Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[C:18]([O:22][C:23]([NH:25][C:26]1[S:27][CH:28]=[C:29]([C:31](OCC)=[O:32])[N:30]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[C:18]([O:22][C:23]([NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][OH:32])[N:30]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A 1.0M diisobutylaluminium hydride toluene solution (142 ml) was added dropwise to a stirred solution of ethyl 2-(t-butoxycarbonylamino)-1,3-thiazole-4-carboxylate (14.9 g) in dichloromethane (250 ml) under cooling at −70° C. After the mixture was stirred successively at −78° C. for 2 hours and at 0° C. for 1 hour, an aqueous potassium sodium tartrate solution was added carefully to the mixture, and the whole was further stirred for 2 hours. The mixture was filtered using dichloromethane, and the filtrate was partitioned between dichloromethane and water. The organic layer was separated and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a crude product of [2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methanol (9.2 g). The product thus obtained was treated with manganese dioxide (70 g) in dichloromethane (300 ml) with stirring at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(B(O)O)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(-c3ccccn3)c21
Yield: 58.2 %

Procedure:
A mixture of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg, 1.28 mmol), 2-bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh3)2Cl2 (10 mg, 2 mmol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH4Cl (10 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with water (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (2:1, v/v) as eluent, yielding 280 mg (58%) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]3[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH:18]=[CH2:19])(O)[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.C(OCC)C>[C:23]([S:24][CH2:19]/[CH:18]=[C:16]1\[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:11]2[S:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:9][C:10]\1=2)(=[NH:22])[NH2:25]
Reactant: NC(N)=S
Reactant: C=CC1(O)CC(C)(C)Cc2sc(-c3cccc(Br)c3)cc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(C)C/C(=C\CSC(=N)N)c2cc(-c3cccc(Br)c3)sc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(3-Bromophenyl)-6,6-dimethyl-4-vinyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (0.39 g, 1.0 mmol) was suspended in acetic acid (2.0 mL). Thiourea (83 mg, 1.0 mmol) was added and the reaction was stirred at 25° C. for 18 hr. The mixture was diluted with diethyl ether and petroleum ether yielding a solid precipitate. The solid was filtered, washed with additional diethyl ether and dried in vacuo to afford the title compound as the acetate salt (0.3 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[O:7][C:6]=2[CH:12]=1.[F:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:9][C:8]([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:26]=[CH:27][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:20][C@H:21]2[CH3:25])=[O:11])=[C:6]([OH:7])[CH:12]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Reactant: O=C1COc2ccc(Cl)cc2O1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1O
Temperature: 95 °C
Yield: 52.9 %

Procedure:
To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (1.003 g, 4.81 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (˜1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[C:19]4[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]6[CH:50]=[CH:51][CH:52]=[C:2]([F:1])[CH:3]=6)[CH:10]=5)=[CH:12][N:13]([S:40]([C:43]5[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=5)(=[O:42])=[O:41])[C:14]4=[N:15][CH:16]=3)=[CH:21][CH:22]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCNCC5)cc4)cnc32)cc1
Yield: 97 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,4-diazepane-1-carboxylate (120 mg, 0.166 mmol) was deprotected in TFA/DCM (3/1 ml) to afford 100 mg (97.0% yield) of the titled compound. MS: m/z=621.2 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.O1CCCCC1[N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C4CCCCO4)=[CH:34][CH:33]=3)[CH:27]=[C:28]2[NH2:31])=[N:23]1>C(Cl)Cl>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[N:22][NH:23]3)=[C:28]([NH:31][C:13]([CH:10]3[CH2:12][CH2:11]3)=[O:14])[CH:27]=2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)C1CC1
Reaction time: 1 h

Procedure:
DIPEA (82 mg, 0.635 mmol) and cyclopropanecarbonyl chloride (15 mg, 0.14 mmol) were added to 2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) in DCM (1 ml) and the reaction was stirred for 1 h. The solvent was removed under a stream of nitrogen. The residue was dissolved in MeOH (2 ml), 4 M HCl in 1,4-dioxane (2 ml) was added and the reaction was stirred for 1 h. The solvent was removed in vacuo. The residue was purified by MDAP (Method B), dried under a stream of nitrogen then freeze dried to give the title compound, 17 mg.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[C:16]([O:18][C@H:19]3[CH2:44][CH2:43][C@H:22]4[C:23](=[O:42])[N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]5[CH2:36][C@@:32]5([C:37]([O:39]C)=[O:38])[NH:33][C:34](=[O:35])[C@@H:21]4[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:47])[C:12]([O:45][CH3:46])=[CH:13][CH:14]=3)[N:9]=2)[S:6][CH:7]=1)#[CH:2].C(OC([C@@H]1C[C@H](O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)CC[C@H]1C(O)=O)=O)(C)(C)C>>[C:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[C:16]([O:18][C@H:19]3[CH2:44][CH2:43][C@H:22]4[C:23](=[O:42])[N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]5[CH2:36][C@@:32]5([C:37]([OH:39])=[O:38])[NH:33][C:34](=[O:35])[C@@H:21]4[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:47])[C:12]([O:45][CH3:46])=[CH:13][CH:14]=3)[N:9]=2)[S:6][CH:7]=1)#[CH:2]
Reactant: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)OC)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Product: C#Cc1csc(-c2cc(O[C@H]3CC[C@H]4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1

