Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Br.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.[OH-].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:23][CH:22]=1
Reactant: CCn1ncc(Br)c(Br)c1=O
Reactant: COCOc1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(OCc2ccc(OCOC)cc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.2 g of 4,5-dibromo-2-ethyl-3(2H)-pyridazinone and 0.88 g of 4-methoxymethoxybenzyl alcohol, and 0.34 g of powdery potassium hydroxide was added thereto. The reaction mixture was stirred overnight at room temperature, poured into water and extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and freed of the benzene by distillation under reduced pressure. The resulting oil was purified by means of TLC [eluting with benzene/ethyl acetate (12/1)] and recrystallization (from benzene/n-hexane) to obtain 450 mg of the aimed compound, m.p. 104°~106.0° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33]>>[CH3:33][C@@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C[C@H]1CNCCN1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (s, 3 H) 3.13-3.74 (m, 7 H) 7.63 (d, J=6.82 Hz, 1 H) 7.71-7.78 (m, 1 H) 7.90-8.67 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:23]#[N:24].CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([C:9](=[O:10])[C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:30][CH2:29]1)[C:23]#[N:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 40.6 mg (0.15 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 39.9 mg (0.18 mmol) 3-Chloro-4-piperazin-1-yl-benzonitrile (WO9625414) and 62.5 ul (0.45 mmol) NEt3 in 1 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 1 ml CH3CN/DMF/HCOOH 3/5/2 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 4.9 mg (8%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:8]([2H])([2H])[C:7]([2H])([2H])[NH:6][C:5]1=[O:13].[CH2:14](OCCNCC1(N)CCCC1)[C:15]1C=CC=[CH:17][CH:16]=1>>[Cl:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:6][C:5]1=[O:13]
Reactant: [2H]C1([2H])NC(=O)N(CCCl)C1([2H])[2H]
Reactant: NC1(CNCCOCc2ccccc2)CCCC1
Product: O=C1NC2(CCCC2)CN1CCCl

Procedure:
This compound was prepared by a procedure analogous to the procedure described for the synthesis of 4c using 12b as starting material.
Reaction SMILES: [P:1]([O-:32])([O:28][CH2:29][CH2:30]Br)([O:3][CH2:4][CH:5]([O:26][CH3:27])[CH2:6][O:7][CH2:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2].[S:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>C1(C)C=CC=CC=1>[P:1]([O-:32])([O:28][CH2:29][CH2:30][C:34]1[S:33][CH:37]=[CH:36][NH+:35]=1)([O:3][CH2:4][CH:5]([O:26][CH3:27])[CH2:6][O:7][CH2:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:2]
Reactant: CCCCCCCCCCCCCCCC(=O)COCC(COP(=O)([O-])OCCBr)OC
Reactant: c1cscn1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)COCC(COP(=O)([O-])OCCc1[nH+]ccs1)OC
Temperature: 60 °C
Reaction time: 96 h

Procedure:
In 3 ml of toluene was dissolved 0.9 g of the above 3-(2-oxoheptadecyloxy)-2-methoxypropyl 2-bromoethyl phosphate (5), and 1 ml of thiazole was added to the solution. The mixture was stirred at 60° C. for 4 days and then concentrated to dryness. The residue was purified by silica gel chromatography [eluent: (1) methanol and (2) chloroform-methanol-water (65:25:4)] to give 0.20 g of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1>CCO>[CH:23]1([CH2:26][NH:27][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH2:25][CH2:24]1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: NCC1CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 65 °C
Reaction time: 18 h
Yield: 19.6 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1 g, 5 mmol, 1 eq.) and DIEA (4.35 mL, 24.9 mmol, 5 eq.) in 7 mL of EtOH was added cyclopropylmethylamine (1.4 g, 20 mmol, 4 eq.). The resulting mixture was heated at 65° C. overnight. After 18 h, the reaction mixture was concentrated in vacuo to give an oil that was purified by silica gel column chromatography (100% CH2Cl2) to give the title compound as a white solid (0.23 g, 20%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.37-4.42 (m, 2H), 3.95 (s, 1H), 3.80-3.88 (m, 3H), 2.63-2.72 (m, 1H), 2.54-2.63 (m, 3H), 0.89-1.05 (m, 1H), 0.42-0.54 (m, 2H), 0.14-0.26 (m, 2H). Exact mass calculated for C12H18N3O2 236.1. MS (ESI) m/z 236.9 (M+H)+. Retention time: 0.56 min (5-95% CH3CN/H2O over 2 min with 0.1% formic acid, Inertsil 3×3 mm C-8-3 column with flow rate of 2 mL/min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([Sn](CCCC)(CCCC)CC=C)[CH2:11][CH2:12]C.[Li+].[Cl-]>C1(C)C=CC=CC=1.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>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH:11]=[CH2:10]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cccc(C#N)c1

Procedure:
To solution of compound 3-bromobenzonitrile (5 g, 27 mmol) and tributyl(prop-2-en-1-yl)stannane (13.5 g, 41.2 mmol) in toluene was added Pd(PPh3)4 (300 mg) and LiCl (2.3 g, 54 mmol) under N2, and then the mixture was stirred at reflux for 18 h. The reaction mixture was quenched by the addition of water. Extracted the mixture with EtOAc and the organic layer was dried and concentrated. The residue was purified by a flash column chromatography to afford 3-(prop-2-en-1-yl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ 7.32˜7.82 (m, 4H), 5.85˜6.00 (m, 1H), 5.05˜5.17 (m, 2H), 3.42 (d, J=6.8 Hz, 2H).
