Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:10]([O:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC[C@@H](CO)N1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Reaction time: 72 h

Procedure:
A mixture of (S)-39 (5.85 g, 45.3 mmol), trityl chloride (16.04 g, 57.5 mmol), i-Pr2NEt (11.6 mL, 66.6 mmol) and DMAP (0.527 g, 4.31 mmol) in DMF (21 mL) was stirred at r.t for 3 days. Reaction mixture was separated between brine (80 mL) and water (80 mL). The aqueous layer was extracted with AcOEt (4×80 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated and separated by SGC with hexane:AcOEt (in gradient, up to 40% AcOEt) to afford (S)-40 as a foam; yield 12.20 g (73%). 1H NMR (250 MHz, CDCl3) δ 1.16-1.34 (m, 1H), 1.58-1.90 (m, 3H), 2.17-2.31 (m, 1H), 2.33-2.47 (m, 1H), 2.94 (t, J=9.1 Hz, 1H), 3.23 (dd, J=9.1, 3.1 Hz, 1H), 3.56-3.68 (m, 1H), 6.21 (s, 1H), 7.21-7.45 (m, 15H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH:15]=[C:14]([C:28]([NH2:30])=[O:29])[C:10]=3[NH:11][C:12]=2[CH:13]=1)([CH3:3])[CH3:2].C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O.N>C(Cl)Cl.C1COCC1.CO.O>[CH:1]([N:4]([CH3:33])[C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH:15]=[C:14]([C:28]([NH2:30])=[O:29])[C:10]=3[NH:11][C:12]=2[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(C)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A suspension of 7-(isopropylamino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (13 mg, 0.032 mmol), formaldehyde (0.023 mL, 0.315 mmol, 37% aq. solution), and sodium triacetoxyborohydride (33 mg, 0.16 mmol) in a mixture of DCM/THF (2/1) (0.3 mL) was stirred at RT overnight. The crude reaction was diluted with MeOH and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (6 mg, 0.011 mmol, 38% yield). MS (ESI) m/z 427.13 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.17 (1H, br. s.), 8.60 (2H, d, J=1.53 Hz), 8.54 (1H, br. s.), 8.35 (1H, s), 8.03 (1H, d, J=8.85 Hz), 7.83 (1H, br. s), 7.73-7.78 (2H, m), 7.07 (1H, d, J=2.14 Hz), 6.87 (1H, dd, J=8.85, 2.14 Hz), 4.24 (septupled, 1H, J=6.6), 2.82 (3H, s), 1.21 (6H, d, J=6.41 Hz).
Reaction SMILES: [CH3:1][N:2]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>ClCCl>[CH3:1][N:2]([C@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:3]1[C:4]([O:17][S:33]([C:36]([F:39])([F:38])[F:37])(=[O:34])=[O:32])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (320 mg, 0.95 mmol) in dichloromethane (30 mL) was added pyridine (313 mg, 3.96 mmol), and Tf2O (559 mg, 1.98 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum to get a residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a yellow solid (432 mg, crude).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=3)[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(c3ccc(C#C[Si](C)(C)C)cc3)CC2)CC1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A suspension of [(4-bromophenyl)ethynyl](trimethyl)silane (2.210 g, 8.73 mmol), Pd2(dba)3 (0.400 g, 0.436 mmol), 2-dicyclohexylphosphino-2′-(N,N′-dimethylamino)biphenyl (0.172 g, 0.436 mmol) in anhydrous THF (60 mL) was degassed and backfilled with Argon for three times. 1-Methyl-4-(piperidin-4-yl)piperazine (4.00 g, 21.82 mmol) was added and the mixture was degassed and backfilled with Argon for three times again. Finally LiHMDS 1 M in THF (17.46 mL) was added by a syringe and the mixture was heated to reflux for 2 h. After cooling to room temperature the reaction mixture was filtered on a pad of celite washing with THF (300 mL). The filtrate was evaporated under vacuum and the black oil so obtained was purified by flash chromatography on silica gel (DCM/MeOH/NH4OH 90/10/0.2) to afford the title compound as a yellow solid (2.55 g, 82%).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:27](OC)=[O:28])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=4)[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:27][OH:28])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 40 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Lithium borohydride (74.3 mg, 3.41 mmol) was added to a stirred solution of methyl 9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (341 mg, 0.853 mmol) in tetrahydrofuran (5.0 mL) at room temperature, and the mixture was stirred at 40° C. for 20 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C., concentrated in vacuo and the precipitate was collected by filtration, washed with water, diisopropyl ether to give the title compound as a colorless powder (317 mg, 0.853 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1.[CH2:29](Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:12]1[C:11](=[O:23])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 99.1 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one and benzyl chloride as starting materials, the procedures of Example 19 were repeated likewise, whereby the title compound was obtained in a yield of 99.1%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH2:6].[Si:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH:24]=O)[CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(N(CC)CC)C>[Si:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][NH:6][CH2:5][C:4]([N:3]([CH3:8])[CH3:2])=[O:7])[CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CN(C)C(=O)CN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from N,N-dimethylglycineamide hydrochloride, triethylamine, and 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde. Purification by column chromatography (0-10% MeOH in DCM) gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.49 (d, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 4.74 (s, 2H), 3.97 (s, 2H), 3.47 (s, 2H), 2.95 (d, 6H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [NH3:1].[C:2]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4]1)=[O:3].C(OC(C)C)(C)C.C(OC)CCC>C(OCC)C.O1CCCC1>[CH2:8]1[CH:9]=[CH:10][C:11]2[C:2]([NH:1][C:5](=[O:4])[C:6]=2[CH2:7]1)=[O:3]
Reactant: N
Reactant: O=C1OCc2ccccc21
Agent: CCCCOC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: O=C1NC(=O)C2=C1C=CCC2

