Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][C:12]1([CH3:25])[CH2:16][C:15]2[C:17]([CH3:24])=[C:18]([CH:22]=O)[CH:19]=[C:20]([CH3:21])[C:14]=2[O:13]1>C(OCC)C>[CH3:11][C:12]1([CH3:25])[CH2:16][C:15]2[C:17]([CH3:24])=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:14]=2[O:13]1
Reactant: Cc1cc(C=O)c(C)c2c1OC(C)(C)C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1C)CC(C)(C)O2
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a suspension of 9.75 g of lithium aluminum hydride in 200 ml of absolute diethyl ether was added 34.27 g of AlCl3 and added dropwise a mixture of 42 g of the 2,3-dihydro-2,2,4,7-tetramethylbenzofuran-5-carboxaldehyde and 27.4 g of AlCl3 in 100 ml of absolute diethyl ether. After stirring for 30 minutes, the reaction mixture was quenched with 10 ml of ethyl acetate and added with 100 ml of water and 100 ml of 2N aqueous solution of hydrochloric acid. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by vacuum distillation to afford 34.5 g of 2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran as colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
(Bromomethyl)cyclopentane was obtained by the following procedure. A solution of commercially available cyclopentanemethanol (20 g) in dry pyridine (220 ml) was stirred at 0° while 4-toluenesulfonyl chloride (42 g) was added. The mixture was stirred at 0° for two hours, and was then held without stirring at 4° overnight. It was then poured into water and the product was extracted into dichloromethane. The dichloromethane extract was washed with 10% (w/v) HCl solution, water, and brine in succession, and was then dried (MgSO4) and evaporated. There was thus obtained the desired intermediate compound, cyclopentylmethyl (4-methylphenyl)sulfonate (44.42 g, 87% yield) as a clear oil. Without further purification, this material was dissolved in dry DMF (175 ml). Lithium bromide (45.5 g) was then added with stirring. The mixture was heated to 45° for three hours, and then cooled to room temperature. The mixture was then diluted with pentane (800 ml), and washed with water (800 ml). The water layer was extracted with an additional portion of pentane (200 ml) and was discarded. The combined pentane layers were washed with water (1000 ml), and brine (200 ml) in succession, and then dried (MgSO4). The solvent was distilled away at atmospheric pressure, and the residue was then vacuum distilled. The desired (bromomethyl)cyclopentane (23.64 g, 83% yield) was obtained as a colorless mobile oil, distilling at 54°-55° at a pressure of 2000 Pascals (15 Torr).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1C[CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
4.75 g of di-tert-butyl dicarbonate are added to a mixture of 2 g of 4-hydroxypiperidine in 4 ml of water and 13.8 ml of a 2N aqueous sodium hydroxide solution. The reaction medium is stirred at ambient temperature for 2 hours and then 50 ml of chloroform are added. The two phases are separated and the organic phase is washed with an aqueous 25% NH4OH solution and then with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated, so as to give 4 g of 2-methylpropan-2-yl 4-hydroxypiperidine-1-carboxylate in the form of a colourless oil. 2.84 g of acetic anhydride are added to a solution of 4.0 g of 2-methylpropan-2-yl 4-hydroxypiperidine-1-carboxylate in 6 ml of pyridine. The reaction medium is stirred for hours at ambient temperature and then concentrated to dryness. The residue is taken up in dichloromethane and an aqueous 25% NH4OH solution. The two phases are separated and the organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and MeOH (95/5), so as to obtain 3 g of 2-methylpropan-2-yl 4-(acetyloxy)piperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([CH2:17][OH:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])([CH2:17][O:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
100 mg (0.369 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 4.0 mL of pyridine and cooled to 0° C., 77.3 mg (0.406 mmol equivalents) of p-toluenesulfonyl chloride was then added thereto, and the mixture was stirred at room temperature (25° C.) for 1 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 115 mg (0.270 mmol equivalents) of 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C4C(=CC=CC=4)C=NC=3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.Br[C:28]1[S:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[S:29][CH:30]=[CH:31][C:32]=3[C:33]#[N:34])[CH2:15][CH2:16]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccsc1Br
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc4ccccc34)CC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3sccc3C#N)CC2)n1
Yield: 22 %

Procedure:
Following the procedure reported for the compound of Example 234 and using 2-bromo-3-cyanothiophene instead of 4-bromoisoquinoline the title compound was prepared. Purification was done by RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording the compound of the title. Yield: 22%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:43]=[CH:42][C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:43]=[CH:42][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=4)[CH2:31][CH2:32]3)=[N:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
Ethyl 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoate (451 mg) was dissolved in EtOH (5 ml) and THF (5 ml), and a 1 M aqueous NaOH solution (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. After neutralization with 1 M hydrochloric acid (2 ml), water was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoic acid (269 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)(=O)C>[C:19]1([C:17]2[N:1]([C:2]3[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][C:3]=3[C:12]([F:13])([F:14])[F:15])[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=3[CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1cc(C(=O)O)c(O)cc1C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)c(C(F)(F)F)cc1O