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:23]1([C:26]([N:20]2[CH2:21][CH2:22][CH:17]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C@@H:11]5[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:18][CH2:19]2)=[O:27])[CH2:25][CH2:24]1
Reactant: O=C(O)C1CC1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to provide the title compound (48 mg, 51%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 0.61-0.81 (m, 4H), 1.16-1.43 (m, 6H), 1.50-1.67 (m, 2H), 1.68-1.98 (m, 8H), 2.13-2.29 (m, 3H), 2.44-2.62 (m, 2H), 2.80-3.10 (m, 5H), 3.48-3.66 (m, 1H), 4.31 (d, J=13.28 Hz, 1H), 4.47 (d, J=13.28 Hz, 1H). MS (M+1): 375.2
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34])=[O:29])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:33]([C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])=[O:34])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of Intermediate 7 (250 mg, 0,83 mmol) and 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)benzoic acid (196 mg, 0.83 mmol, e.g. available from Fluka) in N,N-dimethylformamide (4 ml) was treated with N,N-diisopropylethylamine (0.569 ml, 3.3 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (472 mg, 0.91 mmol) and allowed to stir at room temperature for 4 hours. An additional portion of (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (0.5 equiv., 0.41 mmol) was added and the mixture stirred for an additional hour. The solvent was evaporated and the residue dissolved in ethyl acetate (50 ml) and washed with aqueous sodium bicarbonate solution (2×50 ml); the organic fraction was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel (50 g SPE cartridge), eluting with a gradient of 0-100% ethyl acetate/cyclohexane followed by a gradient of 0-20% methanol/ethyl acetate over 40 minutes. Fractions containing product were pooled and evaporated to give the title compound (292 mg). LCMS showed MH+=523; TRET=2.71 min.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[C:10]([NH:12][NH2:13])=[O:11])([CH3:6])[CH3:5].[C:22](=S)=[S:23]>C(O)C>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([C:10]2[O:11][C:22](=[S:23])[NH:13][N:12]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:3])[CH3:5]
Reactant: S=C=S
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
Potassium hydroxide (1.1 g, 0.019 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazide (5.0 g, 0.019 mole) and carbon disulfide (3.4 g, 0.044 mole) in absolute ethanol (60 ml). The resulting mixture is stirred 30 minutes at 0° C. before warming to room temperature and stirring one hour. The solution is then heated to reflux for 2.5 hours. The solvent is removed in vacuo and the residue dissolved in water (100 ml) and washed with ether. The aqueous layer is made acidic with 2M HCl and the product extracted with a 1:1 mixture of ethyl acetate/ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/isopropyl ether to give 2.2 g (5.8 g theor., 38%) desired 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole2(3H)-thione, mp 253.5° C.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:16]([CH:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH:20]1O)=[N+:17]=[N-:18]>C(Cl)Cl>[N:16]([CH:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH:20]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)OCc2ccccc2)CCCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
TBDMSOTf (0.010 g, 0.038 mmol) was added drop-wise to the mixture of benzyl 4-azido-3-hydroxyazepane-1-carboxylate (0.010 g, 0.034 mmol, WO 2010/114971, Example 90.5) and TEA (0.0096 mL, 0.069 mmol) in DCM (50 mL). The mixture was stirred at about 25° C. for about 3 h. The mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC (EtOAc/pet ether ¼) to give benzyl 4-azido-3-(tert-butyldimethylsilyloxy)azepane-1-carboxylate (0.005 g, 36%). The material was used without characterization.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:4][CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:2]2[CH2:7][CH2:6][C:5]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8]3)[CH2:4][CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine)hydrochloride (65 mg, 293 μmol) and p-toluenesulfonyl chloride (61.9 mg, 325 μmol) were combined in CH2Cl2 and treated with triethylamine (2 drops). The mixture was stirred at ambient temperature for 1 hour, then poured onto a silica gel column and eluted with 35% hexane in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo to provide the title compound which was crystallized from ether, filtered and dried in vacuo overnight at ambient temperature: (m.p. 168°-170°).
