Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CCN(C)C)C.[Li][CH:10]([CH2:12]C)[CH3:11].[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].CSC.BrCC=C>C1COCC1>[CH2:12]([C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH:10]=[CH2:11]
Reactant: [Li]C(C)CC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CSC
Solvent: C=CCBr
Product: C=CCc1c(C(=O)O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of TMEDA (32.2 g, 0.278 mol) in dry THF (150 mL) was added s-BuLi (1.3 M, 0.278 mol, 214 mL) at −78° C. The mixture was stirred at this temperature for 0.5 hour, and then a solution of 3,4-difluorobenzoic acid (20 g, 0.127 mol) in THF (100 mL) was added dropwise. After stirring for 1 hour, CuBr.DMS (3.9 g, 0.019 mol, 15% mol) was added, followed by 3-bromoprop-1-ene (46 g, 0.38 mol) in 50 mL of THF. The reaction mixture was allowed to warm to room temperature and was quenched with water. The aqueous layer was washed with Et2O, and acidified with 4 N HCl. The mixture was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 2-allyl-3,4-difluorobenzoic acid (22 g, 55%). 1H NMR (CDCl3): 3.91 (d, 2H), 5.06 (m, 2H), 6.01 (m, 1H), 7.12 (m, 1H), 7.90 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)CCCOc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(OCCCC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
ethyl 4-[(4-{[3-methyl-6-(methyloxy)-2-phenyl-1 naphthalenyl]oxy}phenyl)oxy]butanoate (288) (0.300 g, 0.638 mmol) was dissolved in a 1:1 THF:EtOH (1:1, 30 mL) mixture. To the above mixture was added 1 N NaOH (6.4 mL) at room temperature and heated to 70° C. The reaction mixture was kept at that temperature for 2 h and cooled at RT. Reaction mixture was concentrated under reduced pressure to afford the residue and the residue was acidified with 25% aqueous HCl (30 mL), and then extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by flash SiO2 column chromatography using hexanes:EtOAc (19:1 to 1:1) as an eluent to afford 0.247 g (88%) of the title product (289) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 2H), 7.24 (m, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.05 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.66 (d, J=9.2 Hz, 2H), 6.47 (d, J=9.2 Hz, 2H), 3.85 (s, 3H), 3.79 (t, J=6.4 Hz, 2H), 2.30 (t, J=7.2 Hz, 2H), 2.16 (s, 3H), 1.83 (quintet, J=6.8 Hz, 2H). LCMS (ESI) m/z 443.18 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:32])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:41][CH2:42][C:43]([CH3:49])([CH3:48])[C:44]([O:46][CH3:47])=[O:45]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([O:30][CH2:41][CH2:42][C:43]([CH3:49])([CH3:48])[C:44]([O:46][CH3:47])=[O:45])=[C:25]([F:31])[CH:24]=2)=[O:32])[C@@H:14]([CH3:33])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(F)c(O)c(F)c2)c2ccccc21
Reactant: COC(=O)C(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1c(F)cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(3,5-difluoro-4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (150 mg, 0.32 mmol) was dissolved in DMF at room temperature and Cs2CO3 (259 mg, 0.80 mmol) was added. Methyl 4-bromo-2,2-dimethylbutanoate (157 mg, 0.48 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford the product (118 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([N:19]=[N+]=[N-])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 149.4 %

Procedure:
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (350 mg), from the synthesis of Example 17 (analogous to 10f), was dissolved in MeOH (5 mL) prior to the addition of 5% Pd/BaSO4 (300 mg). A hydrogen balloon was added and the mixture was stirred. After stirring 1 h, the Pd/BaSO4 was filtered off and the solvent was concentrated to give {(3S)-1-[(1S,2R,4R)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (497 mg). MS found: (M−H)−=496.5.
Reaction SMILES: Cl.CN(C)[C@H]1[C@H](O)C(C)(C)OC2C=CC=CC1=2.Cl.[C:19]([NH:23][C@H:24]1[C@H:29]([OH:30])[C:28]([CH:41]2C(C(C)C)CCC(C)C2)([CH:31]2C(C(C)C)CCC(C)C2)[O:27][C:26]2[CH:51]=[CH:52][CH:53]=[CH:54][C:25]1=2)(C)([CH3:21])[CH3:20].Cl.O1CCN([C@H]2[C@H](O)C(C)(C)OC3C=CC=CC2=3)CC1>>[CH:19]([NH:23][C@H:24]1[C@H:29]([OH:30])[C:28]([CH3:41])([CH3:31])[O:27][C:26]2[CH:51]=[CH:52][CH:53]=[CH:54][C:25]1=2)([CH3:21])[CH3:20]
Reactant: CC1CCC(C(C)C)C(C2(C3CC(C)CCC3C(C)C)Oc3ccccc3[C@@H](NC(C)(C)C)[C@@H]2O)C1
Agent: CC1(C)Oc2ccccc2[C@@H](N2CCOCC2)[C@@H]1O
Agent: CN(C)[C@@H]1c2ccccc2OC(C)(C)[C@H]1O
Agent: Cl
Product: CC(C)N[C@@H]1c2ccccc2OC(C)(C)[C@H]1O

