Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:29]=[C:30]=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:30](=[O:31])[NH:29][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCN=C=O
Reactant: Oc1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) is added dropwise under a nitrogen atmosphere to a solution of 2-phenylphenol (5.0 g, 29.3 mmol) and octyl isocyanate (5.5 g, 35.5 mmol) in 75 mL of methylene chloride. After the addition, the solution is stirred overnight at room temperature. The solution is washed with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.09 g of a tan solid. Recrystallization from diisopropyl ether-hexane gives the title compound as a white crystalline solid (6.88 g, 72%), mp 59°-60° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C1C=CC(O[C:56](OC2C=CC=CC=2)=[N:57][C:58]#[N:59])=CC=1>ClC(Cl)C>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@H:14]([CH3:15])[N:16]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])[C:56](=[N:57][C:58]#[N:59])[NH:39]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=NC#N)N[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
To a solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine (25.1 mg, 0.0424 mmol) in dichloroethane (1.5 mL) was added triethylamine (15 μL, 0.105 mmol) and diphenyl cyanocarbonimidate (13 mg, 0.053 mmol). The reaction was heated at 60° C. overnight, cooled to room temperature, filtered, and loaded directly onto a silica gel column for purification by flash chromatography with 10 to 40% EtOAc/hexanes to afford ((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylidene)cyanamide. Rf=0.20 (25% EtOAc/hexanes). LCMS=643.3 (M+1)+. 1H NMR (C6D6, 500 MHz; atropisomers present, doubling of some peaks) δ 6.53-8.83 (m, 10H), 3.61-4.91 (m, 3H), 3.28-2.70 (m, 5H), 1.14-1.25 (m, 6H), −0.39-0.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: COCCOCOc1cc(N)ccc1C#N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COCCOCOc1cc(NCc2ccc(F)cc2)ccc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
To a solution of 4-amino-2-(2-methoxy-ethoxymethoxy)-benzonitrile (666 mg; 3 mmol) in 1,2-dichloroethan (15 mL) was added 4-fluorobenzaldehyd (496 mmol; 4 mmol) and carefully sodium triacetoxyborohydride (933 mg; 4.4 mmol). The mixture was stirred at 60° C. for 6 hours. The reaction mixture was added 1 M NaOH (aq.), dried by filtering through a silicone filter, evaporated onto SiO2 and purified by column chromatography (SiO2-heptane/EtOAc=2:1) to yield 700 mg pure product.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[NH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.[Br:23]Br.CC(C)=O.CCCCCC>O.C(Cl)(Cl)Cl>[Br:23][C:17]1[N:18]=[C:14]([C:9]2[CH:10]=[C:11]([Cl:13])[CH:12]=[C:7]([Cl:6])[CH:8]=2)[NH:15][C:16]=1[C:19]([F:20])([F:22])[F:21]
Reactant: FC(F)(F)c1cnc(-c2cc(Cl)cc(Cl)c2)[nH]1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1[nH]c(-c2cc(Cl)cc(Cl)c2)nc1Br

Procedure:
Sodium bicarbonate is made into a paste by adding a few drops of water to 1.5 g (9.4 mol). The 2-(3,5-dichlorophenyl)-5-trifluoromethylimidazole is dissolved in 100 ml chloroform and added to the flask containing the paste. 1.5 g of bromine is added and stirred. TLC on alumina using 50:50 acetone-hexane clearly differentiates starting material from product. Additional bromine is added until starting material is no longer present (0.1 g). Water is added and the organic phase removed. The layer is washed with sodium bisulfite, brine and dried over sodium sulfate. The organic phase is stripped and the residue taken up in 1:1 ether hexane and filtered through silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH3:12][CH2:13][CH2:14][CH:15]([NH:19][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(N)CCC
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: CCCC(CCC)NC(=O)c1ccc(O)c(O)c1
Yield: 25 %

