Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:37]=[CH:38][CH:39]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:36][CH2:35][CH2:34][CH2:33][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Cl[C:41](=[O:50])[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:39]=[CH:38][CH:37]=[C:8]([C:9](=[O:10])[NH:11][C:12]3[S:13][C:14]4[CH2:36][CH2:35][CH2:34][CH2:33][C:15]=4[C:16]=3[C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=3)[CH:7]=2)[C:41](=[O:50])[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:2][CH2:3]1
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(CNC2CC2)c1
Reactant: CCOC(=O)CCCC(=O)Cl
Product: CCOC(=O)CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(Cc4ccncc4)cc2)CCCC3)c1)C1CC1
Yield: 69.2 %

Procedure:
By using 120 mg of 2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 120 mg of ethyl 5-chloro-5-oxopentanoate, the reaction similar to Preparation Example 13 was performed, thereby obtaining 105 mg of ethyl 5-(cyclopropyl {3-[(3-{[4-(pyridin-4-ylmethyl)phenyl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}amino)-5-oxopentanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[N+:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]([O-:15])=[CH:3][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(N2CCCCC2)c[n+]([O-])c2ccccc12
Temperature: 25 °C

Procedure:
3-Bromo-4-nitroquinoline-N-oxide (10 g, 0.037 mol) was dissolved in tetrahydrofuran (100 ml). To the solution, piperidine (7.9 g, 0.093 mol) was added and the mixture was stirred at room temperature until gradual crystallization occurred. Tetrahydrofuran was distilled off from the whole reaction mixture under vacuum and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. After distilling off the chloroform under vacuum, the residue was washed with a small amount of ethanol and recovered by filtration under vacuum to obtain 4-nitro-3-piperidinoquinoline-N-oxide in an amount of 6.0 g (yield, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]2[CH2:21][OH:22])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O:22][CH2:21][C@@H:12]2[CH2:13][C@@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:15][N:11]2[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (8.7 g: 24.2 mmole) in dichloromethane(80 ml) are added triethylamine (4.05 ml), p-toluenesulfonyl chloride (5.08 g) and 4-dimethylaminopyridine (148 mg). The mixture is stirred at room temperature overnight. The reaction mixture is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=1:1) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (11.75 g). Yield: 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH2:11].[H-].[Na+].Cl[C:15]1[N:24]=[CH:23][C:22]2[N:21]=[C:20]([C:25]3[C:30]([Cl:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[Cl:36])[C:19](=[O:37])[N:18]([CH3:38])[C:17]=2[N:16]=1>CN(C)C=O>[Cl:31][C:30]1[C:29]([O:32][CH3:33])=[CH:28][C:27]([O:34][CH3:35])=[C:26]([Cl:36])[C:25]=1[C:20]1[C:19](=[O:37])[N:18]([CH3:38])[C:17]2[N:16]=[C:15]([NH:11][C:3]3[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:24]=[CH:23][C:22]=2[N:21]=1
Reactant: COc1cc(OC)c(Cl)c(-c2nc3cnc(Cl)nc3n(C)c2=O)c1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2nc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
To a solution of 2-methyl-6-nitrobenzenamine (100 mg, 1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (53 mg, 1.3 mmol), and the mixture was stirred at RT (10° C.) for 10 mins, followed by the addition of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpteridin-7(8H)-one (322 mg, 1 mmol). The mixture was stirred at RT (10° C.) for another 30 min and then quenched by water. The precipitate was collected via filtration, washed with cold water and dried to give the title compound (180 mg, 75%) as a yellow powder. MS (ES+) C22H18Cl2N6O5 requires: 516, 518. found: 517, 519 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.OO.O.[Na].[ClH:14]>>[NH2:1][C:2]1[C:7]([Cl:14])=[N:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CCc1ccc(N)cn1
Agent: OO
Agent: [Na]
Solvent: O
Product: CCc1ccc(N)c(Cl)n1
Reaction time: 0.25 h

