Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][CH3:48])[C:45]#[CH:46].C(NCC)C>CN(C=O)C.[Cu](I)I>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:46]#[C:45][CH2:44][O:47][CH3:48])=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: C#CCOC
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a mixture of 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (450 mg), 52 mg bistriphenylphosphinpalladium dichloride, 14 mg copperiodide, 146 mg triphenylphosphine and methyl propargyl ether (0.12 mL) in 10 mL DMF is added diethylamine (1.9 μL). The mixture is heated in the microwave oven for 40 min at 120° C. The reaction mixture was cooled to room temperature and partitioned between 1 N hydrochloric acid and ethyl acetate. The organic phase was purified by gradient chromatography on silica gel with heptane:ethyl acetate to yield 0.13 g of the title compound as a light yellow solid, MS (ISP) 399.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14].C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14])=[O:25]
Reactant: COc1cccc2c1C[C@@H](N)[C@H](O)C2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1C[C@@H](NC(=O)CCl)[C@H](O)C2
Reaction time: 2 h

Procedure:
1.01 g (0.005M) of trans-3-amino-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol are dissolved in 50 ml of absolute methylene chloride. 0.81 g (0.008M) of triethylamine are added, and the mixture left to cool to 0°. At this temperature, 0.68 g (0.006M) of chloroacetyl chloride (dissolved in 5 ml of absolute methylene chloride) are then added in drops over the course of 5 minutes. Stirring is effected for 2 hours at room temperature. The reaction mixture is subsequently washed once with 1N hydrochloric acid and once with ice water. It is extracted three times, each with 20 ml of methylene chloride, the combined organic phases are dried, and the solvent is concentrated by evaporation. Trans-2-chloro-N-(1,2,3,4-tetrahydro-2-hydroxy-5-methoxy-3-naphthalinyl)-acetamide is obtained (m.p. 176°-178°, recrystallisation from methylene chloride/ether).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[C:24]([Si:28]([CH3:37])([CH3:36])[O:29][CH2:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reactant: CC(C)(C)[Si](C)(C)OCC1CCNC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 3-[(5-bromo-2-methyl-benzoyl)amino]-2,4-dimethyl-benzoate (0.5 g, 1.32 mmol), tert-butyl-dimethyl-(pyrrolidin-3-ylmethoxy)silane (0.4 g, 1.99 mmol) and Cs2CO3 (1.2 g, 3.99 mmol) in 1,4-dioxane (15 ml) is added Pd2(dba)3 (0.12 g, 0.132 mmol) followed by S-Phos (0.054 g, 0.132 mmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 100° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 20% EtOAc in hexane to afford the title compound as a brown semi solid (0.36 g, 53%). Mass spectrum (m/z): 511.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13]
Reactant: COc1cccc(CC(=O)c2ccco2)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CC(O)C2CCCO2)c1OC
Yield: 70.5 %

Procedure:
A solution of 450 mg (1.8 mmol) of 2-(2',3'-dimethoxyphenyl)-1-furanylethanone, from Step 2, and 20% palladium on carbon (225 mg) in 75 mL of methanol was shaken under 4 atmospheres of hydrogen until hydrogen uptake ceased. The solution was filtered and concentrated in vacuo to give 320 mg (69% yield) of the title compound as an oily solid. This product was carried on without purification to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 71; 1.46 g) was dissolved in dry pyridine (20 ml) and cooled to 0° C. Tosylchloride (822 mg) was added in a single portion. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The foam was purified by flash column chromatography eluting with (40% EtOAc/60% hexanes) to give title compound (1.58 g). MS (ES)(MH+): 560 for C24H31Cl2N3O6S; NMR (CDCl3): 1.46 (brs, 11H), 1.89 (m, 1H), 1.98 (m, 1H), 2.31 (s, 3H), 2.35 (s, 3H), 2.8 (m, 2H), 3.96-4.23 (m, 4H), 6.4 (d, 1H), 7.19 (d, 2H), 7.68 (d, 2H), 10.3 (brs, 1H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[CH:14]([CH3:16])[CH3:15].[OH-].[Na+].Cl>C(O)CO.O>[CH:11]([C:10]1[CH:9]=[CH:5][CH:4]=[C:3]([CH:14]([CH3:16])[CH3:15])[C:2]=1[OH:1])([CH3:13])[CH3:12]
Reactant: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1O
Temperature: 142.5 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To the solution of 4-hydroxy-3,5-diisopropyl benzoic acid 100 g (0.45 M) (example 1) in ethylene glycol (150 ml) was added sodium hydroxide pallets 41.5 g (1.03M) and heated to 140-145° C. under inert atmosphere. After 7 hrs of continued heating at 140-145° C., the reaction mass was cooled to room temperature and diluted with 5 times water. The pH of the mass was then adjusted to 1-2 using concentrated Hydrochloric acid, reaction mixture was stirred for one hour and extracted three times with 200 ml toluene, combined toluene layers were washed twice with 5% aq. sodium bicarbonate solution (50 ml) and finally with water (200 ml), solvent was removed under reduced pressure and a dark brown colored residue which remained was distilled under high vacuum condition (0.2 mm/Hg) to yield 75 g (93.5%) of 2,6-diisopropyl phenol collected as a colourless to pale yellow oily liquid, HPLC Purity 99.93%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C)=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7](C3C=CC(Cl)=CC=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB(C2C=CC(C(OC)=O)=CC=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[CH:12]1[N:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:23][C:6]=3[N:7]=[CH:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Agent: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C1=Nc2ccccc2-n2cnnc2C1
Temperature: 120 °C

