Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:15][CH:14]([CH2:16]OS(C)(=O)=O)[CH2:13][C:8]21[O:12][CH2:11][CH2:10][O:9]2)(=O)=O.[NH3:22]>>[CH2:11]1[O:12][C:8]2([CH2:13][CH:14]3[CH2:15][CH:7]2[CH2:6][NH:22][CH2:16]3)[O:9][CH2:10]1
Reactant: N
Reactant: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)C2(C1)OCCO2
Product: C1COC2(CC3CNCC2C3)O1
Temperature: 60 °C
Yield: 100 %

Procedure:
6,8-Bis(methanesulfonyloxymethyl)-1,4-dioxaspiro[4.4]nonane (14.90 g, 43.3 mmol) was suspended in aqueous ammonia (35%, 150 ml) and heated for 18 h at 60° C. The reaction was cooled to ambient temperature and concentrated by rotary evaporation. The residue was treated with saturated sodium chloride solution (50 ml) and extracted with chloroform (3×50 ml). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to yield a brown oil (7.69 g, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1N1CCCCC1

Procedure:
2-Bromo-5-nitroanisole (5.0 g, 21.5 mmol) and piperidine (8.5 ml) is stirred for 5 h at 105° C. under N2-atmosphere. Water (80 ml) is added and the mixture is extracted twice with CH2Cl2 (2×80 ml). The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is dissolved in AcOEt, SiO2 is then added and the solvent evaporate off In vacuo. The resulting powder is put on top of a chromatography column (SiO2; AcOEt/hexane 9:1) and the title compound eluted with hexane/AcOEt 9:1→4:1: MS: [M+1]+=237; Rf=0.2 (AcOEt/hexane 9:1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[O:40]1[CH2:41][CH2:42][N:37]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:2]3[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:35][CH:34]=2)[CH2:38][CH2:39]1
Reactant: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccccc12
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2ccccc12
Temperature: 130 °C
Yield: 74.2 %

Procedure:
In a sealed 5 ml microwave tubed, a suspension of 2-chloro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 11) (200 mg, 0.66 mmol), 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (preparation 2) (399 mg, 1.31 mmol), potassium phosphate (419 mg, 1.97 mmol) and tetrakis(triphenylphosphine)palladium (0) (22 mg, 0.02 mmol) in DMF/Water 3/1 (4 ml) was heated at 130° C. under microwave irradiation for 30 minutes. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (50 ml) and washed with NaHCO3 saturated aqueous solution (25 ml). The organic layer was separated and dried over MgSO4 before concentration to dryness. The reaction crude was purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired compound as a white solid (220 mg, 0.49 mmol, Yield 57%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[F:44])(=[O:36])=[O:35])[C:28]=2[F:45])[CH:5]=[CH:4][N:3]=1.[CH3:46][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:44][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=1[S:34]([NH:33][C:29]1[C:28]([F:45])=[C:27]([C:9]2[N:10]=[C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:46])[N:7]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (150 mg, 0.221 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (9.00 mg, 0.011 mmol) and dimethylzinc (0.221 mL, 0.441 mmol) were then added. The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to obtain the title compound (75 mg). MS (ESI): 660.5 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:15][CH2:11][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(CO)sc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(CCl)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
To an ice-cold solution of 3-methylbenzothiophene-2-methanol [Reference example 1] (480 mg, 2.69 mmol) in benzene (10 mL) was added dropwise, a solution of thionyl chloride (0.24 mL, 3.2 mmol) in benzene (3.5 mL). The mixture was stirred at room temperature for 3 hour, and concentrated under reduced pressure to give 2-chloromethyl-3-methylbenzothiophene as a yellow oil (548 mg, yield>99%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24](O)=[O:25])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH:30][CH3:31].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:29][N:30]([CH3:31])[C:24]([C:22]1[N:23]=[C:17]2[CH:16]=[C:15]([NH:14][C:12]([C:11]3[N:10]([CH3:27])[N:9]=[CH:8][C:7]=3[C:5]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]2[N:21]=1)=[O:25]
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Reactant: CNC
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (example 33, step d) (658 mg, 1.66 mmol) and lithium hydroxide hydrate (139 mg, 3.31 mmol) in methanol (20 ml) and water (5 ml) and tetrahydrofuran (10 ml) was stirred for 6 hours at 60° C. (soluble when heated). The mixture was neutralized using hydrochloric acid 2N (1.655 ml, 3.31 mmol) and the mixture was evaporated affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (776 mg, 77.4%) as a light brown solid which was used in the following reactions. A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (120 mg, 244 μmol), dimethylamine hydrochloride (99.4 mg, 1.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 359 μl, 609 μmol) and diisopropylethylamine (298 μl, 1.71 mmol) in tetrahydrofuran (7 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium bicarbonate solution, the precipitated solid was filtered off, washed with water and dried. The material was applied on silicagel and purified by flash chromatography over a 5 g silicagel column using dichloromethane/methanol 5% as eluent affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid dimethylamide (39 mg, 40.4%) as an off-white foam. MS: m/z=397.1 (M+H+)
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9][N+]1C=CC=CC=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[N+:26]([CH2:29][CH2:30][CH3:31])([O-:28])=[O:27].O>C(O)C>[CH2:30]([CH:29]([N+:26]([O-:28])=[O:27])[CH2:9][C:8]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:18]([OH:19])=[C:6]([C:2]([CH3:4])([CH3:3])[CH3:5])[CH:7]=1)[CH3:31]
Reactant: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCC[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)[N+](=O)[O-]
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of 16.7 grams of 3,5-di-tert.butyl-4-hydroxybenzylpyridinium chloride in 50 milliliters of ethanol was added dropwise in 15 minutes to a slurry of 2.0 grams of sodium hydroxide and 13.4 grams of 1-nitropropane (200% excess) in 50 milliliters of ethanol. The reaction mixture as stirred for 3 hours and was then poured into 600 milliliters of water. The oil which precipitated was separated by extraction with hexane. The extract was evaporated to give 15.0 grams (98% of theory) of 1-ethyl-2-(3,5-di-tert.butyl-4-hydroxyphenyl)-1-nitroethane which melted at 55°-60° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:18][CH2:17][CH2:16][N:15]([CH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1)[CH3:26]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccnn1-c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)Cc1ccnn1-c1ccc(C#N)cc1
Yield: 85 %