Procedure:
A mixture of 6.5 g. (0.029 mole) of 5-amino-4-trifluoromethylsalicylic acid, 6.35 g. (0.029 mole) of 2-phenacylcyclohexanone, and 30 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was recrystallized from acetic acid to provide 4.6 g. (39%) of gold crystals, m.p. 188°-190°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.O1C[CH2:19][CH2:18][CH2:17]1.[Br-].C([Zn+])CC.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:17]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1)[CH2:18][CH3:19]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCC[Zn+]
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(C(=O)OCC)cn2n1
Temperature: 25 °C

Procedure:
Ethyl 6-chloroimidazo[1,2-b]pyridazin-2-ylcarboxylate (1.00 g, 4.43 mmol) and [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (0.24 g, 0.44 mmol) were added to tetrahydrofuran (8.0 ml) under a nitrogen stream, and a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M, 13.3 ml, 6.65 mmol) was added dropwise thereto with stirring under ice-cooling. The mixture was stirred for 20 minutes under ice-cooling and for 0.5 hour at room temperature, and cold water (50.0 ml) was added to the reaction mixture which was then acidified with dilute hydrochloric acid. The reaction solution was extracted with ethyl acetate, and the extracts were combined and washed with dilute hydrochloric acid and a saturated saline solution. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (acetone:hexane=1:3) to give the title compound as white crystals. The yield was 0.77 g (74.8%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.CN(C)C=O>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: NC(c1ccncc1)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc2c(NC(c3ccncc3)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and C-(4-chlorophenyl)-C-pyridin-4-yl-methylamine. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([C:26]([N:13]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:26]([C:16]45[CH2:25][CH:20]6[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]6)[CH2:23]4)[CH2:17]5)=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]3)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCNCCOCCOCCN1
Product: O=C(N1CCOCCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][C:3]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Cu][C:28]#[N:29]>CN(C)C=O.O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:6]1[CH:5]=[CH:4][C:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: N#C[Cu]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 43.7 %

Procedure:
2-Bromo-4-[(E)-2-(2,4-difluorophenyl)vinyl]-1-(phenylsulfonyl)benzene (Example 55, 130 mg, 0.3 mmol) and copper(I) cyanide (40 mg, 0.45 mmol) were combined in N,N-dimethylformamide (20 mL) and heated to 130° C. for 3 hours. Further copper(I) cyanide (40 mg, 0.45 mmol) was added and heating continued overnight. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20-30% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound (50 mg, 44%). δH (360 MHz, d6 DMSO): 8.41 (1H, d, J=1.6 Hz), 8.28 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.7, 8.4 Hz), 8.01-7.98 (2H, m), 7.86-7.64 (4H, m), 7.58 (1H, d, J=16.6 Hz), 7.37 (1H, d, J=16.8 Hz), 7.32-7.28 (1H, m), 7.17 (1H, td, J=2.4, 8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[O:15][C:16]4[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][CH:19]=[C:18]([C:26]([O:28]CC)=[O:27])[C:17]=4[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[O:15][C:16]4[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][CH:19]=[C:18]([C:26]([OH:28])=[O:27])[C:17]=4[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(-c4ccc(Cl)cc4)ncc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC(F)F)c2oc3c(=O)n(-c4ccc(Cl)cc4)ncc3c12
Yield: 95.6 %

