Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]2=O)=[CH:4][C:3]=1[S:20]([NH2:23])(=[O:22])=[O:21].O=C1C2C(=CC=CC=2)C(=O)N1.C(O)(=O)C.Cl>CN(C)C=O.[Zn].C(O)(=O)C.[Zn]>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8]2)=[CH:4][C:3]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(Cc1ccccn1)C2=O
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(cc1Cl)CN(Cc1ccccn1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc-acetic acid reduction of 6-chloro-2,3-dihydro-1,3-dioxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide. Zinc dust (0.5 mole) is added in one portion to the 1,3-dioxoisoindole (0.1 mole) of part (a) in 800 ml. of acetic acid. The reaction mixture is stirred at room temperature for 1.0 hr. and then heated to reflux for a 6 hr. period during which time additional 9.0 g. portions of zinc are added at the end of 3, 4, and 5 hr., respectively. After stirring overnight, the reaction mixture is filtered and the filtrate concentrated to dryness under reduced pressure with additional water added to the residue and removed in vacuo to remove traces of acetic acid. Residual material is slurried in water, filtered, and the filtrate concentrated to dryness. Residual material is stirred with saturated sodium bicarbonate solution and an immiscible organic solvent such as hot ethyl acetate. The organic fraction is separated, dried over MgSO4 and concentrated to provide the product as the free base. The free base taken up in dimethylformamide and acidified with ethanolic hydrogen chloride affords 6-chloro-2,3-dihydro-3-oxo-2-(2-pyridinylmethyl)-1H-isoindole-5-sulfonamide hydrochloride.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][C@@H:16]4[F:19])[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[F:19][C@H:16]1[CH2:15][C@H:14]2[CH2:18][C@@H:17]1[C@@H:12]([C:6]1[NH:7][C:8](=[O:11])[C:9]3[S:10][C:2]([C:32]4[CH:31]=[N:30][NH:29][C:28]=4[CH3:27])=[CH:3][C:4]=3[N:5]=1)[N:13]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@H]([C@H]1c1nc3cc(Br)sc3c(=O)[nH]1)[C@@H](F)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4C[C@H](C[C@@H]4F)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
tert-Butyl (1R*,3S,4R*,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (55 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was purified by high performance liquid chromatography {column: L-column 2 ODS (20 mm i.d.×50 mm L), mobile phase: 0.1% aqueous trifluoroacetic acid solution/0.1% trifluoroacetic acid-acetonitrile solution}. The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. The residue was collected by filtration and washed with water (3 mL) to give the title compound (106 mg) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])=O.[CH:12]([NH2:14])=O>O>[CH3:11][C:8]1[C:9]2[N:10]=[CH:12][NH:14][C:3](=[O:2])[C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: NC=O
Solvent: O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 150 °C

Procedure:
A mixture of 3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g) and formamide (50 mL) was heated to 150° C. overnight. The reaction mixture was then cooled and diluted with water. The solid formed was collected by filtration, washed with water and dried under reduced pressure to give 2.1 g of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one without further purifications.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].S(O)(O)(=O)=O.[C:11]([CH:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1)#[N:12].S(=O)(=O)(O)[OH:20].[OH-].[Na+]>O.O1CCCC1>[C:1]([NH:12][C:11]([CH:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)O
Reactant: N#CC1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)C1CNCCN1
Reaction time: 3 h
Yield: 73 %

Procedure:
In a reaction vessel were charged 343 g of water and 389 g (5.25 moles) of tert-butyl alcohol and then 219.5 g (1.05 moles) of 2-cyanopiperazine sulfate was dissolved in the mixture with stirring while keeping the temperature below 25° C. Then, while keeping the temperature at 25° C., to the solution was added dropwise 1372 g (8.4 moles) of an aqueous 80% sulfuric acid solution and further, the temperature of the mixture was kept at 40° C. for 3 hours to complete the reaction. Then, after cooling the reaction liquid to 25° C., 2700 g of tetrahydrofuran was added to the reaction liquid and the mixture was kept at a temperature of 0° C. for 3 hours. Precipitates were collected by filtration, dried, 241 g of the precipitates thus obtained was dissolved in 480 g of water and the solution was neutralized with an aqueous solution of 25% sodium hydroxide until pH thereof became 13. The solution was extracted thrice with one liter of chloroform, the extracts were combined with one another and chloroform was removed from the mixed extract under reduced pressure to provide 142 g (yield 73%) of N-tert-butyl-2-piperazine carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:10]=[C:11]([Cl:13])[N:12]=1)[CH3:2]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(-c3ccccc3)cc2)n1
Yield: 39.1 %

