Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=[O:5].[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH3:19].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C.ClCCl.O>[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:2][CH2:3][C:4]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=3)=[O:5])=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH3:19]
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Reactant: CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(-c2ccc(C(=O)NCC(=O)c3ccc(C(=O)OCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a solution of 2-amino-4′-ethoxycarbonylacetophenone hydrochloride (700 mg), 4-(4-propoxyphenyl)benzoic acid (866 mg) and 1-hydroxybenzotriazole (456.5 mg) in triethylamine (0.47 ml) and dichloromethane (7 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) (648 mg), and stirred for 5 hours at ambient temperature. To the reaction mixture was added water (100 ml), and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate aqueous solution and brine. Then the organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate, and collected by filtration to give 2-[4-(4-propoxyphenyl)benzoylamino]-4′-ethoxycarbonylacetophenone (746 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[C:9]1[S:10][C:11]([C:28]#[N:29])=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:18]=2)[N:13]=1>O1CCOCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:17]2[CH:18]=[C:14]([C:12]3[N:13]=[C:9]([O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[S:10][C:11]=3[C:28]#[N:29])[CH:15]=[N:16]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Br)sc3C#N)cn2)cc1
Reactant: Oc1ccccn1
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3nc(Oc4ccccn4)sc3C#N)cn2)cc1
Temperature: 25 °C
Yield: 24.8 %

Procedure:
According to Scheme 7, Step 5: To the reaction mixture of pyridin-2-ol (1.05 mmol, 100 mg) and 2-bromo-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile (1.16 mmol, 434 mg) in dioxane (8 mL) was added Ag2O (3.16 mmol, 733 mg). The resulting mixture was stirred at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC PE/EtOAc (1:1) to give 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile (0.26 mmol, 153 mg, 37%) as a white solid.
Reaction SMILES: [CH2:1]([O:5]C(=O)C=C)[CH2:2]CC.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13]C(O)=O)=[CH2:12].C(OS([O-])(=O)=O)CCCCCCCCCCC.[Na+]>>[CH3:13][C:11]([C:10]([O:18][CH2:2][CH2:1][OH:5])=[O:17])=[CH2:12]
Reactant: C=CC(=O)OCCCC
Reactant: C=C(CC(=O)O)C(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCO

Procedure:
To the solution is added 19 g butylacrylate, 3 g itaconic acid and 1 g 30% sodium laurylsulfate solution. Polymerization is carried out as described before to obtain a stable latex with essentially no coagulum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([CH:57]([NH2:61])[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([CH:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1
Reactant: COCC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 47 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in tetrahydrofuran. Yield: 47%; Rf value: 0.66 (silica gel; dichloromethane/methanol=9:1); C23H25ClN4O3 (440.93); mass spectrum: (M−H)−=439/441 (chlorine isotope).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18]OS(C)(=O)=O)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:26]=[N+:27]=[N-:28])[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (8 g, 19.7 mmol) and sodium azide (4 g, 61.5 mmol) were heated in N,N-dimethylformamide (75 ml) at 80° C. for 2 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with potassium phosphate buffer (pH 7) and with water and dried over sodium sulfate. After evaporation of the solvent the title product was obtained as a brown oil (˜7 g, crude).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>C(O)C>[C:2]([NH:3][C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:5])([F:16])[F:17])=[CH:12][CH:11]=1)=[S:15])#[N:1]
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
The suspension of monosodium cyanamide (0.63 g, 9.8 mmol) in absolute ethanol (50 mL) was slowly treated with 4-trifluoromethylphenylisothiocyanate (2.0 g, 9.8 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title compound (2.0 g) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[C@@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:3]1.[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21]>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:7]([C@@H:5]1[C@@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)[C@@H](c2ccccc2)O1
Solvent: O=[N+]([O-])O
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])[C@@H](c2ccccc2)O1
Yield: 38.9 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 130 mg of (4S,5R)-2-oxo-5-phenyloxazolidine-4-carboxylic acid and 127 mg of N-(2-nitrooxyethyl)amine nitrate, to obtain 72 mg of the title compound as colorless plates, melting at 122°-124° C.
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=O)(OCC1C=CC=CC=1)=O.[BH4-].[Na+].[Br:21][C:22]1[CH:23]=C(N2CCC=C2)[CH:25]=[N:26][CH:27]=1>COCCOC.C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:13]([CH:12]2[CH2:16][CH2:17][CH2:18][NH:11]2)[CH:25]=[N:26][CH:27]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Brc1cncc(N2C=CCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Brc1cncc(C2CCCN2)c1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Carbobenzyloxy-L-proline (37.4 g, 150 mmol) was dissolved in DME (100 mL) and cooled to 0° C. with stirring. Sodium borohydride (1.89 g, 50 mmol) was added in portions (gas evolution) and the resulting mixture was stirred for 2 h at 25° C. affording a colorless solution. The solvents were removed in vacuo and the resuting gum dissolved in methylene chloride (50 mL). To this solution was added a mixture of 5-bromo-3-(2-pyrrolin-1-yl)pyridine (5.63 g, 25 mmol) and carbobenzyloxy-L-proline (6.23 g, 25 mmol) in methylene chloride (50 mL) and this was stirred at 25° C. for 36 h. The solvent was removed in vacuo and 6M HCl (200 mL) was added to the residue. The resulting solution was extracted with isopropyl acetate (200 mL) and the phases separated. The acidic aqueous phase was basified with solid NaOH to pH 14 and then extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine (150 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:19 to 1:9) as eluants to afford 5-bromo-3-(2-pyrrolidinyl)pyridine (4.1 g, 72%) obtained as a pale yellow oil. LRMS (EI) m/e 227 (C9H11N281 Br--H+) 225 (C9H11N279Br--H+); 1H NMR (DMSO-d6, 300 MHz) δ 8.53 (d, J=2.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17 (t, J=7.7 Hz, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s, 1H), 2.00-1.77 (m, 2H), 1.63 (m, 1H).
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([O:16]C)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1COCC1>O>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
LiOH—H2O (0.09 g, 2.1 mmol) was added to a solution of methyl 3-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)propanoate (0.64 g, 1.9 mmol) in 2:1 THF:H2O (20 mL). The reaction was then stirred for 3 hours at room temperature and then diluted with H2O (50 mL) and washed with ether (50 mL). The aqueous layer was next acidified with solid KHSO4, saturated with solid NaCl, and extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 3-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)propanoic acid (0.523 g, 85%) as a solid. MS ESI (−) m/z 312 detected.
Reaction SMILES: BrC1C2C(=NN(C3C=CN=CC=3)N=2)C(Br)=CC=1.Br[C:19]1[C:27]2[C:23](=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[N:26]=2)[C:22](Br)=[CH:21][CH:20]=1>>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([N:25]2[N:26]=[C:27]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]3=[N:24]2)=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(-n2nc3c(Br)ccc(Br)c3n2)cc1
Agent: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Product: O=[N+]([O-])c1ccc(-n2nc3ccccc3n2)cc1
Yield: 16 %

