Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH3:18])[C:9]([CH3:17])=[C:10]([OH:16])[C:11]=2[CH3:15])[O:6]1)=[O:4].[C:20]([Si:24]([CH3:28])([CH3:27])OCl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH3:18])[C:9]([CH3:17])=[C:10]([O:16][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:28])[CH3:27])[C:11]=2[CH3:15])[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)OCl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Temperature: 25 °C
Yield: 99 %

Procedure:
Step a. A solution of 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid methyl ester (i, 41.9 mmol), t-butyl-dimethyl-silyloxy chloride (62.8 mmol), and imidazole (172.2 mmol) in 100 mL of DMF was stirred at 85-95° C. for 16 h, and cooled to room temperature. The solution was diluted with 200 mL of ethyl acetate, washed, in tandem, with H2O, 1% HCl, saturated NaHCO3, and brine, dried with Na2SO4, and concentrated. Purification by flash silica gel chromatography gave the product, 6-(t-butyl-dimethyl-silyloxy)-2,5,7,8-tetramethyl-chroman-2-carboxylic acid methyl ester (ii), as white solid in 99% yield. 1H NMR (300 MHz, CDCl3) δ 0.11 (s, 6H), 1.04 (s, 9H), 1.62 (s, 3H), 1.86-1.76 (m, 1H), 2.01 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22-2.30 (m, 1H), 3.49-3.65 (m, 2H), 3.69 (s, 3H), 4.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.[Fe]>[NH2:27][C:23]1[CH:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=3)[CH:6]=[N:7][C:2]=2[CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 87 °C

Procedure:
To a solution of N-[6-methyl-5-(3-nitrophenyl)pyridin-3-yl]-3-(trifluoromethyl)benzamide (0.150 g, 0.000374 mol) in ethanol (3 mL) was added acetic acid (0.5 mL, 0.009 mol) and iron powder (0.11 g, 0.0020 mol). The reaction was heated at 87° C. for 2 hours. It was then neutralized with Na2CO3 and extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The residue was used in the next reaction without purification. MS (ES) (M+H)=372.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=[O:16])[CH3:2].[H-].[Na+].[CH2:19](I)[CH2:20][CH3:21]>COCCOC>[CH2:1]([C:3]1([CH2:19][CH2:20][CH3:21])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: CCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC1(CC)Cc2cc(OC)c(Cl)c(Cl)c2C1=O

Procedure:
2-Ethyl-2-n-propyl-5-methoxy-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 5, Step E, using the following substances: 2-ethyl-5-methoxy-6,7-dichloro-1-indanone (13 g., 0.05 mole), sodium hydride (1.3 g., 0.055 mole), 1,2-dimethoxyethane (500 ml.) and n-propyliodide (6 ml.). The above procedure gives 6.0 g. of 2-ethyl-2-n-propyl-5-methoxy-6,7-dichloro-1-indanone which after recrystallization from ethanol melts at 92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH2:18][O:19]C)=[C:6]1[CH2:22][CH2:23][CH3:24].B(Br)(Br)Br>ClCCl.CO.O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH2:18][OH:19])=[C:6]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(C(=O)COC)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(C(=O)CO)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-3-methoxyacetyl-2-propylindole-6-carboxamide (168 mg) in a mixture of dichloromethane (10 ml) and methanol (0.5 ml) was added 1M solution or boron tribromide in dichloromethane (2.5 ml) at -53° C. The reaction mixture was warmed gradually to -12° C. during 3 hours. Then 1M solution of boron tribromide in dichloromethane (2.5 ml) was added, and the mixture was stirred for 20 minutes at -12° C. The reaction mixture was diluted with water and extracted with 10% methanol in chloroform. The organic phase was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate and washed with hexane to give 1-(2-chlorobenzyl)-3-hydroxyacetyl-2-propylindole-6-carboxamide (120 mg) as colorless crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH2:9]1)=[O:7].Cl>CO.O1CCOCC1>[NH:16]1[CH2:15][CH:14]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:7])[CH2:9]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3nccs3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1nccs1)N1CC[C@H](NC2CNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 1f (3 g, 8.52 mmol) in MeOH (10 mL) was added an HCl solution in dioxane (4M, 20 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (50 mL) was added to the residue. The white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 1g was used in the next reaction without further purification. MS m/z (M+H+) 253.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]#[C:17][C:18]([OH:20])=[O:19]>S(=O)(=O)(O)O.CC(C)=O>[O:14]=[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16]#[C:17][C:18]([OH:20])=[O:19]
Reactant: CCCCCCCCCC(O)C#CC(=O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCCCCC(=O)C#CC(=O)O