Procedure:
A mixture of 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine,5,6-dihydro-1-methyl-8-bromo-6-(4-chloro-phenyl) (Compound 13; 60 mg, 0.15 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (81 mg, 0.30 mmol), and cesium carbonate (98 mg, 0.30 mmol) in dioxane (2 mL) and water (1 mL) was heated at 120° C. for 20 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The solid was filtered and the filtrate was concentrated to give a residue. To the residue, ethyl acetate (30 mL) was added and the mixture was washed with brine (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford 4H-[1,2,4]Triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1-methyl-8-(4-carboxy-phenyl)-6-(4-chloro-phenyl) as a white solid (30 mg, 47%).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O.CCN(C(C)C)C(C)C>CCCCO>[CH:26]1([C:24]2[N:21]=[C:19]3[CH:18]=[N:17][C:16]4[N:12]([S:2]([C:5]5[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=5)(=[O:3])=[O:4])[CH:13]=[CH:14][C:15]=4[N:20]3[CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Reactant: O=C(CBr)C1CCCCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nc(C4CCCCC4)cn23)cc1
Temperature: 170 °C

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
0.6 g of 4-chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine and 0.28 ml of m-chloroaniline are heated at reflux in 10 ml of ethanol for 17 hours. The brown solution is concentrated to dryness by evaporation, the residue is taken up in ethyl acetate, and the ethyl acetate solution is washed until neutral with sodium hydrogen carbonate solution and water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate/hexane. 4-(m-Chloroanilino)-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine is obtained in the form of white crystals having a melting point of 132-133° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6](=[C:10]1[C:19]2[CH:18]=[C:17]([C:20]([NH2:22])=O)[S:16][C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9].CN(C)C=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH:6](=[C:10]1[C:19]2[CH:18]=[C:17]([C:20]#[N:22])[S:16][C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=C1CCCCc2sc(C(N)=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC=C1CCCCc2sc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Phosphorus oxychloride (0.30 ml) was added to a mixture of 4-n-butylidene-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (0.55 g) and dimethylformamide (DMF) (6 ml) with ice-water cooling under nitrogen atmosphere, and the mixture was stirred under the same condition for 1 hour. The reaction mixture was poured into an ice-cooled mixture of an aqueous solution of NaHCO3 and AcOEt to precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give 4-n-butylidene-5,6,7,8-tetrahydro-2-cyano-4H-cyclohepta[b]thiophene (0.42 g), which was immediately used in the next reaction.
Reaction SMILES: [C:1]12([CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:16][CH:13]1[CH2:12][CH2:11][C:1]2([C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:15][CH2:14]1)(=[O:26])=[O:25]
Reactant: OC1CCC2(CCCc3ccccc32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCC2(CCCc3ccccc32)CC1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To an ice-cooled solution of 3.89 g. (0.018 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol -(obtained in Example 17A) in 40 ml. of pyridine, 4 ml. of methane sulfonyl chloride is added. The mixture is allowed to stand in the cold for about 6 hours and then diluted with water. The material that precipitates is extracted with ether and the combined extracts washed successively with ice cold 2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from cyclohexane to give 5 g. (94.3% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t), having a melting point of 118° to 120° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.[O:21]1CCC[CH2:23][CH:22]1NO.S1C=C(C(Br)C=C)C2C=CC=CC1=2.O>CN(C=O)C>[OH:7][N:8]([CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)[C:22](=[O:21])[CH3:23]
Reactant: C(=Cc1cc2ccccc2s1)CNOC1CCCCO1
Reactant: ONC1CCCCO1
Agent: C=CC(Br)c1csc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(O)CC=Cc1cc2ccccc2s1
Reaction time: 2 h
Yield: 66 %

