Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1.[Sn](Cl)Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc(N)cc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
Benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-vinyl ester (675 mg, 1.26 mmoles) is dissolved in tetrahydrofuran (30 mL). Tin dichloride (SnCl2*2H2O, 2.84 g, 12.6 mmoles) is added and the resulting mixture is stirred at room temperature for 24 hours and at 40° C. for 3 hours. The mixture is diluted with water and a saturated NaHCO3 solution and extracted with DCM; the combined organic layers are dried over sodium sulphate and evaporated to dryness. The crude (468 mg) is purified by preparative HPLC to yield 80 mg of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:14])=[O:13].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[O:19][CH2:20][CH2:21][CH:22]=[O:23])(=[O:14])=[O:13]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2-chloro-5-trifluoromethylphenylsulfonyloxy)-5-methylphenoxy]propanol (600 mg, 1.4 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (410 mg, 69%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.84 (dd, J=8.4, 2.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:25]/[N:24]=[C:6](/[NH2:7])\[C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]4([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:15](=[O:19])[NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1
Reactant: NO
Reactant: Cc1ccc(C#N)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(/C(N)=N\O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 85 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzonitrile (preparation 54b, 0.06 g, 0.20 mmol), hydroxylamine (0.02 g, 0.24 mmol) and sodium acetate (0.02 g, 0.27 mmol) in ethanol (0.60 mL) and water (0.10 mL) were heated to 85° C. in a sealed tube. After 6 hours, the mixture was cooled and concentrated in vacuo. Water was added to the residue and the resultant precipitate was filtered to give the title compound (0.06 g, 19%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])/[C:10](/[C:20]2[CH:25]=[CH:24][C:23]([O:26]COC)=[CH:22][CH:21]=2)=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH3:13])=[CH:4][CH:3]=1.Cl.O>CO.O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])/[C:10](/[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 6a (45 mg, 0.112 mmol) in MeOH (1 ml) was added a solution of 4N HCl in dioxane (0.3 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 7a (76%). 7a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.64 (2H, q, J=7.5 Hz), 6.51 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 7.12-7.25 (5H, m), 7.40 (2H, d, J=8.8 Hz). HRMS calcd for C23H22NO3: 360.1600. Found: 360.1605.
Reaction SMILES: BrC1C=CC2N(N=C(N(CC)CC)N=2)C=1.[N:16]1([C:22]2[N:31]=[C:25]3[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][N:24]3[N:23]=2)[CH2:21][CH2:20]O[CH2:18][CH2:17]1>>[CH2:21]([N:16]([CH2:17][CH3:18])[C:22]1[N:31]=[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][N:24]2[N:23]=1)[CH3:20]
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: CCN(CC)c1nc2ccc(Br)cn2n1
Product: CCN(CC)c1nc2ccc(N)cn2n1

Procedure:
Using (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-diethyl-amine, this compound was prepared following the same methods as for the synthesis of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine. Brown solid (500 mg, 66%). MS: m/z=206 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]2=[CH:12][C:11]=1[C:19]([OH:21])=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][NH:36][C:19]([C:11]2[CH:12]=[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Reactant: O=C(O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)c2cc3ccncn3c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (190 mg, 0.48 mmol), 4-aminooxy-piperidine-1-carboxylic acid tert-butyl ester (154 mg, 0.72 mmol), HOBt (106 mg, 0.79 mmol), EDCI hydrochloride (150 mg, 0.79 mmol) and DIPEA (120 μL, 0.72 mmol) were suspended in DMF (5 mL). The reaction was stirred at RT for 1 hour, during which time the reagents dissolved. