Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][CH:13]([CH3:21])[CH2:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([CH2:14][CH:13]([Cl:12])[CH3:21])(=[O:17])=[O:16])=[O:20])[N:7]=1
Reactant: CC(Cl)CS(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC)n1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)CC(C)Cl)nc(OC)n1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
15.6 g (0.1 mole) of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 150 ml of dichloromethane, and a solution of 19.5 g (0.106 mole) of 2-chloro-n-prop-1-yl-sulfonyl isocyanate in 100 ml of dichloromethane was added at 0° C., while stirring. The mixture was further stirred for 12 hours at room temperature and cooled to 0° C., and 300 ml of n-hexane were added. The precipitated reaction product was filtered off under suction, washed with n-hexane and dried. 30.7 g (90.5% of theory) of N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-(2-chloro-n-prop-1-yl-sulfonyl)-urea of melting point 139°-41° C. were obtained.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][N:59]([C:62]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[O:63])[CH2:58][CH2:57]2)[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38](=[O:47])[NH:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:36][CH2:37]1)=[O:34])[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]2[CH2:55][CH2:54][CH:53]([N:56]3[CH2:57][CH2:58][N:59]([C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:60][CH2:61]3)[CH2:52][CH2:51]2)=[O:12])[CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 147.2 %

Procedure:
To a solution of a crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (300 mg) in N,N-dimethylformamide (4.5 ml) were added benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (684 mg) and triethylamine (0.629 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide a crude product of benzyl 4-{1-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-ylcarbamoyl]piperidin-4-yl}piperazine-1-carboxylate as a pale yellow oil (501 mg). This was dissolved in ethanol (10 ml) and N,N-dimethylformamide (5.0 ml). 1,4-cyclohexadiene (0.633 ml) and 10% palladium on carbon (144 mg) were added thereto, followed by stirring at 65° C. for 1.5 hr. The reaction mixture was allowed to cool down to room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1, then 5:1). Fractions containing the target compound were concentrated to give the residue (56.3 mg). The residue was purified by LC-MS. Fractions containing the target compound were concentrated, which were partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and to the residue was added diethyl ether to suspend a solid. This was collected by filtration, and dried under aeration to provide the titled compound as pale yellow powder (12.7 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].[O:16]1C2C=CC=CC=2CC(=O)N1>>[CH2:1]([O:3][C:4]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:16])=[O:10])=[O:9])[CH3:2]
Reactant: O=C1Cc2ccccc2ON1
Reactant: CCOc1nc2cccc(C)c2c(=O)o1
Product: CCOC(=O)Nc1cccc(C)c1C(=O)O

Procedure:
By following the procedure of Part A, but replacing 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one with the appropriate benzoxazinone prepared in Preparation III, the following compounds of Formula I are prepared:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:22]1([O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:30][C@H:29]([C:28]([O:27][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: O=Cc1ccc(CBr)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCc1ccc(CBr)cc1)C(=O)OC1CCCC1
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (0.940 g, 4.72 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (2.40 g, 6.4 mmol) and sodium triacetoxyborohydride (2.53 g, 11.9 mmol). The reaction mixture was stirred for 1 hour then poured into ethyl acetate (300 mL). The organic fraction was washed with saturated sodium hydrogen carbonate (100 mL, 3 times 50 mL) then dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, gradient 0-3% methanol-dichloromethane) to yield the desired product (1.504 g, 83% yield). LC/MS: m/z 382/384 [M+H]+
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[N:6]=1.C[Sn](C)(C)[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1>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.C1(C)C=CC=CC=1>[OH:27][CH2:26][C:23]1[N:24]=[CH:25][C:20]([C:2]2[S:3][CH:4]=[C:5]([N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])[N:6]=2)=[CH:21][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1c1csc(Br)n1
Reactant: C[Sn](C)(C)c1ccc(CO)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1csc(-c2ccc(CO)nc2)n1
Temperature: 160 °C
Yield: 68.3 %

