Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[C:19]([OH:20])=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:22]Cl)=[N:15][C:16]=2[NH2:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C>[CH2:4]([N:11]1[C:19]([OH:20])=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:22][C:1]#[N:2])=[N:15][C:16]=2[NH2:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1nc(CCl)nc2c1nc(O)n2Cc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
After sodium cyanide (0.20 g, 4.08 mmol) and 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.20 g, 0.69 mmol) were added to DMF (10 ml), the mixture was stirred at 80° C. for 7 hours. After removing the solvent, the residue was poured into water and the solution was neutralized with concentrated hydrochloric acid. The solution was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) and washed with methanol to give 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.16 g, 0.57 mmol) as a pale yellow solid. Thus obtained 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.08 g, 0.29 mmol) was added to a mixed solvent of 5% sodium hydroxide solution (20 ml) and methanol (10 ml), and the mixture was stirred at 60° C. for 8 hours. After the mixture was neutralized with concentrated hydrochloric acid, the solvent was removed. The residue and sulfuric acid (1 ml) were added to methanol (50 ml), and the mixture was refluxed for 3 hours under stirring. After being neutralized with saturated sodium hydrogencarbonate solution in an ice bath, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜30/1) and washed with methanol to give the captioned compound (0.02 g, 0.06 mmol) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([OH:15])(=O)[C@H:11]([CH3:13])[OH:12].Cl.[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1>CN(C)C=O>[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][N:40]([C:10](=[O:15])[C@@H:11]([OH:12])[CH3:13])[CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H](O)C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)[C@H](C)O)CC1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
DIPEA (0.120 g, 0.92 mmol) and L-lactic acid (0.083 g, 0.92 mmol) were added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.10 g, 0.184 mmol) in dimethylformamide at room temperature. O-(1H-Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.295 g, 0.92 mmol) was added and the reaction mixture was stirred for 30 minutes, concentrated and purified by preparative LCMS (standard acidic system) to give the title product (0.044 g, 43.4%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 1.29 (d, 3H), 1.91 (m, 2H), 2.06 (m, 2H), 2.20 (m, 3H), 3.34 (m, 4H), 3.65 (s, 2H), 3.94 (s, 3H), 4.45 (m, 1H), 4.83 (m, 1H), 7.19 (s, 1H), 7.29 (m, 3H), 7.49-7.57 (m, 2H), 8.34 (s, 1H), 8.42 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 545.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.P(Cl)(OCC)(OCC)=O>C(OCC)(=O)C>[C:6]1(=[O:7])[N:2]([O:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)=[O:23])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CCOP(=O)(Cl)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C

Procedure:
Analogous example 3 2,76 g (0.024 mol) of N-hydroxysuccinimide and 5.06 g (0,050 mol) of triethylamine were initially introduced into 5 ml of ethyl acetate and stirred at room temperature. 2.72 g (0.020 mol) of solid 4-toluic acid were added to this suspension in the course of 5 min. and then a solution of 3.47 g (0,020 mol) of diethyl chlorophosphate was added dropwise in the course of 20 min., the reaction mixture warming to about 35° C. The mixture was stirred at room temperature for 3 hours until the reaction was complete. The further proceeding was performed analogous example 3. 2.8 g of crude 4-toluic acid succinimidyl ester were isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH3:5][C:6]1([CH3:28])[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]1[CH2:13][CH2:14][C:15](=O)[CH2:16][CH2:17][CH:18]1[C:23]([CH3:25])([CH3:24])[CH:22]2[CH2:26][CH:19]1[CH2:20][CH2:21]2.N[N].[C:31](#[N:34])[CH:32]=[CH2:33]>>[CH3:5][C:6]1([CH3:28])[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]1[CH2:13][CH2:14][CH:15]([NH:1][CH2:2][CH2:3][NH:4][CH2:33][CH2:32][CH2:31][NH2:34])[CH2:16][CH2:17][CH:18]1[C:23]([CH3:25])([CH3:24])[CH:22]2[CH2:26][CH:19]1[CH2:20][CH2:21]2
