Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][NH2:38]>[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:38][N:37]=[C:24]3[NH2:25])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(F)c(C#N)c2)c1)Cc1c[nH]c2ccccc12
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3[nH]nc(N)c3c2)c1)Cc1c[nH]c2ccccc12
Yield: 84 %

Procedure:
A mixture of Example 97B (120 mg, 0.25 mmol) and 98% hydrazine (5 mL) was heated to reflux for 5 hours, poured over ice, diluted with brine, extracted with ethyl acetate, dried over MgSO4, and concentrated. Purification by flash chromatography (7% MeOH/CH2Cl2) provided the desired product (103 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:20])[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:24][C:25]([F:33])([F:32])[C:26]([C:28]([F:31])([F:30])[F:29])=[O:27]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:26]([C:28]([F:31])([F:30])[F:29])([C:25]([F:33])([F:32])[F:24])[OH:27])[N:9]([CH3:20])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cn1ccc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C(O)(C(F)(F)F)C(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
A mixture of 4.0 g (0.015 mole) of 2,3-bis(4-fluorophenyl)-1-methyl-1H-pyrrole and 3.7 g (0.017 mole) of hexafluoroacetone trihydrate in 75 ml toluene was heated at reflux overnight. Another 3.7 g of hexafluoroacetone trihydrate was added and the mixture was heated at reflux overnight again. An additional 2.0 g of hexafluoroacetone trihydrate was added and the mixture was heated at reflux another eight hours. The mixture was washed twice with water, then the organic layer was dried and concentrated. The crude product was purified by chromatography on silica gel, eluting with hexane/toluene mixtures to give, after recrystallization from hexane, 4.8 g of product, m.p. 130°-131°.
Reaction SMILES: II.[Na+].[C:4]([S-:12])(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[C:4]([S:12][S:12][C:4](=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: S=C([S-])c1ccccc1
Agent: II
Agent: [Na+]
Solvent: CCOCC
Product: S=C(SSC(=S)c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
An aqueous solution of iodine (1.0 N, 100 mL) was added dropwise to a stirred aqueous solution of dithiobenzoic acid sodium salt (0.1 mol in 100 mL of water) at room temperature over 15 minutes. Diethyl ether (100 mL) was added, the organic layer separated and washed twice with water, dried (Na2SO4), filtered and concentrated in vacuo. Di(thiobenzoyl)disulfide (7.5 g, 50%) was obtained after recrystallization from hot ethanol, m.p. 89-91° C. [lit(Houben, Chem, Ber., 39, 3219-3233, (1906). m.p. 92.5° C.]. 1H-nmr (CDCl3) δ (ppm) 7.44 (m, 4H, meta-ArH); 7.62 (m, 2H, para-ArH) and 8.11 (m, 4H, ortho-ArH).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[NH4+:10].[OH-].[Na+]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:10].[NH4+:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/C(=O)[O-]
Reaction time: 0.25 h

Procedure:
A slurry of 11.6 g (0.1 mole) fumaric acid was dissolved in 30 ml water was mixed with 26 g of 30% aqueous solution of ammonium hydroxide (0.22 mol NH3). Carefully warming the slurry to boiling gave a clear solution. This solution was boiled to dryness over a period of 15 minutes to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 140°-150° C. for 8 hours to give a water insoluble, brown, glasslike solid weighing 14 g. This solid was dissolved in 100 g of an aqueous solution containing 2.0 g of sodium hydroxide to form a pale yellow solution, pH 7.0, containing 25% solids.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12](I)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1.[NH2:20][C:21]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:22]=1[C:23]([NH:25][O:26][CH3:27])=[O:24]>>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:20][C:21]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:22]=3[C:23]([NH:25][O:26][CH3:27])=[O:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1
Reactant: CONC(=O)c1ccc(F)cc1N
Reactant: Cc1cc(Nc2cc(I)c(C(F)(F)F)cn2)n(C)n1
Product: CONC(=O)c1ccc(F)cc1Nc1cc(Nc2cc(C)nn2C)ncc1C(F)(F)F