Procedure:
A solution of tert-butyl N-[2-([[1-(4-cyanophenyl)-1H-pyrazol-5-yl]methyl](methyl)amino)ethyl]carbamate (100 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was stirred at 25° C. for 30 min. The resulting mixture was concentrated under vacuum to give 196.2 mg (85%) of 4-(5-(((2-aminoethyl)(methyl)amino)methyl)-1H-pyrazol-1-yl)benzonitrile trifluoroacetate as a colorless oil. 1H-NMR (300 MHz, D2O): δ 7.94-7.91 (m, 2H), 7.80 (d, J=2.7 Hz, 1H), 7.61-7.58 (m, 2H), 6.78 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 3.30-3.18 (m, 4H), 2.57 (s, 3H) ppm. LCMS (method R, ESI): RT=1.18 min, m/z=256.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: N#Cc1cnc(C(=O)O)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3cnc(C#N)cn3)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Yield: 28 %

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-cyano-pyrazine-2-carboxylic acid (CAS 1211533-09-3) following procedure Q yielded the title compound as a light yellow solid (28% yield). MS: m/z=431.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]([NH:19][NH2:20])=[NH:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](O)=O>>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:18]=[CH:21][NH:20][N:19]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1cc(C(=N)NN)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
N-benzyl-5-(hydrazinyl(imino)methyl)-3-methylthiophene-2-carboxamide (0.65 g, 2.24 mmol) in formic acid (20 mL) was stirred at reflux for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then was concentrated in vacuo. The residue was dissolved in saturated aqueous sodium bicarbonate solution (50 mL) and extracted with 5% methanol in dichloromethane (3×75 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a light yellow solid (0.56 g, 84%): 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.48 (s, 1H), 7.39-7.30 (m, 5H), 6.14 (br s, 1H), 4.63 (d, J=5.4 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 299.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[CH2:26][N:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[CH2:26][N:27]([CH3:28])[CH3:29])=[CH:20][CH:19]=1)=[O:8]
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CN(C)CC(=O)Nc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and N-(4-amino-phenyl)-2-dimethylamino-acetamide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:9]1[C:8]2[CH:14]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:26])[CH3:22]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(C(C)=O)cc21
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a mixture of 6-acetyl-4H-benzo[1,4]oxazin-3-one (Alfa, 5 g, 26.18 mmol) and K2CO3 (5.4 g, 39.2 mmol) in acetone (50 mL) was added 2-bromo-propionic acid ethyl ester (14.14 g, 78.54 mmol) and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-acetyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (6.14 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 7.62 (dd, J=2 Hz, J=8.4 Hz, 1H), 7.52 (d, J=2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.29 (t, J=6.8 Hz, 1H), 4.68 (d, J=15.6 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.56 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[O:16][CH2:15][C@@H:10]2[CH2:11][O:12][CH2:13][CH2:14][N:9]2[CH2:8]1)(=O)=O.Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:40].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:5][CH2:6][C@@H:7]4[O:16][CH2:15][C@@H:10]5[CH2:11][O:12][CH2:13][CH2:14][N:9]5[CH2:8]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40]
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1O
Reactant: CS(=O)(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1OC[C@H]1CN2CCOC[C@H]2CO1
Reaction time: 12 h
Yield: 19.1 %