Reactant: C=CC#N
Reactant: NCCN
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Agent: [N]N
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCNCCCN

Procedure:
As an alternative to using an unsymmetrical amine V and obtaining a mixture of Schiff bases VI and VI(a) or VI(b), the reaction can be conducted stepwise. For example, 1,2-diaminoethane may be converted to a Schiff base with 1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanone, catalytically reduced, then the remaining primary amino nitrogen selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentyl]-1,4,8-triazaoctane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[NH2:21][CH2:22][CH2:23][C:24]1[S:25][C:26]([Br:29])=[CH:27][CH:28]=1>>[CH4:2].[Br:29][C:26]1[S:25][C:24]([CH2:23][CH2:22][NH:21][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(Br)s1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: C
Product: Nc1nc(NCCc2ccc(Br)s2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloroadenosine (0.3 g) and 2-(2-aminoethyl)-5-bromothiophene (2.1 g) is stirred under nitrogen at 140° C. over 18 hours. It is concentrated to a small volume under high vacuum (0.1 mm Hg) at 50° C., and the residue is purified by flash chromatography through a silica gel column (25×200 mm) eluting with methylene chloride/ammonia-saturated methanol (9:1). Fractions containing the major product are combined and concentrated to dryness at reduced pressure. The residue is recrystallized from methanol-ether and then from acetonitrile with charcoal to afford 2-[2-(5-bromo-2-thienyl)ethylamino]-adenosine, m.p. 145°-152° dec.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[N:7][CH:6]=1)C.[CH3:13][Mg+].[Br-].CC[O:18][CH2:19][CH3:20]>>[Br:11][C:9]1[CH:10]=[C:5]([C:19]([OH:18])([CH3:20])[CH3:13])[CH:6]=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CCOCC
Reactant: C[Mg+]
Agent: [Br-]
Product: CC(C)(O)c1cncc(Br)c1

Procedure:
To a solution of 5-bromo-nicotinic acid ethyl ester (1.0 eq.) in Et2O (0.3M) at −30° C. was added MeMgBr (2.7 eq.; 3M in Et2O). The mixture was refluxed for 2 h, poured in 0.5M aqueous NaH2PO4 and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:Et2O:CH2Cl2; 2:1:2) afforded the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F:25][C:26]1[C:31]([F:32])=C(O)[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][C:36](OCC)=[O:37]>>[F:25][C:26]1[C:31]([F:32])=[C:11]([O:10][CH2:8][C:4]2[N:5]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:6]=[CH:7][C:3]=2[C:2]([F:13])([F:12])[F:1])[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][CH2:36][OH:37]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: COc1ccc(-n2ccc(C(F)(F)F)c2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-methoxyphenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, (c) then reacting the resulting product with ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Step E, and Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: ClCc1cccnc1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1OCc1cccnc1

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (prepared as described in Example 35 part a), 50.0 mg, 0.16 mmol), caesium carbonate (159 mg, 0.49 mmol) and 3-(chloromethyl)pyridine hydrochloride (31.9 mg, 0.20 mmol) were stirred together in DMF (3 mL) at room temperature under nitrogen overnight. The mixture was partitioned between dichloromethane (3 mL) and water (3 mL), then was filtered through a PTFE cartridge. The separated organic phase was concentrated in vacuo, and residue was purified by flash chromatography on silica gel, eluting with 1:1 dichloromethane:ethyl acetate, then with ethyl acetate, affording 5-[4-fluoro-3-(pyridin-3-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine as a colourless oil, which solidified upon trituration with isohexane (45.1 mg, 70%). δH (400 MHz, CDCl3) 5.22 (2H, s), 7.06-7.12 (2H, m), 7.30-7.38 (2H, m), 7.52 (1H, d, J 4.3), 7.79 (1H, d, J 8.6), 7.81-7.83 (1H, m), 8.39 (1H, d, J 8.6), 8.64 (1H, dd, J 1.6 and 4.7), 8.69 (1H, d, J 2.0), 9.26 (1H, d, J 4.3). m/z (ES+) 400 [MH]+.
