Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.I[CH2:23][C:24]([NH2:26])=[O:25].[H-].[Na+]>CN(C=O)C>[NH2:26][C:24](=[O:25])[CH2:23][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: NC(=O)CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(N)=O)c3ccccc23)CC1
Reaction time: 16 h
Yield: 19.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0994 g, 0.347) and iodoacetamide (0.0704 g, 0.381 mmol, 1.10 equiv.) was dissolved in DMF (1 mL) at rt under N2. NaH (0.033 g, 0.825 mmol, 2.38 equiv., 60% dispersion) was added, and the reaction mixture was stirred for 16 h. Additional NaH (0.039 g) was added and the reaction mixture was stirred for 1.5 h. The reaction mixture was poured over ice, and the resulting mixture was extracted with EtOAc. The organic extracts was washed with water and then with brine. The organic extracts was dried over MgSO4, filtered, and concentrated. The crude product (0.124 g) was purified by PTLC (2×1 mm×20 cm×20 cm SiO2 plates, developed with 3:1 EtOAc:hexane, eluted with 10% MeOH in CH2Cl2) to give tert-butyl 6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0233 g) in 19% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.93-3.07, 3.68-3.79, 4.71, 5.33, 5.90-5.94, 7.15-7.24, 7.50-7.54; MS (ESI+) for C19H25N3O3 m/z 344.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=3)(=[O:40])=[O:39])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-fluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NOC1CCCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccccc1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 1.00 g (8.55 mmol) of O-tetrahydropyran-2-ylhydroxylamine (prepared as described in U.S. Pat. No. 4,607,053, Example 2, Part A) and 1.4 ml (10 mmol) of sieve-dried triethylamine in 15 ml of dry CH2Cl2 cooled to -20 was added a solution of 1.50 g (10.7 mmol) of benzoyl chloride in 5 ml of CH2Cl2 over 10 minutes. The reaction mixture was stirred for 1 hour then diluted with 15 ml of ethyl acetate. The resulting slurry was filtered and the filtrate concentrated in vacuo to give a solid. Recrystallization (EtOAc/petroleum ether) of the solid afforded 1.45 g (77%) of title compound as white crystals, m.p. 130°-134°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred solution of tert-butyl 3-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)propyl(methyl)carbamate (0.1 g, 142 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo. 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[5-difluoromethoxy-1-(3-methylamino-propyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (53 mg, 78%). MS (M+H)+=472; 1H NMR (DMSO-d6) δ: 9.30 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 8.08-8.14 (m, 2H), 7.59-7.68 (m, 1H), 7.12-7.71 (m, 1H), 4.82 (t, J=6.7 Hz, 4H), 3.54 (br. s., 3H), 2.27 (t, J=6.8 Hz, 2H), 1.73 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd].O>[C:1]([CH:3]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)C(C)c1ccccc1