Procedure:
Jones reagent (a 2.67M solution in sulphuric acid; 1.32 ml, 3.5 mmol) was added dropwise to a solution of 4-hydroxytridec-2-ynoic acid (531.8 mg, 2.4 mmol) in acetone (10 ml) at 0° and the reaction mixture was maintained at 0° for 70 minutes. The mixture was quenched with ethanol (1 ml) and dried with magnesium sulphate. On evaporation, the title acid was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:23].C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][CH2:38][CH2:39][NH2:40]>CS(C)=O>[NH2:1][C:2]1[C:17]2[C:16](=[O:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:7]3[CH2:8][C:9]4([CH2:13][CH2:12][CH2:11]4)[O:10][C:5]([C:6]=23)=[C:4]([NH:40][CH2:39][CH2:38][NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[C:3]=1[F:23]
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3CC1(CCC1)O2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3CC1(CCC1)O2
Temperature: 0 °C
Yield: 81.7 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[cyclobutane-1,2′(3′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (200 mg, 0.621 mmol), triethylamine (0.130 mL, 0.933 mmol) and N-2-pyridyl-1,2-ethanediamine (128 mg, 0.933 mmol) in DMSO (4 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and then dried to yield the title compound (223 mg, 82%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.30-1.50 (2H, m), 1.53-1.73 (1H, m), 3.01-3.12 (2H, m), 3.19-3.30 (2H, m), 3.94 (2H, s), 5.65 (1H, brs), 6.01-6.12 (2H, m), 6.29 (1H, t, J=5.5 Hz), 6.43 (2H, brs), 6.90-7.01 (1H, m), 7.52-7.60 (1H, m), 8.13 (1H, s), 14.90 (1H, s). HRESIMS (+):440.17258 (Calcd for C22H23FN5O4, 440.17341).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[CH:24](O)=O.N>CO.O>[CH3:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=CO
Reactant: c1ccc(-c2sc3ccccc3c2N2CCNCC2)cc1
Agent: C=O
Agent: N
Solvent: O
Solvent: CO
Product: CN1CCN(c2c(-c3ccccc3)sc3ccccc23)CC1

Procedure:
A mixture of 7.0 g (24 mmole) of 3-(piperazino)-2-phenyl-benzo(b)thiophene, 3.5 milliliters of formalin at 35% (41 mmole) and 3.5 milliliters of formic acid at 98-100% (92 mmole) is refluxed for 1 hour. After cooling, it is poured into water, made alkaline with ammonia and extracted with CH2Cl2. By evaporating the organic phase dried over K2CO3, 7.2 g (98% of theory) of 3-(4'-methylpiperazino)-2-phenyl-benzo(b)thiophene are obtained: beige crystals, mp 118°-120° (methanol).
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[C:5](=[O:19])[NH:4][CH2:3]1.FC(F)(F)S(O[C:26]1[CH2:27][O:28][C:29](=[O:32])[C:30]=1[CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:26]2[CH2:27][O:28][C:29](=[O:32])[C:30]=2[CH3:31])[CH2:3]1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Product: CC1=C(N2CC(O)C3(CCNCC3)C2=O)COC1=O
Temperature: 90 °C

Procedure:
To a round bottom flask was charged tert-butyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg, 1.48 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (546 mg, 2.22 mmol), Pd2(dba)3 (33.9 mg, 0.037 mmol), Xantphos (64.2 mg, 0.111 mmol), and cesium carbonate (964 mg, 2.96 mmol). The flask was equipped with a condenser, vacuumed and back filled with N2 and filled with dioxane (6 mL). The reaction mixture was heated at 90° C. overnight, and filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to give the title compound as a racemate. LCMS: [(M+1)]+=367. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel OJ, 21×250 mm, 10% MeOH+0.2 DEA, 50 mL/min to afford Isomer A (faster eluting enantiomer) LC/MS: [(M+1)]+=367, and Isomer B (slower eluting enantiomer) LC/MS: [(M+1)]+=367.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:9][CH2:8][CH2:7]2.[C:31]([O:35][C:36](N1CCC2C(=CC(OC)=C(OC)C=2)C1CC1C=CC(Br)=CC=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].COC1C=NC=CC=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([O:35][C:36]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH:10]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:21][CH:22]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)N(C(=O)OC(C)(C)C)CC2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccncc3OC)cc1)NCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cnccc1B(O)O
Product: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccncc3OC)cc1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The synthesis of 6,7-dimethoxy-1-[4-(3-methoxypyridin-4-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride salt 12 is shown in Scheme 3. Reaction of 1-(4-bromobenzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 1 with 3-methoxypyridine-4-boronic acid 10 in the presence of Palladium(II) acetate, triphenylphosphine, and Na2CO3 yielded 6,7-dimethoxy-1-[4-(3-methoxypyridin-4-yl)benzyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 11 which was then treated with 2 M HCl solution in diethylether to get compound 12. N-[4′-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)biphenyl-2-yl]-methanesulfonamide hydrochloride salt 15 was prepared by the reaction of 1-(2′-Methanesulfonyl-aminobiphenyl-4-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 14 with 2 M HCl solution in diethylether. Compound 14 was obtained by the Suzuki coupling of compound 1 with (2-methylsulfonylaminophenyl)-boronic acid 13 using Palladium(II) acetate, triphenylphosphine, and Na2CO3 in isopropanol (scheme-4).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[ClH:1].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:6]2(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2cccc(OC)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(3-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (33 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (21 mg):
Reaction SMILES: [NH2:1][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[NH:23]([C:24]([NH:1][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]([Cl:6])([Cl:4])[Cl:5])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC(N)C(Cl)(Cl)Cl)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(NC(=O)Nc2ccccc2)C(Cl)(Cl)Cl)cc1
Reaction time: 10 h
Yield: 58 %

