Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][CH2:7][C:8]1[C:16]2[C:15]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)C.CO.[NH3:25]>>[Cl:21][C:19]1[CH:18]=[CH:17][C:15]2[C:16]3[C:8]([CH2:7][S:6][CH2:5][C:4]([NH2:25])=[O:3])=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]=2[CH:20]=1
Reactant: CCOC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Reactant: N
Solvent: CO
Product: NC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetic acid ethyl ester (Compound Ic; 3.77 g, 11.8 mmole) in 50 ml 7N methanol/ammonia was stirred at 45° C. for one hour, and then at RT for 2 days. The suspension was filtered, washed by methanol, dried in vacuum to give 2.56 g of white solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.N([O-])=O.[Na+].[ClH:19]>O>[Cl:19][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Nc1cc2c(c(C(=O)O)c1)OCCO2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCO2
Temperature: 5 °C
Yield: 92.7 %

Procedure:
49 g of 7-amino-1,4-benzodioxane-5-carboxylic acid, 200 ml of water and 50 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 5° C. and then a solution of 17.5 g of sodium nitrite in 38 ml of water was added. The suspension was then poured into a solution of 20 g of cuprous chloride in 75 ml of hydrochloric acid. The precipitate was dried off, washed and dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water. The solution was filtered and treated with 100 ml of hydrochloric acid. 50 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid was produced (M.P.: 180° C.; yield: 92.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)=O.C([SiH](CC)CC)C.OS(C(F)(F)F)(=O)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1cc(I)ccc1Br
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 91.2 %

Procedure:
To a stirred solution of (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone (30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL, 67.42 mmol) at room temperature. After stirring for 25 min at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (200 mL×2), water (200 mL), and brine (200 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (26.5 g).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(F)cc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 93.1 %

Procedure:
In a similar manner to that described in Example 2, methyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-(4-fluorophenoxy)propionate (266 mg), which is the product of Example 146, was reacted with aqueous sodium hydroxide solution (1N, 1.04 ml) and the reaction mixture was treated to give the title compound (241 mg) as colorless crystals.
Reaction SMILES: N[C:2]1[C:3]([Cl:18])=[C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[I-:23].[K+].CCOC(C)=O>S(=O)(=O)(O)O.O>[I:23][C:2]1[C:3]([Cl:18])=[C:4]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@](O)(C(=O)Nc1cccc(N)c1Cl)C(F)(F)F
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@](O)(C(=O)Nc1cccc(I)c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a cooled solution of (R)-N-[3-amino-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 32) (12.5 g) in concentrated sulphuric acid (25 ml) and water (70 ml) was added a solution of sodium nitrite (3.15 g) in water (70 ml) dropwise. The reaction mixture was allowed to stir for 10 minutes and for 1 hour at ambient temperature. A solution of potassium iodide (22.2 g) in water (70 ml) was added cautiously and the mixture was heated to 100° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature, EtOAc (500 ml) was added and the organic phase was washed with brine (300 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash column chromatography eluting with 5-20% EtOAc/isohexane to give the title compound (13.5 g) as a cream solid. NMR (CDCl3) 1.76 (s, 3H), 3.63 (s, 1H), 7.05 (t, 1H), 7.68 (d, 1H), 8.36 (d, 1H), 8.97 (brs, 1H); m/z: 392.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[H-].[Na+].C=[O:27]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([OH:27])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(O)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (120 mg) in DMF (dry) (3.4 mL) was added sodium hydride (15.0 mg) at 0° C. After stirring for 30 min, to the mixture was added paraformaldehyde (20.4 mg) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (12.4 mg).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][C@@H]2F)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH2:6]1)C.C([Mg]Br)C.C([C@@H]1CC2[C@H](CCC(=O)C=2)[C@@H]2[C@@H]1[C@H]1[C@@](C[C@@H]2F)(C)C(=O)CC1)C.[CH:51]([Cl:54])(Cl)Cl>>[Cl:54][C@H:51]1[CH2:10][C@@:9]2([CH3:11])[C@@H:5]([CH2:6][CH2:7][C@@H:8]2[OH:23])[C@H:4]2[C@H:13]1[C@@H:14]1[C:19]([CH2:20][C@H:3]2[CH3:1])=[CH:18][C:17](=[O:21])[CH2:16][CH2:15]1
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Reactant: ClC(Cl)Cl
Agent: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: CC[Mg]Br
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2Cl

