Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[N:21]1[CH:26]=NC=N[CH:22]=1>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][NH:21][CH:26]=1
Reactant: c1ncncn1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc(-c2ccccc2F)c1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of sodium ethoxide in ethanol (20%, 1270 μl) was added to a solution of ethyl 4-(2-fluorophenyl)-3-oxobutanoate (697 mg) and 1,3,5-triazine (277 mg) in ethanol (8.0 ml) at room temperature, and the mixture was stirred at 85° C. for four hours. The solvent was distilled off under reduced pressure, followed by dilution with water. A 1 N aqueous hydrochloric acid solution was added, and the precipitated solid was collected by filtration and washed with ethyl acetate to give 406 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NC(=O)c2ccsc2)c1
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.1 eq, 0.17 mmol) was added to a solution 3-thiophenecarboxylic acid (20 mg, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.16 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 17 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (10 mg, 0.03 mmol, 17%). LCMS: [M+H]+=337, Rt=1.58 min, 100% purity.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl>CCO.CCCC(C)C>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[N:9]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: CCCC(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. ⅓ of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2×300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52%); Rt 1.31 min (Method 1); m/z 230 (M+H)+ (ES+); 1H NMR δ: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[Br-:20].[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([N+:13]2[CH:17]=[CH:16][N:15]([CH2:21][CH2:22][CH3:23])[CH:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCCBr
Reactant: FC(F)(F)c1cc(-n2ccnc2)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure 3.60 mmol (1.00 g) 1-(3,5-bis(trifluormethyl)phenyl)imidazole and 4.20 mmol (0,530 g, 0.39 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 18 h to 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Yield: 94.8 %

Procedure:
A mixture of 4′-bromobiphenyl-4-ol (8.41 g, 33.8 mmol), 1-iodododecane (10 g, 33.8 mmol) and K2CO3 (18.64 g, 135 mmol) in butanone (100 mL) was heated at reflux. After 16 h the mixture was poured into water (200 mL), extracted with DCM (3×100 mL), washed with NaOH (2 M, 100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was washed with hot MeOH to give the title compound (13.37 g, 95%) as a colourless powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[NH2:18].CCCCC.[OH2:24]>[OH-].[Na+].CCO>[NH2:18][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:7][C:4]=1[C:5]([NH2:6])=[O:24]
Reactant: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C#N)c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCO
Product: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C(N)=O)c1

Procedure:
A mixture containing 1.02 g of 3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 25 ml of H2O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55°-65° C. under N2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl3. The CHCl3 extract is washed with 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to afford 0.74 g. This solid is stirred with pentane and filtered to afford 0.6 g, mp 135°-145° C., of the title compound.
Reaction SMILES: OC1C=C(N[C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)C=CC=1.[OH:24][C:25]1[C:26]([CH3:32])=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].Cl[C:34]1N=C(Cl)C(F)=CN=1>>[OH:24][C:25]1[C:26]([CH3:32])=[C:27]([NH:28][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=3[CH3:34])[C:12]([F:23])=[CH:11][N:10]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(N)cccc1O
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1c(O)cccc1Nc1ncc(F)c(Nc2cccc(O)c2C)n1
Yield: 88 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3-hydroxy-2-methylaniline (369 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (180 mg, 88%). 1H NMR (acetone-d6): δ 2.14 (s, 3 H), 2.22 (s, 3 H), 6.61 (d, J=8.1 Hz, 1 H), 6.78 (t, J=8.7 Hz, 1 H), 6.87 (d, J=7.8 Hz, 1 H), 6.99 (d, J=9.0 Hz, 1 H), 7.08 (t, J=7.8 Hz, 1 H), 7.13 (dd, J=3.9, 8.4 Hz, 1 H), 8.24 (d, J=5.1 Hz, 1 H), 8.32 (br, 1 H, NH), 8.57 (br, 1 H, NH); LCMS: ret. time: 16.51 min.; purity: 90.47%; MS (m/e): 341.07 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:31])[C:27](=[O:30])[CH2:28][CH3:29])=[N:24][CH:25]=1>>[CH3:31][N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCC(=O)N(C)c1ccc(N)cn1
Product: CCC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propionyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-propionamide. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[O:23][C:22]([C:24](OC)=[O:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][N:14]([S:16]([C:19]2[O:23][C:22]([CH2:24][OH:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of methyl 5-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}-2-furoate (825 mg) in tetrahydrofuran (8 mL) was added dropwise a 1.5 mol/L solution (5.38 mL) of diisobutylaluminum hydride in toluene under ice-cooling and the mixture was stirred for 1 hr. Hydrochloric acid was added to the reaction mixture and the mixture was further stirred for 1 hr and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:2) to give the title compound as a colorless oil (yield 565 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:19])[CH:11](I)[CH2:12][CH2:13]2.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:17][CH2:16][CH2:15][C@H:14]2[N:9]1[C:10](=[O:19])[CH:11]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH2:12][CH2:13]2
Reactant: CCOP(OCC)OCC
Reactant: O=C1C(I)CC[C@@H]2CCC[C@H](c3ccccc3F)N12
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccccc3F)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-6-(2-fluorophenyl)-3-iodooctahydroquinolizin-4-one (500 mg) with triethyl phosphite (6 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 501 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2>Cl>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH2:4][CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(Cl)C1
Agent: Cl
Product: CN1CCC2(Cl)CNCC12