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (180 mg, 65%). LCMS (Method B): RT=3.69 min, M+H+−tBu=540 (100%), M+H+−Boc=496 (95%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=O)[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:41][OH:42].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=[N:41][OH:42])[CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N3CCC[C@H]3C(=O)O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3C=NO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
The compound (20 mg, 0.043 mmol) of Example 43 was dissolved in acetic acid (5 mL), and sodium acetate (45 mg, 0.56 mmol) and hydroxylamine hydrochloride (14 mg, 0.21 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.026 mL, 0.28 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:11]1[OH:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ClC(Cl)C(O)=O.C(O)(=O)C(O)=O.[BH4-].[Na+]>C(OCC)(=O)C.CO.N1C=CC=CC=1.C1C=CC=CC=1.CS(C)=O>[C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[OH:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
To a solution of 1-(3,5-di-O-benzoyl-β-L-xylofuranosyl)uracil 11 (8 g, 17.7 mL) in an anhydrous benzene-DMSO mixture (265 mL, 6:4, v/v) were added anhydrous pyridine (1.4 mL), dicyclohexylcarbodiimide (10.9 g, 53 mmol) and dichloroacetic acid (0.75 mL). The resulting mixture was stirred at room temperature for 4 h, then diluted with ethyl acetate (400 mL) and a solution of oxalic acid (4.8 g, 53 mmol) in methanol (14 mL) was added. After being stirred for 1 h, the solution was filtered. The filtrate was washed with a saturated NaCl solution (2×500 mL), 3% NaHCO3 solution (2×500 mL) and water (2×500 mL). The organic phase was dried over Na2SO4, then evaporated under reduced pressure. The resulting residue was then solubilized in an EtOH absolute-benzene mixture (140 mL, 2:1, v/v). To this solution at 0° C. was added NaBH4 (0.96 g, 26.5 mmol). After being stirred for 1 h, the solution was diluted with ethyl acetate (400 mL), then filtered. The filtrate was washed with a saturated NaCl solution (400 mL) and water (400 mL). The organic phase was dried over Na2SO4, then evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-3%) in dichloromethane to give 12 (5.3 g, 66%) which was crystallized from acetonitrile: mp=182-183° C.; 1H-NMR (DMSO-d6): δ11.35 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2 C6H5CO, H-6), 6.23 (br s, 1H, OH-2′), 6.15 (d, 1H, H-1′, J1′,2′=4 Hz), 5.54 (d, 1H, H-5, J5-6=8.1 Hz), 5.37 (t, 1H, H-3′, J3′-2′=2.6 Hz), 4.7-4.6 (m, 2H, H-5′ and H-5″), 4.5 (m, 1H, H-4′), 4.4 (m, 1H, H-2′); MS: FAB>0 (matrix GT) m/z 453 (M+H)+, 341 (S)+, 113 (BH2)+, 105 (C6H5CO)+; FAB<0 (matrix GT) m/z 451 (M−H)−, 121 (C6H5CO2)−, 111 (B)−; Anal. Calcd for C23H20N2O8: C, 61.06; H, 4.46; N, 6.19. Found: C, 60.83; H, 4.34; N, 6.25.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]>CO.[Pd]>[CH3:20][N:2]([CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:19])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: Cc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Yield: 84 %

Procedure:
10% Pd on carbon (0.5 g, 17.37 mmol) was placed under N2 atm. MeOH (20 mL) was added, followed by a solution of N,N-dimethyl-2-(6-methyl-7-nitro-3,4-dihydro-1(2H)-quinolinyl)-2-oxoethanamine (2.07 g, 7.46 mmol) in MeOH (80 mL). The mixture was placed under H2 atm via balloon and maintained for 1 day. The resulting mixture was filtered through a pad of Celite using MeOH. The filtrate was concentrated, the residue was taken up into Et2O and concentrated again to afford 1-[(dimethylamino)acetyl]-6-methyl-1,2,3,4-tetrahydro-7-quinolinamine as a grey solid (1.55 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.87 (m, 2H), 1.99 (s, 3H), 2.20 (s, 6H), 2.45-2.58 (m, 2H), 3.18 (s, 2H), 3.61 (t, J=6.13 Hz, 2H), 4.66 (br s, 2H), 6.69 (s, 1H), 6.78 (br s, 1H); ESIMS (M+H)+=248.17.
