Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:26]=[C:25]([CH:24]=[C:14]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:13]=1)[O:27][C:37]1[CH:38]=[CH:39][C:34]([C:32]([O:31][CH2:29][CH3:30])=[O:33])=[CH:35][CH:36]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
A suspension of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (4.5 g, 0.011 mol), 4-ethoxycarbonylphenylboronic acid (3.24 g, 0.016-mol), copper (II) acetate (3.06 g, 0.016 mol), triethylamine (7.74 mL, 0.055 mol) and freshly activated 4 Å molecular sieves (13 g) in DCM (180 mL) was stirred at ambient temperature and under ambient atmosphere for 3 days. The reaction mixture was filtered through celite, washed with DCM (2×50 mL). The DCM was removed in vacuo and the residual oil partitioned between ethyl acetate (100 mL) and water (100 mL), filtered and the ethyl acetate layer washed with brine (50 mL), dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (3.78 g).
Reaction SMILES: [K].[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C=O.S(Cl)([Cl:33])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([Cl:33])(=[O:25])=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1O

Procedure:
Ethyl 2-hydroxy-5-[(4-sulfophenyl]ethynyl]benzoate potassium salt (19 g, 50 mmol) was suspended in toluene (100 ml). Dimethylformamide (1 ml) and thionyl chloride (12 g) were added and the suspension was refluxed for 1 h. The reaction mixture was added to a nearly saturated sodium chloride solution and the precipitated oil was extracted with toluene. The solution was dried and taken to dryness. The product was sufficiently pure for the next step. Yield 16 g, 88%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:28])([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1cccc(F)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(=O)(=O)c1cccc(F)c1
Reaction time: 5 h
Yield: 71.1 %

Procedure:
To a stirred solution of methyl 2-(2-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.99 g, 4.2 mmol, 1.0 eq.) in tetrahydrofuran/methanol (25 mL/25 mL) was added sodium hydroxide (24 mL, 22.63 mmol, 5.4 eq.). The mixture was heated to reflux and stirred for 5 h. LC-MS indicated that 2005467-032-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid. The precipitation was filtered, washed with water and dried to give 1.357 g of 2-(2-(3-fluorophenylsulfonamido) phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as off-white solid. yield: 92.7% (for two steps). MS (ESI+APCI) M+1=455.2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:40]([O:42]CCCC)=[CH2:41].CCN(CC)CC.Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[NH2:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([C:40](=[O:42])[CH3:41])=[CH:6][C:5]=1[F:10]
Reactant: Nc1c(F)cc(I)cc1F
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(F)c(N)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A suspension of 2,6-difluoro-4-iodoaniline (1 g, 3.92 mmol) and Pd(OAc)2 (0.025 eq), DPPP (0.05 eq) in [bmim][3F3] (6 mL) was stirred for 10 min. After the mixture was degassed three times, butyl vinyl ether (5 eq) and Et3N (1.2 eq) were injected sequentially. The mixture was stirred for 15 hrs at 115° C. The mixture cooled to room temperature, and then was added 1N-HCl. After the mixture was stirred for 0.5 hour, CH2Cl2 was added. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to give 1-(4-amino-3,5-difluoro-phenyl)-ethanone (300 mg, 45%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][N:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]nnc2c1
Product: ClCCCN1Nc2ccccc2N1
Yield: 40.2 %

Procedure:
2-(3-Chloropropyl)-1H-1,2,3-benzotriazole (200 mg, 44%) was prepared from benzotriazole (300 mg, 2.52 mmol) and 1-bromo-3-chloro propane (397 mg, 2.77 mmol) according to the procedure of Example 291. The title compound was isolated as a yellow oil (26 mg, 54%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 2-(3-chloropropyl)-1H-1,2,3-benzotriazole (44 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.81-1.93 (m, 2H), 1.96-2.14 (m, 3H), 2.41 (td, 1H, J=3.7 , 11.7 Hz), 2.64-2.72 (m, 1H), 2.80-2.90 (m, 1H), 2.92-3.00 (m, 1H), 3.02-3.16 (m, 4H), 3.21-3.26 (m, 1H), 3.51-3.62 (m, 1H), 3.78-3.86 (m, 1H), 4.85 (t, 2H, J=7.0 Hz), 6.61 (t, 1H, J=7.5 Hz), 6.83 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.2, 8.1 Hz), 7.36-7.41 (m, 2H), 7.84-7.88 (m, 2H) ppm.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])([C:28]([F:31])([F:30])[F:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C:25]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([OH:6])=[O:40])([C:28]([F:29])([F:30])[F:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)(C(F)(F)F)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
A solution of sodium chlorite (120 mg; 1.32 mmol; 5 eq.) and sodium dihydrogenphosphate (127 mg; 1.06 mmol; 4 eq.) in water (2 mL) was added dropwise to a mixture of 2-methyl-2-butene (0.25 mL) and 3-(2-formyl-phenoxy)-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg; 0.26 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 3 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with EA (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (100 mg, quantitative) as a colourless oil. HPLC (max plot) 93.5%, Rt 4.22 min. UPLC/MS: (MS−) 374.3 ([M−H]−).
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[N:9]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:17])([CH3:15])[CH3:16])[N:9]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)c1cccc(CO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
Imidazole (2.27 g, 33.3 mmol) was added to a stirred solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.30 g, 31.7 mmol) and tert-butyldimethylsilylchloride (5.02 g, 33.3 mmol) in DMF (70 mL) and the mixture was stirred for 16 h at room temperature. The mixture was poured onto water, extracted with EtOAc, the organic portion was separated, dried (MgSO4), filtered and evaporated to give the title compound (8.19 g, 92 To) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.74-7.70 (1H, m), 7.40-7.38 (1H, m), 7.20-7.18 (1H, m), 5.34 (1H, s), 4.83 (2H, s), 1.52 (6H, s), 0.97 (9H, s), 0.13 (6H, s); (M+H)+ 282.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:22])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH3:21])=[S:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.BrBr>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:22])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]4[N:17]=[C:18]([NH:20][CH3:21])[S:19][C:15]=4[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CNC(=S)Nc1ccc(-c2nc3ccc(Cl)cn3c2C)cc1
Agent: BrBr
Product: CNc1nc2ccc(-c3nc4ccc(Cl)cn4c3C)cc2s1
Yield: 38.4 %