Reaction SMILES: C[N:2]([C:4](/[C:6](/[Br:14])=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:3].[CH2:15]([O:17][C:18]([C:20]1[C:21](N)=[N:22][NH:23]C=1)=[O:19])[CH3:16].Br>C(O)C.C(O)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[C:7]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:6]([Br:14])[CH:4]=[N:2][C:3]=12)=[O:19])[CH3:16]
Reactant: CN(C)C(=O)/C(Br)=C/C1CCCCC1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(Br)cnc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a mixture of 1.69 g (6.50 mmol) of 2-bromo-1-cyclohexyl-3-dimethylamino-propenone and 1.01 g (6.50 mmol) of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester in 6 mL of ethanol was added 1.0 mL of 30% hydrogen bromide in acetic acid solution, and the resulting mixture was heated at reflux for 1 h. Then the reaction mixture was cooled to rt and concentrated to give a residue which was chromatographed on silica gel (gradient elution with dichloromethane to 25% ethyl acetate in dichloromethane) to give 620 mg (27% over 2 steps) of 6-bromo-7-cyclohexyl-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (δ8.70s, 1H8.49s, 1H), 4.44 (q, J=6.8 Hz, 2H), 2.70-2.57 (b, 1H), 1.98-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.69 (m, 2H), 1.59-1.42 (m, 4H), 1.43 (t, J=6.8 Hz, 3H)); LC-MS—calcd for C15H18BrN3O2 [M++H]+: 352.06, found: 352.0.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:3][CH:2]=1.C(OCC)(=[O:32])C.O>CO.O>[C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:26])([F:27])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[O:32])=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(SCCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-p-Tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (8.8 g) was dissolved in a mixed solvent of methanol-water (2:1 v/v) (300 ml). Sodium periodide (6.78 g) was added under cooling with an ice water bath, and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (8.87 g). The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:23].[OH:45]O>C(OCC)(=O)C>[OH2:23].[OH2:45].[CH2:1]([N+:15]([O-:23])([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reactant: OO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC[N+](C)(C)[O-]
Product: O
Temperature: 65 °C

Procedure:
In a 250 milliliter glass reaction flask was placed 100 grams of tetradecyldimethylamine (0.41 mole; amine value 230.0 mg KOH/g amine) and 0.5 gram (1.27 mmol) of diethylenetriaminepentaacetic acid. This was heated with stirring to 65° C. and then 23 grams (0.47 mole) of 70 weight percent aqueous hydrogen peroxide was added dropwise over a 15-minute period. The mixture was then heated to 76° C. and stirred at that temperature for seven hours. As needed, ethyl acetate (34 mL) was added dropwise to the reaction mass in order to maintain a clear, gel-free liquid. Analysis of the crude reaction mass by proton NMR showed 99 percent amine conversion. The crude reaction mass was added to 400 mL additional ethyl acetate. The solution was then cooled to 15° C. forming a non-hygroscopic white crystalline solid tetradecyldimethylamine oxide dihydrate melting at about 41° C. in 86% recovered yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc([C@@H]2CO2)cc1
Reactant: C1COCCN1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
(2R)-2-(4-Bromophenyl)oxirane crude (250 g) was added to morpholine (8 mL, 1 mol) in 100 mL CH2Cl2 solution at 0° C. with magnetic stirring. Montmorillonite K10 clay (20 g) was added portionwise to the brown mixture and the resulting dark brown mixture was maintained under argon for 60 h at room temperature with magnetic stirring. The clay was filtered off and the filtrate was concentrated to a brown oil. The oil was loaded onto a 3 inch plug of silica gel. 12 L of 30% EtOAc/Hexane was used to elute off less polar impurities and then 40 L of 30%-40% EtOAc/Hexane with 1% ammonia was used to elute off the desired product. The fractions were combined, concentrated, and then crystallized from Et2O. The white crystals were filtered and dried to yield the title compound (109 g, 41.6%). MS (ES) m/e 287 [M+H]+. Chiral HPLC analysis (Chiralpak AD-RH, 5 micron, 150×4.6 mm, mobile phase: 50% CH3CN/50% aqueous borate buffer (pH 9.0), 0.50 mL/min, UV 220 nm, 5 uL inj in MeOH) confirmed the product is a single enantiomer (>99% ee).