Procedure:
The 3-substituted phthalimidines of formula (I) wherein Z is OH can be prepared by reacting, under nondehydrating conditions, equivalent amounts of a 3-substituted phthalide of the formula ##STR3## wherein R, X, Y, a and b have the same meanings as above, and ammonia, or a primary aliphatic or aromatic amine. The reaction is preferably carried out in the presence of an inert organic solvent for the phthalide such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl n-butyl ether and the like. The solvent should have a boiling point below about 100° C. to permit ready separation from the reaction product by distillation at moderate temperatures. This serves to minimize dehydration of the 3-hydroxy group on the phthalimidine product. The primary amines employed in the reaction are those of the formula H2N--Q where Q has the same meaning as above. When the reaction is conducted at temperatures above about 100° C., dehydration takes place to produce a 3-substituted phthalimidine of formula (II).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[C:12](\[C:18]3[CH:31]=[CH:30][C:29]4[S:28](=[O:33])(=[O:32])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21](C(OC(C)(C)C)=O)[C:20]=4[CH:19]=3)/[C:13]([O:15]CC)=[O:14])[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+].Cl>CO.CC(C)=O>[O:33]=[S:28]1(=[O:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]2[CH:19]=[C:18](/[C:12](=[CH:11]\[CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)/[C:13]([OH:15])=[O:14])[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)/C(=C/C1CCC2(CC1)OCCO2)c1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C1CCC(/C=C(/C(=O)O)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.14 g of tert-butyl 2-[(E)-2-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-ethoxycarbonylvinyl]-5,5-dioxo-5H-phenothiazine-10-carboxylate are dissolved in 130 ml of methanol, and 7.0 ml of a 2 M NaOH solution are added. The reaction mixture is heated at the boil under reflux for two hours. Methanol is removed under reduced pressure and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. The precipitated solid is dissolved in 200 ml of ethyl acetate and dried over MgSO4, and the solvent is then removed under reduced pressure. The residue obtained in this manner is dissolved in 20 ml of acetone, and 4 ml of 50% strength hydrochloric acid solution are added. The reaction mixture is stirred at room temperature for 30 minutes. The acetone is removed under reduced pressure and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 840 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(4-oxocyclohexyl)acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:21]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:21][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1coc(=O)c2ccc(F)cc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Temperature: 80 °C