Procedure:
A similar two-step procedure as that of Intermediate A was applied to give 2-(4-nitrophenyl)-2H-benzo[d][1,2,3]triazole (16% yield) in the first step and 4,7-dibromo-2-(4-nitrophenyl)-2H-benzo[d][1,2,3]triazole (Intermediate C, 75%) in the second step. 1H NMR (400 MHz, CDCl3): δ 8.65 (m, 2H, 4-nitrophenyl), 8.44 (m, 2H, 4-nitrophenyl), 7.54 (s, 2H, benzotriazole).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:45][CH2:46][CH2:47][N:48]4[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:50][CH2:49]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 19 h
Yield: 85 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 19 h to obtain the title compound (85%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)c1

Procedure:
3-(3′-Acetylamino-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=362.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[C:16]1([CH2:22][C:23]([N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=[O:11])[C:10]3=[CH:1][S:2][CH:3]=[C:4]23)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)Cc2ccccc2)c2cscc21
Reaction time: 3 h

Procedure:
A reaction mixture comprising 6.48 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 25 g. of phenylacetyl chloride in 100 ml. of benzene is refluxed with stirring for 3 hours. The mixture is evaporated to an amber oil, combined with 100 ml. of ethanol and 6 ml. of 5 N sodium hydroxide and allowed to stand at room temperature for one hour. This solution is evaporated to an oily residue which is triturated with water and filtered, giving the desired product as pale pink crystals, mp. 165°-168° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10]C(=O)C(F)(F)F.[OH-].[K+]>CO>[F:9][C:8]1[C:3]([S:2][CH3:1])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:10]
Reactant: CSc1c(F)cccc1NC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1c(N)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
N-(2-Methylthio-3-fluorophenyl)trifluoroacetamide (2.36 g crude, 9.33 mmol, prepared as described by McKittrick, J. Het. Chem. 1990, 27, 2151-2163) was taken up in methanol (40 mL), and solid potassium hydroxide (1.57 g, 28.0 mmol) was added portionwise at room temperature. The mixture was heated to reflux. After 1.5 hours, the mixture was cooled to room temperature, and the solvent volume reduced to 5 mL by evaporation under reduced pressure. The residue was taken up in deionized water (30 mL) and extracted with diethyl ether (3×40 mL). The extracts were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the volatiles were removed by evaporation under reduced pressure. The product was purified by silica gel chromatography using 10% ethyl acetate in hexanes. 1.2 g of 3-fluoro-2-(methylthio)aniline was isolated.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C[Al](C)C.CCCCCC.[C:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46](OC)=[O:47])=[CH:42][CH:41]=2)=[C:36]([CH3:50])[CH:35]=1)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1.ClCCl>[C:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:47])=[CH:42][CH:41]=2)=[C:36]([CH3:50])[CH:35]=1)(=[O:31])[CH3:30]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(-c2ccc(CNC(C)=O)cc2C)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)NCc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 47.7 %