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:23].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[C:8]4([CH2:13][CH2:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[C:3]=1[F:23]
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (360 mg, 1.12 mmol), N-2-pyridinyl-1,2-ethanediamine (230 mg, 1.68 mmol) and triethylamine (0.234 mL, 1.68 mmol) in DMSO (5 mL) was stirred for 3 hours at 100° C. The reaction mixture was poured into ice-water and stirred for 30 minutes. The resulting precipitate was collected by filtration, washed with water, suspended in EtOH (10 mL) and stirred at reflux for 1 hour. The suspension was cooled to room temperature, and the resulting precipitate was collected by filtration and dried to yield the title compound (459 mg, 93%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.91-2.03 (2H, m), 2.08-2.17 (2H, m), 2.61-2.69 (2H, m), 3.44-3.48 (2H, m), 3.58-3.66 (2H, m), 6.35-6.40 (1H, m), 6.45-6.49 (2H, m), 6.71 (1H, t, J=5.5 Hz), 6.88 (2H, brs), 7.35 (1H, td, J=6.7, 1.8 Hz), 7.97 (1H, dd, J=4.9, 1.2 Hz), 8.71 (1H, s), 15.30 (1H, s). HRESIMS (+): 440.17267 (−0.74 mmu).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:29]=[C:30]2[N:34]([C:35]=1[S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:32][S:31]2>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:36]([C:35]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[Cl:27])(=[O:37])=[O:38])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 67.7 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 132 mg, 0.52 mmol) in THF. 172 mg (65%) of 102 was obtained as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[OH:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[C:60]3[C:55](=[CH:56][C:57]([O:61][CH2:62][O:63][CH3:64])=[CH:58][CH:59]=3)[S:54][CH2:53][C:52]2([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][O:74][CH3:75])=[CH:68][CH:67]=2)[CH3:65])=[CH:47][CH:46]=1>O.C1C=CC=CC=1.CN(C)C=O>[CH3:64][O:63][CH2:62][O:61][C:57]1[CH:56]=[C:55]2[C:60]([CH:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:50][CH:49]=3)[C:52]([C:66]3[CH:71]=[CH:70][C:69]([O:72][CH2:73][O:74][CH3:75])=[CH:68][CH:67]=3)([CH3:65])[CH2:53][S:54]2)=[CH:59][CH:58]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reactant: O=S(=O)(CCCCCCl)CCCC(F)(F)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
5-(5-Chloropentylsulfonyl)-1,1,1,2,2-pentafluoropentane (27 mg, 0.082 mmol), potassium carbonate (34 mg, 0.25 mmol) and 18-crown-6 (21 mg, 0.08 mmol) were added to benzene-dimethylformamide (1:1) solution (2 ml) of (3RS,4RS)-4-(4-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (37 mg, 0.082 mmol) and then stirred for 8 hours at 100° C. under argon atmosphere. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 41 mg (yield: 67%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.ClCCl>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:4]([C:3]=1[CH3:12])[C:5]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]=1[O:14][CH3:13])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: Cc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1B (1.3 g, 5.7 mmol), 3,4,5-trimethoxytoluene (1.0 g; 5.7 mmol), P2O5 (3.5 g) and dichloromethane (20 ml) is stirred at room temperature for 16 hours. Subsequently, water (5 ml) and ice are added and dichloromethane is distilled off and the residue is extracted with toluene. The organic phase is washed with water and concentrated. The residue is recrystallized from petrol ethers/toluene. The solid material is collected by vacuum filtration, washed with cold petrol ethers and dried, yielding white crystals, 1.4 g, mp 859° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Cl-].[NH4+]>O1CCCC1>[OH:16][CH2:15][C@@H:14]([NH:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Following the literature procedure (Panek, J., J. Org. Chem., 1998, 63, 2382), triethylamine (6.2 ml, 44.5 mmole) was added to a solution of (S)-phenylglycinol (5 g, 36.45 mmole) in anhydrous tetrahydrofuran (150 ml) under argon at 0° C. After stirring for 15 min, tert-butyl bromoacetate (5.9 ml, 39.96 mmole) was added slowly to this cooled solution. The resulting mixture was warmed to room temperature, and stirred for 15 h. Saturated ammonium chloride aqueous solution was added, and the aqueous layer was extracted with diethyl ether (3 times). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting solid was recrystallized from a diethyl ether/n-hexane mixture to give tert-butyl (S)-(2-Hydroxy-1-phenyl-ethylamino)-acetate as a white solid (3 g, 33%).