Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35]>>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH3:35])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCOC
Product: COCCN(C)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and 2-Methoxyethylmethylamine were converted to yield (2-Methoxy-ethyl)-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine as orange oil, MS: 433 (MH+).
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:10]1[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
Reactant: OB(O)c1cc(F)ccc1F
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
A deoxygenated mixture of crude tert-butyl (2S)-2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (2-4, 7.65 mmol), 2,5-difluorophenyl boronic acid (1.81 g, 11.5 mmol), aqueous Na2CO3 solution (2 M, 11.5 mL, 23.0 mmol), and Pd(PPh3)4 (0.442 g, 0.383 mmol) in dioxane (100 mL) was heated at 90° C. for 45 minutes. The reaction mixture was cooled, then partitioned between brine (200 mL) and a 1:1 mixture of ethyl acetate and hexane (200 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (SiO2, O-50% EtOAc/hexanes gradient) to provide tert-butyl (2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (2-5) as a white solid. LRMS nvz (M+H-CH3) 358.0 found, 358.2 required.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[F:1])([CH3:32])[CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)#[N:18]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=494, RT=0.73 min.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[C:12](=[O:36])[N:11]1[CH3:37])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][C@H:10]1[CH2:14][N:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:35])[F:34])[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[C:12](=[O:36])[N:11]1[CH3:37]
Reactant: [H][H]
Reactant: CN1C(=O)N(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)N(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C[C@@H]1CO
Yield: 104.5 %

Procedure:
The 7-((R)-4-benzyloxymethyl-3-methyl-2-oxoimidazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (13 mg, 0.025 mmol) prepared in Example 1-35 was dissolved in methanol (5 ml). Thereafter, 10% Pd—C (3 mg) was added to the obtained solution, and the obtained mixture was then stirred in a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was then concentrated. The obtained residue was purified by silica gel TLC used for preparative separation (dichloromethane:methanol=20:1), so as to obtain 7-((R)-4-hydroxymethyl-3-methyl-2-oxoimidazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.9 mg, quantitative) in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]1=[O:25].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[CH:19][C:18](=[O:25])[N:17]([CH3:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(=O)n(C)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[N:13]1([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH2:23])[CH:17]=[N:16][CH:15]=[N:14]1>>[N:13]1([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-n1cncn1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cncn2)cc1

Procedure:
The title compound was prepared from 2-(4-methoxyphenyl)acetic acid (233 mg, 1.41 mmol) and 2-(1H-1,2,4-triazol-1-yl)thiophen-3-amine (234 mg, 1.41 mmol) according to protocol B. Retention time (min)=2.847, method [7], MS (ESI) 315.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.31 (s, 1H), 7.99 (d, J=5.3 Hz, 1H), 7.83 (s, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.09 (d, J=5.3 Hz, 1H), 6.94 (d, J=8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 2H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1.N1CCCCC1>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:23]=1
Reactant: OCCCc1cccnc1
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2cccnc2)C(=O)N1CCCCOc1cccn2ccnc12

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 676 mg (5.0 mmol) of 3-(3-pyridyl)-1-propanol in 20 ml of ethanol, 43 mg (0.5 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1→25/1) to yield 0.49 g (23.0%, yellow oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]>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>[N:6]1[CH:7]=[CH:2][CH:3]=[C:4]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Yield: 171.5 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (from Example 23a, 500 mg, 1.28 mmol) in toluene (10.0 mL) was added 3-pyridinyltributyltin (564 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (428 mg, 86%). MS (CI/NH3) m/z 390 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.24-1.67 (m, 2H), 1.44 (s, 9H), 1.86-2.10 (m, 2H), 3.32-3.45 (m, 2H), 3.95-4.27 (m, 3H), 7.28-7.44 (m, 2H), 7.81-7.86 (m, 1H), 8.14-8.17 (m, 1H), 8.65-8.73 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH:28]C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH2:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][C:7]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CN(c1ccc(Oc2ccccc2)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(Oc2ccccc2)cc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-phenoxyphenyl)glycine methyl ester (0.375 g, 0.69 mmol) in 6 mL TFA/DCM (1:1) is stirred at ambient temperature for 20 min. The solvent is removed under reduced pressure. Methylene chloride is added to the residue and removed under reduced pressure. The resulting oil is purified by flash chromatography using 10% EtOAc/DCM to elute N-sulfamoyl-N-(2-benzyloxy-4-phenoxyphenyl)glycine methyl ester as an oil: 1H NMR (CDCl3) δ 7.44 (d, J=8.59 Hz, 1H), 7.33-7.26 (m, 7H), 7.09 (t, 1H), 6.97-6.93 (m, 2H), 6.60 (d, J=2.52 Hz, 1H), 6.43 (dd, J=8.59, 2.53 Hz, 1H), 4.96 (s, 2H), 4.26 (s, 2H), 3.62 (s, 3H); MS (M−H)−=441.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(#N)C>[C:17]([C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:4]([CH:1]1[CH2:2][CH2:3]1)=[CH:12]2)#[N:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) (1.0 g, 4.0 mmol) in dry acetonitrile (25 mL) was added cesium carbonate (2.6 g, 8.0 mmol) and t-butyl bromoacetate (768 uL, 5.2 mmol) at rt. The mixture was stirred at 85° C. overnight. The solid was filtered and the filtrate was then concentrated in vacuo. The residue was triturated with EtOAc-hexane to afford the title compound (1.23 g) in quantitative yield: MS (ES) m/z 365 (M+1).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C=CC=CC=1>C(N(CC)CC)C>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:18]3[N:20]=[CH:21][C:22](=[O:23])[O:24]3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)NCC(=O)O)cc2C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC1Cc2ccc(C3N=CC(=O)O3)cc2C1
Temperature: 25 °C

