Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[NH:3]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.Cl>O1CCCC1.CN(C)C=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Under a nitrogen stream, (R)-3-methylisothiazolidine 1,1-dioxide (149 mg) described in Preparation Example 2 was dissolved in a solution of tetrahydrofuran (5 mL) and N,N-dimethylformamide (4 mL), sodium hydride (44 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Then, a solution of methyl 4-bromomethylbenzoate (229 mg) in tetrahydrofuran (5 mL) was added, and the mixture was stirred under ice-cooling for 1.5 hr, and at room temperature for 2 hr. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (159 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH2:19]([O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=O)=[C:27]([CH3:34])[CH:26]=1)[CH3:20]>CO>[CH2:19]([O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=4)[CH:15]=[CH:16][C:17]=3[N:18]=2)=[C:27]([CH3:34])[CH:26]=1)[CH3:20]
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reactant: CCOC(=O)COc1cc(C)c(C=O)c(C)c1
Solvent: CO
Product: CCOC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), (4-formyl-3,5-dimethyl-phenoxy)-acetic acid ethyl ester (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenoxy}-acetic acid ethyl ester: MS (m/z) 478 (M+1).
Reaction SMILES: N=[S:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].O.OP(O)(O)=O>CO>[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH:26][C:3]2[S:2][C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc2c(c1)S(=N)C=N2
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
100 mg (0.38 mmol) of 1-imino-6-methoxybenzothiazole and 1b were heated under N2 atmosphere at 220° C. for 30 min, in a similar manner to 234a. After cooling to rt, the reaction mixture was suspended in MeOH and the side product bis(6-methoxybenzo[d]thiazol-2-yl)amine (46.3 mg) was eliminated by filtration. The mother liquors were purified by preparative HPLC to yield Example 233. tR=7.861 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elation 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H24N3O2S [M+H]+ 406.1589. found 406.1576.
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[O:9]C=[N:7]1)=[O:5])[CH3:2].C(N(C)C([C@H]1[C@H](C2C=CN=CC=2)OC=N1)=O)C.Cl>CO>[NH2:7][CH:6]([CH:10]([OH:9])[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[C:4]([N:3]([CH2:1][CH3:2])[CH3:17])=[O:5]
Reactant: CCN(C)C(=O)C1N=COC1c1ccncc1
Agent: CCN(C)C(=O)[C@@H]1N=CO[C@H]1c1ccncc1
Agent: Cl
Solvent: CO
Product: CCN(C)C(=O)C(N)C(O)c1ccncc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of N-ethyl-4,5-dihydro-N-methyl-5-(pyridin-4-yl)oxazole-4-carboxamide SLA 09190 (144 mg, 0.6 mmol) in MeOH (5 mL) was added a solution of HCl 37% (240 μL). The reaction was stirred for 3 h at 50° C. and concentrated under reduced pressure. The resulting product was dissolved in MeOH and treated with amberlite (OH− form), filtered to give after evaporation a residue that was purified by column chromatography (SiO2, with a gradient of MeOH 10% in CH2Cl2) to yield to 2-amino-N-ethyl-3-hydroxy-N-methyl-3-pyridin-4-yl-propionamide. The hydrochloride salt was formed by treatment of this free base with a solution of HCl 1 M in MeOH (1 mL) to give after evaporation 2-amino-N-ethyl-3-hydroxy-N-methyl-3-pyridin-4-yl-propanamide dihydrochloride Compound 250 as a pale yellow solid (80 mg, 44% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CN(C)C(=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(C(F)(F)F)nc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)pyridine-3-amine (1.00 g, 6.15 mmol) and pyridine (1.50 ml, 18.5 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.17 ml, 8.51 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.83 g, 88.0%) as a solid was collected by filtration.