Procedure:
A mixture of methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g) and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid was heated at 80° C. for 16 h. The reaction was cooled to 40° C., diluted with 8 ml of water and the solid collected by filtration (1.38 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCCCC)[CH2:15][CH2:16]C.IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C.C(OCC)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCSSCCCC
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCSc1c[nH]nc1-c1cccnc1
Yield: 18.4 %

Procedure:
Compound 21F was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 1-butyldisulfanyl-butane as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (flash chromatography conditions ethyl acetate/diethyl ether 3/1).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28].Cl>CC(O)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=4)[O:24]3)[CH2:12]2)=[CH:18][CH:19]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc(F)cc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc(F)cc3)C1)O2
Yield: 96 %

Procedure:
This ester was hydrolyzed with aqueous 20% HCl solution and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (305 mg, 0.73 mmol, 96%) as a light brown solid (hydrochloride salt). This was treated with NH2OTHP following the procedure described in Example 1, Step C, giving (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (288 mg, 0.60 mmol, 82%) as a light yellow solid. This was treated with HCl in diethyl ether as described in example 3, Step D, giving (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide (188 mg, 0.43 mmol, 74%) as a light pink solid (hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:11]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC.CCCCCCC.C(C1C=CC=CC=1)C>[CH3:1][O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COC(=O)C1(C)CCOCC1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
Into a solution of 6.18 g (42.9 mmol) of tetrahydropyran-4-carboxylic acid methyl ester in tetrahydrofuran (140 mL) was dropped, at −78° C. under an atmosphere of argon, 25.7 mL (51.5 mmol) of 2 mol/L lithium diisopropylamide in hexane-heptane-ethylbenzene (available from Aldrich), and stirred for 90 minutes. To this solution, 8.5 g (60.1 mmol) of methyl iodide was added at −78° C. and stirred for 4 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture and stirred for 10 minutes. Then the reaction mixture was concentrated to about one third of its volume under a reduced pressure and the residue was extracted with ethyl acetate-hexane (3:1). The organic layer was washed with water (twice) and saturated brine successively, and dried over anhydrous magnesium sulfate, and then the solvent was removed. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent: hexane:ethyl acetate) to obtain 5.9 g (yield 86.4%) of 4-methyltetrahydropyran-4-carboxylic acid methyl ester (IX-60) as colorless liquid. Its physical property is shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1.CI.[C:33](=O)([O-])[O-].[K+].[K+].CC(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([N:26]([CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([OH:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-{3-fluoro-4-[(5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]dec-7-yl]phenyl}methanesulfonamide (20 mg, 0.00006 mol, example 312), methyl iodide (4.1 μL, 0.000066 mol), and potassium carbonate (10 mg, in excess) in acetone (2 mL, 0.03 mol) was stirred at rt for 2 h and then heated to 40° C. for 2 h. The reaction mixture was allowed to cool to rt and was purified by prep-HPLC to afford the desired product. LC-MS: 454.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[CH2:14]([O:16]CC)C.CN(C)C=O>C(OCC)(=O)C>[Br:6][C:7]1[N:8]=[C:9]([CH2:14][OH:16])[C:10]([F:13])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1nc(Br)ccc1F
Temperature: 0 °C
Yield: 42 %