Reaction SMILES: CO.Br[C:4]1[C:9]([Cl:10])=[C:8]([F:11])[N:7]=[C:6]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[F:17]>[Pd].C(N(CC)CC)C>[C:13]([NH:12][C:6]1[C:5]([F:17])=[CH:4][C:9]([Cl:10])=[C:8]([F:11])[N:7]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)Nc1nc(F)c(Cl)c(Br)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)Nc1nc(F)c(Cl)cc1F
Reaction time: 120 h
Yield: 98.6 %

Procedure:
To 30 ml of methanol were added 12.8 g of 4-bromo-2-(t-butylamino)-5-chloro-3,6-difluoropyridine and 2.5 g of triethylamine together with 0.57 g of 10% palladium on carbon, and the mixture was hydrogenated at 50° C. for 5 days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 80 ml of chloroform, and the mixture was washed with 70 ml of distilled water, and the chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.3 g of the title compound as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:6]([CH3:32])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=4[C:25]=3[CH3:26])=[O:20])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O.O>[F:31][C:28]1[CH:29]=[CH:30][C:23]2[O:22][C:21]([C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][N:8]4[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[N:7]4)=[CH:13][CH:14]=3)=[O:20])=[C:25]([CH3:26])[C:24]=2[CH:27]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (400 mg, 1.46 mmol) in 5 mL dichloromethane are added diisopropylethylamine (1.5 mL, 8.8 mmol) and 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (369 mg, 1.9 mmol). After stiffing at room temperature for 10 minutes a 50% solution of 1-propylphosphonic acid cyclic anhydride in ethyl acetate (1.725 mL, 2.93 mmol) is added with cooling and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated in vacuo and the residue is purified by MPLC (dichloromethane/methanol 98:2) to yield 410 mg of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=450; TLC: Rf=0.56 (dichloromethane/methanol 95:5, silicagel 60 F254)). b) To a solution of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (410 mg, 0.91 mmol) in dioxane/water (10 mL/10 mL) is added 1 M NaOH (2.3 mL) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with water and acidified with hydrochloric acid (1 M, 3.25 mL). The precipitate is filtered, washed with water and dried to yield 338 mg of the title compound (ESI mass spectrum: [M+H]+=436; Retention time HPLC: 0.85 min (method D).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21].C1C(=O)N([Br:33])C(=O)C1>ClCCl>[CH3:25][O:24][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:10]=[C:9]([Br:33])[C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(OC)OC
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(OC)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 2 L flask equipped with a mechanic stirrer were charged with methyl 1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 23 as obtained above and 500 mL of dichloromethane. To this flask was added NBS (30 g, 0.17 mole) portion-wise. The reaction was stirred at room temperature until its completion (monitored by TLC, ˜6 hours). The mixture was then diluted with dichloromethane and washed with NaHCO3 (ss). The organic phase was dried over Na2SO4 before evaporation of the solvents. The crude product was purified by column chromatography (silica gel, EtOH/DCM: 0-40%) to afford methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 as a light brown solid (50 g, 60% over three steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.7 (s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3 (s, 2H), 4.4 (s, 1H), 3.8 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calcd 426, obsd 426.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[N:20]=[CH:21][N:22]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[OH:18][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1)([C:19]1[N:20]=[CH:21][N:22]([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:23]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(O)(c1ccc(-c2cc(N)ccn2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-[4-(4-amino-2-pyridyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.40 g), acetic anhydride (0.46 ml), triethylamine (0.71 ml) and p-dimethylaminopyridine (20 mg) was stirred in THF (20 ml) at 60° C. for 16 h. The solvent was evaporated and ethyl acetate and water were added to the residue for partitioning. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile (10 ml)—water (10 ml) and tetrabutylammonium bromide (13 mg) was added. The mixture was stirred at room temperature for 10 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and the mixture was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate gave the title compound (630 mg) as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([N:1]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])=[N:3]1)#[N:10]
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N(C(=O)C2CC2)C(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in DCM at RT, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09 g, 79%): mp 104-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51 (dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm−1.