Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]2[CH2:14][C:15](=[CH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)([OH:32])[CH2:28][CH2:27]3)[C:16]3[C:17]([O:22][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[N:18][CH:19]=[CH:20][CH:21]=3)(=O)C.[OH-].[Na+].O.C(OCC)(=O)C>C(O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:29]2([OH:32])[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH:23]=[C:15]3[C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[O:22][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=4[CH2:14]3)[CH2:31][CH2:30]2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Yield: 92.8 %

Procedure:
To a solution of 1-[3-(7-(2-acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol (Example 50) (140 mg) in ethanol (5 ml) were added 15% sodium hydroxide aqueous solution (2 ml) and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound (120 mg).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]2[CH2:15][C@@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2].[OH:27][NH:28][C:29](=N)[CH2:30][O:31][CH3:32]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@H:13]2[CH2:15][C@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[O:27][N:28]=[C:29]([CH2:30][O:31][CH3:32])[N:23]=3)[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2]
Reactant: COCC(=N)NO
Reactant: CCS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)cc1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OCC[C@H]2C[C@H]2C2CCN(c3nc(COC)no3)CC2)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-{2-{4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile (Step D; 100 mg, 0.27 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.8 mL, 0.5 M in tetrahydrofuran, 0.4 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound. MS (ESI) m/z 468 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Li+].[B-](CC)(CC)CC>C1COCC1>[CH3:1][C@H:2]1[C@@H:11]([OH:12])[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: CC1CC2(CCC1=O)OCCO2
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC2(CC[C@@H]1O)OCCO2
Temperature: 0 °C

Procedure:
Dissolve 7-methyl-1,4-dioxa-spiro[4.5]decan-8-one (11.45 g, 67.28 mmol) in THF (300 mL) and cool the solution to 0° C. under N2. Add super-hydride (74.0 mL, 74.0 mmol, 1 M in THF) and stir the reaction mixture overnight. Add water (200 mL), and extract the aqueous layer with dichloromethane (3×300 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-50% of EtOAc/Hexane) to give cis-7-Methyl-1,4-dioxa-spiro[4.5]decan-8-ol.
Reaction SMILES: [NH3:1].O1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:21]([NH2:1])(=[O:23])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Reactant: N
Solvent: CC#N
Solvent: C1COCCO1
Product: NS(=O)(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
In a reaction flask, 100 ml of aqueous ammonia and 100 ml of dioxane were added, and a solution of 17.9 g 2-benzyloxyformamidoethylsulfonyl chloride in acetonitrile (30 ml) was added dropwise under ice-bath condition. The mixture was stirred for 2 h at room temperature. Upon the end of the dropping, the mixture was concentrated under a reduced pressure, and was then filtered, the filter cake was washed with water, and dried to obtain 12.3 g of white solid, yield 74%.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:23]([OH:25])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:54][CH2:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:75])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=2[C:71]([F:74])([F:73])[F:72])[CH2:60][CH2:59]1)=[O:57]>CN(C=O)C.O>[O:57]=[C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:75])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=2[C:71]([F:74])([F:73])[F:72])[CH2:62][CH2:63]1)[CH2:55][NH:54][C:23]([C:11]1[CH:12]=[CH:13][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[CH:10]=1)=[O:25]
Reactant: O=C(O)c1ccc2oc3ccccc3c2c1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
DIPEA (137 mg, 0.18 mL, 1.06 mmol) was added to a stirred solution of dibenzofuran-2-carboxylic acid (75 mg, 0.35 mmol) in DMF (3 mL). HOBT (47.8 mg, 0.35 mmol) and EDCI (81.3 mg, 0.42 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (166 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitated to afford 60 mg (33.3%) of dibenzofuran-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.09%. 1H NMR (DMSO-d6): δ 8.7 (bs, 2H), 8.2 (d, 1H), 8.06 (d, 1H), 7.9-7.55 (m, 7H), 7.55 (t, 1H), 4.41-4.3 (bs, 2H), 3.8-3.6 (bs, 4H), 3.5-3.4 (bs, 2H), 3.2-3.0 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21]C)=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][CH:16]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:24])[CH:3]=1
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 182, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was converted to the title compound by treatment with concentrated HCl in dioxane. Colorless solid. MS (m/e)=410.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 34 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15mmol) and 1-amino-2-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (22 mg, 34% yield) as a yellow solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.27 (br s, 1 H), 8.49 (s, 1 H), 7.52 (s, 1 H), 7.14-7.10 (m, 2 H), 6.99-6.94 (m, 2 H), 4.26 (m, 2 H), 4.09 (s, 2 H), 3.95 (m, 1 H), 3.55-3.47 (m, 3 H), 3.29 (m, 1 H), 1.79 (m, 2 H), 1.19 (d, J=6 Hz, 3 H); MS m/z 430 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([F:12])([F:11])[O:8][C:7]([F:14])([F:13])[C:6]=2[CH:15]=1>CO.CC#N.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([F:12])([F:11])[O:8][C:7]([F:14])([F:13])[C:6]=2[CH:15]=1)=[O:10]
Reactant: FC1(F)Oc2ccc(Br)cc2C(F)(F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 75 °C
Reaction time: 8 h
Yield: 169.8 %

