Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)[C:13](Cl)=O.CCO>C(Cl)Cl>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[I:11])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)ccc1I
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-Bromo-2-iodo-benzoic acid (25.0 g, 76.47 mol) was dissolved in CH2Cl2 (75 ml) at room temperature. Oxalyl chloride (14.5 ml, 152.94 mmol) was added and the mixture was stirred at 40° C. for 30 minutes. The mixture was allowed to cool to room temperature and EtOH (6.69 ml, 114.71 mmol) was added. The mixture was concentrated under reduced pressure to give 27.2 g (quantitative) of 5-bromo-2-iodo-benzoic acid ethyl ester as a yellow crystalline solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:29])[C:7]([CH3:28])([CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:25][OH:26])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:26][CH2:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:28])([CH3:27])[C:6]([OH:29])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(CO)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(CO)CCCCC(C)(C)C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a homogeneous solution of potassium hydroxide (1.18 g, 21 mmol) in water (1.12 mL) and ethanol (3.8 mL) was added 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (2.9 g, 7.5 mmol) and the reaction mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo, cooled to room temperature, and the residue was extracted with diethyl ether (2×50 mL). The pH of the aqueous layer was adjusted to 1 by addition of hydrochloric acid. The product was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude product which was purified by column chromatography on silica (hexanes:ethyl acetate=60:40) to yield 7-hydroxymethyl-2,2,12,12-tetramethyltridecanedioic acid (2.0 g, 81%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.64 (br., 3H), 3.50 (d, 2H, J=4.4 Hz), 1.60-1.20 (m, 17H), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 65.2, 42.1, 40.5, 40.1, 30.6, 27.1, 25.2, 25.0. HRMS (LSIMS, nba): Calcd. for C18H35O5 (MH+): 331.2484. found 331.2484.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:9])=[O:11]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1n[nH]c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-3-methyl-1H-pyrazole-4-carbonitrile (15.0 g, above) was added to stirred concentrated sulfuric acid (47 mL, 95%) cooled with cold water bath. After the addition, the reaction mixture was stirred at room temperature for 2 hours before it was poured with stirring into a mixture of ice and water. The precipitate was collected by filtration, washed with cold water to remove excess sulfuric acid, and dried in a vacuum desiccator to give 5-amino-3-methyl-1H-pyrazole-4-carboxylic acid amide. (Yield 19.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:39]O)[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:39][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([NH:23][CH2:22][CH2:21][C:20]([OH:42])=[O:19])=[O:41])=[CH:26][CH:27]=3)[CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CO)CCCC(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OCC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 8, using 4′-tert-butyl-biphenyl-4-ol and 3-[4-(5,5,5-trifluoro-1-hydroxymethyl-pentyl)-benzoylamino]-propionic acid methyl ester as starting materials. MS (ES): 554.2 [M+H]−.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH3:2].[CH2:26]([SH:29])[CH2:27][CH3:28].C[Si](Cl)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:24]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:3]([CH2:1][CH3:2])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([S:29][CH2:26][CH2:27][CH3:28])[S:29][CH2:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Reactant: CCCS
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCSC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)SCCC
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a mixture of 0.39 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.16 g of 1-propanethiol and 10 ml of chloroform was slowly added dropwise 0.16 g of trimethylsilyl chloride with stirring at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into 5% aqueous sodium carbonate solution and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-di(propylthio)ethoxy)butyloxy)benzene (yield, 41%), nD26.4 1.5300.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[O:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: C1COCCN1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)N2CCOCC2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (180 mg), WSC (230 mg), morpholine (100 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 4-[3-[4-[2-(2-furyl)-5-methyl1–4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetylmorpholine (440 mg, yield 96%), which was then recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2)(=[O:4])=[O:3]
Reactant: Cc1ccc(C2CC[C@@H](CO)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CC[C@@H](COS(C)(=O)=O)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Reaction time: 1.75 h