Reaction SMILES: FC(F)(F)C1C=C(N[C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])NN=1.C[O:26][C:27]([C:29]1[N:33]=[C:32]([NH2:34])[NH:31][N:30]=1)=[O:28]>>[NH2:17][C:16]1[C:11]([C:9]([NH:34][C:32]2[NH:31][N:30]=[C:29]([C:27]([OH:26])=[O:28])[N:33]=2)=[O:10])=[N:12][C:13]([Br:22])=[C:14]([C:18]([F:19])([F:21])[F:20])[N:15]=1
Reactant: COC(=O)c1n[nH]c(N)n1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1nc(C(=O)O)n[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) by replacing 3-(trifluoromethyl)-1H-pyrazol-5-amine with 5-amino-1H-[1,2,4]triazole-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:13])=[O:22])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(SC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.4 %

Procedure:
Methyl 2-chloro-6-(methylthio)isonicotinate (Intermediate 83; 290 mg), was dissolved in anhydrous DCM (5 ml). mCPBA (345 mg) was added and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with EtOAc and washed with water, 10% sodium thiosulfate, water, brine and dried over sodium sulfate. The mixture was concentrated in vacuo and purified by flash chromatography eluting with EtOAc:Hexane (7:3) to afford the title compound (129 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH3:28]>>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH2:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: N
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CN)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.7 mmol), NH3 (6 ml, 7N in methanol) was heated under microwave radiation at 120° C. for 20 min. The product was evaporated to dryness and was purified on an SCX-3 column (TEA/MeOH) Yield 0.34 g. MS m/z (rel. intensity, 70 eV) 261 (M+, bp), 217 (49), 97 (39), 69 (55), 56 (79).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: OCC1CCC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OCC1CCC2CN(c3ncc(Cl)cc3Cl)CCN2C1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 0.75 g (4.4 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 4.02 g (22.1 mmol) of 2,3,5-trichloropyridine, 1.12 g (10.6 mmol) of sodium carbonate and 30 mL of isoamylalcohol was refluxed for 72 h. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and evaporated, and the crude product was purified by flash chromatography on silica gel eluting with 95:5 chloroform:methanol to give 1.10 g (80%) of (7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([NH:27][C:22]2[C:21]([NH:20][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2Nc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
0.35 g (1.58 mmol) of Pd(OAc)2 and 4.8 ml (4.86 mmol) of tri-tent-butyl-phosphine (1 M solution in toluene) are added to 660 ml of degassed toluene, and the mixture is stirred for 5 min. 37.2 g (160 mmol) of 4-bromobiphenyl, 29.4 g (160 mmol) of N-phenyl-o-phenylenediamine and 22.4 g (233 mmol) of sodium tert-butoxide are then added to the solution, which is then degassed and stirred for 10 h at 140° C. under a protective-gas atmosphere. After the solution has cooled, 200 ml of NH4Cl solution and 50 ml of ethyl acetate are added, the phases are separated, washed with water, dried over MgSO4 and evaporated. The solid is dissolved in toluene and filtered off via Celite. The crude product is washed by stirring with hot heptane and washed with MeOH, giving 47 g (140 mmol) of a crystalline solid. The overall yield is 80%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)CC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCCCOc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCOc2ccccc2)cc1O
Yield: 64 %

Procedure:
Methyl 2,4-dihydroxybenzoate (33.6g; 0.2 mole) and anhydrous sodium carbonate (34.8g; 0.3 mole) in dry butanone (300 ml) were stirred at reflux during the addition of 1-bromo-3-phenoxypropane (43.0g; 0.2 mole) in butanone (50 ml) and the mixture stirred at reflux for 24 hours. The mixture was cooled and filtered and the filtrate evaporated to a white solid. Recrystallisation from ethanol gave 38.7g (64%) of material of mp 90°-92°, νmax (mull) 1660, 1615, 1598, 1580 cm-1. (Found; C. 67.69; H, 6.22; C17H18O5 requires; C, 67.54; H, 6.00%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[C@H:10]([CH:11]=[O:12])[CH2:9][C@@H:8]2[CH2:13][C@H:6]1[C:7]2([CH3:15])[CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[C@H:10]([CH2:11][OH:12])[CH2:9][C@@H:8]2[CH2:13][C@H:6]1[C:7]2([CH3:15])[CH3:14]
Reactant: COCC[C@H]1[C@H](C=O)C[C@@H]2C[C@H]1C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC[C@H]1[C@H](CO)C[C@@H]2C[C@H]1C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 150A (407 mg) in tetrahydrofuran (10 mL), which was cooled in a room temperature water bath, was added dropwise LAH (1.0M in tetrahydrofuran, 2.3 mL). The reaction was stirred at room temperature for 1 hour then quenched with water (25 mL). The resulting suspension was filtered through diatomaceous earth, and the filter cake was rinsed with ether (50 mL). The layers were separated and the aqueous layer was extracted with ether (2×25 mL). The extracts were washed with brine (25 mL), dried (MgSO4), filtered, and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.C(N(CC)CC)C.[CH3:40][CH:41]([CH3:47])[CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][NH:18][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:43]([CH2:42][CH:41]([CH3:47])[CH3:40])(=[O:45])=[O:44])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A solution of N-[2-(aminomethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-yl]-N-(2,2-diphenylethyl)amine (3.70 g, 8.63 mmol) (Preparation 6) and triethylamine (2.20 g, 21.78 mmol) in dry dichloromethane (20 ml) was treated with 2-methyl-1-propanesulfonyl chloride (1.48 g, 9.46 mmol) and the mixture was stirred at room temperature for 18 hours. TLC indicated that some starting material still remained and so further 2-methyl-1-propanesulfonyl chloride (0.2 g, 1.28 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) to afford the title compound as a foam (4.4 g).