Procedure:
Slowly add n-Butyllithium (2.5 M in hexanes, 9.40 mL, 23.3 mmol) to a −78° C. solution of 2-bromo-5-fluoro-pyridine (3.42 g, 19.4 mmol) and diethyl ether (200 mL). Stir the reaction at −78° C. for 1 h, then add dimethylformamide (2.00 mL, 25.5 mmol) and continue stirring for an additional hour. Warm the reaction to room temperature and remove the solvent under vacuum. Dissolve the crude material in methanol (50 mL) and cool to 0° C. Add sodium borohydride.(1.47 g, 38.9 mmol) and allow the reaction is to slowly warm to room temperature over 12 h. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) then add ethyl acetate (100 mL). Separate the layers and dry the resultant organic layer with magnesium sulfate, filter, and concentrate under vacuum to give a yellow solid. Purify the crude solid by column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 1.66 g (42%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.50-7.40m, 1H), 7.35-7.25 (m, 1H), 4.80 (s, 2H), 3.30 (s, 1H).
Reaction SMILES: N([C:3]1[C:4]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:5]=2[N:6]=[N:7][N:8]=1)N>O>[N:6]1[C:5]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:4]=2[CH:3]=[N:8][N:7]=1
Reactant: NNc1nnnc2c1sc1ccccc12
Solvent: O
Product: c1ccc2c(c1)sc1cnnnc12

Procedure:
A 2.1 g. portion of the 4-hydrazino product of Example 5 was suspended in 130 ml. of water containing 5.4 g. of mercuric oxide and the mixture was stirred at reflux temperature for 4 hours. The mixture was then cooled and filtered, and the solids were triturated with hot ethyl acetate. After filtration, the filtrate was evaporated under vacuum. The residue was redissolved in ethyl acetate-hexane and was chromatographed over a silica gel column with 1:1 ethyl acetate-hexane as the eluant. The second product off the column was the desired product, which was recrystallized from denatured ethanol-water. The yield was 1.0 g. of [1]benzothieno[3,2-d]-v-triazine, m.p. 190°-191° C.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)(=[O:4])=[O:3].[NH3:17]>C(Cl)Cl>[CH3:16][C:7]1[CH:6]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:17])[S:9][C:8]=1[CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OCCc1sc(S(=O)(=O)Cl)cc1C
Reactant: N
Solvent: ClCCl
Product: CC(=O)OCCc1sc(S(N)(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
To a solution of the above prepared crude acetic acid 2-(5-chlorosulfonyl-3-methyl-thiophen-2-yl)-ethyl ester (53.3 g, ca. 177 mmol) in DCM (180 mL) were added 25% aqueous NH3 (53 mL, ˜700 mmol) and the biphasic reaction mixture was vigorously stirred at rt for 18 h. After the addition of DCM (1200 mL) the reaction mixture was washed with 10% brine (2×400 mL) and the aqueous layers were extracted with DCM (600 mL). The combined organic layers were dried (Na2SO4) and evaporated affording 48.5 g yellow crystalline residue which was crystallized from hot isobutyl acetate (500 mL) affording 34.8 g (74.7%, GC 97.9%) product as a off white powder. ESI-MS (m/z) 286 (M+Na+, 59); 264 (M+H+, 19).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])=O.[K+].[Br:14]Br>CC(O)=O>[Br:14][C:4]1[N:3]=[C:2]([F:1])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Nc1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-fluoropyridin-3-amine (44.6 mmol) and KOAc (44.6 mmol) in AcOH was stirred at room temperature for 1 h. The mixture was cooled to 0 C and Br2 (44.6 mmol) was added dropwise. The mixture was stirred at 0° C. for 15 min. The mixture was concentrated and the residue was dissolved in EtOAc/MeOH. The organic solution was washed (sat. NaHCO3, sat. Na2S2O3), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 100:0 to 80:20 petroleum ether/EtOAc) to yield the desired product.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[N:13]#[C:14][NH2:15]>>[CH2:1]([NH:4][C:5]([NH:15][C:14]#[N:13])=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCN=C=Nc1ccccc1
Reactant: N#CN
Product: C=CCNC(=Nc1ccccc1)NC#N

Procedure:
0.6 g of N-allyl-N'-phenylcarbodiimide in 8 ml of 1,2-dichloromethane is reacted with 0.17 g cyanamide and the reaction mixture is worked up as described in Example 4. Recrystallisation from diethyl ether yields a colourless crystalline product which melts at 99.5°-100.5° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:25][CH2:24][C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([OH:22])[CH2:28][CH2:27]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-hydroxy-4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=463.