Procedure:
Methanesulfonyl chloride (0.483 mL, 6.20 mmol) was added to a solution of (7S)-7-(hydroxyl methyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (1.3 g, 3.10 mmol) and triethylamine (1.296 mL, 9.30 mmol) in DCM (30 mL). The mixture was stirred at room temp. for 105 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic extract was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-75% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCCl.CCN=C=NCCCN(C)C.Cl.Cl.[F:44][C:45]([F:53])([F:52])[CH2:46][NH:47][C:48]([NH:50][NH2:51])=[O:49]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][NH:50][C:48]([NH:47][CH2:46][C:45]([F:53])([F:52])[F:44])=[O:49])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: NNC(=O)NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution containing (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 mL) was added sequentially EDC.HCl (70.6 mg, 0.368 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl then with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography afford the title compound as a glassy oil (40 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, J=15.8 Hz, 1H), 6.42 (dd, J=16.0, 7.7 Hz, 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −68.56, −73.02; ESIMS m/z 627.9 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1
Reactant: NCCN1CCOCC1
Product: CC(C)c1ccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)cc1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(4-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.11 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=6.8 Hz, 6 H) 2.4 (m, 4 H) 2.6 (m, 2 H) 2.9 (qt, 1 H) 3.3 (m, 1 H) 3.4 (m, 1 H) 3.6 (m, 4 H) 6.6 (m, 1 H) 7.0 (s, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.5 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[C:22]([CH3:25])([CH3:24])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])([CH3:24])[C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCC2=C1C(C)(C)C=C2
Product: CC1C2=C(C=CC2(C)C)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7,7-trimethyl-2,3,4,7-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=O>CO>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[N:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NC1CCNC1
Solvent: CO
Product: Fc1cc(F)cc(C=NC2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.72 g (20 mmol) of 3-amino-pyrrolidine are initially introduced into 20 ml of methanol, and 2.84 g (20 mmol) of 3,5-difluorobenzaldehyde are added dropwise at 20° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for one hour and is concentrated in vacuo on a rotary evaporator, and the residue (4.5 g) is distilled. 0.9 g of an oil, boiling points 80° C.-85° C./0.04 mbar, are obtained, which decomposes to give a highly viscous mass within 4 weeks when stored at room temperature.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.87 min, m/z=459.0 [M+H]+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][O:5][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:9]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OCCc1cccc(OS(C)(=O)=O)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=O)cc2)c1
Yield: 86.1 %

Procedure:
9.3 g (31.6 mmole) 3-(methylsulfonyloxy)phenethyl methanesulfonate, 9.91 g (82 mmole) p-hydroxybenzaldehyde and 13 g (94.8 mmole) potassium carbonate in 200 ml acetonitrile were refluxed for 4 hours. The precipitate was filtered off and the solvent was evaporated in vacuo. Dichloromethane was added and the organic phase was washed with water, dried (magnesium sulfate), filtered and the solvent was evaporated to give 8.72 g (yield 88%) of 3-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>CN1C(=O)CCC1>[C:10]([NH:14][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Yield: 100.9 %

Procedure:
A solution of 2-amino-4,6-dichloropyrimidine (400 mg, 2.44 mmol) and t-butylamine (2.6 ml, 25.0 mmol) in NMP (1 ml) was heated in a microwave at 150° C. for 60 minutes. The reaction mixture was partitioned between water (10 ml) and ethyl acetate (10 ml), the organic phase separated, dried and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with ethyl acetate:pentane (30:70 changing to 80:20 by volume) to yield the title compound as a colourless solid (494 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:18][CH:17]=2)=[C:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:21][CH2:20]1
Reactant: Br[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=C(c2ccc(O)cc2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.76 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 6 mL of dry THF under argon atmosphere. To the stirred solvent was added 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.6 g, 2.41 mmol). The resulting mixture was cooled to 0° C. and was added cyclopropylmagnesium bromide (25 mL, 0.5 M in THF, 7.25 mmol). The resulting mixture was stirred at ambient temperatures for 2 h. Then, the reaction mass was quenched with 20 mL of 1N HCl then, ethyl acetate (50 mL) was added, stirred well and the layers were separated. The organic layer was washed with water (100 mL×3), brine solution. Then the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting crude compound is purified by column chromatography on silica gel (60-120 meshes) using petroleum ether (60-80) and ethyl acetate as eluent. The product was obtained as yellow solid. Yield: 42.76% (0.3 g) MS (ESI, 120 ev): m/z=291.1 (M+1). (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 6.95-6.98 (d, 2H), 6.53-6.56 (d, 2H), 4.42-4.43 (d, 1H), 2.54-2.59 (m, 1H), 1.61 (s, 4H), 1.29 (s, 3H), 0.40-0.49 (m, 2H), 0.23-0.28 (m, 1H), 0.03-0.01 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2[CH2:8][O:9][C:48](=[O:50])[NH:1][C:2]=2[N:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 154.1 %