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (10.00g.) prepared as described by R. Livingstone, J.Chem.Soc., 76, (1962), was treated with isopropylamine (12 ml: an excess) in refluxing ethanol (50 ml.) for 16 hours. The solution was then evaporated to dryness in vacuo to give an off-white solid (13.00g.). This residue was dissolved in diethyl ether and treated with ethereal hydrogen chloride to give a crystalline hydrochloride (12.06g). Re-crystallisation from ethanol/diethyl ether yielded trans-4-isopropyl-amino-3, 4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride as colourless crystals, m.p. 172° - 174°. Similarly prepared were trans-4-dimethylamino-3,4-dihydro-2,2-dimethyl-2H-benzo[b] pyran-3-ol hydrochloride as colourless crystals m.p. 175° - 176°, trans-4-t-butylamino-3,4-dihydro-2,2-dimenthyl-2H-benzo[b] pyran-3-ol hydrochloride as colourless crystals m.p. 239°-241°, trans-4-morpholino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride m.p. 181°-187°.
Reaction SMILES: Cl[CH2:2][CH:3]([O:9][C:10](=[O:12])[CH3:11])[CH2:4][O:5][C:6](=[O:8])[CH3:7].[F:13][C:14]([F:35])([F:34])[C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19]4=[C:20]([C:29](=[O:33])[NH:30][C:31](=[O:32])[N:18]4[C:17]=2[CH:16]=1)[CH:21]=[CH:22][CH:23]=3.[H-].[Na+].[I-].[K+]>CN(C)C=O>[C:10]([O:9][CH:3]([CH2:4][O:5][C:6](=[O:8])[CH3:7])[CH2:2][N:30]1[C:29](=[O:33])[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[S:25][C:26]4[CH:27]=[CH:28][C:15]([C:14]([F:35])([F:34])[F:13])=[CH:16][C:17]=4[N:18]([C:19]=23)[C:31]1=[O:32])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC(CCl)OC(C)=O
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(Cn1c(=O)c2cccc3c2n(c1=O)-c1cc(C(F)(F)F)ccc1S3)OC(C)=O