Procedure:
A mixture of ethyl 3-(4-chlorophenyl)-6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step I) (160 mg, 0.36 mmol) and sodium hydroxide (24 mg, 0.51 mmol) in methanol (10 ml) was heated to reflux temp. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum. Then water (50 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. 140 mg yellow colored solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[S:5][CH:6]=1.[ClH:18]>CC(C)=O>[ClH:18].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][CH2:8][CH2:9][NH2:10])[S:5][CH:6]=1
Reactant: Cc1csc(NCCNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1csc(NCCN)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl N-[2-[(4-methylthiazol-2-yl)amino]ethyl]carbamate (435 mg, 1.69 mmol) in acetone (20 mL) was added HCl (4N in dioxane, 2.6 mL, 10.40 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was isolated by filtration, washed with acetone and diethylether and allowed to dry at ambient conditions to yield 290 mg of an off-white solid (1.497 mmol, 89%). MS(ESI) m/z=158.1 [M+1]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1([CH3:19])[O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]1.O>C(Cl)Cl>[CH3:11][C:12]1([CH3:19])[O:16][CH:15]([CH:17]=[O:18])[CH2:14][O:13]1
Reactant: CC1(C)OCC(CO)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)OCC(C=O)O1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of anhydrous DMSO (3.41 mL, 48 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of oxalyl chloride (1.92 mL, 22 mmol) in CH2Cl2 (50 mL) at −60° C. To this mixture was added a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (2.48 mL, 20 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred for 15 min at −60° C. TEA (13.9 mL, 100 mmol) was added dropwise. The reaction mixture was then warmed to room temperature. Water (50 mL) and CH2Cl2 (50 mL) were added. The organic layer was separated and washed with water (25 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde that was used directly without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH:17]2[CH2:20][NH:19][CH2:18]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[F:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26]([CH:29]=O)=[CH:27][S:28][C:24]=2[CH:23]=1>CO.C(O)(=O)C>[F:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26]([CH2:29][N:19]3[CH2:20][CH:17]([CH2:16][S:13]([C:10]4[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=4)(=[O:15])=[O:14])[CH2:18]3)=[CH:27][S:28][C:24]=2[CH:23]=1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: O=Cc1csc2cc(F)ccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(CC1CN(Cc2csc3cc(F)ccc23)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (13 mg, 0.20 mmol) was added to a stirred solution of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4, 49 mg, 0.18 mmol) and 6-fluoro-1-benzothiophene-3-carbaldehyde (36 mg, 0.20 mmol) in methanol (3 mL) and acetic acid (50 μL). The reaction was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue partitioned between sodium carbonate and ethyl acetate. The aqueous layer was extracted with further ethyl acetate and the combined organic layers washed with water and brine, dried over MgSO4 and evaporated. The residue was purified by preparative TLC (40% ethyl acetate/isohexane) to give the title compound which was treated with ethereal HCl to give the hydrochloride salt (46 mg, 59%). 1H NMR (400 MHz, CD3OD) δ 8.00–7.96 (3H, m), 7.88 (1H, s), 7.74 (1H, dd, J=2.4, 8.8 Hz), 7.43–7.37 (2H, m), 7.31–7.27 (1H, m), 4.68 (2H, s), 4.24 (2H, s), 4.16 (2H, t, J=9.7 Hz), 3.67 (2H, d, J=7.6 Hz), 3.30–3.22 (1H, m); m/z (ES+) 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]=[N+:16]=[N-:17])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
To a suspension of 12 g of 2-chloro-5-chlorosulphonylbenzoic acid in 150 ccs of ethanol, a solution of 10 g of sodium azide in 30 ccs of water and 120 ccs of ethanol is dropwise added whilst stirring. Stirring is continued overnight and the inorganic constituents are precipitated with acetone. After allowing to stand at 0° C for a relatively long period, the precipitate is filtered off and the mother liquor is carefully evaporated to dryness by means of a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (6.00 g, 0.03508 mol) in CH2Cl2 (50 ml) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (5.65 g, 0.03157 mol), and N,N-diisopropylethylamine (15.1 ml, 0.0877 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 22.32 g, 0.07016 mol) is added via syringe and stirred at 60° C. After 3 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (8.70 g, 74%). Mass spectrum (m/z): 333.2 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[C:9]1([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:21][CH:22]1[CH2:25][CH2:24][CH2:23]1.[Li+].[I-]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH:22]1([CH2:21][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([O:18][CH3:19])=[O:17])[CH2:25][CH2:24][CH2:23]1
Reactant: BrCC1CCC1
Reactant: COC(=O)Cc1ccccc1
Agent: [I-]
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of freshly prepared lithium diisopropylamine (76.5 mmol) in 500 mL of tetrahydrofuran at 0° C. was added methyl phenylacetate (10.44 g, 69.50 mmol) in 125 mL tetrahydrofuran dropwise over 30 minutes. After stirring at 0° C. for 1 hour the reaction mixture was cooled to −78° C. and treated with 50 mL of hexamethylphosphoric triamide followed by the dropwise addition of bromomethyl cyclobutane (9.37 mL, 83.4 mmol) and LiI (200 mg). The reaction mixture was stirred for 18 hours warming to 25° C. The reaction was quenched over 1 L of water containing 250 mL of sat. NH4Cl and extracted 3× with ethyl acetate. The combined organic layers were washed sequentially with saturated sodium bicarbonate, brine, and dried over MgSO4 yielding the crude product as an oil that was used without further purification. 1H NMR (300 MHz, CDCl3): δ ppm 1.59 (m, 2H) 1.89 (m, 5H) 2.17 (m, 2H) 3.47 (t, J=7.54 Hz, 1H) 3.64 (s, 3H) 7.31 (m, 5H). MS (ESI+) m/z=236 (M+NH4)+.