Procedure:
6-(6-Chloro-3-methylimidazo[1,2-a]pyridin-2-yl)-2-methylaminobenzothiazole (1.68 g) was prepared in substantially the same manner as that of Example 36 from 6-chloro-3-methyl-2-[4-(3-methylthioureido)phenyl]imidazo[1,2-a]pyridine (4.4 g) and bromine (2.05 g).
Reaction SMILES: B.[ClH:2].Cl.[CH3:4][N:5]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:6](=O)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:12]2[CH2:11]1.Cl>O1CCCC1>[ClH:2].[ClH:2].[ClH:2].[CH3:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:12]2[CH2:11]1)[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1
Reactant: COc1cc(N(C)C(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(N(C)CCCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
10 ml of a 1M solution of borane in tetrahydrofuran are added to 0.4 g of the compound obtained in Example 35 in solution, under argon, in 50 ml of tetrahydroftiran and the mixture is refluxed for 8 hours. After hydrolysis with 2 ml of 4N hydrochloric acid, evaporation to dryness and conversion to the base, the hydrochloride is prepared using an ethanolic hydrogen chloride solution.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[O:9][N:8]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)O)on1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (450 mg, 1.43 mmol) in dioxane (5 mL) was added aqueous sodium hydroxide (2 N, 3 mL). After heating at reflux for 1 h the mixture was cooled to room temperature and acidified with HCl (4 N, 2 mL). Purification by filtration and drying afforded the title compound (400 mg, 93%) which was obtained as a white solid. MS: m/e=300.1 [M−H]−.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C([Mg]Cl)(C)C.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>O1CCCC1>[CH2:17]([O:16][C:14]([C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1)=[O:15])[CH3:18]
Reactant: Brc1cscc1Br
Reactant: CCOC(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cscc1Br
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of 3,4-dibromothiophene (1.0 Kg, 4.13 mol) in tetrahydrofuran (7.4 Kg) was added iPrMgCl (2.0 M solution in tetrahydrofuran, 2.58 Kg, 5.17 mol) keeping the temperature below 5° C. The resulting mixture was stirred at 0-5° C. for 5 hours. To the cooled Grignard solution was added ethyl chloroformate (896 g, 5.17 mol) dropwise keeping the temperature below 10° C. The resulting mixture was warmed to room temperature, and stirred for 16 hours. Water (200 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 10 min The majority of the tetrahydrofuran was then removed under vacuum and ethyl acetate (4.5 Kg) was added to the mixture followed by 1N aqueous hydrochloric acid. The layers were separated, and the organic layer was washed with 12% brine (5.0 Kg) The solvent was removed under vacuum to give a yellow oil, which was filtered to remove salts to provide 956 g (98% yield) of 4-bromo-thiophene-3-carboxylic acid ethyl ester, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, 1H, J=3.5 Hz), 7.30 (d, 1H, J=3.6 Hz), 4.34 (q, 2H, J=7.10 Hz), 1.38 (t, 3H, J=7.20 Hz); 13C NMR (400 MHz, CDCl3): δ14.49, 60.95, 110.49, 124.86, 130.93, 133.67, 160.68.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.[N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=O>>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
When using the procedure of Example 1 an equivalent amount of 2-nitro-2'-hydroxy-5'-tert-octylazobenzene is substituted for 2-nitro-2'-hydroxy-5'-methylazobenzene, the above noted product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][O:22][C:15]3[C:16]([Cl:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[Cl:13])=[CH:27][CH:28]=2)[C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Reactant: COc1cc(Br)ccc1CC#N
Product: COc1cc(Br)ccc1C(C#N)Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using (4-bromo-2-methoxyphenyl)acetonitrile (III.4) and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol 50 to 75%, afforded the desired compound as a colorless oil.
Reaction SMILES: [CH3:1]I.[P:3]([O:10]CC)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]>>[CH3:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCOP(OCC)OCC
Reactant: CI
Product: CCOP(C)(=O)OCC
Temperature: -10 °C