Procedure:
Compound 46 was synthesized from compound 45 as described for compound 38 to yield compound 46 as a beige solid. MS (ESI, EI+): m/z=643 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 6-fluoro-2(3H)-benzothiazolone (47.58 g) in 100% sulfuric acid (760 ml) was cooled at 0° to 5° C., and 98% fuming nitric acid (d=1.52; 18.79 g) was dropwise added thereto, followed by stirring at the same temperature for 60 minutes. The reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzothiazolone (48.48 g) as pale brown crystals. m.p., 180°-182° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:14]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NNc1nc2ccccc2nc1Cl
Reactant: CCOC(OCC)OCC
Product: Clc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Yield: 94 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (9.0 g., 0.046 mole), the product of Example 1, was stirred with triethyl orthoformate (90 ml.) at 100° C. for one hour. The mixture was cooled to room temperature and the solid precipitate was collected by filtration and washed with cyclohexane and dried to afford 8.8 g. (94% yield) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 287°-290° C. (decomp.). Mass spectrum: m/e, 204 (P).
Reaction SMILES: ClC1C=CC=C(Cl)C=1N1C=C2C(NC3C=C(C)N=C(N)N=3)=NC=CC2=N1.C(OC(=O)[NH:33][C:34]1[CH:39]=[C:38]([NH:40][C:41]2[C:46]3=[CH:47][N:48]([C:50]4[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=4[Cl:57])[N:49]=[C:45]3[CH:44]=[CH:43][N:42]=2)[N:37]=[C:36]([CH3:58])[N:35]=1)(C)(C)C>>[Cl:56][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:57])[C:50]=1[N:48]1[CH:47]=[C:46]2[C:41]([NH:40][C:38]3[CH:39]=[C:34]([NH2:33])[N:35]=[C:36]([CH3:58])[N:37]=3)=[N:42][CH:43]=[CH:44][C:45]2=[N:49]1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)n1
Agent: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(N)n1
Product: Cc1nc(N)cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)n1
Yield: 55 %

Procedure:
Following the procedure described for N4-[2-(2,6-dichloro-phenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-6-methyl-pyrimidine-2,4-diamine, {6-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-2-methyl-pyrimidin-4-yl}-carbamic acid tert-butyl ester was reacted to afford the title compound as a white solid (40 mg, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.16 (s, 1H), 7.90 (d, J=6.4 Hz, 1H), 7.84-7.78 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 7.57 (s, 1H), 7.12 (d, J=6.4 Hz, 1H), 6.59 (s, 2H), 2.28 (s, 3H). LCMS (Method B): RT=2.90 min, m/z: 386 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18]Br)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH:3]=1
Reactant: N#Cc1ccc2[nH]cc(Cl)c2c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(C#N)ccc21
Temperature: 80 °C
Yield: 90.3 %

Procedure:
A mixture of 3-chloro-1H-indole-5-carbonitrile (D94) (1.8 g, 10 mmol), ethyl-3-bromopropionate (1.92 ml, 15 mmol), cesium carbonate (6.5 g, 20 mmol) and DMF (50 ml) was heated at 80° C. for 4 hours to give complete reaction. After allowing mixture to cool to room temperature diethyl ether (300 ml) was added and the solution washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to give a brown solid. The solid was triturated with a mixture of diethyl ether and hexane to obtain 2.5 g of the title compound as a tan solid. Crude product used in the next stage (synthesis of D96).
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[BH4-].[Na+].CS(O[CH2:17][CH:18]([O:39][CH3:40])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=O)=O>O1CCCC1.CO>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4][CH2:17][CH:18]([O:39][CH3:40])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Reactant: OCCCCS
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCCCO)OC
Reaction time: 1.5 h