Procedure:
A suspension of 6-bromo-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (4.75 g, 16.6 mmol) and Pd(PPh3)4 (950 mg, 8.23 mmol) in MeOH (20 mL), MeCN (30 mL) and Et3N (10 mL) was stirred under carbon monoxide atmosphere (55 psi) at 75° C. (oil bath temperature) overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column (Petroleum Ether) to give 2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine-6-carboxylic acid methyl ester (3.75 g, 85%). 1H NMR (CDCl3, 300 MHz) δ 8.34 (s, 1 H), 8.26 (dd, J=2.1, 8.7 Hz, 1 H), 7.22 (d, J=8.7 Hz, 1 H), 3.96 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].[BH4-].[K+].O>O1CCCC1>[OH:12][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[C:4]=2[CH2:5][CH2:6]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc2c1CCC2O
Yield: 94.7 %

Procedure:
1.46 g of 4-cyano-1-indanone in 131 ml of tetrahydrofuran is cooled to +5° C., 1 g of potassium borohydride is added in small fractions, with agitation for one hour 15 minutes, followed by pouring over 200 ml of water containing sodium chloride, and extraction with isopropyl ether. The organic phase is dried, brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture (6-4). 1.40 g of expected product is obtained, M.p.=98° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C([N:14]1[CH2:19][CH2:18][C:17]([CH2:20][CH2:21][CH3:22])=[C:16]([CH3:23])[CH:15]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)C1C=CC=CC=1>[Pd].C(O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH:15]2[C:16]([CH3:23])=[C:17]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:19][NH:14]2)=[CH:30][CH:29]=1
Reactant: CCCC1=C(C)C(Cc2ccc(OC)cc2)N(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCCC1=C(C)C(Cc2ccc(OC)cc2)NCC1

Procedure:
A mixture of 1-benzyl-2-(p-methoxybenzyl)-3-methyl-4-propyl-1,2,5,6-tetrahydropyridine oxalate (377 g.), palladium-on-carbon (10%, 10.0 g.) and ethanol (to make 4,500 ml.) was hydrogenated for thirty minutes under pressure (about 50 p.s.i.g.), then filtered. The filtrate was concentrated, affording 2-(p-methoxybenzyl)-3-methyl-4-propyl-1,2,5,6-tetrahydropyridine oxalate in two crops (196 g. and 35 g.), which melted at 146°-147° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].S(O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH:7]=[CH:8]2)[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2ccn(CC3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To 6-cyanoindole (1.7 g, 12 mmol) in N,N-dimethylformamide (100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.48 g, 12 mmol). The mixture was stirred at room temperature under nitrogen for 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.8 g, 12 mmol) added and the mixture heated at 80° C. under nitrogen for 15 hours. The solvent was removed in vacuum and replaced with methylene chloride (400 mL). The solution was washed with 350 mL portions of water, saturated aqueous sodium bicarbonate, and saturated brine and dried over sodium sulfate. Filtration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent gave 4.4 g of 4-(6-cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester. This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon (0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixture refluxed under nitrogen for 15 hours. Filtration through celite, followed by concentration in vacuum gave 1.9 g of the title compound as a white solid. 1H-NMR (CDCl3): doublet 7.6 δ (1 H); singlet 7.55 δ (1 H); doublet 7.2 δ (1 H); singlet 7.13 δ (1 H); singlet 6.25 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.45 δ (2 H); doublet 1.45 δ (2 H); multiplet 1.18 δ (2 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]#[N:20]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:19]#[N:20])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC#N)cc(C)c1Br
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (500 mg) and Cs2CO3 (1.3 g) in N,N-dimethylformamide (5 mL) is added 2-bromoacetonitrile (290 μL) and the mixture is stirred for 2 hours at 35° C. The mixture is poured on water and stirred for 15 minutes. The precipitate is folitered off and dried to give the title compound. Yield: 535 mg; Mass spectrum (EI): m/z=239 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)cc1-c1cccc(Cl)c1
Yield: 89.5 %

Procedure:
To a mixture of 2-(3-chlorophenyl)-4-nitroanisole (0.5 g, 1.9 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added platinum (IV) oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chlorophenyl)-4-methoxyaniline as a light yellow oil (405 mg, 1.7 mmol).
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:14])=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:10]2[C:11]([CH3:14])=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2c(C)csc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2c(C)csc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Ethyl 4-(acetyloxy)-3-methyl-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (35 g, 0.25 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 19.5 g (82 mmol, 60%) as a cream solid. 1H NMR (DMSO-D6): δ ppm 1.35 (t, 3H), 2.60 (s, 3H), 4.20 (qt, 2H), 7.29 (m, 1H), 7.35 (s, 1H), 7.95 (s, 1H); MS (APCI, pos): 237.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:15](=[O:16])[CH2:14][C:13]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[CH2:1]([O:8][C:9]([CH:11]1[CH:15]([OH:16])[CH2:14][C:13]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2(CCCC2)CC1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: O=C(OCc1ccccc1)C1CC2(CCCC2)CC1O