Procedure:
This compound was prepared from N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine and 2-amino-4-fluoro-N-methoxybenzamide. 81 mg, 48%; triturated in Et2O; NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 3.55 (s, 3H), 3.70 (s, 3H), 6.04 (s, 1H), 6.74 (s, 1H), 6.97 (ddd, 1H), 7.43 (dd, 1H), 7.66 (dd, 1H), 8.28 (s, 1H), 9.07 (s, 1H), 10.04 (bs, 1H), 11.96 (bs, 1H); Mass spectrum: MH+ 439.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:20][CH:19]2[CH2:21][CH:11]([CH2:12][C:13]3[CH:14]=[C:15]([O:22][CH2:23][CH3:24])[CH:16]=[CH:17][C:18]=32)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH2:23]([O:22][C:15]1[CH:16]=[CH:17][C:18]2[CH:19]3[CH2:21][CH:11]([CH2:12][C:13]=2[CH:14]=1)[CH2:10][NH:9][CH2:20]3)[CH3:24]
Reactant: CCOc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: CCOc1ccc2c(c1)CC1CNCC2C1
Yield: 62.7 %

Procedure:
11-Benzyl-5-Ethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (160 mg, mmol), ammonium formate (220 mg, 3.49 mmol) and 10%Pd(OH)2/C (100 mg) were combined in methanol (MeOH) (5 mL) and warmed to reflux for 15 min. The mixture was cooled, filtered, concentrated, diluted with sat. aq. Na2CO2 soln. and extracted with EtOAc (3×20 mL). The extracts were dried (MgSO4), filtered and concentrated to an oil (94 mg, 83%). (TLC 50%EtOAc/hexanes (NH3) Rf 0.20). 1H NMR (CDCl3) δ6.90 (d, J=9.0 Hz, 1H), 6.66 (2H), 3.97 (m, 2H), 3.08 (dd, J=18.0,6.0 Hz, 1H), 2.94 (m, 3H), 2.76-2.65 (3H), 1.96 (m, 2H), 1.88 (d, J=11.0 Hz, 1H), 1.38 (t, J=7.0 Hz, 3H). This material was dissolved in excess 1N HCl MeOH and concentrated. Recrystallization from CH2Cl2/Et2O provided a solid (74 mg, 68%). mp 243-245° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.NN>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Yield: 90 %

Procedure:
A mixture of 400 mg of 6,7-dihydro-2-methyl-7-(4-nitrobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine, 87 μl of anhydrous hydrazine and 40 mg of 10% Pd/C in 22 ml of ethyl alcohol is heated at reflux for 1.25 hours, filtered through diatomaceous earth and the pad washed well with methyl alcohol. The combined filtrates are evaporated in vacuo to a residue which is dissolved in ethyl acetate and filtered through a pad of hydrous magnesium silicate and the filtrate concentrated in vacuo to a residue which is dissolved in methyl alcohol and evaporated again to give 330 mg of the desired product as a yellow foam. HR FABMS: Exact mass (M+H): 331.1555.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)([OH:49])=[O:3]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)OCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-ethoxy-2-oxoethyl)ureido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (7 mg, 10.40 mmol) was dissolved in dioxane (2 ml). Sodium hydroxide solution, 1N (0.021 ml, 0.021 mmol) was added. The mixture was stirred at 70° C. for 2 h. The solvent was evaporated and the residue was purified by prep. HPLC to afford the title compound as a white solid (4 mg, 32.8%). LCMS: m/e 645.3 (MH+), 2.58 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.90 (m, J=8.3 Hz, 2H), 7.20 (m, J=8.3 Hz, 2H), 5.21-5.36 (m, 1H), 4.70 (d, J=1.8 Hz, 1H), 4.57 (s, 1H), 3.83 (s, 2H), 3.44 (d, J=13.8 Hz, 1H), 2.95 (d, J=13.6 Hz, 1H), 2.38-2.60 (m, 1H), 2.13 (dd, J=17.1, 6.5 Hz, 1H), 1.93-2.08 (m, 1H), 1.76-1.93 (m, 2H), 1.60-1.76 (m, 8H), 1.40-1.60 (m, 6H), 1.35-1.40 (m, 1H), 1.29-1.35 (m, 1H), 1.18-1.29 (m, 3H), 1.16 (s, 3H), 1.05-1.13 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([N:6]([CH3:25])[CH2:7][C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:9])=[O:5])[CH3:2]>[C].[Pd].CO>[CH2:1]([O:3][P:4]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([N:6]([CH3:25])[CH2:7][C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)N(C)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CCCCc1ccccc1)N(C)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
A mixture of the diester product from part (d) (2.0 g., 4 mmole), 10% palladium-carbon catalyst (350 mg.) and methanol (40 ml.) is hydrogenated in a Parr apparatus at 50 psi. for 1 hour. The catalyst is removed by filtration through a Celite bed and the filtrate evaporated to give 1-[N-[ethoxy(4-phenylbutyl)phosphinyl]-N-methylglycyl]-L-proline as a foam. Tlc (methanol/acetic acid/dichloromethane; 5:5:100) shows a major spot at Rf 0.6.
Reaction SMILES: Cl.[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:19]C)[C:13]=3[O:17]C)[C:8]2=[O:21])[CH2:5][CH2:4][CH2:3]1.[BrH:22].C(OC(=O)C)(=O)C>>[BrH:22].[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:19])[C:13]=3[OH:17])[C:8]2=[O:21])[CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c(c1OC)CCC(NC1CCC1)C2=O
Agent: Br
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccc(O)c(O)c2CCC1NC1CCC1