Procedure:
In analogy to Example 1 7α-Ethyl-11β-fluoro-17β-hydroxy-estr-4-en-3-one, using ethylmagnesium bromide instead of methylmagnesium bromide, is obtained; Fp. 115.1° C., [α]D20=+62,1° (in chloroform). The intermediate 7α-Ethyl-11β-fluoro-estr-4-en-3,17-dione shows Fp.=174.9° C. and [α]D20=+107,1° (chloroform).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@@H:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1cc2c(Cl)ncnc2s1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ncnc2s1
Yield: 98 %

Procedure:
1-BOC-3-(S)-methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=98%, ES-MS: (M+H)+ 363.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][O:21][CH3:22])=[N:4][CH:5]=1
Reactant: COCOc1ccc(Cl)cc1C(C#N)c1ncc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COCOc1ccc(Cl)cc1C(C#N)c1ncc(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
In acetic acid (300 ml) was dissolved 3-chloro-2-(5-chloro-a-cyano-2-methoxymethoxybenzyl)-5-nitropyridine (15.0 g). To the solution were added water (10 ml) and powdery iron (11.4 g). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue were added ethyl acetate and an aqueous solution of sodium carbonate. Insolubles were filtered off by using celite. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate), followed by concentration. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to afford 5-amino-3-chloro-2-(5-chloro-α-cyano-2-methoxymetho-xybenzyl)pyridine (12.4 g) (Compound D-13). Physico-chemical properties and spectrum data are shown in Table 13 and Table 15.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]1[C:13]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)(=O)C.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]>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:15]2[CH2:16][CH2:17][CH2:18][C:13]3([CH2:12][N:11]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:10][CH2:9]3)[CH2:14]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)C1
Reactant: Cc1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccnc(N2CCCC3(CCN(C(=O)OC(C)(C)C)C3)C2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Bromo-4-methylpyridine (172 mg, 1 mmol) and tert-butyl 3,7-diazaspiro[4.5]decane-3-carboxylate (1 mmol, 240 mg) were dissolved in anhydrous dioxane (5 ml) under argon. Pd2(dba)3 (0.0165 mmol, 15 mg), Brettphos (30 mg, 0.0495 mmol), and sodium tert-butoxide (80 mg, 0.83 mmol) were added and the mixture was stirred at 100° C. overnight. Additional 2-bromo-4-methylpyridine (0.9 mmol, 100 μl) was added and stirring was continued at 100° C. overnight. The mixture was diluted with ethyl acetate, filtered through a plug of silica and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient of 0 to 20% ethyl acetate in DCM) to yield 50 mg (0.15 mmol, 15%) MS(ESI) m/z=332.2 [M+1]+.
Reaction SMILES: CS([O-])(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[S+:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CO.[F:23][C:24]([F:51])([S:47]([OH:50])(=[O:49])=[O:48])[C:25]([F:46])([F:45])[C:26]([F:44])([F:43])[C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>O>[F:51][C:24]([F:23])([S:47]([O-:50])(=[O:49])=[O:48])[C:25]([F:45])([F:46])[C:26]([F:44])([F:43])[C:27]([F:41])([F:42])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[S+:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CS(=O)(=O)[O-]
Agent: c1ccc2cc([S+]3CCCC3)ccc2c1
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
6.0 g of 1-(naphthalen-2-yl)tetrahydrothiophenium methane sulfonate synthesized in the same manner as in Example 1 was added dropwise to 5.0 g of previously prepared 30 wt % methanol solution of perfluoro-n-octane sulfonic acid. After the addition, the reaction solution was poured into 50 g of water. White precipitate was collected by filtration, washed several times with water, and dried under vacuum to obtain 2.1 g of 1-(naphthalen-2-yl)tetrahydrothiophenium perfluoro-n-octane sulfonate as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH2:14][NH:15][CH2:16][CH2:17][NH2:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)(=O)C>[C:8]1([CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCNCc1ccccc1
Reactant: Brc1ccccn1
Solvent: CCOC(C)=O
Product: c1ccc(CNCCNc2ccccn2)cc1
Yield: 39.2 %