Procedure:
A solution of Example 38A (183 mg, 0.650 mmol) and phenyl isocyanate (77 mg, 0.65 mmol) in THF (4 mL) at ambient temperature was treated with triethylamine (0.93 mL, 0.66 mmol). The mixture was stirred for 10 hours, diluted with ethyl acetate (20 mL), and washed with aqueous NH4Cl (10 mL), water (10 mL), and brine (5 mL). The organic portion was dried (MgSO4), filtered, and concentrated to provide an oily residue which was purified by flash chromatography (elution with 5% methanol/CH2Cl2) to provide 151 mg of the desired product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH3:36])=[C:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19]([F:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:22].[ClH:37].[NH:26]1[CH2:27][CH:24]([C:18]2[C:17]([O:35][CH3:36])=[C:16]([CH:14]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH:11]([F:13])[F:12])=[N:9]3)[CH3:15])[CH:21]=[C:20]([Cl:22])[C:19]=2[F:23])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Yield: 89 %

Procedure:
tert-Butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.21 g, 0.40 mmol) was treated with 4.0 M hydrogen chloride in dioxane (1 mL, 4 mmol) in methylene chloride (4 mL) at room temperature for 2 h. The mixture was concentrated to give the desired product (0.177 g, 89%). LCMS calculated for C18H19ClF3N6O (M+H)+: m/z=427.1; Found: 427.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[C:9](=[O:21])[CH2:10][C:11]1[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Li+]>>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[C@@H:9]([OH:21])[CH2:10][C:11]1[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1cccnc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Li+]
Product: CC(=O)Nc1cccnc1C[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 3 with [(R)-3-(3-Acetylaminopyridin-2-yl)-1-(2,5-difluorobenzyl)-2-oxopropyl]carbamic acid tert-butyl ester (1.68 mmol; 729.00 mg) and lithium triacetoxyborohydride (8.41 mmol; 2.22 g) as the reducing agent gives the title compound.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CC=CC=1.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CS(C)=O.O.C(OCC)(=O)C>[O:1]([CH2:9][C@H:10]1[C:15](=[O:16])[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H]1OCC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A solution of (2R,4S,5R)-4-t-butyldimethylsiloxymethyl-5-hydroxy-2-methyl-1,3-dioxane (4.2 g) in a mixture of benzene (30 ml) and dimethylsulfoxide (5.7 ml) were added pyridine (1.30 ml), trifluoroacetic acid (0.62 ml) and N,N'-dicyclohexylcarbodiimide (9.90 g) under cooling in an ice bath and the mixture was stirred at room temperature for 3 hours. The resulting solution were added ethyl acetate (50 ml) and water (30 ml) and stirred for 30 minutes. After removal of insoluble urea by filtration, the organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified with silica gel column (50 g) (n-hexane : ethyl acetate=10:1) to give (2R,4S) 4 t-butyldimethylsiloxymethyl-2-methyl-1,3-dioxan-5-one (3.22 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3cccc(O)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled with 3-(2-amino-ethyl)-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 556. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 2H) 7.9 (d, 1H) 7.5 (m, 2H) 7.2 (m, 1H) 7.0 (d, 1H) 6.8 (m, 3H) 4.9 (s, br, 1H) 4.5 (s, 2H) 3.8 (m, 2H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.7 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Reactant: O=C(Cl)CCCCCl
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)CCCCCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester (2.3 g, 7.28 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 5-Chlorovaleryl chloride (1.13 g, 7.28 mmol) was dissolved in THF (15 mL) and added dropwise to the mixture over 15 min. The mixture was stirred at 0° C. for 1 h., the solvent removed in vacuo, and the residue was extracted using CH2Cl2 /water. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (1:1 to 1:0 EtOAc:hexane gradient) of the concentrate gave the title compound (3.16 g, 100%) as a pale yellow foam.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(#N)C.CCOC(C)=O>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2C1
Temperature: 80 °C
Yield: 62 %

Procedure:
A solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 35) (0.104 g, 0.276 mmol) was stirred in acetonitrile (2 ml). DIPEA (0.097 ml, 0.553 mmol) and ethyl 4-bromobutanoate (0.059 ml, 0.414 mmol) were added and the reaction mixture stirred and heated at 80° C. under Argon for 6 hours. Additional ethyl 4-bromobutanoate (0.059 ml, 0.414 mmol) and DIPEA (0.097 ml, 0.553 mmol) were added and the reaction mixture stirred and heated at 80° C. under argon overnight. Then the reaction mixture was dissolved in EtOAc, washed with saturated NaHCO3 solution (3×15 ml) and water (15 ml) and the organics dried (MgSO4) and evaporated. The crude was purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-20% (Biotage Column) and evaporated to give the title compound (84 mg) as an oil. MS (ES): C27H30N4O5 requires 490; found 491 [M+H]+.