Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[CH2:28]([C:30]1[C:38]2[C:37]([NH2:39])=[CH:36][CH:35]=[CH:34][C:33]=2[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]>CC(N(C)C)=O>[CH2:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[NH:39][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:22])[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]
Reactant: CCc1nn(Cc2nc(C)cs2)c2cccc(N)c12
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nn(Cc2nc(C)cs2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.346 g, 0.997 mmol) in DMA (5 mL) was cooled to 0° C. and treated with phosphorous oxychloride (0.182 mL, 1.99 mmol). The mixture was warmed up to ambient temperature and after stirring for an hour, the mixture was cooled to 0° C. again and treated with a solution of 3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine (0.181 g, 0.665 mmol) in DMA (2 mL). The mixture was allowed to warm up to ambient temperature and stirring continued overnight. The mixture was concentrated and then quenched with saturated aqueous lithium hydroxide, stirred at ambient temperature for 30 minutes and then diluted with DCM. The organic layer was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (2-10% 7N NH3/MeOH in DCM) to provide N-(3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.133 g, 36% yield) as beige solids. MS (APCI) m/z=559 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C([BH3-])#N.[Na+].C(O)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc(CNc2cccc(C(=O)O)c2)cc1
Yield: 75.3 %

Procedure:
4-cyanobenzaldehyde (0.65 g; 5 mmoles), 3-aminobenzoic acid (0.68 g; 5 mmoles) and sodiumcyanoborohydride (0.35 g; 5 mmols) were stirred in N,N-dimethylformamide (25 ml) containing 1% acetic acid at room temperature for 2 hrs. The product was precipitated out by addition of water. The solid was filtered and dried in vacuo to give 0.95 g white solid. FAB-MS: MH+ =253.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(=O)([O-])O.[Na+].[CH:26]1([C:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=3)[NH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>COCCOC.O.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>[CH:26]1([C:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:39]=3)[NH:34][C:33]=2[C:2]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=2[O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1cccc(Br)c1OCCOC1CCCCO1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)[nH]c2c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of 2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (12.30 g, 35.6 mmol) in 1,2-dimethoxyethane (150 ml) and water (75 ml) was added sodium hydrogen carbonate (9.74 g, 117.0 mmol) and tetrakis(triphenylphosphine)palladium (4.52 g, 3.91 mmol) and the mixture was heated at 85° C. for 15 min. Methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (16.40 g, 35.6 mmol) was added in 6 divided portions to the reaction mixture at 30 min intervals, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3.5:1) to give methyl 3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-indole-6-carboxylate (14.40 g, yield 77%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C=O)C>[F:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[C:15]([F:22])=[CH:14][C:10]=1[C:11]([Cl:25])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1cc(F)c(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(F)c(C(=O)Cl)cc1F

Procedure:
To 20 ml of toluene were added 1.4 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid, 0.8 ml of thionyl chloride and 10 mg of DMF, and the mixture was heated to reflux for 2 hours. Then, the reaction mixture was concentrated under reduced pressure, and 1.5 g of 2,5-difluoro-4-(2-propynyloxy)benzoyl chloride was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:23][C:22]=1[CH3:28]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.80 mmol) and 4-chloro-3-methyl-aniline (0.592 g, 4.18 mmol) in CH2Cl2 (5 mL) were treated with HOBT (0.582, 3.80 mmol) and EDC (1.46 g, 7.60 mmol), and stirred at rt for 16 h. The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes) to afford the title compound. HPLC/MS: 387.2/389.1 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)Cl>CC#N>[CH3:1][O:2][C:3]1[CH:19]=[C:18]2[C:6]([CH2:7][CH2:8][N:9]=[C:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCNC(=O)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC2
Yield: 661.6 %

Procedure:
A mixture of 4.0 g (15.7 mmol) of N-(4-methoxyphenethyl)benzamide and 21.1 ml (227.0 mmol) of POCl3 in MeCN (120 ml) was refluxed for 16 h. The mixture was then concentrated to small volume under vacuum, taken up with MeOH and concentrated to small volume under vacuum again. This step was repeated three times. 24.65 g of the crude product 7-methoxy-1-phenyl-3,4-dihydroisoquinoline were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [CH2:1]([C:5]1C=CC=[C:7]([OH:8])[C:6]=1O)CCC.C([O-])([O-])=O.[Na+].[Na+].[NH2:19][C:20]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(CC(Cl)=O)=C>CC(C)=O>[C:7]([NH:19][C:20]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[CH:6]=[CH:5][CH3:1]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CCCCc1cccc(O)c1O
Agent: C=CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC=CC(=O)Nc1cc(C(=O)OC)ccc1C(=O)OC

