Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:7]=1.C(Cl)(=O)OCC>C(N(CC)CC)C>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[C:9](=[O:11])[CH2:10][C:6]([CH3:5])=[N:7]2)=[CH:20][CH:19]=1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccc(CO)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Into 250 ml of anhydrous chloroform were added 5.0 g of 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 25 ml of triethylamine and, further under ice-cooling, 12.5 ml of ethyl chlorocarbonate was added dropwise into the mixture. After evaporation of the solvent, the residue was dissolved in 200 ml of THF, the insolubles were filtered off, and then a solution of 2.08 g of NaBH4 dissolved in 60 ml of water was added dropwise into the filtrate, followed by stirring at room temperature for 2 hours. After evaporation of the solvent, water was added to the residue, and the mixture was adjusted with dil. hydrochloric acid to pH 4-5 and then extracted with chloroform. The organic layer was dried, concentrated and purified on silica gel column chromatograph with the use of chloroform-ethanl (100:1) as eluant, followed by recrystallization from chloroformethyl ether to give 1.16 g of 1-(4-hydroxymethylphenyl)-3-methyl-2-pyrazolin-5-one as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)c(F)c3)cc(C(F)(F)F)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
A stirred mixture of 4-(3,4-difluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.13) (0.21 g, 0.34 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.11 g, 0.37 mmol), tetrakis(triphenyl-phosphine)palladium (0.024 g, 0.02 mmol) in toluene (3 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[CH3:14]
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4cc[nH]c4c3)c2cc1OCC
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A solution of 964 mg (3.50 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 830 mg (6.29 mM) of 6-Aminoindole in 5 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 712 mg of 6,7-Diethoxy-4-(1H-indol-6-ylamino)-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 373.0, mp=128-130° C.
Reaction SMILES: [N:1]1([C:5](=O)[C@@H:6]([NH:10][C:11](=O)OC(C)(C)C)[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:1]1([CH2:5][C@@H:6]([NH:10][CH3:11])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@H](CN1CCC1)C(C)C
Temperature: -5 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
A solution of (S)-tert-butyl 1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound D) (20 g, 78 mmol) in THF (200 mL) was dropwise charged (over approximately 90 min) to a jacketed reactor containing a 1M solution of LAH in THF (200 mL, 200 mmol) under a nitrogen atmosphere. The resultant mixture was heated at 60° C. over night. The reaction was cooled to −5° C. and H2O (7.6 mL) was slowly added. The mixture was diluted with THF (200 mL). A 15% aq. NaOH (7.6 mL) solution and additional H2O (22.8 mL) were added. The mixture was warmed to 25° C. and stirred for 1 h. The slurry was filtered and solids were washed with THF. The filtrate was concentrated under reduced pressure to give the title compound (1.7 g, 79%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CH3OD) δ 0.86, 1.75-1.90, 1.94-2.18, 2.18-2.36, 2.38, 2.99-3.29. Total no of protons: 19.
Reaction SMILES: C1(=O)N(CCCO[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][C:11]=2[Cl:23])C(=O)C2=CC=CC=C12.O.NN>C(O)(C)C>[NH2:20][CH2:19][CH2:18][CH2:17][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[Cl:23]
Reactant: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: NCCCc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 122.4 %

Procedure:
A mixture of 5.4 g (13.1 mmol) of the phthalimide prepared above and 700 microliters (14.4 mmol) of hydrazine monohydrate in 150 ml of isopropanol is heated at reflux overnight. The solvent is removed under vacuum, the residue is taken up in 15 ml of 70:30 (CH3OH:NH4OH) and flash chromatographed on silica gel (90:10:2 CHCl3 :CH3OH:NH4OH) to give 2.13 g of 6-[4-(3-aminopropyl)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a pale yellow solid. Yield, 58%.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 3-aminophenylboronic acid, a mixture of the E and Z isomers of the title compound is prepared.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:18]([O:20]C(C)(C)C)=[O:19])[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:11]([OH:13])=[O:12])[C:18]([OH:20])=[O:19])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C(C(=O)O)c1ccc2sccc2c1
Yield: 82.6 %

