Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19]O)[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19][Cl:25])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)c1cc(CO)c2nc(C)c(C)c(OC(C)=O)c2c1
Product: CCC(C)c1cc(CCl)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 23.5 %

Procedure:
50 Milligrams of 4-acetoxy-6-s-butyl-8-hydroxymethyl-2,3-dimethylquinoline obtained in Example 34 was dissolved in 0.3 ml of thionyl chloride and stirred at room temperature for 4.5 hours. After thionyl chloride was evaporated under reduced pressure, 0.5 ml of acetic anhydride was added to the resultant crude product and the mixture was stirred at 120° C. for 2 hours. After acetic anhydride was evaporated under reduced pressure, the resultant residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 12.5 mg of 4-acetoxy-6-s-butyl-8-chloromethyl-2,3-dimethylquinoline (yield 23.5%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]([OH:12])[CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-tert-butyl 1-cyclohexyl-3-oxopentan-2-ylcarbamate in THF/MeOH (604/15 mL) at 0° C. was carefully added NaBH4 (630 mg, 16.66 mmol). After 20 min, sat. aq. NH4Cl was added to quench the reaction, and extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated to give (S)-tert-butyl 1-cyclohexyl-3-hydroxypentan-2-ylcarbamate (4.77 g, 96%, in a ratio of 40:60) as a white solid. MS ESI +ve m/z 286 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 75 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and 1-amino-2-propanol (0.05 mL) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 75% yield) as a white solid. 1H NMR (CDCl3) δ 10.22 (br s, 1 H), 8.53 (s, 1 H), 7.31-7.25 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.92 (m, 4 H), 6.72 (s, 1 H), 4.03 (m, 1 H), 3.94 (s, 2 H), 3.56 (m, 1 H), 3.36 (m, 1 H), 1.24 (d, J=6.4 Hz, 3 H). MS m/z 466 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[H-].[Na+].CI.[C:25](OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12]
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc(=O)n(C)c2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc(=O)n(C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-[2-(2-chloro-5-methoxy-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one (9.35 g) in tetrahydrofuran (110 ml) was added sodium hydride (60% dispersion in mineral oil, 1.35 g) in three portions. The mixture was stirred at 40° C. for 1 h and then placed in an ice bath. Methyl iodide (5.01 g) was added dropwise. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was washed with cyclohexane, filtered and dried to give the title compound as an off-white solid (9.45 g). MS (m/e)=306.2 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[O:24]1[C:28]2([CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1>>[O:27]1[C:28]2([CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:32][CH2:33]2)[O:24][CH2:25][CH2:26]1
Reactant: NCCCCN1CCC2(CC1)OCCO2
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC2(CC1)OCCO2

Procedure:
Batch size: 4.0 g (26.8 mmol) 3-(3-pyridyl)-acrylic acid, 5.7 g (35.2 mmol) CDI and 6.4 g (29.9 mmol) 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-butylamine.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=O)[CH2:14][CH3:15])[C:5]2=[CH:17][S:18][CH:19]=[C:4]2[C:3]1=O.B.Cl>O1CCCC1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[CH:17][S:18][CH:19]=[C:4]2[CH2:3]1
Reactant: CCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCN1c2cscc2CN(C)c2ccccc21

