Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C(C)=CC=CC=1>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 51.1 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 51.9 g (0.2 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine and 400 ml of xylene were charged and dissolved. To this solution, 160 g (0.4 mol) of a 10% sodium hydroxide aqueous solution and 6.4 g (0.02 mol) of tetrabutylammonium bromide were added, and the mixture was reacted under reflux for 5 hours. The reaction mixture was cooled and subjected to liquid separation. The xylene layer was washed with water. The xylene layer was concentrated and subjected to column chromatography to obtain 22.8 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 51.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:40]([Cl:42])=[O:41])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (46 g, 95.97 mmol, example 1) and triethylamine (66.9 mL, 479.9 mmol) in methylene chloride (2 L) cooled to 0° C. was added phosgene (124.3 mL, 239.9 mmol, ˜20% solution in toluene) dropwise over a period of 30 min. The reaction mixture was stirred at room temperature for 1 h. Nitrogen gas was bubbled through the reaction mixture to remove excess phosgene. The reaction mixture was concentrated to dryness, and the residue was dried in vacuo for 1 h to give 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (51 g, 98% yield) as off-white solids. The product was used without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16]>C1COCC1.CCCCCC>[OH:16][CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC#Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)C#Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 4.40 mL (40.0 mmol) of phenylpropyne in 30 mL of THF under nitrogen at -75° C. was added a solution of 16 mL (40 mmol) of 2.5M n-butyllithium in hexane over 20 min. The resulting light yellow solution was warmed to 0° C. and stirred for 30 min. This solution was added via syringe to a slurry of 6.25 g (38.0 mmol) of methyl 4-formylbenzoate in 30 mL of THF at -30° C. over 20 min. The resulting light yellow solution was warmed to room temperature and stirred for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ether, dried (MgSO4) and evaporated. Purification by flash chromato-graphy (5×15 cm column, 1:19 ether/dichloromethane as elutent) gave title compound as a white solid, mp 48°-50° C., 9.36 g, 88% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[CH:31]=[CH:32][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Yield: 73 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-chloro-4-methylsulfonylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 73% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-chloro-4-methylsulfonylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 583.0263. Calcd. mass, 583.0264 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([CH3:18])[NH:13]1>C(#N)C>[CH3:11][CH:12]1[NH:13][CH:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Solvent: CC#N
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Temperature: 90 °C
Yield: 68 %

Procedure:
1-Fluoro-4-nitro-benzene (1.00 g, 8.75 mmol) and 2,6-dimethyl-piperazine (1.20 g, 10.5 mmol) were dissolved in 100 ml of acetonitrile forming a yellow homogeneous mixture. Mixture is heated at 90° C. overnight. Mixture is reduced on rotovap to afford the product as an orange solid (1.40 g, 65%); 1H NMR (DMSO-d6) δ 1.00 (d, J=6.3 Hz, 6H), 2.37-2.80 (m, 5H), 3.87 (dd, J=2.1, 12.4 Hz, 2H), 7.00 (d, J=9.5 Hz, 2H), 8.00 (d, J=9.5 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28]Br)=[N:26][CH:27]=1.CN(C=O)C>C(#N)C>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:26][CH:27]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.29 g (16.7 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) in acetonitrile is added at RT subsequently 4.63 g (33.4 mmol) potassium-carbonate and 4.20 g (16.7 mmol) 5-bromo-2-bromomethyl-pyridine. The reaction mixture is stirred 3 h at RT and 5 mL DMF is added. The reaction mixture is stirred overnight and the solvent is evaporated. To the residue water and tert-butylmethylether is added. The precipitate is collected and dried.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13]O.S(=O)(=O)(O)O>>[C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CCCCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCC(C)(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
neo-Decanoic acid (1,376 g, 8.0 mol) and methanol (1,280 g, 40 mol) were placed in a 5-liter four-neck round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer. To the mixture at ambient temperature was added conc sulfuric acid (548 g, 5.6 mol) in a dropping funnel for 15 min, raising the pot temp to 55° C. at the end of the addition. The resulting mixture was kept overnight (20-24 h) under reflux with vigorous stirring and then cooled to ambient temperature. The aqueous phase separated, and the remaining organic layer was washed with water until the pH of the last washing was >4. One gram of the organic phase was withdrawn and titrated with 1.0 N NaOH. The calculated amount of NaOH was added to remove the unreacted neo-decanoic acid present in the crude ester. Then the ester was washed with water (88 mL×3) followed by brine (NaCl-saturated, 500 mL). About 100 mL methanol was added into the crude ester and then the resulting mixture was distilled to obtain methyl neodecanoate (749 g, 4.03 mol) at 175-205° C. at atmospheric pressure. The purity of the ester was >99%, and the yield 50% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][O:10][C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:15](Cl)=[N:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(N(C(C)C)C(C)C)C.[Cu]I>[CH3:9][O:10][C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:14][CH:13]=1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnc(C#Cc2ccccn2)c(-c2ccc(Cl)cc2)c1
Temperature: 120 °C