Procedure:
A stirred mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.4 g of 4-aminobiphenyl and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to initiate precipitation. The precipitate was recrystallized from ethanol to give 3.1 g of product, mp. 110°-112°C..
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([CH:17]([F:19])[F:18])=[CH:10][N:9]=1)=[O:7])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:19][CH:17]([F:18])[C:11]1[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C(F)F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ncc(C(F)F)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
In a mixture of 5 ml DCM and 2.5 ml TFA was dissolved 345 mg (1.26 mmol) 5-difluoromethyl-3-nitro-pyridine-2-carboxylic acid tert-butyl ester and the reaction mixture was stirred for 4 h. Toluene was added and the solvents were evaporated to provide the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:14]([CH:17]([CH2:22][CH3:23])[CH2:18][C:19](=O)[CH3:20])[CH2:15][CH3:16].Cl.C(OCC)(=[O:27])C>C1COCC1.CCCCCC>[CH2:14]([CH:17]1[CH2:22][CH2:23][C:20]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([OH:27])[CH2:19][CH2:18]1)[CH2:15][CH3:16]
Reactant: CCOC(C)=O
Reactant: CCCC(CC)CC(C)=O
Reactant: Fc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CCC(O)(c2cccc(F)c2)CC1
Reaction time: 2 h

Procedure:
3-Fluorobromobenzene (8) (10.0 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyllithium (1.57 M, in a n-hexane solution; 40.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Subsequently, 4-propylhexanone (16) (12.0 g) in a THF (50 ml) solution was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for another 8 hours while allowing the temperature to come to 25° C. The reaction mixture obtained was poured into a vessel containing a 1N—HCl solution (500 ml) and ethyl acetate (300 ml), and mixed. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, giving 13.5 g of 4-propyl-1-(3-fluorophenyl)-cyclohexanol (18). The compound (18) obtained was a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CC(N(C)C)=O.O>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: NC1CCOCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 120 °C
Yield: 92.1 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.45 g, 4.5 mmol) was added to (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.48 g, 0.89 mmol) in DMA (4 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed three times with dilute aqueous NaCl, water, twice with brine, dried over MgSO4, filtered, and evaporated to yield the desired (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.46 g, 0.82 mmol, 92% yield) as a film.
Reaction SMILES: C(O[CH:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=O)C1C=CC=CC=1.C([O-])(=O)[CH:31](C)[OH:32].C([O-])(=O)C(C)(C)C.C([O-])(=O)CCCCCCC>>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:31][OH:32])[CH2:10][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(O)C(=O)[O-]
Reactant: CCCCCCCCCCCC(CCCCCCCC)OC(=O)c1ccccc1
Agent: CC(C)(C)C(=O)[O-]
Agent: CCCCCCCC(=O)[O-]
Product: CCCCCCCCCCC(CO)CCCCCCCC

Procedure:
Octyldodecyl Benzoate, Lactate, Neopentanoate or Octanoate
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15])[CH2:9]1)C1C=CC=CC=1.[H][H].[OH2:24]>[Pd]>[OH:24][C:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15]
Reactant: O
Reactant: [H][H]
Reactant: O=P(O)(O)C(C1CCN(Cc2ccccc2)C1)P(=O)(O)O
Agent: [Pd]
Product: O=P(O)(O)C(O)(C1CCNC1)P(=O)(O)O