Procedure:
9.3 g (40 mmol) of ethyl 5-chloro-2-methyl-2,7-diazabicyclo[3.3.01octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 30 ml of water, and the mixture is rendered alkaline with potassium carbonate and extracted five times with 50 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C@H:9]1[CH2:16][O:17][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.3 %

Procedure:
To a stirred solution of trans-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (330 mg, 0.68 mmol) in THF (5 ml) was added TBAF (1.0 M solution in THF, 1.0 ml, 1.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (3:97 to 20:80, v/v) as eluent to give trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (180 mg, quant.) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 2.23 (s, 6H), 1.65–1.75 (m, 2H), 2.75–4.10 (m, 4H), 3.61 (d, J=5.6 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@@H:21]([OH:22])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:36][C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@@H:21]([OH:22])[CH2:20][NH:19][CH2:18]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CNC[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of cis-tert-butyl 3-(2-(3-fluorophenyl)pyrimidine-5-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (1.22 g, 3.03 mmol) in DCM (6 mL) was added TFA (2 mL). The solution stirred at room temperature for 3 hrs and then diluted with toluene (5 mL) and the solvent removed to give a solid, cis-2-(3-fluorophenyl)-N-(4-hydroxypyrrolidin-3-yl)pyrimidine-5-carboxamide-TFA salt (1.26 g, 98%). LC/MS (M+H)=303.1 observed, 303.13 expected.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[CH2:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([Cl:19])=[O:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
To a solution of α-phenyl-o-toluic acid (4 g, 18.28 mmol) in dry CH2Cl2 (30 mL) was added thionyl chloride (5 mL, 68.50 mmol), followed by a drop of dry DMF. The reaction mixture was refluxed for 5 hr. The solvent and excess SOCl2 was removed in vacuo to give 2-benzyl-benzoyl chloride 18 as a pale yellow oil which was used directly in next step.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.ClCCl>[CH2:34]([O:33][C:31]([N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:18][CH2:19]1)=[O:32])[CH3:35]
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 87.7 %

Procedure:
A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (92 mg, 0.306 mmol) produced in Example (10a), triethylamine (0.085 mL, 0.612 mmol) and dichloromethane (2 mL) was cooled in an ice bath and stirred. Ethyl chloroformate (0.032 mL, 0.337 mmol) was added to the mixture, followed by stirring for 2 hours under the same conditions. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 100 mg of the title compound as a colorless oil, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:37][NH2:38]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:38][N:37]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)ccc1-n1cnc(Cl)c1
Yield: 79 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (4.0 g, 13.48 mmol, from preparation A) and 6-chloro-2-(4-fluorophenyl)hexanoic acid (3.63 g, 14.83 mmol, from preparation AC) were coupled and then reacted with hydrazine (1.69 mL, 53.9 mmol) using a procedure analogous to Step A of Example 13 to afford 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (5.2 g, 10.63 mmol, 79% yield) as a reddish foam solid. LC-MS (M+H)+ 489.1. Used the crude isolate in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.P([O-])([O-])(O)=O.[Na+].[Na+].O>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(I)nn1
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (10.0 g, 45.2 mmol) in N,N-dimethylacetamide (100 mL) were added tert-butyl (chloroacetyl)carbamate (14.0 g, 72.4 mmol) and disodium hydrogenphosphate (16.1 g, 113 mmol), and the mixture was stirred at 120° C. for 3 hr. After cooling the mixture to room temperature, water (400 mL) was added to the mixture, and the precipitated crystals were filtrated, and washed with acetonitrile and petroleum ether to give the title compound (10.2 g, 63%) as a green powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of 4-chloro-iodobenzene (0.99 g, 4.15 mmol), (4-bromophenyl)boronic acid (1.0 g, 4.98 mmol), anhydrous potassium carbonate (860 mg, 6.22 mmol) and dichlorobis(triphenylphosphine) palladium (II) (87 mg, 0.12 mmol) in toluene (40 ml) was heated at 90° C. for 4 hours under an argon atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The organic solution was washed successively with 1M hydrochloric acid (2×30 ml), saturated aq. sodium hydrogen carbonate (2×30 ml) and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to leave an orange solid, which was purifed by trituration with ethyl acetate-hexane (1:6) to provide 4'-chloro-4-bromo-biphenyl (0.5 g, 45%) as a pale orange solid. 1H-NMR; δ (CDCl3) 7.49 (m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>ClCCl>[CH3:16][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH2:13][CH:14]=[O:15]
Reactant: CC(C)(CCO)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Step B To a solution of oxalyl chloride (1.7 g, 13 mmol) (Aldrich) in dichloromethane (50 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.9 mL, 27 mmol) in dichloromethane (10 mL) dropwise. After 5 mins, the solution of 3-methyl-3-phenyl-butan-1-ol (2 g, 12 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (6.1 mL, 44 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methyl-3-phenyl-butyraldehyde as a colorless oil (Yield: 1.8 g, 90%).