Procedure:
A degassed solution of 2-ethynyl-pyridine (2.0 mmol, CAN 1945-84-2) in tetrahydrofuran and N-ethyldiisopropylamine (1:1, 10 ml) was added to a degassed suspension of 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester (1.0 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (49 mg, 0.06 mmol), polymer supported triphenylphoshine (135 mg, 1.48 mmol/g, 0.2 mmol) and copper(I)iodide (11 mg, 0.06 mmol) in tetrahydrofuran and N-ethyldiisopropylamine (1:1, 5 ml). The reaction mixture was heated at 120° C. for 20 hours under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The solids were washed with ethyl acetate (100 ml), the organic liquors were combined and washed with saturated aqueous ammonium chloride solution (3×50 ml). The organic layer was then dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate/heptane) gave the title compound as brown oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].[Cl:9][C:10]1[C:15]([F:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([O:8][CH2:3][C:4]#[C:5][CH2:6][CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CCC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC#CCOc1ncnc(Cl)c1F
Reaction time: 0.17 h
Yield: 102.9 %

Procedure:
0.58 g of sodium hydride (60% oil suspension) was suspended in 20 ml of tetrahydrofuran. 1 ml of tetrahydrofuran solution of 0.88 g of 2-pentyn-1-ol was added dropwise at 0° C. therein slowly, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 5 ml of tetrahydrofuran solution of 2 g of 4,6-dichloro-5-fluoropyrimidine at 0° C., and stirred for 70 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.31 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[N:5]([C:26](=[O:27])[CH2:25][CH2:24][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](C)NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@@H](C)C(=O)OC

Procedure:
The starting material can be obtained, for example, analogously to Example 2: Reaction of 2.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester, 1.23 ml of triethylamine and 0.92 ml of n-butyryl chloride yields N-butyryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester. (TLC: N2) Rf : 0.5.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:53][C:54]([F:69])([F:68])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[O:18]=[C:16]([N:65]1[CH2:64][CH2:63][CH:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[C:54]([F:53])([F:68])[F:69])[CH2:67][CH2:66]1)[CH2:15][C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)=[O:19]
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole) After 2 minutes (2-trifluoromethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.075 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 73.7 mg (64%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-propionamide. LC-MS purity: 483.19 (M+1)+, 95.78%, 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (dd, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.5-7.4 (m, 4H), 7.0 (d, 1H), 6.8 (t, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.8-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.9-2.8 (m, 1H), 2.0 (m, 1H), 1.6-1.5 (m, 1H), 1.5-1.4 (m, 1H).
Reaction SMILES: O[C@@H:2]1[C@@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:8]2[C:17]([O:20][CH3:21])([O:18][CH3:19])[C@@:4]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])([C:5]([O:23][CH3:24])=[CH:6][C:7]2=[O:22])[CH2:3]1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N-]CC)C.[Li+].Cl[Si](C)(C)C>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:5]1[C:4]2([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])[C:17]([O:18][CH3:19])([O:20][CH3:21])[C:8]3([C:7](=[O:22])[CH:6]=1)[CH:2]([C:9]3([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3]2
Reactant: COC1=CC(=O)[C@H]2C(OC)(OC)[C@]1(CC=C(C)C)C[C@H](O)[C@@]2(C)CCC=C(C)C
Agent: CC[N-]CC
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC1=CC(=O)C23C(CC1(CC=C(C)C)C2(OC)OC)C3(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A DCM (2.3 mL) solution of 25 (47.7 mg, 0.12 mmol, 1 equiv.) and pyridine (57 μL, 0.70 mmol, 6 equiv.) was cooled to −40° C. in a 10-mL recovery flask, and trifluoromethanesulfonic anhydride (99 μL, 0.59 mmol, 5 equiv.) was added dropwise. The yellow slurry was allowed to slowly warm to 0° C. over 45 min, whereupon it was quenched at 0° C. with saturated aqueous NaHCO3. The mixture was extracted thrice with EtOAc. The combined organic extracts were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil, which was used without further purification due to its propensity to decompose upon standing. A THF (1 mL) solution of this brown oil was cooled to −78° C. in a 10-mL test tube, and a freshly prepared THF solution of lithium diethylamide (0.50 M, 1.2 mL, 0.59 mmol, 5 equiv.) was added. The resulting brown-orange solution was allowed to slowly warm to 0° C. over 40 min and stirred at 0° C. for 10 min. At this time, chlorotrimethylsilane (150 μL, 1.2 mmol, 10 equiv.) was added. The red solution subsequently turned bright orange and was stirred at 0° C. for 15 min. The solution was then quenched at 0° C. with saturated aqueous NaHCO3 and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil. Flash column chromatography (30 mL SiO2, 9:1 to 8:2 hexane:EtOAc) afforded 16.5 mg (42 μmol, 35% yield over 2 steps) of 26 as a yellow oil. TLC Rf 0.39 (8:2 hexane:EtOAc). TLC Rf 0.39 (8:2 hexane:EtOAc). 1H NMR (500 MHz; C6D6): δ 5.58 (t, J=6.9 Hz, 1H), 5.50 (t, J=7.2 Hz, 1H), 5.45 (s, 1H), 3.05 (s, 3H), 3.02 (s, 3H), 3.01 (s, 3H), 2.87-2.79 (m, 2H), 2.37 (m, 2H), 1.99 (dd, J=13.4, 6.6 Hz, 1H), 1.87 (td, J=12.3, 5.2 Hz, 1H), 1.79 (s, 3H), 1.77-1.73 (m, 2H), 1.70 (s, 6H), 1.60 (s, 3H), 1.56 (s, 3H), 0.89 (t, J=7.0 Hz, 1H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[CH:23]=1)#[N:6]>CCOCC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][Br:2])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[CH:23]=1)#[N:6]
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc2c(c1)Sc1ccc(CO)cc1CC2
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)Sc1ccc(CBr)cc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Phosphorous tribromide (0.2 ml) was added to a suspension of 3-cyano-8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin (500 mg; 1.87 mmole) in ether (7 ml). The reaction mixture was stirred at room temperature for one hour, then poured onto ice, extracted with ether (3×50 ml), dried over Na2SO4 and evaporated to afford 581 mg (95%) of 3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin as an oil.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:23])[CH2:21][CH2:20][O:19][CH:18]3[CH3:22])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:23])[CH2:21][CH2:20][O:19][CH:18]3[CH3:22])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: [H][H]
Reactant: CC1OCCC1(O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Product: CC1OCCC1(O)c1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2-methyl-tetrahydro-furan-3-ol and hydrogen. Yellow oil. MS (m/e): 220.3 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:7]=1)[O:8][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: Cc1ccc(Br)cc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Yield: 90.3 %