Procedure:
A mixture of 2-(2 bromothiazol-4-yl)-isoindole-1.3-dione (10.0 g, 32.3 mmol) and (5-trimethylstannyl-pyridin-2-yl)-methanol (12.2 g, 26.9 mmol) in abs. toluene (50 mL) was placed in sealed tube, degassed and filled with tetrakis(triphenylphosphine)palladium(0) (932 mg, 0.8 mmol). The reaction mixture was heated at 160° C. for 1.5 hr and filtered while the reaction mixture was hot. After being cooled to room temperature for 2 hr, a solid was filtered through fritted funnel, washed with toluene (30 mL) and dried on vacuum to provide the title compound (6.2 g, 75%) as a pale yellow solid. MS-ESI m/z 338.02 (M+H)+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]([NH:32][NH2:33])=[O:31])=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]3[O:31][C:1](=[O:2])[NH:33][N:32]=3)=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NN)cn(C)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2n[nH]c(=O)o2)cn(C)c1=O
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL). After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. Some of the product precipitated and was collected by filtration. The filtrate was diluted with 1 N HCl and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether to give the desired product which was combined with the earlier obtained product. The combined yield of clean desired product was 482 mg (75%); MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.88 (s, 1H), 7.50 (dd, 1H), 7.21 (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[S:14]([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: BrCCc1ccc2ccccc2c1
Product: O=S(=O)(O)c1c(CCBr)ccc2ccccc12
Temperature: 0 °C
Reaction time: 30 h

Procedure:
2-(2-bromoethyl)naphthalene (120 g) was stirred in an ice bath while fuming sulfuric acid (50 g) was slowly added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 30 hours, whereby 2-(2-bromoethyl)naphthalenesulfonic acid and a plurality of isomers were obtained, and then separated and purified.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cn1cc2c(C=O)c(F)ccc2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(F)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a suspension of sodium hydride (0.88 g, 21.9 mmol) in tetrahydrofuran (20 mL) was added a solution of ethyl diethylphosphonoacetate (4.38 mL, 21.9 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-fluoro-2-methyl-2H-indazole-4-carbaldehyde (3.0 g, 16.8 mmol) in tetrahydrofuran (8.7 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (4.10 g, yield 98%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)(=[O:10])=[O:9].[NH2:18][C:19]1[C:20]([C:41]#[N:42])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[F:40])=[CH:23][N:24]=1>>[NH2:18][C:19]1[C:20]([C:41]#[N:42])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)(=[O:10])=[O:9])=[CH:27][C:26]=2[F:40])=[CH:23][N:24]=1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: N#Cc1nc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cnc1N

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((2-bromophenyl)sulfonyl)piperazin-2-one and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C21H17FN6O3S, 452.11; m/z found, 453.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=2.1, 1H), 8.05 (dd, J=8.1, 1.3, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.36 (dd, J=7.6, 1.3, 1H), 7.26-7.17 (m, 2H), 3.29 (s, 2H), 3.04 (s, 4H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]([CH3:23])=[CH:20][CH2:21][OH:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1.Br[CH2:26][CH:27]=[C:28]([CH3:40])[CH:29]=[CH:30][C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39]>O1CCCC1>[OH:22][CH2:21][CH:20]=[C:19]([CH3:23])[CH:18]([S:15]([C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)(=[O:16])=[O:17])[CH2:26][CH:27]=[C:28]([CH3:40])[CH:29]=[CH:30][C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCBr
Reactant: CC(=CCO)CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CCC(C(C)=CCO)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
The lithium diisopropylamide solution was then added over a 75 minute period to a -70°C. solution of 5.0 g. of 1-p-toluenesulfonyl-2-methyl-4-hydroxy-but-2-ene and 7.0 g. of 1-bromo-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-penta-2,4-diene in 50 ml. of tetrahydrofuran. After the addition, the reaction mixture was stirred for an additional 45 minutes at -70°C. and was then warmed to 0°C. and was poured onto 400 ml. of ice water. The mixture was extracted with three 300 ml. portions of diethyl ether, and the combined extracts were washed with two 400 ml. portions of brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent at reduced pressure gave a yellow oil which was immediately chromatographed on 300 g. of silica gel eluting with 5 to 30% diethyl ether in benzene followed by ethyl acetate. From the chromotography there was obtained 6.43 g. of pure 1-hydroxy-3,7-dimethyl-4-p-toluenesulfonyl-9 -(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene (70% yield) and 1.21 g. of recovered hydroxysulfone starting material. The product had UV in isopropanol at λmax = 228-9 mμ ( ε= 25,740); 260-2 mμ ( ε = 17,070) and 274-5 mμ ( ε = 15,010).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:10][CH:9]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>CC#N>[NH2:20][C:17]1[C:16]([C:21]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:29])=[N:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:13][CH:12]=2)=[CH:19][N:18]=1
Reactant: COCCCN
Reactant: CS(=O)(=O)OCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCNCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A mixture of the product of step (iv) (250 mg, 0.61 mmol), K2CO3 (250 mg, 1.8 mmol), 3-methoxypropylamine (82 mg, 0.92 mmol) in MeCN (20 mL, Aldrich, HPLC grade) was stirred at 90° C. under N2 atmosphere overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue subjected to prep-HPLC for purification, the eluents were concentrated and 1N NaOH solution added into the residue to control the pH=8˜9. The mixture was extracted with DCM three times. The combined extracts was dried over anhydrous sodium sulphate, filtered, concentrated in vacuo, which afforded the title compound (yellow solid, 158 mg)
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2nnco2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2nnco2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate (0.049 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (25 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.034 g of tert-butyl 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[C:8]2[CH3:14].O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:10]1[N:9]=[C:8]([CH3:14])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(C)nc(O)nc12
Solvent: O
Product: COc1cccc2c(C)nc(Cl)nc12
Temperature: 100 °C