Procedure:
110 mg of butylpyrocatechol (as a polymerization inhibitor) and 180 g of dry Na2CO3 (anhydrous) are added to 167.4 g (0.8 mol) of dimethyl aminoterephthalate in 3 1 of acetone. 89 g (0.85 mol) of vinylacetyl chloride are added dropwise to this mixture at 35°-40 ° C. in the course of 20 minutes and the mixture is then boiled under reflux for 4 hours. The filtered solution is concentrated to 1 1 and the concentrate is crystallized in the cold. The crystals of dimethyl N-butenoylaminoterephthalate isolated are recrystallized once from 1.2 1 of methanol and then from a mixture of 426 ml of ethyl acetate and 344 ml of methanol.
Reaction SMILES: FC(F)(C)C(F)(F)C(F)(F)O.[C:12]([CH:16]([C:18]([CH2:21][OH:22])([F:20])[F:19])[F:17])([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:33][C:34](=[C:36]([F:38])[F:37])[F:35])([F:32])([F:31])[F:30]>C(#N)C>[C:12]([CH:16]([C:18]([CH2:21][O:22][C:36]([CH:34]([O:33][C:29]([F:32])([F:31])[F:30])[F:35])([F:38])[F:37])([F:20])[F:19])[F:17])([F:15])([F:14])[F:13]
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: OCC(F)(F)C(F)C(F)(F)F
Agent: CC(F)(F)C(F)(F)C(O)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(C(F)(F)F)C(F)(F)COC(F)(F)C(F)OC(F)(F)F
Temperature: 45 °C
Reaction time: 18 h

Procedure:
Hexafluorobutanol, CF3CFHCF2CH2OH (65.3 g, 0.34 mol), prepared essentially as described above (Compound 2), was combined with potassium carbonate (9.9 g, 0.072 mol) and 133 g of acetonitrile in a 600 mL Parr reactor. The temperature of the reactor was raised to 45° C. and CF3OCF═CF2 (65.6 g, 0.39 mol) added as a gas over about two hours. The resulting reaction mixture was stirred for about 18 hours at 45° C. The reactor was cooled and the contents of the reactor filtered to remove the potassium carbonate. The resulting product-containing filtrate was distilled using a concentric tube column, with the product cut boiling at 115-119° C. The product structure was confirmed by GCMS.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH:18][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: COc1ccc(OC)c(N)c1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cc(OC)ccc1OC
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,5-dimethoxyaniline (9h, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10h as pure product. To a solution of 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10h, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1h (201 mg, 78%); mp: 154-156° C.; 1H NMR (300 MHz, CDCl3) δ 10.71 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.32 (dd, J=3.0, 1.5 Hz, 1H), 7.76 (dd, J=2.2, 1.5 Hz, 1H), 7.54 (s, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.18-7.06 (m, 2H), 6.97-6.84 (m, 5H), 6.76 (d, J=8.3 Hz 1H), 6.66-6.62 (m, 1H), 6.42-6.38 (m, 1H) 6.40 (dd, J=3.0 Hz, 1H), 5.45 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 537 [M+H]+. Yield: 78%
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][OH:23])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-hydroxypropyl)pyrrolidine (17.1 g) in dichloromethane (170 ml) were added successively triethylamine (10.4 ml) and methanesulfonyl chloride (4.63 ml) under an ice-bath. The mixture was stirred at 0° C. for 1.5 hours and quenched by the addition of water (85 ml). The aqueous layer was separated and extracted with dichloromethane (50 ml×2). The organic layers were combined and washed with 1N hydrochloric acid (85 ml), brine (85 ml) and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methanesulfonyloxypropyl)pyrrolidine (21.2 g) as a yellow paste.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C.[Cl:51]C1C=CC(S)=CC=1>>[Cl:51][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester and 4-chloro-thiophenol.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[OH:13].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1>>[N:14]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=2[OH:13])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: OCc1cc(C(F)(F)F)ccc1O
Reactant: c1nc[nH]n1
Product: Oc1ccc(C(F)(F)F)cc1Cn1cncn1

Procedure:
Following Example 21, the title compound was synthesized (1.55 g; 45%) from 2-hydroxymethyl-4-(trifluoromethyl)phenol (2.7 g) from Example 61 and 1H-1,2,4-triazole (1.07 g).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C@@H:45]1[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:59][C:60](=[O:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C@@H:47]([C:68]2[N:72]=[CH:71][N:70]([CH2:73][CH3:74])[N:69]=2)[O:46]1)(=O)C1C=CC=CC=1.C(O[C@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)[C@@H](C2N=CN(CC)N=2)O1)(=O)C1C=CC=CC=1>>[C:60]([O:59][C@H:48]1[C@@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:45]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:46][C@@H:47]1[C:68]1[N:72]=[CH:71][N:70]([CH2:73][CH3:74])[N:69]=1)(=[O:67])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCn1cnc([C@H]2O[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Agent: CCn1cnc([C@H]2O[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Product: CCn1cnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1