Procedure:
188 g (1.32 mol) of methyl iodide are poured under nitrogen into a dry three-necked flask surmounted by an alcohol condenser (-10° C.), and then heated to the refluxing temperature. 168 g (1.02 mol) of triethyl phosphite are then added dropwise. The reaction is exothermic, and the temperature rises in the course of one hour to 73° C. The temperature of the mixture is maintained for one hour at between 70° and 75° C., and the solution is then cooled and concentrated in a rotary evaporator. The diethyl methylphosphonate is distilled under nitrogen, under reduced pressure.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:21]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:14][CH3:13])[CH:22]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(N2CC[C@@](O)(C3CC3)[C@@H]2C)ccc1C#N

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2-methoxy-4-fluorobenzonitrile (277 mg) and lithium carbonate (180 mg), the title compound was obtained as a pale-yellow solid (yield: 192 mg, yield: 58%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N+:17]([O-])=O)[CH:8]=1)(=[O:4])=[O:3].Cl.[H][H]>CO.[Pd]>[NH2:17][C:9]1[CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Yield: 87.5 %

Procedure:
13.25 g (46 mmol) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate are dissolved in 200 ml of methanol. After addition of 1.4 ml (46 mmol) of concentrated hydrochloric acid and 1 g of Pd catalyst (10% on active charcoal), the mixture is hydrogenated with hydrogen under atmospheric pressure until the hydrogen uptake is complete. The mixture is removed from the catalyst by filtration and the filtrate is concentrated completely. Crystallization of the residue from water yields 10.4 g (88%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 121–122° C.
Reaction SMILES: [BH4-].[Na+].[H][H].[Si:5]([O:12][CH:13]([C:27]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=1[CH3:36])[CH:14]([CH2:23][N+:24]([O-])=O)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:24][CH2:23][CH:14]([CH:13]([C:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:28]=1[CH3:36])[O:12][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(O[Si](C)(C)C(C)(C)C)C(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N)cc1C(O[Si](C)(C)C(C)(C)C)C(CN)CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Adapting literature known protocols (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2.6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of tert-butyl 4-(tert-butyl(dimethyl)silyl)oxy-4-(2-methyl-5-nitro-phenyl)-3-(nitromethyl)butanoate (17c) (4.69 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS till completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are evaporated to dryness under reduced pressure using a rotary evaporator. The crude tert-butyl 3-(aminomethyl)-4-(5-amino-2-methyl-phenyl)-4-(tert-butyl(dimethyl)silyl)oxy-butanoate (17d) is used directly in the next step without further isolation and purification procedures.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].B.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 2-(3-fluoro-4-hydroxyphenyl)acetic acid (9.8 g, 57.6 mmol) in THF (500 mL) was added dropwise 57.6 mL of borane (10M in Me2S) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was added to CH3OH and was concentrated under reduced pressure. The residue was partitioned between EtOAc (800 mL) and water (100 mL). The organic layer was dried and concentrated to dryness to give the title product (8.5 g, 76%).
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH:13]([O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:18]=[O:19])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:1][OH:3])[CH2:18][OH:19])([CH3:15])[CH3:14]
Reactant: CC(C)OC(C=O)c1ccccc1
Reactant: CCOC(C=O)c1ccccc1
Product: CC(C)OC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-isopropoxy-2-phenylethanal, to obtain 2-isopropoxy-2-phenyl-1,3-propanediol.
Reaction SMILES: I[CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:22]([CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2N=[N+]=[N-])cc1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
A solution of 2,3,4,5-tetrahydro-3-iodo-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one (270 mg, 0.687 mmol) in 2mL of dimethylformamide was treated with sodium azide (65 mg, 1.0 mmol, 1.5eq) and the mixture was heated at 60° C. in an oil bath for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and filtered. Removal of the solvent under vacuum followed by column chromatography on silica gel (eluant 2:1; hexane/ethyl acetate) gave 148 mg (70%) of the product as a single isomer. 1H NMR (400 MHz, CDCl3): 295 (dd; 7,14 Hz; 1H), 3.15 (dd; 13, 14 Hz; 1H), 3.75 (m, 1H), 3.80 (s, 3H), 4.11 (d, 7Hz, 1H), 6.89 (d, 8Hz, 2H), 7.04 (d, 8Hz, 1 H), 7.20-7.30 (m, 5H), 7.88 (br s, 1H). FAB-MS: calculated for C17H16N4O2 308; found 309 (40%).