ml of phosphorus oxychloride and 47.5 ml of dimethylaniline and the mixture is heated at reflux until the added solid has dissolved. The mixture is then heated at reflux for a further 90 minutes. After cooling, the reaction mixture is added to ice water while observing the safety precautions for phosphorus oxychloride. The aqueous phase is extracted with methylene chloride, the organic phase is separated off and dried with sodium sulfate, and the drying agent is filtered off. Following concentration by evaporation, 47.8 g of a crude mixture are obtained. Following column chromatographic separation with ethyl acetate/heptane as eluent, 8.5 g of 4-chloro-6-trifluoromethylpyrimidin-2-ylamine were obtained (solid, 22% yield, purity 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: Brc1ccccn1
Reactant: C#CCCO
Product: OCCC#Cc1ccccn1
Yield: 63.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (10.3 g, 65.1 mmol) and but-3-yn-1-ol (5.08 mL, 67.1 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 3:7 to 1:9) to yield 6.10 g (41.4 mmol, 64%) of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH3:30])[C:8](=[O:29])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:11][CH:10]=1.C(N(CC)CC)C.CS([Cl:51])(=O)=O.C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH3:30])[C:8](=[O:29])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH:22]([Cl:51])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:11][CH:10]=1
Reactant: CCCCCC(O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(Cl)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
A solution of 50 mg (0.090 mmol) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(1-hydroxy-hexyl)-N-methyl-4-o-tolyl-nicotinamide (Example 77) and 0.032 ml (0.23 mmol) triethylamine in 3 ml dichloromethane was treated with 0.008 ml (0.1 mmol) methanesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to room temperature. After 1 h 3 ml toluene were added, and the mixture was stirred at 80° C. over night. Cooling to room temperature was followed by dilution with dichloromethane, washing with water, drying with sodium sulfate and concentration. Column chromatography gave 43 mg (83%) of the title compound as a light yellow viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(S(C)(=O)=O)cc2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
100 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 145 mg of 4-(methylsulfonyl)phenylboronic acid, 123 mg of sodium carbonate and 17 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solvent of 3 ml of 1,4-dioxane and 1.2 ml of water, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 124 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>C(N(CC)CC)C>[OH:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:14]([O:16][CH3:17])=[O:15])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(O)C1
Agent: [C]=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
In an analogous manner to that described in Example 22(d), by carbonylating tert-butyl (3RS,4RS)-4-(4-bromo-phenyl)-3-hydroxy-piperidine-1-carboxylate using PdCl2 (CH3CN)2 and 1,3-bis(diphenylphosphino)-propane as the catalyst in the presence of triethylamine under 10 bar of carbon monoxide at 100° C. for 40 hours there was obtained tert-butyl (3RS,4RS)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate as white crystals; m.p.: 145.5-146° C., MS: 279 (M-C4H8)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1>[CH3:15][C:13]1[N:14]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=2)[O:11][C:12]=1[CH3:16]
Reactant: COC(=O)c1ccc(-c2nc(C)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(=O)O)cc2)oc1C
Temperature: 90 °C
Yield: 65.8 %

Procedure:
To a solution of 4-(4,5-dimethyl-oxazol-2-yl)-benzoic acid methyl ester (0.5 g, 2.1 mmol) in THF (20 mL), an aq. solution of 5 N sodium hydroxide (10 mL) was added. The reaction mixture refluxed at 90° C. over night. THF was removed completely under reduced pressure and the residue was acidified with conc. HCl, then E extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (25 mL×2) and with brine, then dried over anhydrous sodium sulphate and concentrated to get the title compound (0.3 g, 63.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:10][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:10][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2cc(Cl)ncc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 6-chloro-2-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine (847 mg, 3.66 mmol) and N,N-diisopropylethylamine (5.11 mL, 29.20 mmol) in anhydrous DMF (25.0 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (3.24 mL, 18.28 mmol). The reaction was stirred under N2 at RT for 18 h, then added to EtOAc (1.4 L) and washed with saturated NH4Cl (0.3 L). The aqueous layer was separated and back-extracted with EtOAc (0.3 L). The combined organic layers were evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 40 g silica RediSep Rf® Gold column and employing a 0-30% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C13H20ClN3O3SSi 361.07 observed m/e: 362.31 (M+H)+ (Rt 1.32/2.0 min)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>CCO>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CNc2ccc([N+](=O)[O-])c(C#N)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To an ice-cooled solution of 6-chloro-2-cyano-3-nitropyridine (52.0 g, 283 mmol) and triethylamine (43.0 mL, 425 mmol) in EtOH (950 mL) was added dropwise 2,4-dimethoxybenzylamine (53.2 mL, 312 mmol). The reaction was stirred at ambient temperature for 1.5 hours. The precipitate was filtered and washed with petrol to afford 75 g of 6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridine-2-carbonitrile as a yellow solid. NMR 1H NMR (400 MHz, Me-d3-OD): 8.19 (1H, d), 7.24 (1H, d), 6.77 (1H, d), 6.57 (1H, d), 6.49 (1H, dd), 4.56 (2H, s), 3.86 (3H, s), 3.80 (3H, s). MS: [M+H]+=315.
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)C>[CH2:6]([C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To 3.00 g (42.80 mmol) of cyclobutanone in 143 mL of tetrahydrofuran at 0° C. was added 51.36 mL (51.36 mmol) of a 1 M solution of benzyl magnesium chloride in diethyl ether and the mixture was allowed to warm to RT and stirred for 20 h. The reaction was quenched with methanol, followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6.52 g (94%) of 1-benzylcyclobutanol. Then, 1.90 g (11.69 mmol) of the compound was dissolved in 12 mL of toluene and 2.00 g (11.69 mmol) of methyl(2S)-2-isocyanatohexanoate was added. The mixture was heated at 85° C. for 3 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:6) to give 2.44 g (63%) of methyl (2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate. Rf=0.30 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.48 (d, J=8 Hz, 1H), 7.29-7.13 (m, 5H), 4.02-3.94 (m, 1H), 3.64 (s, 3H), 3.16 (ABq, JAB=16 Hz, Δ84 AB=12 Hz, 2H), 2.22-2.02 (m, 4H), 1.82-1.44 (m, 4H), 1.36-1.18 (m, 4H), 0.86 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[C:43](/[N:42]=[C:40]1\[S:41][CH2:37][C:38](=[O:56])[N:39]\1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[CH:53]([CH3:54])[CH3:55])=[O:44])[CH3:2]
Reactant: CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB25) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a red solid (0.075 g, 56%).