Procedure:
N-(heptan-4-yl)-3,4-dihydroxybenzamide was prepared in a similar manner to example 4 using 3,4-dihydroxybenzoic acid and heptan-4-amine. Yield: 25%. MS (M+H, 252.1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].Cl>C1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:2]([NH:1][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[C:3]([C:7]=1[CH3:17])[C:4]([OH:6])=[O:5])=[O:13])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(NC(=O)C(C)C)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To an ice-cooled mixture consisting of 500 mg of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 15 ml of benzene, and 0.3 ml of pyridine was added dropwise with stirring a solution of 323 mg of isobutyryl chloride in 2 ml of benzene. After completion of the addition, the reaction mixture was further stirred for 5 hours at room temperature, and then heated to reflux for one hour. After cooling, the mixture was shaken with dilute hydrochloric acid and the layers were separated. The slightly acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was recrystallized from ethyl ether/n-hexane to yield 523 mg of 5-ethoxycarbonyl-2-isobutyrylamino-4,6-dimethylbenzoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[C:15]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16]>>[C:15]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:25]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: CC(=O)C1(c2cccc(O)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CC(=O)C1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Yield: 52 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-acetyl-4-(3-hydroxyphenyl)tetrahydropyran to give 4-acetyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 52% yield, m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH:10]=[CH2:11])[CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: C=Cc1cc(Cl)c(Cl)cc1N
Agent: [Pd]
Solvent: CO
Product: CCc1cc(Cl)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
A mixture of 4,5-dichloro-2-vinylbenzenamine (3.0 g, 15.95 mmol), Pd/C (3.3 g, 10%) in MeOH (20 mL) was stirred at room temperature under H2 (1 atm) atmosphere for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product (2.4 g, 80% yield).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3]CC)=[O:2].Cl>C(O)(=O)C>[C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCC1CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCCC1CCCC1=O

Procedure:
In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13](O)([CH3:15])[CH3:14])[CH:10]=[N:11][CH:12]=1)([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][C:13]([C:9]1[CH:10]=[N:11][CH:12]=[C:7]([CH2:6][O:5][Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:1]([CH3:3])[CH3:2])[CH:8]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[Si](OCc1cncc(C(C)(C)O)c1)(C(C)C)C(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si](OCc1cncc(C(C)(C)F)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To 2-(5-((triisopropylsilyloxy)methyl)pyridin-3-yl)propan-2-ol (1.1 g, 3.4 mmol) in DCM (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST) (0.67 mL, 5.1 mmol) and stirred at the same temperature for 1 hr, then warmed to 0° C. for 3 hrs. The resulting mixture was quenched with MeOH and saturated aqueous NaHCO3. The mixture was extracted with EtOAc three times and dried with anhydrous NaSO4, filtered and concentrated to dryness. Careful purification by flash chromatography (silica gel, hexanes/EtOAc) gave the desired fluoride (3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine) as a light yellow solid (0.43 g). 1H NMR (CDCl3): d: 1.127 (d, J=6.3 Hz, 18H), 1.204 (m, 3H), 1.712 (s, 3H), 1.786 (s, 3H), 4.922 (s, 2H), 7.781 (s, 1H), 8.566 (s, 2H). 3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine was deprotected with excess aqueous HF in THF to provide (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol as a white solid. (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol was then oxidized to 5-(2-fluoropropan-2-yl)nicotinaldehyde using standard Swern Oxidation conditions.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (2.8 ml, 32 mmol) in dichloromethane (150 ml) was added dimethylsulfoxide (5.0 ml, 64 mmol) at −78° C. The mixture was stirred for 5 minutes at −50° C. A solution of cis/trans-4-hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (3:1) (5.0 g, 27 mmol) in dichloromethane (30 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (18.7 ml, 134 mmol). The cooling bath was removed 15 minutes after completed addition, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated to approximately 20-30 ml by rotating evaporation. The residue was partitioned between ethyl acetate (200 ml) and 0.5 M aqueous hydrochloric acid solution (100 ml). The layers were separated. The aqueous layer was extracted with one 100-portion of ethyl acetate. The combined organic layers were washed with one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (4.9 g, 98%) as light yellow oil, which was used in the next step without further purification. MS m/e: 185 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:20])([F:22])[F:21])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[C:3]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: Cc1sc2nc(Cn3cc(C=O)c(C(F)(F)F)n3)[nH]c(=O)c2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1sc2nc(Cn3cc(CO)c(C(F)(F)F)n3)[nH]c(=O)c2c1-c1ccccc1
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a stirred solution of 1-((6-methyl-4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (97 mg, 0.232 mmol) in DCM (2 mL) and MeOH (2 mL) was added sodium borohydride (26 mg, 0.696 mmol) and the mixture was stirred overnight. Sodium borohydride (53 mg, 1.39 mmol) was added and the mixture was stirred for a further 20 h. The reaction mixture was quenched with water and concentrated in vacuo. The residue was taken up in 1:1 DMSO:MeCN, filtered and purified by preparative LCMS to give the title product as a white solid (10 mg, 0.024 mmol, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([F:22])[F:21])=[CH:16][CH:17]=2)[C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:27]>C(#N)C>[Cl:27][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)[C:9]([CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:24])=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc12
Solvent: CC#N
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Yield: 97.8 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-difluoromethoxy-2H-phthalazin-1-one (6.64 g, 17.8 mmoles), prepared as described in example 98, in acetonitrile (70 ml), under N2, was added with POCl3 (8.3 ml, 89 mmoles). After 4.5 hours under reflux and 1 night to stand, the mixture was dried under vacuum, taken up in CH2Cl2 and washed with an aqueous Na2CO3 solution, then discoloured with charcoal, filtered over celite and dried again to give 6.8 g of the title compound (yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:39]=[CH:38][C:25]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([F:37])[F:36])[CH:30]=3)=[O:27])=[C:24]([O:40][CH3:41])[CH:23]=2)[N:17]=1>[OH-].[K+].N>[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:39]=[CH:38][C:25]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([F:37])[F:36])[CH:30]=4)=[O:27])=[C:24]([O:40][CH3:41])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Agent: N
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 27.3 %