Procedure:
To a solution of the crude product (5.23 g) containing 3-oxo-spiro[4.4]nonane-2-carboxylic acid benzyl ester obtained in Step 3 in methanol (100 mL) was added sodium borohydride (254 mg) under ice-cooling, followed by stirring under ice-cooling for 30 minutes. Then, after addition of 10% aqueous potassium hydrogen sulfate solution (10 mL) to the reaction mixture, methanol was evaporated off in vacuo, followed by extraction with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=10:1 to 3:1) to give 3-hydroxy-spiro[4.4]nonane-2-carboxylic acid benzyl ester (less-polar isomer; 1.29 g, more-polar isomer; 2.23 g).
Reaction SMILES: [F-].[K+].CN(C=O)C.C[Si](C)(C)[C:10]([F:13])([F:12])[F:11].[F:16][C:17]1[N:22]=[C:21](I)[C:20]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1>CN1C(=O)CCC1.[Cu]I.ClCCCl>[F:16][C:17]1[N:22]=[C:21]([C:10]([F:13])([F:12])[F:11])[C:20]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COCCOCOc1ccc(F)nc1I
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCOCOc1ccc(F)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A dry 25 mL was charged with potassium fluoride (1.0 g, 18 mmol), copper(I) iodide (3.4 g, 18 mmol) and a stirbar. The flask was evacuated to <1 mm Hg and the solid was heated using a 170° C. oil bath for 2 h. The flask was cooled to room temperature and the vacuum was released with nitrogen. The flask was fitted with a septa/inert atmosphere inlet. The solids were treated with 5 mL freshly distilled DMF, trimethyl(trifluoromethyl)silane (2.7 ml, 18 mmol), and a solution of 6-fluoro-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine (3.90 g, 12 mmol) in 5 mL dry NMP. The reaction was stirred at room temperature for 16 h, and then poured onto 150 mL dry DCE. The slurry was stirred for 1 h, and then filtered through a 0.22 μm PTFE membrane. The solids were washed with DCE (2×50 mL), and the combined DCE filtrates were concentrated in vacuo. The residue was taken up in 250 mL dry EtOH, and cooled using an ice-water bath. The slurry was filtered through a pad of Celite® (diatomaceous earth), and concentrated in vacuo to afford ˜7 mL of sample (in NMP). The sample was loaded onto a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group (50 mm×300 mm, PN PA0000-050730, 10 μm particle size, spherical shape; gradient: 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min@100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 19.3 to 21.7 minutes was isolated. The solvent was removed in vacuo to afford 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (2.0964 g, 65% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.36 (s, 3H) 3.52-3.59 (m, 2H) 3.84-3.90 (m, 2H) 5.35 (s, 2H) 7.10 (ddd, J=8.95, 3.77, 0.59 Hz, 1H) 7.86 (ddd, J=9.00, 6.06, 0.59 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −75.45 (dd, J=6.50, 3.90 Hz, 1 F) −66.65 (s, 3 F). 13C NMR (101 MHz, chloroform-d) δ ppm 58.91 (s, 1 C) 68.32 (s, 1 C) 71.30 (s, 1 C) 113.61 (q, J=1.01 Hz, 1 C) 114.00 (d, J=0.87 Hz, 1 C) 120.73 (qd, J=274.47, 1.52 Hz, 1 C) 133.80 (dq, J=35.26, 13.00 Hz, 1 C) 149.84 (d, J=5.20 Hz, 1 C) 156.28 (dq, J=238.58, 1.00, 0.87 Hz, 1 C). HPLC-MS: 2.04 min (>99%@215 nm; >99% @254 nm; m/z=270.0, calculated for C10H11F4NO3+H+=270.1).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1NCCCNC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 86.9 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.81 g, 5 mmol), tert-butyl 3-aminopropylcarbamate (0.85 g, 4.88 mmol) and DIPEA (1.8 mL, 10.5 mmol) in EtOH (5 mL) was heated at 130° C. in the microwave for 90 min. On cooling the reaction mixture was concentrated under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a yellow gum (1.27 g, 85%). A mixture of this gum (0.3 g, 1 mmol), K2CO3 (0.41 g, 3 mmol) and methyl iodide (0.1 mL, 1.58 mmol) in DMF (5 mL) was stirred at 60° C. for 18 hr. More methyl iodide (0.1 mL, 1.58 mmol) was added and stirring at 60° C. was continued for 24 hr. The reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated in DCM (100 mL), filtered and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate as a pale yellow gum (0.122 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.60 (s, 1H), 3.77 (s, 3H), 3.20-3.14 (m, 4H), 2.86 (s, 3H), 1.72-1.61 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=1
Reactant: CCCCCC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
n-Hexyl magnesium bromide (2.0 M in Et2O, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1.5 h at 0° C., the reaction was quenched slowly with 3 N HCl (20 mL) and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with Et2O (3×150 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→10% EtOAc/Hex) afforded 5.6 g (76%) of 1-(4-bromophenyl)-heptan-1-ol.