Procedure:
To toluene (2.5 mL) solution of 0.25 g of di(tert-butyl) 2-(1-benzothiophen-5-yl)malonate was added 0.01 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 1 hour. After cooling the reaction mixture, the precipitate was collected by filtration to provide 0.14 g of 2-(1-benzothiophen-5-yl)malonic acid as white solid form.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH2:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22]>ClCCl>[Cl:12][C:3]1[C:2]([NH:1][S:23]([CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:10][CH:9]=[C:8]([Cl:11])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1Cl
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
3-Amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol) was dissolved in dry dichloromethane (66.7 mL). Triethylamine (4.09 mL, 29.4 mmol) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (2.48 mL, 22 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was concentrated in vacuo and diluted with diethyl ether. The mixture was washed with 0.25M NaOH (80 mL), and the aqueous layer was acidified to a pH of 1 using 1.0M HCl. The aqueous layer was extracted with 15% 2-propanol:DCM (2×300 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-(propylsulfonamido)benzoic acid (1.55 g, 4.96 mmol, 74.4% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.77-9.75 (s, 1H), 7.84-7.80 (d, 1H), 7.71-7.68 (d, 1H), 3.82-3.72 (m, 2H), 1.89-1.70 (m, 2H), 1.05-1.03 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[N:3]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1nn(C2CCCCO2)c2ccccc12
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 3-bromo-1H-indazole (500 mg) synthesized according to a method of the literature (V> Auwers, et al., J. Prakt. Chem., 1924, 314) in toluene (25 mL, manufactured by Wako Pure Chemical Industries, Ltd.), 3,4-dihydro-2H-pyrane (640 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) and p-toluenesulfonic acid monohydrate (10 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was heated for one hour at 80° C. The reaction solution was cooled to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added thereto. The mixture was extracted with ethyl acetate (3×20 mL), washed with brine (40 mL), and dried (MgSO4), and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 570 mg of the title compound. LC-MS: HPLC retention time 4.93 minutes, m/z 281 (M+H), condition B-1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH3:19][CH:20]1[N:25]([CH2:26][CH2:27][NH2:28])[CH:24]([CH3:29])[CH2:23][O:22][CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:28][CH2:27][CH2:26][N:25]1[CH:24]([CH3:29])[CH2:23][O:22][CH2:21][CH:20]1[CH3:19])=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: CC1COCC(C)N1CCN
Product: CC1COCC(C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 2-(3,5-dimethylmorpholino)ethylamine [see Preparation 12]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 95:5, by volume, dichloromethane:methanol to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[2-(3,5-dimethylmorpholino)ethyl]-2-piperidinecarboxamide as a solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]C=3)C2=O)[CH2:3]1.C1(NN)C=CC=CC=1.N1C2C(=CC=CC=2)C=C1>>[CH2:2]1[C:3]2[CH:4]([N:7]=[C:15]3[C:14]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH2:5][CH2:6]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Agent: c1ccc2[nH]ccc2c1
Solvent: NNc1ccccc1
Product: c1ccc2c(c1)=NC1CCCC=21

Procedure:
In Scheme II, Step B, (±)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (9) is reacted with a phenylhydrazine of formula (10) in a typical Fischer indole synthesis to give a tetrahydrocyclopenta[b]indole of formula (11). The skilled artisan will recognize that there are a variety of acidic conditions to effect a Fischer indole synthesis, including both proton and Lewis acids. The preferred conditions use a mixture of glacial acetic acid with 4N HCl in dioxane, at a temperature of 50° C. to the reflux temperature of the solvent, for about 4 to 24 hours. The product is isolated by addition of water followed by filtration of the resulting solid. The solid is sonicated in methanol to give material of sufficient purity. Alternatively, the reaction is effected using a Lewis acid, such as zinc chloride, in an amount of about 2 to 4 equivalents.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)C)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:20]>CO>[ClH:20].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)N[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 5.25 g. of trans N-[4-(p-nitrophenyl)cyclohexyl]acetamide (prepared as in Example 81) in 50 ml. of hydrochloric acid and 50 ml. of methanol is heated at reflux for about 72 hours. The bulk of the methanol is then removed under vacuum and the residue dissolved in 100 ml. of hot water. The solution is then made strongly basic and extracted with ether and the organic layer then evaporated to dryness to give trans 4-(p-nitrophenyl)cyclohexylamine (I). The residue is dissolved in a small amount of ether which is then treated with 4.9 g. hydrochloric acid in ether to give 4.78 g. (99% yield) of trans N-4-(p-nitrophenyl)cyclohexylamine hydrochloride (I). The analytical sample has a melting point of 293° to 294° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Product: COc1cc(OC)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3,5-dimethoxy-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=512.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:37]=CN(C)C)=[N:11][C:10](=[O:42])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([NH2:37])=[N:11][C:10](=[O:42])[C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 63 %