Procedure:
O-Tetrahydropyranyl-3-benzo[b]thien-2-ylprop-2-enyl hydroxylamine. Tetrahydropyranylhydroxyl amine (0.51 g, 4.34 mmole) in DMF (10 mL) was added to a solution of 3-benzo[b]thienylbromoprop-2-ene (0.50 g, 1.98 mmole) in DMF (10 mL). After being allowed to stir for two hours the reaction was poured into water and extracted with ether. The organic layer was washed with NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 40% ether in hexanes to give the desired product as a yellow oil (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C@H:16]3[O:25][C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]3[CH2:26][C:27](OCC)=[O:28])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C@H:16]3[O:25][C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]3[CH2:26][CH2:27][OH:28])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1CCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCO)[C@H]2O1
Reaction time: 3 h

Procedure:
To a solution of the compound obtained from step h above (0.75 g) in tetrahydrofuran (15 mL), lithium aluminum hydride (0.096 g) was added at 0° C. The resulting mixture was stirred for 3 hours at same temperature, and a saturated solution of ammonium chloride was then added. The reaction mixture was then filtered through silica gel (100 to 200 mesh) and concentrated. Ethyl acetate and water were added to the resulting residue. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.65 g).
Reaction SMILES: [OH-].[K+].Cl[O-].[Na+].[CH2:6]([SH:9])[CH2:7][CH3:8].[C:10]([N:14]=[N:15][C:16](Cl)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>O.CO>[C:10]([N:14]=[N:15][C:16]([S:9][CH2:6][CH2:7][CH3:8])([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Reactant: CCCS
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CO
Product: CCCSC(C)(C)N=NC(C)(C)C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To 200 ml. of a methanol solution containing 18.2 grams (0.275 moles) of 85% potassium hydroxide pellets in a 11/2 liter jacketed reactor equipped with a mechanical stirrer, thermometer, condenser connected to a bubbler filled with sodium hypochlorite, was added 20.0 grams (0.263 moles) of 1-propanethiol from a pressure equalizing dropping funnel. After the addition of the mercaptan the reaction mixture was stirred for an additional 1/2 hour and then 45.5 grams (0.25 moles) of 88.9% 2-t-butylazo-2-chloropropane was added dropwise over 5 minutes controlling the reaction temperature at 22°C ± 3°C by running cold water through the reactor jacket. The reaction was stirred for an additional 1 hour at 25°C, 5 grams (0.0625 moles) of 50% NaOH added along with 400 mls. of water. The product was extracted with 200 mls. of pentane, the pentane layer separated and washed with 50 ml. of 5% NaOH for 5 minutes, 50 mls. of 10% NaOH for 5 minutes, and then 50 ml. portions of water, 5% HCl, 10% HCl, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered, and the pentane evaporated under reduced pressure to leave 45.9 grams (91.4%) of crude 2-t-butylazo-2-propylthiopropane. Gas chromatographic analysis indicated there was small amounts of 2-t-butylazo-2-methoxypropane and propyl disulfide present in the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]([C:21]1([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:23][CH2:22]1)=[O:20])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[ClH:56].C[N:58](C)C=O>N1C=CC=CC=1>[ClH:56].[NH2:58][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:22][CH2:23]3)=[O:20])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 33 h
Yield: 54.9 %

Procedure:
4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (1.0 g) was dissolved in N,N-dimethylformamide (10 ml) under a nitrogen atmosphere, and water (0.199 ml), [bis(trifluoroacetoxy)iodo]benzene (1.96 g) and pyridine (1.07 ml) were added at room temperature in this order, followed by stirring for 33 hr. The reaction mixture was partitioned after addition of ethyl acetate (30 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (10 ml, twice) and brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was dissolved in ethyl acetate (10 ml), 5N hydrochloric acid (0.486 ml, 1.1 equivalents) was added under sonication. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under aeration for 1 hr. The solid was hot air-dried at 80° C. overnight to provide the titled compound as pale brown powder (559.3 mg, 54.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH2:15][OH:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]#[C:31][CH3:32])[CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:11][C:12]1([CH2:15][O:16][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:30]#[C:31][CH3:32])[CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH2:13][CH2:14]1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: N#Cc1ccc(OCC2(CO)CC2)cc1Cl
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccc(C#N)c(Cl)c3)CC2)cc1

Procedure:
Analogously to example 1, 2-chloro-4-(1-hydroxymethylcyclopropylmethoxy)benzonitrile and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[1-(3-chloro-4-cyanophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].F[C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:1]([S:3][C:5]1[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCS
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1.5 mL of ethyl mercaptan was added to a mixture of 3.83 g of 2-fluoro-4-trifluoromethylbenzoic acid, 10 mL of NMP and 15 g of cesium carbonate, and the mixture was stirred at 60° C. for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. Hydrochloric acid was added to the aqueous layer, and the precipitated solid was taken by filtration and dried under reduced pressure to obtain 4.6 g of 2-ethylsulfanyl-4-trifluoromethylbenzoic acid.