Procedure:
A mixture of 21.8 g. (0.112 mol.) of 3-chloro-1,2-diacetoxypropane, 28.0 g. (0.083 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione and 3.36 g. (0.080 mol.) of sodium hydride in 200 ml. of dry dimethylformamide was heated at 100°-110° for 40 hours in the presence of a catalytic amount of potassium iodide. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 2-(2,3-diacetoxypropyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].C(O)(=O)C(O)=O.[N:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[N+:13]=[N-:14].CCCCCC>C(Cl)Cl>[N:20]([CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:12]=[N+:13]=[N-:14])[N:1]=[O:4])=[N+:21]=[N-:22]
Reactant: O=[N+]([O-])[O-]
Reactant: [N-]=[N+]=NCCNCCN=[N+]=[N-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: [N-]=[N+]=NCCN(CCN=[N+]=[N-])N=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
A suspension of sodium nitrate (13.4 g; 0.194 mol), oxalic acid (24.4 g; 0.194 mol) and N,N-bis(2-azidoethyl)amine LI (15 g; 0.097 mol) in DCM (300 mL) was stirred vigorously at r.t. for 2.5 h. Silica gel (20 g) and hexane (200 mL) was added to the reaction mixture and the resulting suspension was filtered. The solids were washed (1:1 hexane/DCM, 200 mL). The solvent was evaporated under reduced pressure to afford N,N-bis(2-azidoethyl)-N-nitrosoamine LII (15 g; 0.081 mol; 84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:33])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)=O>[OH:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][O:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc(NC(=O)OCc2cccc(O)c2)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OCc2cccc(O)c2)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (0.63 g), 3-hydroxybenzyl (2-chloromethyl-3-methylphenyl)carbamate (1.2 g), sodium carbonate (1 g) and sodium iodide (0.14 g) in acetone (20 ml) is stirred at RT for 16 h. The precipitate is filtered off, washed with acetone and concentrated. The residue is taken up in sodium hydrogencarbonate solution (40 ml) and extracted with dichloromethane (3×40 ml). The combined organic extracts are washed with water, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 13:1). After concentration of the main fraction and crystallization from acetone, 0.4 g (22%) of the title compound of m.p. 190-193° C. is obtained.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:10]1[CH:11]=[C:1]2[C:2]([O:4][C:5](=[O:12])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:3])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Temperature: 41 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Isatoic Anhydride (25.0 g, 153.25 mmol) is suspended in acetic acid (50 mL) with efficient stirring. The reaction vessel is placed in a pre-heated oil bath at 40° C. and red fuming nitric acid (99.5%, 75 mL, 1.67 mol) is added over 35 minutes (Caution: Exothermic). The reaction mixture is stirred for an additional 4 hours at 38-44° C., then cooled to 20° C. using an ice bath. The reaction mixture is poured on ice (400 mL). After the ice melts, the yellow solid is isolated by vacuum filtration and washed with cold water (5×100 mL). The yellow solid is dried under high vacuum to constant weight at 60-70° C. affording 27.92 g (87%) of product; 1H-NMR (300 MHz, DMSO-d6); δ12.33 (s, 1H), 8.58 (d, J=2.5 Hz, 1H), 8.53 (dd, J=2.6 Hz, 9.0 Hz, 1H), 7.31 (d, J=8.9 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.CCCCCC.C(Cl)Cl>C1(C)C=CC=CC=1.C(O)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[S:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)CCCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: NC(=S)CCCc1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 4-phenylbutyramide (0.373 g, 2.28 mmol) in toluene (15 mL) was added Lawesson's reagent (0.461 g, 1.14 mmol). The reaction was refluxed overnight, cooled to room temperature and concentrated yielding an orange oil. Flash chromatography of this oil (1:1 hexane:methylene chloride with 1% acetic acid) yielded 4-phenylthiobutyramide (0.184 g) as a white solid: 1HNMR (DMSO d6 ) 400 mHz 9.33 (s, 1 H), 9.13 (s, 1 H), 7.29-7.23 (m, 2 H), 7.20-7.15 (m, 3 H), 2.56 (t, J=7.58 Hz, 2 H), 2.50-2.42 (m, 2 H), 2.00-1.85 (m, 2 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH3:16][S:17][C:18]1[C:26](O)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][NH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:16][S:17][C:18]1[C:26]([O:1][CH:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]2)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][NH:22]2
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reactant: CSc1c(O)ccc2[nH]ncc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1c(OC2CCCN(C(=O)OC(C)(C)C)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
The tert-butyl 4-hydroxyazepane-1-carboxylate (0.0504 g, 0.23 mmol) obtained in Example 322, (c) and triphenylphosphine (0.0723 g, 0.28 mmol) were added to a solution of the 4-(methylthio)-1H-indazol-5-ol (0.0377 g, 0.21 mmol) obtained in Example 607 in tetrahydrofuran (2 ml), and the resulting mixture was ice-cooled. A solution of diisopropyl azodicarboxylate (0.0557 g, 0.28 mmol) in tetrahydrofuran (1 ml) was added dropwise thereto, and the resulting mixture was slowly heated to room temperature and stirred overnight. The reaction solution was concentrated and then diluted with chloroform, and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform (twice). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=3/1˜2/1˜3/2) to obtain tert-butyl 4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate (0.0318 g, 40%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
2.28 g of p-benzyloxybenzoic acid and 10 ml of thionyl chloride were heated for 3 hours under reflux, followed by distilling off excess thionyl chloride to obtain p-benzyloxy-benzoyl chloride. This was used without purification in the following step, as a solution in toluene. Into 2.76 g of 1-trifluoromethylheptanol dissolved in 15 ml of pyridine and cooled with ice bath, was added drop-wise over 30 minutes the toluene solution of the above acid chloride, followed by stirring for 5 hours under heating with 90° C. water bath. After cooling, the resulting solution was acidified with addition of 6N hydrochloric acid and ice, and the organic layer was separated and washed with water, then with saturated aqueous solution of sodium bicarbonate, and again with water, followed by distilling off toluene under reduced pressure. Hexane-soluble matter of the resulting crude product was purified with silica gel colmun to obtain 2.85 g of oily optically active 1-trifluoromethylheptyl ester of p-benzyloxybenzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[N:13]1C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:13])=[O:7])([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The free amine obtained from the BOC deprotection step was dissolved in pyridine and nitrobenzoyl chloride (1.2 equiv.) was added to this solution. After stirring for 2 h at 90° C., the reaction mixture was concentrated and the resulting crude product was used for the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][S:4][C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[N:2]1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][S:4][C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[N:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(C2=NOCCS2)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc(C2=NOCCS2)c1