Procedure:
2 g (16.4 mmol) of 5-amino-2-ethylpyridine (for the preparation see G. H. Cooper and R. L. Rickard, J. Chem. Soc. C, 3257-60 (1971) are dissolved in 17.7 ml of concentrated HCl, and 2.2 ml (21.4 mol) of 30% strength H2O2 solution are then carefully added. An exothermic reaction starts. The temperature is kept at about 50° C. by cooling with an ice-bath, and when the reaction has subsided the mixture is subsequently stirred at this temperature for a further 15 minutes. For working up, the mixture is poured onto 200 ml of water, the pH is brought to 10 with 40% strength sodium hydroxidde solution and the mixture is extracted twice with 100 ml of methylene chloride each time. After drying with Na2SO4, the mixture is evaporated and the residue is stirred with petroleum ether and filtered off with suction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][C:12]([NH2:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([NH2:14])=[O:13])#[N:6]
Reactant: NC(=O)CBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(OCC(N)=O)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of 3-hydroxybenzonitrile (2.38 g, 20.0 mmol), 2-bromoacetamide (3.04 g, 22.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (30 mL) was stirred at 75° C. overnight. It was then cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (1.00 g, 28%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=3)[C:22]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#CCc1ccc(B(O)O)cc1
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(CC#N)cc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of (4-Cyanomethylphenyl)boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA45. ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][O:18][CH2:19][O:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2O
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC1CCC(C)(C)c2cc(C(C)=O)ccc21
Yield: 61.7 %

Procedure:
A solution of (+/−) 1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (Compound D25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol), triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount of tetrabutylammonium bromide in 2 ml of CH2Cl2 was stirred at room temperature for 5 h. Purification by column chromatography (silica) with ethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:28][CH3:29])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (56.0 g) was dissolved in N,N-dimethylformamide (1000 mL). To this solution, sodium bicarbonate (46.6 g) and then ethyl iodide (22.2 mL) were added and the mixture was stirred at 50 to 60° C. for 5 hours. Subsequently, additional sodium bicarbonate (46.6 g) and ethyl iodide (22.2 mL) were added and the mixture was stirred for additional 3 hours. The insoluble materials in the mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (700 mL) and the solution was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1→ethyl acetate) to give ethyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (56.8 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][NH:27][CH3:28]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([N:27]([CH3:28])[CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: CNC
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: CCO
Product: CN(C)c1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 40% aq. dimethylamine (2 ml) in ethanol (1 ml) for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate/isohexane mixtures and the title product collected by filtration as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.I[CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19]>>[CH3:1][C@:2]1([CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:7]1
Reactant: CC[C@H](C)CI
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Product: CC[C@H](C)C[C@]1(C)N[C@@H](c2ccccc2)COC1=O

Procedure:
The title compound was prepared from (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (2S)-1-iodo-2-methylbutane according to the procedure outlined in Preparation 1. The total amount of compound synthesised was 0.586 g.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[CH3:1][C@H:2]1[CH2:7][CH2:8][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:3]1
Reactant: C[C@@H](N)CO
Reactant: COC(=O)C[C@H](C)C(=O)OC
Product: C[C@H]1CCN([C@H](C)CO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (S)-dimethyl 2-methylsuccinate and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.60 (dd, 1H), 3.58 (br s, 1H), 3.40 (dd, 1H), 2.89 (dd, 1H), 2.72 (m, 2H), 2.63 (m, 1H), 2.24 (m, 1H), 2.17 (dd, 1H), 2.00 (m, 1H), 1.35 (m, 1H), 1.04 (m, 6H); MS: 144.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH2:33]([O:32][C:30]([N:24]1[CH2:25][CH2:26][N:27]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:28][CH2:29]1)=[O:31])[CH3:34]
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CCOC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol), ethyl piperazine-1-carboxylate (471 mg, 3.00 mmol), absolute ethanol (20 ml), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.31 ml, 7.88 mmol) and STAB (2.84 g, 13.6 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a white solid containing residual 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg). The material was dissolved in DCM (14 ml) and PS-AMPS (loading 2.04 mmol-1 g, 23 mg) was added and shaken for 24 hours. The resin was filtered and the solution concentrated in vacuo at 30° C., the crude material was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a white solid (130 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.08 (q, 2H), 4.02 (t, 2H), 3.79-3.70 (m, 2H), 3.57-3.47 (m, 2H), 3.27 (br s, 4H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.38 (s, 2H), 2.21-1.73 (m, 14H), 1.21 (t, 3H).
Reaction SMILES: Cl.[Na+].[C:3]1([S:9]([O-:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([S:9]([OH:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=S(O)c1ccccc1
Yield: 77 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g), until the solid dissolved. This mixture was extracted with ethyl acetate (15 ml) dried (Na2SO4) and concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium chloride (0.25 g, 2.23 mmol) in dry CH2Cl2 a solution of (2RS, 6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g, 1.86 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layers were washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS, 6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [N:1]1[C:2]([C:12](OCC)=[O:13])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6](=[O:11])(=[O:10])[C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:12]=[O:13])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6](=[O:10])(=[O:11])[C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)S(=O)(=O)CCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn2c(n1)S(=O)(=O)CCC2
Temperature: -70 °C