Procedure:
Prepared by the same method as Preparation 27 from 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) and a mixture of (2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate and (2S,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate (Preparation 22).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.CCN(CC)CC.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=1)=O.[BH3-]C#N.[Na+]>CO>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][CH2:28][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=3)=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:17]
Reactant: O=Cc1ccccc1NC(=O)c1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCNCc2ccccc2NC(=O)c2cccc(O)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (Step F) (0.64 g, 2.03 mmol) in MeOH (15 mL) was added NEt3 dropwise to pH=4.5. To this solution was added N-(2-formyl-phenyl)-3-hydroxy-benzamide (0.64 g, 2.64 mmol) and NaCNBH3 (0.255 g, 4.06 mmol), and the reaction was stirred 18 h at 25° C. The MeOH was removed in vacuo, and the residue was partitioned with EtOAc and saturated NaHCO3. The organic layer was separated and washed 3× with 10% HCl. The acidic layers were combined, made basic with Na2CO3, then extracted 3× with EtOAc. These layers were combined, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the crude product which was purified by prep HPLC to obtain the title compound.
Reaction SMILES: COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:10]2)=CC=1.[CH3:23][N:24]1[C:29]2[C:30](=[O:41])[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:32](=O)[O:33][C:28]=2[C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[S:25]1(=[O:47])=[O:46]>C1(C)C(C)=CC=CC=1>[CH3:23][N:24]1[C:29]2[C:30](=[O:41])[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:32](=[S:10])[O:33][C:28]=2[C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[S:25]1(=[O:47])=[O:46]
Reactant: CN1c2c(oc(=O)n(-c3ccccn3)c2=O)-c2ccccc2S1(=O)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CN1c2c(oc(=S)n(-c3ccccn3)c2=O)-c2ccccc2S1(=O)=O
Temperature: 140 °C

Procedure:
8.1 g (0.02 mols) of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane and 3.6 g (0.01 mol) of 5-methyl-3-(2-pyridyl)-2H,5H-1,3-oxazino[5,6-c][1,2]benzothiazine-2,4-(3H)dione-6,6-dioxide in 80 ml of xylene are maintained under reflux at 140° C. for 36 hours. The mixture is subjected to chromatography over a column containing silica gel as the stationary phase by initially eluting with xylene and then with chloroform. 1.4 g (38%) of 5-methyl-3(2-pyridyl)-2H,5H-1,3-oxazino[5,6-c][1,2]benzothiazine2(3H)thione-4-one-6,6-dioxide corresponding to the following formula are recovered from the chloroform solution: ##STR9##
Reaction SMILES: [O:1]1[C@H:3]2[C:4]3[CH:13]=[C:12]([S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)(=[O:16])=[O:15])[CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[C@@:2]12[CH3:25].[NH3:26]>C(O)C>[NH2:26][C@H:3]1[C@@:2]([OH:1])([CH3:25])[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]1=2
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)c1
Reactant: N
Solvent: CCO
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H](N)[C@](C)(O)C(C)(C)O3)c1
Temperature: 50 °C

Procedure:
(3S,4S)-3,4-Dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (2.0 g) (see Preparation 17) was dissolved in ethanol (15 ml) and 35% aqueous ammonia solution (10 ml) was added. The mixture was heated at 50° C. for 48 hours before adding further ammonia solution (5 ml) and heating for another 8 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 5:95 methanol:dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.9 g) as a foam. Found: C,58.65; H,5.77; N,3.29. C19H23NO5S, 0.22 CH2Cl2 requires C,58.28; H,5.96; N,3.53%.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.C(O)C.[NH2:21]N>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
The (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3-[3-(trifluoromethyl)phenyl]-1H-pyrazole as an oil (0.25 g, 89%), LC/MS (M+H)+: 213, 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.99 (d, 1H, J=7.5), 7.66 (d, 1H, J=2.4), 7.57 (m, 1H), 7.55 (d, 1H, J=7.5), 6.69 (d, 1H, J=2.4).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:13]=1[NH:23][NH2:24]>CCO>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([Cl:22])[C:13]=1[N:23]1[C:1]([CH3:2])=[C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:24]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)C1CCCCC1=O
Solvent: CCO
Product: Cc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CCCC2
Yield: 67 %

Procedure:
2-Acetylcyclohexanone (0.12 mL, 1 mmol) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (245 mg, 1 mmol) in EtOH (10 mL) was heated under reflux for 12 hr. EtOH was removed under reduced pressure and the product purified by flash chromatography on silica (10% EtOAc:Hexane): yield 67%. 1H NMR (CDCl3) δ 7.8 (s, 2H), 2.7 and 2.05 (m, 2H each), 2.05 (s, 3H), 1.9 (m, 4H); MS (M+) 349.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:12]([I:13])=[C:11]([CH3:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:12]1[C:11]([CH3:14])=[CH:10][CH:9]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[NH2:8]
Reactant: NN
Reactant: Cc1ccc(C#N)c(F)c1I
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(N)n[nH]c2c1I
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of hydrazine monohydrate (0.56 mL, 11.6 mmol) and 2-fluoro-3-iodo-4-methylbenzonitrile (WO2006094187, 1.00 g, 3.8 mmol) in ethanol (7 mL) was stirred and heated to 100° C. in a sealed tube. After stirring overnight, the mixture was cooled and water was added. The resultant precipitate was filtered, washed with water and hexanes, and then dried in vacuo to give the title compound (0.91 g, 87%) as a yellow solid.