Procedure:
3-(5,6-Dihydro-1,4,2-oxathiazine-3-yl)benzoic acid (15 g, 0.07 mol) was suspended in methylene chloride (200 ml). Thionyl chloride (10 ml) was added and the reaction was refluxed until homogenous and all gassing had ceased. The solvent was removed, the remaining oil was taken up in methylene chloride and treated portionwise with aniline (12.5 g, 0.12 mol). An exotherm was observed. After several hours, water was added, the organic material separated, washed successively with water, aqueous bicarbonate, dilute hydrochloric acid, water and then dried over anhydrous magnesium sulphate. Evaporation of the solvent left a solid which was recrystallised from ethanol to give crystals of 3-(5,6-dihydro-1,4,2-oxathiazin-3-yl)-N-phenylbenzamide, mp 149°-150° C. (Found: C,64.65; H,4.92; N,9.65. C16H14N2O2S requires C,64.42; H,4.73; N,9.39).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[F:10][C:11]1[CH:16]=[C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:14]=[CH:13][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc(Br)cc1F
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(-n2ccc3ccccc32)cc1F

Procedure:
Indole (60 g, 0.51 mole), o-fluoro-p-bromoanisole (112.2 g, 0.547 mole), K2CO3 (76 g, 0.55 mole) and Cu2Br2 (14 g) were combined in 600 ml N-methylpyrrolidone and heated at 185°-200° for 48 hours, stirring under N2. The reaction mixture was cooled, poured into ice and water and extracted several times with ethyl acetate. The combined organic layers were washed with H2O, then brine, dried over MgSO4, treated with activated carbon, and concentrated to an oil (148 g). A portion of the oil (25 g) was chromatographed on silica gel (7.5×18 cm) eluting with 1:9 CH2Cl2 : hexane, yielding title product as an oil which crystallized on standing in vacuo overnight, 7.2 g, m.p. 65°-67°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[NH:13][CH:14]=[CH:15]3)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc(Cl)n1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cncc(-c2ccc3[nH]ccc3c2)n1
Temperature: 85 °C
Yield: 55.4 %

Procedure:
6-Chloro-pyrazine-2-carboxylic acid ethyl ester (1.35 g, 7.23 mmol) was added to indole-5-boronic acid (1.16 g, 7.23 mmol), cesium carbonate (9.43 g, 28.9 mmol) and PdCl2(dppf).DCM (591 mg, 0.72 mmol) in 30 mL of dioxane. The mixture was degassed (evacuate in vacuo and pressurize with nitrogen), 14.5 mL of water was added and the mixture degassed. The mixture was heated at 85° C. for 2.5 h. and the mixture was allowed to cool and the layers were separated. The aqueous phase was extracted with chloroform and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Chromatography of the residue on silica gel, eluting with ethyl acetate/pentane afforded 1.07 g of product. LC/MS: Retention time, 3.21 min; (M+H)=268.1.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([CH:9]=O)[CH2:8][CH2:7]1.C([BH3-])#N.[Na+].Cl.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:26])=[O:20])[CH3:17].Cl>CO>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:26][CH2:9][CH:6]1[CH2:7][CH2:8]1)=[O:20])[CH3:17]
Reactant: O=CC1CC1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.5 %

Procedure:
Sodium acetate (0.423 g, 5.16 mmol), powdered 4 Å molecular sieves (0.60 g), cyclopropanecarboxaldehyde (0.193 mL, 2.58 mmol) and sodium cyanoborohydride (0.324 mg, 5.16 mmol) were added sequentially to a solution of (1R,2S)-2-amino-cyclopentanecarboxylic acid ethyl ester hydrochloride (prepared as described in Example 28b, 0.500 g, 2.58 mmol) in methanol (15 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then was acidified to pH=2 by the addition of 1.0 M aqueous hydrochloric acid solution. After stirring for 5 min at 25° C., the mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (3×50 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-40% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(cyclopropylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester (0.101 g, 0.478 mmol, 18%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.07 (m, 2H), 0.38-0.43 (m, 2H), 0.84-0.91 (m, 1H), 1.23 (t, 3H, J=7.2 Hz), 1.48-1.61 (m, 2H), 1.76-1.87 (m, 3H), 1.91-1.98 (m, 1H), 2.29-2.34 (m, 1H), 2.46-2.51 (m, 1H), 2.84-2.90 (m, 1H), 3.20-3.26 (m, 1H), 3.63 (s, 1H), 4.09 (q, 2H, J=7.0 Hz). LC-MS (ESI) calcd for C12H21NO2 211.16, found 212.4 [M+H+].