Procedure:
Subsequently, 1.55 g (4.68 mM) of N-(2-octylindan-5-carbonyl)glycine and 25 ml of dry benzene were placed in a 50 ml-three necked flask. Under stirring at room temperature, 0.66 ml (4.74 mM) of triethylamine and 0.46 ml (4.81 mM) were successively added to the above mixture, followed by further stirring for 23 minutes at room temperature to precipitate a crystal. After the reaction, the precipitated triethylamine hydrochloride was removed by filtration and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was dried under reduced pressure to obtain 2-(2-octylindan-5-yl)-5-oxazolone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:26]([O:28][CH:29]([O:32][CH2:33][CH3:34])[C:30]#[CH:31])[CH3:27]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH:29]([O:32][CH2:33][CH3:34])[O:28][CH2:26][CH3:27])=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C#CC(OCC)OCC
Reactant: C=C(c1ccccc1I)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(c1ccc(C#CC(OCC)OCC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-3-(iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (4.0 g, 8.8 mmol-see Preparation 20), 3,3-diethyloxyprop-1-yne (1.52 ml, 10.6 mmol), copper(l)iodide (0.02 g) and bis(triphenylphosphine)palladium dichloride (0.12 g) In triethylamine (40 ml) and tetrahydrofuran (13 ml) was stirred at room temperature for 18 hours. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was flash chromatographed on silica by elution with ethyl acetate. Fractions containing the desired product were combined and evaporated under reduced pressure to yield 2-(2,4-difluorophenyl)-3-(4-[3,3-diethoxyprop-1-yn-1-yl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol as a yellow gum (2,4 g, 60%). Trituration with cyclohexane gave an off-white solid which was characterised by NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:15]#[N:16])[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]#[N:9])[CH3:2].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19].COCCOC>[OH-].[Pd+2].[OH-].[C].C(N(CC)CC)C>[S:18]([OH:22])([OH:21])(=[O:20])=[O:19].[NH2:9][CH2:8][C:7]1[C:6]([C:15]#[N:16])=[C:5]([F:17])[C:4]([O:3][CH2:1][CH3:2])=[C:11]([O:12][CH2:13][CH3:14])[CH:10]=1
Reactant: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Agent: [Pd+2]
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCOc1cc(CN)c(C#N)c(F)c1OCC
Temperature: -22 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 4,5-diethoxy-3-fluorophthalonitrile (2.34 g, 10 mol) prepared in Preparation Example 1, sulfuric acid (0.56 mL, 10 mol), 20% palladium hydroxide-carbon (0.59 g, 50% hydrate) (20% palladium-carbon powder, palladium hydroxide type (hydrate), N.E. Chemical Corporation) and 1,2-dimethoxyethane (23 mL) was stirred at −22° C. under hydrogen atmosphere (atmospheric pressure) for 24 hours. After insoluble matter in the reaction mixture was filtered off, the residue was washed with methanol (23 mL) and the combined filtrate was divided into five equal portions. After one of them was concentrated at room temperature under reduced pressure, 1,2-dimethoxyethane (9.2 mL) was added thereto, and the mixture was stirred. Then, triethylamine (0.56 mL, 4 mol) was added dropwise thereto and the mixture was stirred at room temperature for one hour. Precipitated crystals were filtered, washed with a 5% methanol-1,2-dimethoxyethane solution, and dried at room temperature under reduced pressure to give 0.59 g of the ½ triethylamine solvate of the title compound (yield: 76%) as dark white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[N+:24]([O-:26])=[O:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of 3-(benzyloxy)phenol (1.145 g, 5.72 mmol) and 2,5-dichloronitrobenzene (1.154 g, 6.01 mmol) in 15 mL of DMSO was added cesium carbonate (3.72 g, 11.4 mmol). The reaction was heated to 70° C. under argon for one hour, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]([N:16]1[CH2:17][C:18](=[O:19])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])([CH3:15])[CH3:14]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (6.8 g) as a light pink solid, m.p. 112°-114° C. Anal. Calcd. for. C15H2O N2O S: C, 65.18; H, 7.29; N, 10.13, Found: C, 65.51; H, 7.25; N, 10.32. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][O:20][C:13]3[C:14]([Cl:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[Cl:11])=[CH:25][CH:26]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CBr)cc2)c(Cl)c1
Reactant: N#CCc1ccc(Br)cc1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using commercially available (4-bromophenyl)acetonitrile and 1,3-dichloro-2-{2-[4-(bromomethyl)phenoxy]ethoxy}-5-methylbenzene (II.2) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 15%, afforded the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][C:23](C)(C)C)=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a cooled (0° C.) solution of (rac)-tert-butyl 2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetate (example 97) (102 mg, 0.26 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (0.26 mL, 1.04 mmol) and the reaction mixture was stirred at room temperature for 16 h. The solution was cooled (0° C.) again and treated with 4M HCl in dioxane (0.39 mL, 1.56 mmol). After 1 h at room temperature, the solution was evaporated to dryness. The residue was suspended in EtOAc, filtered and dried to give the title compound (46 mg, 51%, 80% purity with 20% of corresponding acid) as a grey solid. MS: 352.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[C:11]1([O:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
Phenyl-3-chlorobenzoate is prepared by reacting 3-chlorobenzoyl chloride with phenol in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that evolves. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:17][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:21][N:20]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Oc3ccccc3)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of 0.09 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.45 g of 2-chloro-4-phenoxyphenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.34 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 2-chloro-5-(2-chloro-4-phenoxyphenoxy)methylpyridine. Yield, 71%. n22 1.6173 Yield, 71%. nD22 : 1.6173