Procedure:
A solution of (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl methanesulfonate (0.215 g, 0.856 mmol), 4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (0.247 g, 0.570 mmol), and potassium carbonate (0.400 g, 2.90 mmol) in DMF (1.9 mL) was heated in a sealed reaction tube at 75° C. for 12 h, then 90° C. for 12 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 10% methanol in ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (3×50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo then taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (0.10 mL). Removal of solvent in vacuo provided 32.1 mg (10%) of N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride. MS (EI) for C23H23N4O4FClBr: 554 (M+).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:6][C:5]([CH3:12])([C:7]([O:9]CC)=[O:8])[CH2:4]1.[OH-].[Na+]>C1COCC1.O>[F:1][CH:2]([F:13])[CH:3]1[CH2:4][C:5]([CH3:12])([C:7]([OH:9])=[O:8])[CH2:6]1
Reactant: CCOC(=O)C1(C)CC(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CC(C(F)F)C1

Procedure:
A solution of Intermediate 258D (0.07 g, 0.364 mmol) and NaOH (0.036 g, 0.910 mmol) in THF (2 mL) and water (1 mL) was stirred at RT for 16 h. The volatiles were evaporated under reduced pressure, the pH was adjusted to =3 with a 1.0N aq. solution of HCl, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 258E (0.05 g, 84%, a mixture of cis and trans isomers) as a yellow liquid. The crude product was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.20-12.36 (m, 1H), 5.86-6.24 (m, 1H), 2.57-2.86 (m, 1H), 2.27-2.46 (m, 2H), 1.77-1.93 (m, 2H), 1.36 (s, 1H), 1.27 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[C:2]1([NH:1][CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(NC2CCC3(CC2)OCCO3)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of aniline (0.58 mL, 6.4 mmol) and acetic acid (0.73 mL, 12.8 mmol) in MeOH (6 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (1.0 g, 6.4 mmol). The mixture was stirred at 50° C. for 2 h. Then, NaCNBH3 (402 mg, 6.4 mmol) was added at 0° C. The mixture was stirred at room temperature for 2 h. Then, 2 M aqueous NaOH was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to 70:30 hexane/EtOAc) to give the crude title compound (1.39 g, 93%) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[C:3]([C:14]([F:15])([F:16])[F:17])=[CH:4][C:5]([C:6]([NH2:7])=[O:19])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
4-Chloro-3,5-bis(trifluoromethyl)benzonitrile (1 g, 1.0 eq.) was dissolved in DMSO (10 mL). K2CO3 (0.55 g, 1.1 eq.) and H2O2 (1 mL) were added to the reaction mixture and stirred at room temperature for 2-3 h, then poured into ice water (20 mL). The precipitate formed was collected by filtration and washed with petroleum ether to afford 1.0 g of crude product (90% yield), which was used without further purification in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[NH:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][S:7]1)=[O:5].[C:15](Cl)(=[O:17])[CH3:16].C(N(CC)CC)C>>[CH3:2][O:3][C:4]([CH:6]1[N:10]([C:15](=[O:17])[CH3:16])[CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1CSC(C(=O)OC)N1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CSC(C(=O)OC)N1C(C)=O

Procedure:
Thiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester hydrochloride (0.50 g, 2.07 mmol) was subjected to acylation with acetyl chloride (0.22 ml, 3.09 mmol) in the presence of triethylamine (0.58 ml, 4.17 mmol) to give N-acetylthiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester (with the ratio of two kinds of stereoisomers of about 49:51 as confirmed by NMR) as a pale-yellow oil (0.42 g, 83.0%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(C)(C)C.[ClH:23]>C(Cl)Cl.O1CCOCC1>[ClH:23].[ClH:23].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCCCC(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold mixture of [5-(Pyridin-3-ylcarbamoyl)pentyl]carbamic acid tert-butyl ester (3, 3.07 g, 10 mmole) in methylene chloride (30 mL) was added a solution of HCl in dioxane (4M, 10 mL). The mixture was stirred at room temperature overnight. The separated solid was filtered, washed with methylene chloride, dried in vacuum oven to give the product 4 as the hydrochloride salt (2.7 g, 96%). The 1H NMR spectrum of the pure solid was consistent with structure 4. 1H NMR (D2O) δ 9.20 (s, 2H), 7.91 (m, 1H), 2.90 (t, 2H), 2.42 (t, 2H), 2.62 (m, 4H), 1.36 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]([CH2:13][NH:14][C:15](=O)[CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]2[N:8]([C:15]([CH2:16][C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[N:14][CH:13]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(CNC(=O)Cc2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccn2c(Cc3n[nH]c4ncccc34)ncc2c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-{[3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-yl]methyl}-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (77 mg, 0.158 mmol) in toluene (2 mL) was added phosphorus oxychloride (120 μL, 0.79 mmol). The resulting mixture was then heated at 100° C. for 1 hour, after which the solvent was removed in vacuo and the residue was stirred with CH2Cl2 (50 mL) and saturated aqueous Na2CO3 (30 mL) for 30 minutes. The layers were partitioned and the organic extract was dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified using RediSep column (12 g) eluting with a gradient of 0-10% MeOH/CH2Cl2. The pure fractions were combined and the solvent removed in vacuo to give the title compound. LRMS (M+1)=469.7.