Procedure:
To a solution of 5-bromo-2-methylphenol (1.0 g, 0.005 mol) in DMF (10 mL) was added K2CO3 (1.38 g, 0.01 mol) at RT. 2-Chloro-5-(trifluoromethyl)pyridine (908 mg, 0.005 mol) was added and the reaction was refluxed at 110° C. for 12 h. The reaction mixture was quenched with water and extracted with EtOAc three times. The organic extract was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.5 g, 88%). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.92 (d, J=2.15 Hz, 1H), 7.32 (t, J=6.45 1H), 7.23 (d, J=1.5 Hz, 1H), 7.17 (d, J=8.05 Hz, 1H), 7.03 (d, J=8.65 Hz, 1H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.C[N:16]1CCOCC1.C(=O)=O.ClC(OCC(C)C)=O.N.CO.[Cl-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH2:16])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCCC(N)=O)cc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4-(4-Methoxyphenyl)butyric acid (1) (450 g, 2.32 mole) was combined with dry THF (4 L) and 4-methylmorpholine (268 mL, 2.43 mole) in a 12 L three neck flask with mechanical stirring, an ice-methanol cooling bath and nitrogen atmosphere. Small pieces of dry ice were used to bring the bath temperature below −20° C. Isobutyl chloroformate was added at a rate so as not to exceed an internal temperature of −10° C. After stirring for 30 min. at −10 to −20° C., a 4.7 M solution of ammonia in methanol (990 mL, 4.64 mole) was added in one portion. During the addition, the reaction temperature rose to 0° C. The reaction was allowed to stir for 30 min. and then allowed to stand overnight. The product mixture was transferred to a 22 L separatory funnel with ethyl acetate (6 L), and 10% sodium chloride solution (1.5 L). The layers were separated and the organic solution was washed with 10% sodium chloride solution (4×1 L) and then brine (3×500 mL). The organic layer was dried over sodium sulfate, filtered, evaporated and placed under high vacuum overnight. This afforded 432 g (97%) of the pure amide (117) as an off white solid.
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][NH:9][C:10]([NH2:12])=[NH:11].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](OC)=O>CO>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([C:18]2[NH:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Reactant: N=C(N)NN
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(-c2cccc(C(F)(F)F)c2)[nH]1
Temperature: 0 °C
Yield: 13.4 %

Procedure:
To a solution of sodium methanolate (1.05 g, 19.44 mmol, 4.00 equiv) in methanol (40 mL) at 0° C. was added aminoguanidine bicarbonate (2.66 g, 19.54 mmol, 4.00 equiv) in several batches. To this was added dropwise a solution of methyl 3-(trifluoromethyl)benzoate (1 g, 4.90 mmol, 1.00 equiv) in methanol (10 mL) with stirring at 0° C. The resulting solution was then stirred overnight at 75° C. in an oil bath. The reaction was then quenched with 10 mL of water/ice, the solution adjusted to pH 3-4 with hydrochloric acid (1 mol/L), and the solids were collected by filtration To afford 150 mg (13%) of 5-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-amine as a yellow solid.