Procedure:
The product of step c) (3.1 g, 5.15 mmol) was dissolved in acetonitrile (ACN, 130 ml) and treated with 1N HCl (13 ml, 13 mmol). The mixture was stirred at room temperature until no starting material was present (˜18 h). The reaction mixture was neutralized by addition of a saturated solution of sodium bicarbonate. The solvent was then evaporated in vacuo (temp <40° C.) to give a light yellow solid. The solid was slurried in DCM (50 ml) and filtered. The filtrate was evaporated and the residue purified by flash silica-gel chromatography (gradient elution 0 to 20% methanol in DCM) to give the sub-titled product (1.75 g, 63%, ˜9:1 regioisomeric mixture). 1H NMR (CD3OD) δ 5.10-4.98 (m, 1H), 4.20-4.10 (m, 1H), 4.02-3.90 (m, 1H), 3.72 (d, J=12.3 Hz, 1H), 3.59 (d, J=9.6 Hz, 1H), 3.20 (dd, J=4.5 Hz, J=12.9 Hz, 1H), 2.16-1.96 (m, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.30 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H). MS: ESI (positive): 541 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:27][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (WO 2011/017513) (3.00 g, 7.83 mmol) in methanol (40 mL) cooled to 0° C. was added sodium borohydride (0.296 g, 7.83 mmol). The reaction mixture was stirred for 1 hour. The mixture was acidified with aqueous hydrogen chloride (1 N) and diluted with ethyl acetate. The pH was adjusted to 7 by aqueous sodium bicarbonate. The organic phase separated, rinsed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a solid (3.01 g, 100%): ESIMS m/z 386 ([M+H]+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:10][C:11](=[O:15])[O:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: C#CC(O)(CC)CC
Reactant: Cc1cccc(-c2cc(=O)oc3cc(CN=[N+]=[N-])ccc23)c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4cccc(C)c4)cc(=O)oc3c2)nn1
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-methylphenyl)-2H-chromen-2-one (100 mg, 0.34 mmol) and 3-ethyl-1-pentyn-3-ol (46 mg, 0.41 mmol) in THF (4 mL) N,N-diisopropylethylamine (296 uL, 1.7 mmol) and copper iodide (97 mg, 0.51 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 20:80) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.90 (s, 1H), 7.54 (d, 1H), 7.47 (t, 1H), 7.43-7.33 (m, 4H), 7.25 (d, 1H), 6.33 (s, 1H), 5.78 (s, 2H), 3.70 (s, 1H), 2.45 (s, 3H), 1.95-1.75 (m, 4H), 0.79 (t, 6H).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH:13]C(=O)[O-])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.[Si](I)(C)(C)C.CO.O>C(#N)C>[F:17][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH2:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(NC(=O)[O-])c1cccc(OC(F)F)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC(C)(N)c1cccc(OC(F)F)n1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 mL) was added TMSI (10 mL). The reaction was stirred 30 min and then poured into methanol (100 mL) and water (5 mL). The mixture was concentrated, dissolved in ethyl acetate (200 mL), and then washed with 1N NaOH (2×30 mL). The organic layer was separated, dried over Na2SO4, concentrated, and chromatographed with silica gel (50% EtOAc/hex, then 5-20% MeOH/CH2Cl2) to afford 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-amine (8.8 g, 92%) as a yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[O:5][CH2:4]1.[F:6][C:7]([F:15])([F:14])[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:6][C:7]([F:15])([F:14])[C:8]1([C:10]([F:13])([F:12])[F:11])[O:5][CH:3]([CH:2]=[CH2:1])[CH2:4][O:9]1
Reactant: C=CC1CO1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: C=CC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 120 °C
Yield: 12.1 %

Procedure:
Butadiene monoepoxide (9.8 g, 0.14 mole, Aldrich Chemical Co.) was mixed with hexafluoroacetone (50 g, 0.30 mole) in a 210 ml Hastelloy®C shaker tube in the presence of tetrabutylammonium bromide (0.12 g) and water (0.12 g). The tube was sealed and heated at 80° C. for 1 hour, 100° C. for 1 hour and 120° C. for 6 hours. The product mixture was distilled to afford the desired 2,2-bis(trifluoromethyl)-4-vinyl-1,3-dioxolane, 4.0 g (12.1% yield), as a clear, colorless liquid. Bp. 78°-80° C. 1H-NMR (CDCl3): δ 5.84 (m, 1H), 5.48 (m, 2H), 4.88 (dd, J=6.6, 5.4 Hz, 1H), 4.46 (t, J=6.6 Hz, 1H), 3.87 (t, J=6.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:24]([F:25])=[CH:23][C:22]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:21][C:4]=1[O:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[C:24]([F:25])=[CH:23][C:22]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:21][C:4]=1[O:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)cc(F)c1C#N)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.3 %

Procedure:
A solution of ethyl (RS)-4-(2-cyano-3-fluoro-5-(3-thienylmethoxy)phenoxy)-4-(2-methylphenyl)butanoate (200 mg) in methanol (20 mL) containing 1 N sodium hydroxide (5 mL) is stirred at ambient temperature for 16 hours. The reaction mixture is poured into 0.5 N HCl (30 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases are washed with brine (20 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. Crystallisation with cyclohexane gives (RS)-4-(2-cyano-3-fluoro-5-(3-thienylmethoxy)phenoxy)-4-(2-methylphenyl) butanoic acid, (70 mg) in the form of a white solid, m.p. 150-151° C. [Elemental analysis:- C,64.9, H, 4.74, N, 3.29%. Calculated:- C,64.8, H, 4.81, N, 3.13%]