Procedure:
A 5 g. portion of 4,9-dihydro-9-methyl-4-propionyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is added to 200 ml. of tetrahydrofuran. To this is added 140 ml. of 1M borane, over a 15 minute period in an ice bath under nitrogen. The mixture is refluxed for 20 hours, then cooled in an ice bath and 40 ml. of 6N hydrochloric acid is added dropwise, with stirring. The tetrahydrofuran is distilled off. The reaction mixture is stirred with ice bath cooling and 31 g. of sodium hydroxide pellets are carefully added portionwise. The mixture is extracted twice with 250 ml. of benzene. Water is added to solubilize some salts. The mixture is extracted with 250 ml. of ether. The ether and benzene extracts are combined, dried over sodium sulfate, filtered and concentrated to an oil. This oil is treated with 75 ml. of ether:hexane (50:50), cooled and filtered. The filtrate is diluted with 50 ml. of hexane and cooled for a prolonged period. The solvent mixture is decanted from the insoluble material and concentrated to a solid residue. The residue is dissolved in 60 ml. of 10% methylene chloride in hexane and chromatographed on an alumina column. The column is eluted with 10% methylene chloride in hexane, discarding the first 500 ml. of eluant. Fractions 2 and 3 are collected (200 ml. each) and the eluate is changed to 20% methylene chloride in hexane. Fractions 2-7 (200 ml. each) are combined and concentrated giving the desired product as pale yellow crystals, mp. 90°-92° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]3=[O:25])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:25]=[C:13]1[N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:39]=[N:38][CH:37]=[C:36]([NH:40][S:41]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)(=[O:43])=[O:42])[CH:35]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Br)cc3n2)C(=O)C1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)C(=O)C1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A slurry of 1,1-dimethylethyl 4-(7-bromo-2-quinoxalinyl)-3-oxo-1-piperazinecarboxylate (1.30 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (1.35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.10 mmol), in 1,4-dioxane (6 ml) and saturated sodium bicarbonate solution (2 ml) was stirred at 100° C. for 1 hour. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (150 mg, 22%) as a tan solid. MS(ES)+ m/e 561.1 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=O)C.[OH-].[Na+].Cl>CO>[CH:23]([C:21]1[C:19]([NH2:20])=[N:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4])=[CH2:24]
Reactant: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)c(=O)nc1N
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution of 2′,3′-di-O-acetyl-5′-deoxy-5-vinylcytidine (111 mg, 3.29 mmol) in 5 ml of methanol was added 1N NaOH (0.32 ml, 0.32 mmol) at room temperature. After stirring for 1 hour, 1 N HCl (ca.0.3 ml) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction (MEGA Bond Elute LRC, eluent:H2O˜H2O:MeOH=1:1, step gradient) to give 5′-deoxy-5-vinylcytidine (82 mg, 98%) as colorless solid:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cccs6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (60 mg, 0.3137 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 76% yield (0.110 g, 0.1951 mmol).
Reaction SMILES: [Li].C(NC(C)C)(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][CH:17]=1.[CH2:28]=[O:29].Cl>C1COCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH:24]([CH2:28][OH:29])[C:25]([OH:27])=[O:26])=[CH:20][CH:21]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: C=O
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(CCC(CO)C(=O)O)cc1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium diisiopropylamide (prepared from diisopropylamine (16.16 g, 0.16 mol and n-butyl lithium (1.6M in hexane, 100 ml, 0.016 mol) in THF (50 ml) at -78° C., was added a solution of 4-(4-methoxyphenyl)butanoic acid (13.80 g, 0.07 mol) in THF (100 ml) over 20 min. The solution was warmed to -20° C. and stirred for 2.5 h. Formaldehyde gas generated by warming paraformaldehyde (10 g) was then passed into the reaction mixture in a stream of nitrogen. After stirring for a further 2 h. at -20° C., hydrochloric acid (2N, 500 ml) was added and the reaction mixture was diluted with ethyl acetate (800 ml). After washing with water, the organic phase was extracted with sodium hydroxide solution (0.5N, 3×200 ml). The combined aqueous extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3×200 ml), the combined organic phase (MgSO4) was dried and solvent removed at reduced pressure to give the product as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40](Cl)=[O:41])[CH:33]=2)=[CH:28][CH:27]=1>ClCCl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40]([NH:1][C:2]3([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]3)=[O:41])[CH:33]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.94 g (15.44 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 1.56 g (15.44 mmol) of triethylamine were dissolved in 56 ml of dichloromethane. 3.92 g (14.03 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetyl chloride (Example 2A), dissolved in 56 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 6.81 g (97% of theory) of the title compound as a white powder.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1c[nH]c(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution (100 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.16 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (24 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was further stirred at −78° C. for 1 hr, water (2 mL) was added dropwise over 2 min, and the mixture was further stirred at room temperature for 1 hr. To the reaction mixture were added celite and anhydrous magnesium sulfate, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a pale-red powder (yield 1.51 g, 87%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[N:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=3[S:14][C:13]=12.[BH4-].[Na+].[OH-].[NH4+]>>[F:1][C:2]([F:7])([F:6])[CH2:3][NH:21][C:18]1[CH:19]=[CH:20][C:15]2[S:14][C:13]3=[N:8][CH2:9][CH2:10][CH2:11][N:12]3[C:16]=2[CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Product: FC(F)(F)CNc1ccc2c(c1)N1CCCN=C1S2