Procedure:
Ethyl 6,7-Dihydro-5H-imidazo[2,1-b][1,3]thiazine-2-carboxylate-8,8-dioxide (200 mg, 0.82 mmol) was dissolved in dry dichloromethane (minimum volume) under argon and cooled to −70° C. Diisobutylaluminium hydride (1.5M in toluene, 1 ml, 1.5 mmol) was added at <−70° C. and the mixture stirred at −70° C. until thin layer chromatography and infra-red spectroscopy showed little or no starting material remaining. Water (5 ml) was added carefully, cooling removed and the mixture stirred at ambient temperature for 1 h. Celite was added to the mixture and the resulting mixture filtered through a Celite pad. The Celite pad was washed with dichloromethane and water and the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was re-evaporated with ethanol (2×), triturated under diethyl ether and the product collected by filtration, washed with diethyl ether and dried in air (274 mg, 30%) (Found: M+200.0256. C7H8N2O3S requires M 200.0253); nmax (Nujol) 1678, 1316, 1161 and 1191 cm−1; dH [250 MHz; (CD3)2SO] 2.50-2.57 (2H, m), 3.81-3.85 (2H, m), 4.31 (2H, t, J 6 Hz), 8.27 (1H, s), 9.80 (1H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=1.CO>O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[N:18]=[C:17]3[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[N:16]3)=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 31.5 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 4-trifluoromethylbenzoic acid (2.7 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (2.1 g) is dissolved in boiling methanol (50 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-4-trifluoromethylbenzamide (1.3 g), m.p. 198° C., is obtained.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].O.[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[OH:5][CH2:4][CH2:3][C@H:2]1[CH2:1][O:7][C:9]([CH3:14])([CH3:10])[O:6]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 21 h
Yield: 6655.7 %

Procedure:
To a solution of (s)-1,2,4-butanetriol (0.842 g, 7.9 mmol) dissolved in acetone (12 ml) was added p-toluenesulfonic acid hydrate (20 mg) and the mixture was stirred for 21 hours at room temperature. Sodium carbonate (20 mg) was added to the mixture. After stirring for 1 hour, the mixture was filtered and condensed in vacuo to give (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (1.023 g, yield 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=6)[C:26](=[O:37])[N:25]([CH3:38])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1>O>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:39])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=2)[C:26](=[O:37])[N:25]([CH3:38])[CH:24]=1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)ncn1
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)ncn1
Yield: 32 %

Procedure:
At 0° C., to a solution of 180c with water (1 mL). It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 180 (47 mg, 32%). MS-ESI: [M+H]+ 526.2. 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J=2.5 Hz, 1H), 8.68 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.35 (d, J=5.0 Hz, 1H), 6.84 (s, 1H), 6.62 (s, 1H), 5.13 (t, J=6.5 Hz, 1H), 4.67-4.52 (m, 2H), 4.29-4.15 (m, 3H), 3.88-3.86 (m, 1H), 3.72 (s, 3H), 2.57 (d, J=5.5 Hz, 2H), 2.51 (s, 2H), 2.43 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Yield: 74.1 %

Procedure:
In a 250 mL round-bottomed flask, 1.49 grams (10 mmol) of 2,4-dichloropyrimidine was combined with 2,3,4-trimethoxyphenylboronic acid (2.12 g, 10 mmol), sodium carbonate (2.12 g, 2 equivalents), and 1.15 g (0.1 equivalents) of tetrakis-triphenylphosphinepalladium. Toluene (50 mL) and water (5 mL) were added. The reaction was allowed to reflux under nitrogen overnight. The reaction was diluted with toluene and water and the organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to afford the crude pyrimidine 5. The compound was purified on silica gel using an eluent of 30% acetone/hexane to afford 2.08 g (74%) of the product 5 as a white solid.