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:8][C:9]3[N:10]([CH3:5])[N:13]=[N:12][N:11]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1nc(N2CC[C@H](O)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(NC(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol and 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 374.3 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1ccc2sccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCc2ccc3sccc3c2)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of NaH (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (50 ml) heated at 60° C. with stirring under N2 was added dropwise a solution of 5-(2-hydroxyethyl)benzo[b]thiophene (8.9 g, 0.05 mol) in DMF (50 ml). After 1/2 hour, a solution of benzyl bromide (10.3 g, 7.2 ml, d=1.438, 0.06 mol) in DMF (50 ml) was added dropwise. After 15 hours, the solution was poured into H2O and the aqueous phase extracted with ethyl acetate (3×). The organic layers were backwashed with H2O saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 10% (V/V) ethyl acetate-hexane to yield 9.7 g (72%) of product. The material was used directly in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:19]=[C:18]([NH:20][C:21](=[O:30])[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=1)=O)(C)(C)C.Cl.C(OCC)C>C(OCC)(=O)C>[ClH:28].[NH2:8][C:9]1[CH:19]=[C:18]([NH:20][C:21](=[O:30])[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=1
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(NC(=O)OC(C)(C)C)cc2c1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Yield: 183.7 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino)-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (1.56 g) in 4N-hydrogen chloride in ethyl acetate (10 ml) was stirred at ambient temperature for 1 hour and to the reaction mixture was added diethyl ether. The separated solid was collected, washed with diethyl ether and dried to give 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (1.23 g).
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:36]([F:39])([F:38])[F:37])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:18])[F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:36]([F:37])([F:39])[F:38])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:17])[F:18])[N:15]=1
Reactant: O=C(NC1=N[C@](c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1
Temperature: 80 °C
Yield: 13.8 %

Procedure:
To a solution of N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (16 mg, 0.028 mmol) in MeOH (74.60 in a flask was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (336 μl, 2.249 mmol). The vial was sealed and was heated at 80° C. for 4 h. The reaction was diluted with MeOH and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min, then neutralized with solid NaHCO3 and extracted with DCM to provide N-(6-((4R,6S)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (1.8 mg, 3.85 μmol, 13.75% yield) as a off-white solid. MS m/z=467, 469 M+; Calculated for C17H12ClF6N5O2: 467.75.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][CH:48]1[CH:53]2[CH2:54][CH2:55][N:50]([CH2:51][CH2:52]2)[CH2:49]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:47][CH:48]2[CH:53]3[CH2:54][CH2:55][N:50]([CH2:51][CH2:52]3)[CH2:49]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8 mmol) in anhydrous N, N-dimethylformamide (6 mL) under nitrogen was stirred for 30 minutes, treated with 1,3-dicyclohexylcarbodiimide (1.71 g, 8.3 mmol) in anhydrous N,N-dimethylformamide (2 mL), and stirred for 2 hours. A solution of 3-aminoquinuclidine (1.52 g, 12 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added, and the mixture was stirred for 18 hours, filtered, and the filtrate concentrated in vacuo. The residue was dissolved in 20% methanol/tetrahydrofuran and filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and the residue was triturated from acetonitrile and recrystallized (2 crops) from 95% ethanol to afford 1.25 g (31%) of colorless solid; mp 196°-197° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2cc(C#C[Si](C)(C)C)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.6 mmol) of 4,4-dimethyl-7-trimethylsilylethynyl-thio-chroman (Compound 47) in 10 ml of isopropyl alcohol was added 5 ml of 1N KOH solution. The reaction mixture was stirred at room temperature for 18 hours and the isopropanol was then removed under vacuum. The residue was extracted with ether and the ether extracts were combined and washed with dilute HCl solution, water and saturated NaCl solution, and were thereafter dried (MgSO4). The solvent was removed in vacuo to give impure 4-4-dimethyl-7-ethynyl-thiochroman (Compound 48) as a pale yellow oil. This mixture was used in the next step without further purification. A solution of 281 mg of this impure 4,4-dimethyl-7-ethynylthiochroman (Compound 48) and 384 mg (1.4 mmol) of ethyl 4-iodo-benzoate in 1 ml of triethylamine was placed in a heavy walled glass tube and degassed under nitrogen. The mixture was treated with 60 mg of cuprous iodide and 30 mg of bis (triphenyl phosphine) palladium (II) chloride. The reaction mixture was degassed again under nitrogen, and the tube was sealed. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under high vacuum and the residue purified by flash column chromatography (silica; 3% EtOAC/hexane) to give the title compound as an off-white solid.