Procedure:
2-Bromopyridine (6.1 mL, 64 mmol) was added to N-(phenylmethyl)-1,2-ethanediamine (50 ml, 322 mmol) and the mixture was heated at 130–140° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate (500 mL), washed with water (3×150 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:8:1), to give the title compound as a yellow oil (5.7 g, 40%). m/z (ES+) 228 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][CH2:34][C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][N:36]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:39]3[CH2:38][CH2:37][NH:36][C@@H:35]([CH2:34][CH2:33][OH:32])[CH2:40]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CCO)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-(hydroxy-ethyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: CC(C)Cc1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cnc(N)c(N)c1
Yield: 87.3 %

Procedure:
0.46 g of 2-amino-3-nitro-5-(2-methylpropyl)pyridine (starting material D2) dissolved in 20 ml of methanol are hydrogenated over 0.05 g of 10% strength Pd/C until no starting material is detectable by TLC. After filtration, the solvent is evaporated and the residue is chromatographed over silica gel (dichloromethane/methanol 25:1). Concentration of the pure fractions and drying in vacuo gives 0.34 g of the title compound as an oil. The mass spectrum shows the molecular peak MH+ at 166.2 Da.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[N:7][C:6]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:37])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1COCC1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[O:9][C:5]([CH2:3][OH:2])=[C:6]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([OH:36])([C:32]([F:34])([F:35])[F:33])[C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH3:37])[N:7]=1
Reactant: COC(=O)c1oc(-c2ccccc2Cl)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1nc(-c2ccccc2Cl)oc1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
At 0° C., a solution of 10 mg (0.018 mmol) of 2-(2-chloro-phenyl)-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazole-5-carboxylic acid methyl ester (example 130) in 0.3 mL of THF was treated with 1 mg (0.026 mmol) of LiAlH4 and stirred at RT for 6 hrs. Ice was added and the mixture distributed between Et2O and water. Drying of the combined organic phases and evaporation yielded 9 mg (95%) of 2-{1-[2-(2-chloro-phenyl)-5-hydroxymethyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, off-white solid, MS:518 (MH+), 1 Cl.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1I
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1I
Yield: 98 %

Procedure:
A mixture of 3,5-dichloro-2-iodo-benzoic acid (9.0 g, 28 mmol) and SOCl2 (100 mL) was heated to reflux overnight. The solvent was removed to give crude 3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 98%). 1H NMR (CDCl3): 7.64 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: C1CCNCC1
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: c1ccc2c(-c3ccc(OCCCN4CCCCC4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, piperidine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=352.
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:13]([O-:15])=[O:14])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>>[Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:13]([O-:15])=[O:14])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Yield: 91 %

Procedure:
96 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid and 200 ml of thionyl chloride were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated under reflux and then the excess thionyl chloride was removed under vacuum. The residue was dissolved in 100 ml of isopropyl ether and then the solvent removed and the product air-dried. 91 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 215° C.; yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12].C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2c(Cl)cccc21
Yield: 97.2 %

Procedure:
tert-Butyl N-((5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (204 mg, 537 μmol) was stirred in TFA (2 mL, 26924 μmol) for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give a white solid (169 mg). MS m/e=324 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Br.[C:10]1([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN1C(=O)CCC1>[C:10]1([C:16]2([C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1(c2ccccc2)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To NaH (60% dispersion in mineral oil (14.2 g, 355 mmol)) was added NMP (142 mL), and the mixture was cooled to 0° C. A solution of 1-bromo-2-(2-bromoethoxy)ethane (17.8 mL, 142 mmol) and methyl phenylacetate (20.00 mL, 142 mmol) in NMP was added dropwise, and the resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water, acidified to pH=2 with concentrated HCl, extracted with 200 mL of diethyl ether, washed 2 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound after flash chromatography (15.40 g) as a white solid. MS m/e=221 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](C)[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:30])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)cc1
Yield: 59.62 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (11-06) (2.2 g, 59.62%) was synthesized as a yellow sticky solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (10-06) (3.7 g, 8.92 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).