Procedure:
A mixture of methyl cyanoacetate (198 g, 2.0 moles), acetophenone (240 g, 2.0 moles), ammonium acetate (30.8 g, 0.4 moles) and acetic acid (96 g, 1.60 moles) in toluene was refluxed with a Dean and Stark trap until water separation ceased (about 4 hours). The resulting Knoevenagel adduct was cooled and stirred under hydrogen (60 psig) with 5% palladium on carbon (8 g) for 2 days. The solution was then depressurized, degassed, filtered and evaporated. The liquid residue was distilled and the fraction with bp 110°-140° C. (about 0.03 mm) collected as mixed stereoisomers of methyl 2-cyano-3-phenylbutyrate as identified by the nmr spectrum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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]>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Cc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1N(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
The above general procedure was followed using 2-bromotoluene (188 mg, 1.10 mmol) and diphenylamine (169 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After four hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 2.5% ethyl acetate/hexanes to give 247 mg (95%) of N-(2-tolyl)diphenylamine as a colorless oil that crystallized to a white solid. 1H NMR (500 MHz, C6D6) δ 7.05-6.96 (m, 12 H), 6.78 (tt, J=7.25, 1.30 Hz, 2H), 1.99 (s, 3H). 13C NMR (125 MHz, C6D6) δ 148.0, 146.0, 136.6, 132.0, 129.9, 129.4, 127.7, 126.1, 122.0, 121.8, 18.7.
Reaction SMILES: C(O[C:4]([C:6]1[C:18](=[O:19])[N:14]2[CH2:15][CH2:16][O:17][C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[C:7]=1[OH:20])=[O:5])C.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[OH:20][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:13]=2[N:14]([CH2:15][CH2:16][O:17]3)[C:18](=[O:19])[C:6]=1[C:4](=[O:5])[N:22]([CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Solvent: c1ccncc1
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccccc1
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (6 g) and N-methylaniline (4 ml) in pyridine (30 ml) was stirred at 125° C. for 4 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (200 g) eluting with a mixture of chloroform and methanol (5:1). The product was recrystallized from a mixture of ethanol and isopropyl ether to give pale brown crystals of 2,3-dihydro-7-hydroxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.7 g).
Reaction SMILES: CN(S(F)(F)[F:5])C.[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20]O)[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9].O>ClCCl>[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20][F:5])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]
Reactant: CN(C)S(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CO)c1SC(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1SC(F)(F)F
Reaction time: 3 h
Yield: 84 %

Procedure:
Dimethylaminosulfur trifluoride (2.27 mL) was added to a solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole (2.9 g) in dichloromethane. After stirring for 3 hours, water was added followed by dichloromethane. The organic phase was washed with an aqueous solution of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (2.45 g, 84%). 1H NMR: (400 MHz, CDCl3): 5.38 (d, J=47.5 Hz, 2H) and 7.83 (s, 2H). 19F NMR (376 MHz, CDCl3): −43.83 (s, 3F), −63.76 (s, 3F) and −84.12 (t, J=47.5 Hz, 1F).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccccc2)sc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-(4-methyl-2-phenyl-thiazol-5-yl)-ethanol [U. H. Lindberg, G. Bexell, B. Ulff, Acta Pharmaceutica Suecica 1971, 8, 49-58] in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield {6-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][N:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])=[CH:20][N:19]=1)=[O:17])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-5-methanesulfonyloxy methylpyridine-2-carboxylic acid amide (Reference Compound No. 4-1, 4.9 g, 12 mmol) was added to a suspension of N,N-dimethyl-1,3-propanediamine (3.0 mL, 24 mmol) and potassium carbonate (3.3 g, 24 mmol) in DMF (40 mL), and then the reaction mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate (100 mL) was added thereto, and then the whole was extracted with ethyl acetate (100 mL) twice. The organic layer was washed with water (100 mL) three times, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.9 g of the title reference compound as a yellow amorphous product. (Yield 38%)
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOC(COC2C=CC=CC=2)C1)(=O)=O.[Br:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[N:48](S(C1C=CC=CC=1)(=O)=O)[C:47]([C:61](OCC)=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][CH:71]([CH2:75][O:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:70]1)(=[O:68])=[O:67]>>[Br:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[NH:48][C:47]([C:61]([NH2:7])=[O:62])=[C:46]2[S:66]([N:69]1[CH2:74][CH2:73][O:72][C@@H:71]([CH2:75][O:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:70]1)(=[O:68])=[O:67]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCO[C@@H](COc2ccccc2)C1