Procedure:
To 40 ml of a methanol solution of sodium methoxide (1 M solution) are added 3.1 g of 4-mercaptobutanol and 0.5 g of sodium borohydride, to which is added dropwise a solution of 4.36 g of 2-methoxy-3-octadecyloxypropyl methanesulfonate in 40 ml of tetrahydrofuran at room temperature with stirring. The mixture is stirred at room temperature for 14 hours and then at 40° C. for 1.5 hours. The solvent is distilled off under reduced pressure and the residue is acidified with hydrochloric acid and extracted with hexane. The extract layer is washed with water, dried and concentrated to leave crude 2-methoxy-3-octadecyloxypropyl 4-hydroxybutyl sulfide. This sulfide is dissolved in 75 ml of dichlromethane, to which 7.6 g of m-chloroperbenzoic acid is added little by little at room temperature with stirring. The mixture is then stirred at room temperature for 1 hour and is filtered to remove precipitates. The filtrate is washed with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution and water, dried and concentrated to leave a residue which in turn is purified by silica gel column chromatography to obtain 2.5 g of the captioned compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:65])[C@H:53]([OH:64])[C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])[CH3:50]>C(Cl)Cl>[Cl:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[CH2:55][C@@H:54]([NH:63][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[C@H:53]([C:52]([O:51][CH2:49][CH3:50])=[O:65])[OH:64]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Yield: 27.9 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the mixture was stirred. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. The product was purified using preparative HPLC to yield the title compound (30 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H26ClNO6, 448.14. found 448.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:28])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH:20]C(=O)OC(C)(C)C)=[N:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:28])[CH2:15][C@@H:14]([C:16]([F:18])([F:19])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(NC(=O)OC(C)(C)C)=N1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
tert-Butyl ((4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (0.56 g, 1.196 mmol) was treated with trifluoroacetic acid, 99% (10 ml, 135 mmol) and the mixture was stirred at room temperature for 15 min. The solvent was removed and the residue was worked up with saturated sodium bicarbonate solution and extracted with dichloromethane three times. The combined organic layers were dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 10-60% EtOAc/hexane to give (4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.366 g, 0.994 mmol, 83% yield).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>C(O)C>[CH2:10]([O:9][C:1]([CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)CCCCCCCBr
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
Diethyl malonate (9.85 g, 61.5 mmols) was added to an ethanol (170 ml) solution of sodium ethoxide (4.61 g, 67.7 mmols) with cooling with ice, and then stirred for 15 minutes at room temperature, and thereafter ethyl 8-bromooctanoate (17.0 g, 67.7 mmols) was added thereto. The reaction mixture was heated under reflux for 2 hours, and then an aqueous saturated ammonium chloride solution was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated in vacuo. The thus-obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the entitled compound (13.7 g) as an oil.
Reaction SMILES: C=C.[C:3](OC)(=O)[C:4](C)=C.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[CH:11]1>>[CH2:3]=[CH2:4].[C:13]([O:15][CH3:10])(=[O:14])[CH:12]=[CH2:11].[C:13]1(=[O:14])[O:15][C:10](=[O:16])[CH:11]=[CH:12]1
Reactant: C=C(C)C(=O)OC
Agent: C=C
Agent: O=C1C=CC(=O)O1
Product: C=CC(=O)OC

Procedure:
(MFR=3.6 g/10 min, ethylene content=94.1% by weight, methyl methacrylate content=2.0% by weight and maleic anhydride content=3.9% by weight)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccncc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: c1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-aminophenol (10.9 g, 100 mmol), isonicotinic acid (12.3 g, 100 mmol) and boric acid (6.1 g, 100 mmol) in xylene (500 ml) was heated at reflux, under a nitrogen atmosphere, for 17 hours. The mixture was cooled to room temperature and the orange suspension partitioned between sodium hydroxide solution (4N, 500 ml) and ethyl acetate (500 ml), the phases were separated and the organic layer washed with sodium hydroxide solution (2N, 2×300 ml), water (100 ml) and brine (100 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](=[O:23])=[O:22].O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([C:21]([OH:23])=[O:22])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.34 g 3-bromo-4-chlorobenzoic acid tert-butyl ester in 60 ml dry THF were cooled to −78° C. 12.59 ml (1.1 equivalents) of a 1.6 M solution of n-butyl lithium in hexane were added slowly and stirring was continued at −78° C. for 30 min. 20 g solid carbon dioxide were quickly crushed and added to the mixture. Cooling was continued for another 30 min before the mixture was allowed to warm up to room temperature. After 1 hr at room temperature, water and ethyl acetate were added and the organic phase was separated. The water phase was extracted with ethyl acetate and the combined organic phases were evaporated and purified by chromatography on silica in a heptane/ethyl acetate gradient.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])(C)(C)C.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1ccc2c(Br)cccc21
Agent: O=P(O)(O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 67 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon gas atmosphere, then added dropwise with a 1.62 M solution of t-butyllithium in pentane (28.8 ml) over 30 minutes, and stirred for 30 minutes. This reaction mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature, and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) containing ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was made acidic with 5 N hydrochloric acid under ice cooling, and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 68, 3.17 g).