Reaction SMILES: [H-].[Na+].[C:3](=O)(OCC)[O:4]CC.F[C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.[OH-].[Na+]>C1C=CC=CC=1>[OH:20][C:18]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:17]=2)[O:21][C:3](=[O:4])[CH:19]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=c1cc(O)c2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred suspension of sodium hydride (Aldrich, 60% dispersion in mineral oil) (1.2 g, 30.0 mmol) and diethyl carbonate (Aldrich) (5.9 g, 50 mmol) in anhydrous benzene (Aldrich) (100 mL) under a dry nitrogen atmosphere was added dropwise a solution of 5'-fluoro-2'-hydroxy-acetophenone (Aldrich) (1.54 g, 10 mmol) in anhydrous benzene. The mixture was then refluxed under a nitrogen atmosphere overnight. The reaction mixture was cooled and 50 mL 1N NaOH was added. The mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and washed with ether (100 mL×2). The dark solution was acidified to pH 2 with 6N HCl. The white precipitate was collected by filtration, washed with water and dried to afford product (4) (4-hydroxy-6-fluoro-coumarin) as an off-white solid (1.38 g, 7.66 mmol, 77%). 300-MHz 1H-NMR (CDCl3) δ 5.79 (s,1H), 7.25-7.28 (m,2H), 7.52 (d,1H). Mass/EI: 179 (M-H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=O.Cl>>[Cl:15][CH:16]([Cl:20])[C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Product: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 17.44 g of 2-amino-3-trifluoromethylbenzoic acid prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106 and 34.63 g of dichloroacetyl chloride was progressively heated with stirring and at about 50° C., a hardening of the mass with rapid gas evolution of regular hydrogen chloride occured for one hour. Towards 100° C., one observed a fluidization of the reaction mixture, an intensification of hydrogen chloride evolution and an increase in the temperature to 127° C. The heating was continued until hydrogen chloride evolution ceased to obtain a brown solution which was cooled in an ice bath with stirring. The mixture was vacuum filtered and the product was empasted with ether, then with methanol and was washed with methanol to obtain 23.82 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 179° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].IC.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester (10 g, 28 mmol) from Step 1 was dissolved in DMF (100 mL) and cooled to 0° C. To the stirred solution was added iodomethane (6.1 g, 43 mmol) and Cs2CO3 (10 g, 31 mmol). The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 12 h. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([N:15]([CH3:23])[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.[NH:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(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>[NH:28]1[C:36]2[C:31](=[C:32]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([N:15]([CH3:23])[CH2:16][CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:14])[CH2:7][C@@H:6]5[CH2:24][O:25][CH2:26][CH2:27][N:5]5[C:4]=4[N:3]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 43.6 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x79, 70 mg, 0.177 mmol), indole-4-boronic acid (42.7 mg, 0.265 mmol), tetrakis(triphenylphosphine)palladium(0) (20.43 mg, 0.018 mmol), and sodium carbonate (37.5 mg, 0.354 mmol) in 1,4-dioxane (0.7 mL) and water (0.35 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica-NH, gradient 0-10% MeOH/CHCl3) to afford the title compound as an off-white solid (36.8 mg, 43.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.61 (m, 4 H), 1.78-1.97 (m, 1 H), 2.80-3.09 (m, 4 H), 3.12-3.38 (m, 7 H), 3.58 (t, J=9.98 Hz, 2 H), 3.78-4.16 (m, 5 H), 4.41-4.60 (m, 2 H), 7.11 (t, J=7.71 Hz, 1 H), 7.26-7.64 (m, 4 H), 7.86-7.95 (m, 1 H), 11.11 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C26H32N6O3, 477.26; found 477.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([O:10]C)=[O:9])=[O:4].Cl>P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)[C@@H]1C[C@H]1C(=O)O
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
Suspend trans-cyclopropane-1,2-dicarboxylic acid dimethylester (59.8 g, 0.378 mol) is suspended in 1.0N phosphate buffer (1.5 L, pH=7) add pig liver esterase (2.25 mL, 7500 units), and monitor NaOH consumption with a pH meter to control the reaction. After 3 h the consumption of 189 mL of 2N NaOH indicates the complete hydrolysis of the diester to the monomethylester. Acidified the clear solution by the addition of SN HCl to a pH=1. Separate the enzyme by addition of dichloromethane (500 mL) and diatomaceous earth (25 g). Stir for 5 min, and then filter the mixture. Saturate the filtrate with NaCl, and extract with ethyl acetate (5 times). Combine the extracts, dry (Na2SO4) and evaporate to obtain 50.8 g (93%) of solid, mp 46-47° C., m/z=45 (M+H)+
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a suspension of 0.2463 g (0.000563 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) in 15 mL of dimethylformamide was added 0.1222 g (0.00091 mole) of 1-hydroxybenzotriazole, 0.3307 g (0.00087 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.59 mL (0.00339 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0980 g (0.00086 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.166 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide (I-54).