Procedure:
To a stirred mixture of 45 parts of trifluoroacetic acid and 2 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine are added portionwise, during a 4 hours-period, 3 parts of sodium borohydride at 30°-40° C. while nitrogen gas is introduced. The reaction mixture is poured onto ice-water and the whole is alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 8 parts of acetonitrile, yielding 0.55 parts of 3,4-dihydro-N-(2,2,2-trifluoroethyl)-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 186.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]1([N:34]=[C:35]=[S:36])[CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH:31]2[CH2:33][CH2:32]2)=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: S=C=NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC2CC2)CC1
Yield: 41.1 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.2 ml (1.8 mmol) of cyclopropyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. The crude product obtained after purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) was crystallized from methanol/diethyl ether. 195 mg (41%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37]C(=O)C(F)(F)F)[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>[NH4+].[OH-]>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH2:37])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc(=O)n([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)cc1C#CCOCCOCCNC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: NCCOCCOCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)nc1N
Temperature: 48 °C
Reaction time: 3 h

Procedure:
The purified protected triphosphate 22 was taken up in concentrated aqueous NH4OH (2 mL) and stirred for 3 h at approximately 48° C. The reaction mixture was concentrated to give compound 23 which was formulated with 0.1 M TEAB pH 7.0 to a concentration of 3.5 mM. The concentration and purity of the formulated bulk were confirmed by UV/Vis spectroscopy and analytical ion pair HPLC as described above, respectively. See FIG. 12.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.BrCCC(Br)C>C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH:9]1[CH3:8]
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: CC(Br)CCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CSC1(S(C)=O)CCC1C
Reaction time: 1.33 h

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.571 g) was dissolved in 15 ml. of tetrahydrofuran, and 8.9 ml. of an n-hexane solution of n-butyl lithium (1.4 millimols/milliliter) was added at -10° C. The mixture was stirred for 80 minutes, and then at -70° C., 1.125 g of 1,3-dibromobutane was added, and the mixture was stirred for 46.5 hours at room temperature. Methylene chloride (100 ml) was added. The mixture was washed with water and dried with anhydrous magnesium sulfate. It was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 746 mg of 2-methylcyclobutanone dimethyl mercaptal S-oxide. The product was oxidized with hydrogen peroxide and Na2WO4 to form its disulfone derivative.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([OH:27])=O)[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl.C(#N)C>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([NH:39][S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])(=[O:37])=[O:38])=[O:27])[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
A stirred solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21 mg, 0.054 mmoles), 2-methyl-benzenesulphonamide (19 mg, 0.108 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of dichloromethane (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4 mg, 0.060 mmoles). The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 177(2.9 mg) as a solid. LC/MS System D; Rt=11.21 mins, m/z (ES+)=541 (M+H for C28H26F2N2O5S).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N+:12]([O-:25])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide (0.3 g, 0.00096 mole), glacial acetic acid (2.5 ml), and m-chloroperbenzoic acid (0.66 g, 0.00384 mole) was heated at 60° C. for a total of 4 hrs. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfite. The aqueous solution was evaporated to dryness and the residue was dissolved in methylene chloride. The methylene chloride was extracted with a minimum of saturated sodium bicarbonate. The methylene chloride was dried and evaporated to a residue which crystallized upon standing. The solid was recrystallized from tetrahydofuran-hexanes with refrigeration overnight. The solid was collected by filtration and dried under high vacuum overnight to give 0.28 g (88%) of the title compound mp. 200°-201.5° C.