Procedure:
0.88 g. Ammonium salt of 1-(1-benzylpyrrolidin-3-yl)-methane-1,1-diphosphonic acid (see Example 1 e) is dissolved in 30 ml. water and hydrogenated in the presence of 0.7 g. palladium on charcoal at ambient temperature and normal pressure. After ending of the hydrogen take up, the catalyst is filtered off with suction, the filtrate is evaporated and the residue is treated with acetone. After suction filtration, there is obtained 0.44 g. (65% of theory) of the amorphous ammonium salt x 1 mole water, Mrel : 0.47.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:15]4[N:16]=[C:17]([NH:20][C@H:21]5[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:30][N:20]([C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)[C:17]1[CH:18]=[CH:19][C:14]2[N:15]([C:11]([C:9]3[S:10][C:3]4[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][C:4]=4[CH:8]=3)=[CH:12][N:13]=2)[N:16]=1
Reactant: Cc1cncc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cncc2cc(-c3cnc4ccc(N(C)[C@H]5CC[C@H](O)CC5)nn34)sc12
Reaction time: 2 h

Procedure:
To a solution of trans-4-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol (37 mg, 0.0975 mmol, 1.0 equiv) in DMF (2.00 mL) was added sodium hydride (20 mg, 0.488 mmol, 5.0 equiv) and methyl iodide (68 mg, 0.488 mmol, 5.0 equiv). After 2 h, the reaction mixture was quenched with water and extracted with ethyl acetate. Purification by column chromatography gave 20 mg (50%) of N-((1r,4r)-4-methoxycyclohexyl)-N-methyl-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine as the less polar product and 10 mg (25%) of trans-4-(N-methyl-N-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol as the more polar product.
Reaction SMILES: N[C:2]1([CH3:19])[N:13]2[C:14]3[C:9]([C:10](=[O:16])[NH:11][C:12]2=[O:15])=[CH:8][C:7]([F:17])=[C:6](F)[C:5]=3[CH2:4][CH2:3]1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C([N:35](CC)CC)C.CS(C)=O>O>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:6]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:19])[N:13]4[C:14]=3[C:9]([C:10](=[O:16])[N:11]([NH2:35])[C:12]4=[O:15])=[CH:8][C:7]=2[F:17])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCN(CC)CC
Reactant: CC1(N)CCc2c(F)c(F)cc3c(=O)[nH]c(=O)n1c23
Solvent: O
Solvent: CS(C)=O
Product: CC1CCc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 0.12 g (0.45 mmol) of 5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione (Example 24i), 0.34 g (1.8 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.2 g (2.0 mmol) of triethylamine and 7 mL of dimethyl sulfoxide is heated at 110° C. for 18 hours. The reaction is cooled to room temperature, diluted with 80 mL of ice and water and stirred at 5° C. for 1 hour. The resulting precipitate is removed by filtration, washed with water and dried in vacuo. The solid is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (9:1) to give 0.14 g of the title compound, mp 98-100° C.
Reaction SMILES: IC.BrC1C=C(C(C)(C)C)C=CC=1O.[Br:15][C:16]1[C:25]2[O:24][CH2:23]N(C(C)(C)C)C[C:20]=2[CH:19]=[C:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]([C:30]([CH3:31])([CH3:33])[CH3:32])[CH:19]=[CH:20][C:25]=1[O:24][CH3:23]
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Agent: CC(C)(C)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 100 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[C:20](C#N)[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[CH:22]=2)=O.C1CCN2[C:42](=[N:43]CCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH2:24][C:23]([C:42]#[N:43])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3F)ccc2c1O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2c(c1O)=CCC(C#N)(Oc1ccccc1F)C=2)C1CC1
Temperature: 150 °C

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (15 mg), 1-cyano-7-(2-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (11 mg) and DBU (0.0074 mL) in DMA (0.5 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product (10 mg). LC-MS ESI+: 492 (M+1)+.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:9][CH2:8][C@@:7]([NH:18][C:19]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:20])([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C@H:6]([C@@H:30](O)[CH2:31][F:32])[CH2:5]2)[CH2:3][CH2:2]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([C@@H:4]2[O:9][CH2:8][C@:7]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[N:18]=[C:19]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C@H:30]([CH2:31][F:32])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1[C@@H](O)CF)c1ccccc1
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@H]2[C@@H](CF)S1)c1ccccc1