Procedure:
In a manner similar to that of Reference Example 4, 5.16 parts of 2-cyclobutylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is hydrolyzed in a mixture of 75 volume parts 48 % hydrobromic acid and 15 volume parts acetic anhydride. The procedure yields 4 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide. Melting point: 229°-240° C (decomposition).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)cc2)c1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (44 mg, 0.093 mmol) in methanol (0.5 mL) and tetrahydrofuran (THF) (0.500 mL) was treated with LiOH (0.278 mL, 0.556 mmol) and stirred at 60° C. for 18 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to afford 2-(tert-butoxy)-2-(1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (30.8 mg, 0.066 mmol, 71.4% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69-7.56 (m, 1 H), 7.43-7.30 (m, 3 H), 7.29-7.25 (m, 2 H), 7.08-6.91 (m, 3 H), 6.24 (d, J=3.6 Hz, 1 H), 5.65-5.38 (m, 3 H), 2.77 (s, 3 H), 2.46 (s, 3 H), 0.94 (s, 9 H); LCMS (m/z) ES+=461 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:27]=[N:26][CH:25]=[CH:24][C:11]=1[C:12]([NH:14][O:15][CH2:16][C@H:17]1[CH2:21][O:20]C(C)(C)[O:18]1)=[O:13]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:27]=[N:26][CH:25]=[CH:24][C:11]=1[C:12]([NH:14][O:15][CH2:16][C@H:17]([OH:18])[CH2:21][OH:20])=[O:13]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccncc2Nc2ccc(I)cc2Cl)O1
Solvent: CC(=O)O
Product: O=C(NOC[C@H](O)CO)c1ccncc1Nc1ccc(I)cc1Cl
Temperature: 90 °C
Yield: 43.6 %

Procedure:
3-[(2-chloro-4-iodophenyl)amino]-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}isonicotinamide (100.00 mg, 0.198 mmol.) from the reaction described above was dissolved in acetic acid (1 ml) was heated at 90° C. for 2 h. The reaction was monitored by HPLC. After completion, acetic acid was removed and the crude was purified on Flashmaster II to obtain 40 mg (43%) of 3-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}isonicotinamide. LC/MS: [7.97 min; 464, 466 (M+1)]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CC(=O)OCC>[OH:15][CH2:14][CH:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A 1M solution of borane-tetrahydrofuran complex in THF (8.65 mL; 8.65 mmol; 2 eq.) was added to a cold (0° C.) solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (1 g; 4.32 mmol; 1 eq.) in THF (10 mL) and the resulting mixture was stirred at room temperature for 1 hour. The solution was diluted with EA, washed with sat. aq. NaHCO3 then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA/heptane) afforded the title compound (600 mg, 64%) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([Li])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.CCCCC>[CH3:10][C:9]([CH3:12])([CH3:11])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:8]
Reactant: [Li]C(C)(C)C
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: CC(C)(C)C(O)c1cccnc1
Yield: 18 %