Procedure:
To a cold (0° C.) solution of tert-butyl 1-[2-amino-6-[2-(benzyloxy)phenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-phenylethylcarbamate (0.210 g, 0.400 mmol) in THF (3.0 mL) including triethylamine (0.167 mL, 1.199 mmol) was added dropwise a solution of triphosgene (0.059 g, 0.200 mmol) in THF (1.0 mL). After stirred at 0° C. for 45 min, the mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction mixture was cooled at 0° C., and then quenched with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 2:1) to give tert-butyl 1-{7-[2-(benzyloxy)phenyl]-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-2-phenylethylcarbamate as a colorless oil (0.170 g, yield; 77%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([N:24]([CH3:25])[CH3:23])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: CNC
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Product: C[C@@H](C(=O)N(C)C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and dimethylamine: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.8, 2.6 Hz, 1H), 4.63 (q, J=6.6 Hz, 1H), 3.19 (m, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.38 (d, J=6.8 Hz, 3H), 0.93 (m, 1H), 0.57 (m, 2H), 0.26 (m, 2H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]#N)[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-:20].[K+].Cl.[OH-:23].[Na+]>O>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:19])[C:14](=[CH:17][CH:18]=2)[C:15]([OH:23])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-c2ccc(C#N)c(=O)[nH]2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1

Procedure:
A mixture of 92.5 g (0.37 mol) of 6-(3-acetylaminophenyl)-1,2-dihydro-2-oxonicotinonitrile, 185 g of potassium hydroxide, and 740 ml of water was heated at 105° for 30 hrs. The cooled reaction mixture was poured into 285 ml of concentrated hydrochloric acid and ice. The pH of the suspension was adjusted to 5.0 with aqueous sodium hydroxide solution and the solid filtered, washed with water, and dried to give 81.2 g of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid. ##EQU21##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([NH2:13])[CH2:6][CH2:5]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(F)c(F)cc2C1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1F)CC(N=C=S)CC2
Yield: 79.1 %

Procedure:
A mixture of (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56 g, 3.06 mmol), prepared as in Example 8, and 1,1'-thiocarbonyldiimidazole (0.82 g, 4.59 mmol) in 15 mL of ethyl acetate was stirred until the reaction was complete. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 5% acetone/methylene chloride) gave (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.55 g, 2.42 mmol). [α]D25 -15.5°, (C=1.0, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:19]([Cl:18])(=[O:21])=[O:20])[CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:13])([F:12])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccccc1Cl)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl)C(F)(F)F
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
(R)-N-(2-Chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 74) (13.8 g, 52 mmol) was added in portions to a cooled (0° C.) solution of chlorosulphonic acid (25 ml) over 15 mins and then the mixture was heated to 85° C. After 4.5 h the reaction mixture was cooled in an ice bath and then poured very slowly onto a stirred ice-water mixture. After stirring for 15 mins. the mixture was extracted with ethyl acetate (2×100 ml) and the combined organic layer washed with brine, dried and concentrated to yield a brown oil. This oil was purified by flash column chromatography using 10:1, iso-hexane: ethyl acetate to yield the title compound as a pale yellow solid (11 g, 30 mmol). NMR: 1.6 (s, 3H), 7.55 (dd, 1H), 7.6 (d, 1H), 7.95 (d, 1H), 9.7 (brs, 1H); MS: 364.