Procedure:
To 8-methoxy-4-methylquinazolin-2-ol was added POCl3 and the mixture was added heated to 100° C. for 16 h when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2-chloro-8-methoxy-4-methylquinazoline. ES/MS m/z 209 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])#[N:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13].C1(O)C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:3]2[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=2[O:10][S:12](=[O:14])(=[O:13])[N:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1c(O)cccc1F
Agent: Cl
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: NC1=NS(=O)(=O)Oc2cccc(F)c21
Temperature: 50 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
8.0 g (58.3 mmol) of 2-cyano-3-fluorophenol are dissolved in 100 ml of anhydrous toluene. With exclusion of moisture and under protective argon gas, a solution of 8.489 g (60 mmol) of chlorosulphonyl isocyanate is added dropwise, in the course of which slight exothermicity occurs. The mixture is stirred at 50° C. for 16 hours; phenol is no longer detectable by thin-layer chromatography. The mixture is heated under reflux for 16 hours; no further evolution of HCl gas takes place. The mixture is concentrated under reduced pressure, taken up in acetonitrile and admixed with aqueous acetonitrile. After stirring at room temperature for 1 hour, the mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 13 g of a reaction mixture are obtained, which is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 1.3 g of a fraction are isolated, which consists of two components at log P=0.76 and 1.06. After separating this mixture by means of HPLC, 0.8 g of 4-amino-5-fluoro-1,2,3-benzoxathiazine 2,2-dioxide is obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Cl:8][C:7]1[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17][CH:18]2[CH3:22])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC1CN(Cc2ccccc2)CCN1c1nccnc1Cl
Temperature: 115 °C
Reaction time: 17 h
Yield: 28 %

Procedure:
A mixture of 2,3-dichloropyrazine (0.332 g, 2.23 mmol), 1-benzyl-3-methylpiperazine* (0.423 g, 2.23 mmol), and K2CO3 (0.339 g, 2.45 mmol) in acetonitrile (2.5 mL) was stirred at 115° C. for 17 h in a sealed tube. The reaction mixture was diluted with ether, filtered, and concentrated. The brownish oily residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 0.19 g (28%) of the title product as a viscous oil that was sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][C@@H:23]([C@H:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH3:24])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:14]=[C:13]([O:22][C@H:23]([CH3:24])[C@H:25]([OH:26])[CH2:29][OH:28])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-methanesulfonamide (the product of step i) (0.23 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.25 g). The reaction mixture was stirred at ambient temperature for 2 h then saturated aqueous sodium bicarbonate (2 mL) was added. The layers were separated and the aqueous material extracted with DCM (×3) and ethyl acetate (×3). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residual yellow solid was precipitated from 10% DCM in Et2O, filtered and the resulting material washed with minimal Et2O (2×1 mL) to afford the title compound as a white powder. Yield: 24 mg.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.O>[CH2:31]([O:30][C:28]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([N:9]2[CH2:8][CH:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:10]2)=[O:12])[CH2:14][CH2:15]1)=[O:29])[CH3:32]
Reactant: O=C(N1CCNCC1)N1CC(Oc2ccc(F)cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)N2CC(Oc3ccc(F)cc3)C2)CC1
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 1-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]piperazine and 1.4 g (0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.01 mole) of ethyl chloroformate. After stirring for 15 minutes, a small piece of ice was added and stirring continued for 72 hr. The reaction mixture was diluted with water and the oil which separated solidified on standing. The solid residue was purified by column chromatography (silica gel; washed with chloroform and eluted with ethyl acetate) to give the product 2.5 g (71%) which was recrystallized from benzene/ligroin to yield 2.35 g (66.7%) of white crystalline product, m.p. 89°-90° C.