Procedure:
rel-N-({(3S,4R,6R)-6-Cyclopropyl-3-(2,4-difluorophenyl)-4-[(1R)-2-fluoro-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C46) was converted to the product using the chemistry described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1. The product was obtained as an oil. Yield: 36 mg, 78 μmol, 65%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.21 (br d, J=7.2 Hz, 2H), 7.50-7.56 (m, 1H), 7.43-7.49 (m, 2H), 7.39 (ddd, J=9.0, 9.0, 6.3 Hz, 1H), 6.86-6.96 (m, 2H), 4.61 (ddd, half of ABX pattern, J=46.9, 9.5, 7.8 Hz, 1H), 4.44 (ddd, half of ABX pattern, J=46.2, 9.5, 6.6 Hz, 1H), 4.10 (dd, J=12.1, 1.8 Hz, 1H), 3.82 (d, J=12.3 Hz, 1H), 3.47-3.56 (m, 1H), 3.16-3.23 (m, 1H), 2.94 (ddd, J=11.0, 8.0, 2.5 Hz, 1H), 1.81-1.93 (m, 1H), 1.75-1.81 (m, 1H), 0.95-1.04 (m, 1H), 0.51-0.62 (m, 2H), 0.40-0.47 (m, 1H), 0.24-0.31 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([F:9])[C:5]([F:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[C:15]([O:17][CH3:18])=[O:16].CS(C)=O.[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>O>[CH3:24][C:23]([NH:28][C:7]1[C:2]([F:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([F:10])[C:6]=1[F:9])([CH3:25])[CH2:26][CH3:27]
Reactant: CCC(C)(C)N
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)Nc1c(F)c(F)c(C(=O)OC)c(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5,6-Tetrafluoro-1,2-benzenedicarboxylic acid, dimethyl ester (Example 1), 2.66 g, is treated with 8 g of dimethylsulfoxide and the mixture is warmed to dissolve the solid. The solution is cooled in an ice bath and 2.65 g of tertiary-pentylamine is added. The resulting solution is then stirred at room temperature for three hours, 50 ml of water added, and the solution extracted with heptanes (2×30 ml). The combined heptane extract is extracted with a 5% aqueous solution of hydrochloric acid (2×4 ml) and concentrated to give 4-[(1,1-dimethylpropyl)amino]-3,5,6-trifluoro-1,2-benzenedicarboxylic acid, dimethyl ester as an oil. Hydrochloric acid (36% aqueous solution), 20 ml, is added to this oil and the resulting mixture is heated at reflux for 20 hours. The solution is concentrated to 4-5 ml and then diluted with water (20 ml). Cooling gave crystals which are collected and vacuum dried to give 1.2 g of 3-amino-2,4,5-trifluorobenzoic acid (63%); mp 133° -136° C.; GC (97.9%); HPLC (94%).
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:10]([CH:13]=1)[CH2:11][NH2:12].[C:21]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30](O)=[O:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:14][N:15]2[CH2:16][C:17]([F:20])([F:19])[CH2:18]2)=[C:10]([CH:13]=1)[CH2:11][NH:12][C:30](=[O:31])[C@@H:29]1[CH2:33][CH2:34][CH2:35][N:28]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Yield: 51.7 %

Procedure:
EDC (80.2 mg, 0.42 mmol) was added to a stirred mixture of 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzylamine (68.8 mg, 0.28 mmol), N-BOC-L-proline (60.0 mg, 0.28 mmol) and HOAT (19.0 mg, 0.14 mmol) in DMF (2.5 mL). After 66 h the reaction mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (eluting with EtOAc/CHCl3, 1:5) to give N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (64.2 mg) as a glass: MS: 444.4 (M+1).