Procedure:
Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 493.85 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([Cl:18])=[O:15])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1conc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1conc1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 0.3 g of Compound 8D in 1.05 mL of thionyl chloride was refluxed for 1 h under N2 atmosphere. After cooling to r.t., the solvent was evaporated to dryness and the so obtained crude 3-(4-fluorophenyl)isoxazole-4-carbonyl chloride dissolved in 10 mL of chloroform. Afterwards a solution of 0.48 g of Compound 8B and 0.6 mL of triethylamine in 10 mL of chloroform was added and the resulting mixture stirred at r.t. for 18 h. The solvent was washed with water, dried (sodium sulphate), filtered and evaporated in vacuo. The crude was purified by flash chromatography (ethyl acetate-2N ammonia in methanol 95:5) to give 0.607 g (79.8%) of the title compound. M.p.: 122.4-123° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[C:6](=O)([O:15]C1C=CC=CC=1)[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[NH2:4][CH2:3][CH2:2][CH2:1][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)Oc1ccccc1
Reactant: NCCCN
Solvent: CCO
Product: NCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1,3-propanediamine (6.50 g, 87.0 mol) in 250 mL of abs. EtOH was added benzyl phenyl carbonate (20.0 g, 87.0 mmol). The solution was stirred overnight. A white precipitate formed. The solvent was removed in a rotary evaporator, and the residue was taken up with 100 ml of distilled H2O. This was followed by acidification with 2M HCl to pH 1-2, and 4× extracting with 250 mL of CH2Cl2 each time. The aqueous phase was rendered strongly alkaline with 2M NaOH and extracted 4× with 250 mL of CH2Cl2 each time. The combined organic phases were dried over Na2SO4, subsequently the solvent was removed in a rotary evaporator to obtain the product as a viscid white mass (4.70 g, 26%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+].[CH3:31][OH:32]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:31][O:32][C:23]1[CH:22]=[C:21]([CH:10]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc(N)c2)c1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl]amine (2.79 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3 .49 g) and sodium borohydride (1.17 g) were reacted, and the residue was purified by chromatography through a silica gel column, using mixtures of toluene and ethyl acetate ranging from 8:1 to 5:1 by volume as the eluant, and reverse phase chromatographly through a Lobar column under medium pressure using a 35:65 by volume mixture of acetonitrile and an acetic acid buffer solution (water/acetic acid/triethylamine=1000:2:2) as the eluant, to afford isomer A of the title compound (700 mg) as a yellow oil and isomer B of the title compound (220 mg) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=[O:2].P([O-])(O)(O)=[O:32].[Na+].OO.Cl([O-])=O.[Na+].S([O-])(O)(=O)=O.[Na+].Cl>C(#N)C.O>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([NH:22][C:5]1[C:4]([CH3:30])=[C:3]([C:1]([OH:32])=[O:2])[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]=1[CH3:21])=[O:29]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: O
Solvent: CC#N
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(=O)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 2 h
Yield: 269.1 %

Procedure:
To a mixed solution of N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.23 mmol) obtained in Example 20, sodium dihydrogenphosphate (40 mg), and hydrogen peroxide (0.125 mL) in acetonitrile (5 mL)-water (2 mL) was added at room temperature a solution of sodium chlorite (190 mg, 1.69 mmol) in water (2 mL) and the resulting mixture was stirred at the same temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfate solution, added 1 N hydrochloric acid to make the mixture acidic, and the mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 380 mg (yield: 73%) of the title compound. Melting point: 194-195° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:21]([F:23])([F:24])[F:22])=[CH:13][CH:14]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethanol (450 mg, 1.35 mmol) and triethylamine (377 μL, 2.70 mmol) in dichloromethane (13 mL) was added methanesulfonyl chloride (126 μL, 1.62 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure to give the title compound as a brown oil (quant.). MS (EI) m/z 410 [M]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:23]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccnc(-c2cccc3c2oc2ccccc23)c1
Yield: 81.8 %

Procedure:
Dibenzo[b,d]furan-4-ylboronic acid (25 g, 118 mmol), 2,4-dichloropyridine (19.2 g, 130 mmol), Pd(PPh3)4 (4.1 g, 3.5 mmol) and potassium carbonate (48.9 g, 354 mmol) were added to dimethoxyethane (200 mL) and water (200 mL). The reaction mixture was degassed with nitrogen before being heated to reflux overnight. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane to yield 33.4 g of crude product. The product was crystallized from hexane to give 27.0 g (82%) of 4-chloro-2-(dibenzo[b,d]furan-4-yl)pyridine as white needles. The product was confirmed by GC/MS and NMR.