Procedure:
The solution of 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide (0.070 g, 0.11 mmol) in 20% aq. KOH (10 mL) and aq. NH3 (2 mL) was stirred for 24 h at RT. Excess of solvent was removed under vacuum and filtered off to afford 0.015 g of desired product.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (47 grams) in N,N-dimethylformamide (886 mL) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6:1 hexane/methylene chloride to afford 32 grams of the title compound. 1H NMR δ 7.02 (s, 2), 3.71 (br s, 2), 2.91 (qq, 2, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz), 6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]=[CH2:14])[C:5]([O:7][CH3:8])=[O:6].[Zn](CC)[CH2:16]C.ClCI.[NH4+].[Cl-]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=COc1ccc(C(=O)OC)cc1Br
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of methyl 3-bromo-4-vinyloxy-benzoate (1.00 g, 3.89 mmol, 1.00 eq) in DCM (15.00 mL) was added ZnEt2 (960.91 mg, 7.78 mmol, 2.00 eq) at 0° C. under N2 protection. Then the mixture was stirred at 0° C. for 30 min, and ClCH2I (1.72 g, 9.73 mmol, 2.50 eq) was added. The formed mixture was stirred at 25° C. for 16 hrs. The mixture was poured into NH4Cl solution, and extracted with EA, the combined organic layer was dried over Na2SO4, concentrated, the residue was diluted in THF (5.00 mL) and H2O (5.00 mL), NaIO4 (832.00 mg, 3.89 mmol, 1.00 eq) and K2OsO4 (74.01 mg, 389.00 umol, 0.10 eq) was added, the mixture was stirred at 25° C. for 30 min, then the reaction was quenched by saturated Na2SO3, extracted with EA, the combined organic layer was dried over Na2SO4, concentrated, the residue was purified by silica gel chromatography (PE:EA=10:1) to afford product methyl 3-bromo-4-(cyclopropoxy)benzoate (530.00 mg, 1.95 mmol, 50.26% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.01 Hz, 1H), 8.00 (dd, J=8.78, 2.01 Hz, 1H), 7.28-7.33 (m, 1H), 3.92 (s, 3H), 3.88 (t, J=4.39 Hz, 1H), 0.76-0.99 (m, 4H).
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>O>[CH2:1]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOCCOCCS(=O)(=O)c1ccc(C)cc1
Yield: 80.8 %

Procedure:
A mixture of 116 g of 2-[2-(decyloxy)ethoxy]-ethanol, 98.73 g of tosyl chloride and 600 ml of pyridine was stored in a chill room overnight, then poured into water and extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid and dilute aqueous sodium bicarbonate, dried and the ether removed, giving 146.3 g of the desired compound as an oil.
Reaction SMILES: N1C2C(=CC=CC=2)CC1.[F:10][C:11]([F:40])([F:39])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(=O)C)[CH2:31][CH2:30]4)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>O1CCOCC1>[F:39][C:11]([F:10])([F:40])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH2:31][CH2:30]4)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Agent: c1ccc2c(c1)CCN2
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75 %

Procedure:
5-|4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl|-2,3-dihydro-1H-indole: 1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanone was refluxed in 1,4-dioxane (5 mL) and concentrate HCl (2.5 mL) for 2 h. The reaction was then diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, dried (Na2SO4), filtered and concentrated to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (1.03 g, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48-7.20(m, 4H) 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33 (m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:15][CH:14]=1
Reactant: COc1ccc(NN)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (459 g, 2.63 mol), 4-bromobenzyl bromide (715 g, 2.86 mol) and milled potassium carbonate (771 g, 5.58 mol) was suspended in 2 L DMF at 0° C. with overhead stirring. The ice bath was removed and the mixture was stirred for 4 h, then diluted with 15 L of ice water. The mixture was stirred vigorously for 1 h, then the aqueous layer was decanted from the gummy solid. The solid was washed with 2×4 L of water, then was dissolved in 2.5 L toluene and dried over Na2SO4. The mixture was filtered, and the filtrate was cooled in an ice bath and treated with a stream of HCl gas for 1 h with vigourous stirring. The precipitate was filtered and washed with 3×0.5 L of cold toluene and dried under a stream of nitrogen to give 682 g of the title compound.