Procedure:
A stirred solution of 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 85 mg, 0.35 mmole) in toluene (10 ml) at room temperature under argon was treated with 2M trimethylaluminium in hexane (0.74 ml, 1.5 mmole). The mixture was stirred for 0.75 h, then treated with a solution of methyl 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylate (D21, 120 mg, 0.40 mmole) in toluene (5 ml) and heated at 90° C. for 2 h. The solution was allowed to cool, then poured carefully into a stirred slurry of silica gel (10 g) in dichloromethane (30 ml) and stirring continued until the effervescence had ceased. The silica gel slurry was then packed into a chromatography column and eluted with 0-10% MeOH/CH2Cl2 to afford the title compound (85 mg, 48%). This was converted to the oxalate salt, which crystallised form acetone.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:5].CNC(N1C[C@H](P(C2CCCCC2)C2CCCCC2)C[C@@H]1CP(C1C=CC=CC=1)C1C=CC=CC=1)=O.C(N(CC)CC)C.[H][H]>CO>[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[OH:5]
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)CN)c1
Agent: CNC(=O)N1C[C@H](P(C2CCCCC2)C2CCCCC2)C[C@@H]1CP(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(F)c([C@@H](O)CN)c1
Yield: 85.7 %

Procedure:
3'-(2-Aminoacetyl)-4'-fluoromethanesulfonanilide hydrochloride (21 g) was suspended in 210 ml of methanol, then a catalyst prepared from 50 mg of (2R,4R)-N-methylcarbamoyl-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine and 18 mg of di-μ-chlorobis(cyclooctadiene)dirhodium (I) was added thereto together with 19 mg of triethylamine and the mixture was reduced at 50° C. in an atmosphere of hydrogen of 20 atm. The reaction mixture was concentrated and made into a free base using ion exchange resin (Dowex 50W X2) to give 15.8 g of crude (R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide.
Reaction SMILES: B.[CH2:2]([O:18][CH2:19][C:20]1[O:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-:26].[Na+].OO>O1CCCC1.O>[CH2:2]([O:18][CH2:19][C@H:20]1[C@H:21]([OH:26])[CH2:22][CH2:23][CH2:24][O:25]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCOCC1=CCCCO1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11 ml of a 1M tetrahydrofuran solution of borane was added dropwise, whilst ice-cooling, to a solution of 5.53 g of 6-hexadecyloxymethyl-3,4-dihydro-2H-pyran (prepared as described in Preparation 1) dissolved in 12 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours, after which 4 ml of a 3N aqueous solution of sodium hydroxide were added to it, and then 4 ml of 30% hydrogen peroxide were added dropwise into it at 30°-40° C. The reaction mixture was then stirred at room temperature for 1 hour, after which it was poured in water. The mixture was then washed with a saturated aqueous solution of sodium chloride, and then the organic layer was separated, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography through 100 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:2 by volume gave 5.18 g of the title compound as crystals. Recrystallization from hexane gave needles, melting at 41.5°-43° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:22][CH2:23][CH2:24][OH:25])(=[O:10])=[O:9])[CH:7]=1
Reactant: OCCCO
Reactant: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.39 g (3.72 mmol) 3-(5-bromo-2-methoxyphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 2.69 mL (37.2 mmol) of 1,3-propanediol and 1.95 g (7.44 mmol) of triphenylphosphine in 25 mL of anhydrous tetrahydrofuran was added 1.17 mL (7.44 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 250 g of silica gel with 60% ethyl acetate-hexane to give a mixture of desired product and triphenylphosphine oxide. A second chromatography on 120 g of silica gel with 8% acetone-dichloromethane afforded 1.43 g (89% yield) of the pure title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 7.95 (d, 1 H, J=2.5 Hz), 7.70 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.62 (br s, 1 H), 6.52 (br s, 1 H), 6.46 (t, 1 H, J=2.0 Hz), 4.03 (t, 2 H, J=6.0 Hz), 4.00 (s, 3 H), 3.84 (q, 2 H, J=5.7 Hz), 2.26 (s, 3 H) and 2.00 (m, 2 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H1981BrO6S: 455.0 (M+Na). Found: 454.8.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[OH:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH:11]([C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[OH:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Product: CS(=O)(=O)c1ccc(C(O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-phenyl)-methanol was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 413. (400 MHz, CDCl3): 3.00 (3H, s, CH3), 3.82-3.84 (4H, m, CH2), 3.99-4.01 (4H, m, CH2), 6.21 (1H, b, NH), 7.29 (1H, d (J=0.80), ar), 7.43 (1H, t (J=7.80), ar), 7.53 (1H, d (J=8.30), ar), 7.66 (2H, d (J=8.26), ar), 7.91 (2H, d (J=8.46), ar), 8.18 (1H, d (J=6.56), ar), 8.91 (1H, s, ar). (M+H)+ 522.21