Procedure:
3-Pyridinecarboxaldehyde (200 μL, 2.12 mmol) was dissolved in tetrahydrofuran (5.0 mL). To this, tert-butyllithium (a 1.46 mol/L solution in pentane, 4.37 mL, 6.36 mmol) was added dropwise under a nitrogen atmosphere at 0° C. and the mixture was stirred at the same temperature for 1. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1, hexane/ethyl acetate=1/1) to give 3-(2,2-dimethyl-1-hydroxypropyl)pyridine (Compound CG) (64.0 mg, yield: 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of methyl 3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (1.63 g) in tetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 13 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol (1.53 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 66–67° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@@H](CC(C)C)NC(=O)OC(C)(C)C)c2=O)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)CC(C)C)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of compound 4a (30 mg, 0.048 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.3 mmol) and stirred at room temperature for 1.5 hours. After concentration, the residue was taken up in DCM and saturated aq. NaHCO3 was added. The aq. layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 4b. MS (CI) m/z 528.0, 530.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]([CH3:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>COCCO.O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[C:8]([F:15])[C:9]=1[CH3:14])[C:4]([OH:6])=[O:5]
Reactant: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1N

Procedure:
18.5 g of 2-chloro-5-fluoro-4-methyl-3-nitro-benzoic acid and 51.5 g of Na2S2O4 are boiled in a mixture of 160 ml of glycol monomethyl ether and 160 g of water for 3 hours. 230 ml of 1/2-concentrated HCl are added to the still warm solution. The mixture is boiled up once more, cooled and poured into 560 ml of water. The solid which has precipitated is isolated and dried. Yield: 12.4 g, melting point: 182°-84°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH:20]4OC(=O)[CH2:21]4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CCCCCCC>[CH:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:19][CH2:18]1)=[CH2:21]
Reactant: Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C4CC(=O)O4)CC3)CC2)cc1
Solvent: CCCCCCC
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C)cc3)CC2)CC1
Temperature: 170 °C

Procedure:
4-(trans-4-(trans-4-(4-Methylphenyl)cyclohexyl)-cyclohexyl)-2-oxetanone (3 g, 9.2 mmol) obtained in Example 8 was placed in a reactor, the interior of which was then sufficiently replaced by nitrogen. The reactor was heated, and after heating to 170° C. for 3 hours, it was cooled to room temperature. The resulting solid was dissolved in heptane and purified with silica gel chromatography to provide trans-1-ethenyl-4-(trans-4-(4-methylphenyl)cyclohexyl)-cyclohexane (2.4 g, 8.5 mmol, yield: 89%).
Reaction SMILES: [Cl-].[CH3:2][N:3]([Al+]C)[CH3:4].[CH2:7]([CH:14]([OH:19])[C:15](OC)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C=CC=CC=1>[CH2:7]([CH:14]([OH:19])[C:15]([N:3]([CH3:4])[CH3:2])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Al+]N(C)C
Reactant: COC(=O)C(O)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To dimethylamino(methyl)aluminum chloride [prepared from dimethylamine hydrochloride (3.4 g, 42 mmoL) and trimethyl aluminum (21 mL of 2 M solution, 42 mmol)] in toluene (40 mL) was added methyl benzylglycolate (3.0 g, 17 mmol). After stirring at rt for 1.5 h, the mixture was poured into 3 N HCl and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 9-50% EtOAc/Hex. The title compound was obtained as a colorless oil (1.2 g, 37%): 1H NMR CDCl3): d 7.4-7.1 (m, 5H); 4.61 (s, 2H); 4.18 (s, 2H); 2.98 (s, 3H); 2.95 (s, 3H).
Reaction SMILES: [Br-].[C:2]([CH2:7][S+](CC)CC)([O:4][CH2:5][CH3:6])=[O:3].N12CCCN=C1CCCCC2.[C:24]1(=[O:29])[CH2:28][CH2:27][CH:26]=[CH:25]1.Cl.[Cl-].[Na+]>C1(C)C=CC=CC=1>[O:29]=[C:24]1[CH2:28][CH2:27][CH:26]2[CH:25]1[CH:7]2[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C[S+](CC)CC
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A suspension of carbethoxymethyl diethylsulfonium bromide (45.5 g) in toluene (350 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (30.2 g). The resulting mixture was stirred at room temperature. After one hour, the reaction mixture was treated with 2-cyclopenten-1-one (19.57 g). After an additional 18 hours, the reaction mixture was added to a 1N hydrochloric acid/sodium chloride solution. The resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica-gel chromatography, eluting with a linear gradient of 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, to give 22.81 g of the title compound. Melting point: 36°-38° C.