Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromobutane (0.38 g, 2.7 mmol) and potassium carbonate (0.56 g, 4.0 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.35 g, 83%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20]([N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1>[C:20]([N:24]1[C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Cl)cc1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nn(-c3ccc(Cl)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1

Procedure:
200 mg 4-Bromo-2-(4-chloro-phenyl)-2H-phthalazin-1-one (prepared as described in Method R), 91 mg 1-tert.-butyl-3-methyl-1H-pyrazol-5-ylamine, 310 mg cesium carbonate, 21 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 16.4 mg tris-(di-benzylideneacetone)-dipalladium in 2 ml dry dioxane were stirred under nitrogen at 100° C. for 18 hrs. The solvent was removed under vacuum and the residue stirred with 50 ml water. The crude product was isolated by filtration, washed with water and purified by chromatography on silica, eluting sequentially with heptane, DCM and finally DCM/MeOH 60:1. Yield 180 mg (74%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[CH:39][CH:38]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(N)nc1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.21 mmol) were added 70 mg (0.32 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, 19 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 317 μl of a 2M aqueous solution of sodium carbonate in dioxane. The mixture was stirred under argon atmosphere at 80° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified first by flash chromatography (0% to 15% MeOH/DCM) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 28 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]3([CH3:12])[CH3:13])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: OB(O)c1cccnc1
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: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3cccnc3)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (265 mg, 625 μmol, see Example 53), 3-pyridylboronic acid (115 mg, 937 μmol), and tetrakis(triphenylphosphine)palladium (72 mg, 62 μmol) were mixed in dioxane (4 mL) in a microwave tube under a nitrogen atmosphere. 2M Na2CO3 (937 μL, 1874 μmol) was added via syringe, and the reaction mixture was stirred at 75° C. for 15 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude product as a yellow solid. The crude product was purified by silica flash chromatography (0-10% EtOAc/DCM) to give the desired compound as an off-white solid (190 mg). MS (m/e)=423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[NH:23][CH2:24][CH2:25][CH2:26]OS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[C:20]4[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=4[F:21])[O:14][CH2:13][CH:12]2[NH:23][CH2:24][CH2:25][CH2:26]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCNC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)ccc(F)c12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Methanesulfonic acid 3-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-ylamino]-propyl ester (0.28 g, 0.57 mmol) was dissolved in 25 ml of tetrahydrofuran then 1 M potassium tert-butoxide solution (2.40 ml, 2.40 mmol) was added. The reaction was stirred at room temperature for 3.5 h. The reaction was quenched with 50 ml of water and washed with 50 ml of ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The product was purified by prep TLC (EtOAc/Hex. 50/50). Yield: 140 mg, 60%. 1H NMR (CDCl3 400 MHz) δ 7.60 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.08 (td, J=9.5, 4.4 Hz, 1H), 6.47-6.40 (m, 1H), 5.21 (dd, J=11.8, 2.2 Hz, 1H), 4.33 (d, J=11.8 Hz, 1H), 3.70 (s, 1H), 3.00 (d, J=13.2 Hz, 1H), 2.76 (td, J=12.4 Hz, 2.9 Hz, 1H), 2.68 (d, J=13.2 Hz, 1H), 2.17 (tt, J=13.2, 2.9 Hz 1H), 1.66-1.44 (m, 2H), 1.21-1.07 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(#N)C.Cl.[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-2-fluorobenzoate (14.34 g, 33.4 mmol) were added acetonitrile (250 mL), water (160 mL) and then 3 M aqueous solutionueous HCl (55.6 mL, 167 mmol). The reaction mixture was stirred at 25° C. for 30 min which was monitored by LCMS. The mixture was basified with 2 M NaOH aqueous solution under stirring to pH 9. Light yellow solid was precipitated out. Acetonitrile was removed under reduced pressure at room temperature. The solid was filtered and washed with water (2×30 mL), and dried under high vacuum overnight to afford tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (12 g, 31.1 mmol, 93%) as a light yellow solid. LCMS (m/z): 386.1 (MH+), 0.89 min; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.05-7.89 (m, 2H) 7.73-7.51 (m, 2H), 5.14 (br. s., 2H), 3.30-3.08 (m, 1H), 2.64-2.48 (m, 2H), 2.40 (br. s., 2H), 2.30-2.17 (m, 2H), 2.12-1.99 (m, 2H), 1.96 (dt, J=4.99, 2.40 Hz, 4H), 1.61 (s, 9H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18].C([N-]C(C)C)(C)C.[Li+].Br[CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].Cl>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[C:15]([CH:16]([CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]1=[O:45])[C:17]([OH:19])=[O:18])([F:21])[F:20]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C(O)CC(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCN1C(=O)c2ccccc2C1=O)C(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 1) in tetrahydrofuran cooled to -78° C. is added dropwise two equivalents of lithium diisopropylamide. The solution is stirred for 30 minutes at -78° C. followed by the dropwise addition of a solution of N-(3-bromopropyl)phthalimide (1 equivalent) in tetrahydrofuran. The reaction mixture gradually warms to 0° C., at which time aqueous hydrochloric acid (HCl) (1 M) is added. The product is partitioned between ethyl acetate and water, the layers separated, and the organic portion is washed with brine, dried (MgSO4), and concentrated in vacuo. The crude product is purified using silica gel chromatography (elution with chloroform/methanol) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[N:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].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+]>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>[NH2:18][C:12]1[N:11]=[C:16]([NH:17][C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1cccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cccc(N)n2)c1=O
Temperature: 110 °C
Yield: 48.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (20 mL), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.06 g, 4.0 mmol), pyridine-2,6-diamine (872 mg, 8.0 mmol), Pd2(dba)3 (732 mg, 0.80 mmol), XantPhos (462.4 mg, 0.80 mmol), and cesium carbonate (2.6 g, 8.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford 221a (570 mg, 48%) as a white solid. MS-ESI: [M+H]+ 295.0
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: NC(=O)Cn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)Cn1ccc2c(N)cccc2c1=O
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)acetamide (0.98 g, 0.0040 mol), methanol (200 mL, 4 mol) and palladium, 10% weight on charcoal (0.1 g, 0.001 mol) was added and the reaction was stirred under hydrogen atmosphere (1 atm) for 1 hour. The reaction mixture was filtered and the solvent removed under reduced pressure and the residue purified by flash chromatography (40 g, 0-10% MeOH/DCM) to yield the product as an off white solid. MS m/z=218.3 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH2:11][O:12][S:30]([CH3:29])(=[O:32])=[O:31])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Ex-13A: To a solution of 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propan-1-ol (25.0 g, 74.3 mmol) and triethylamine (22.6 g, 223 mmol) in dichloromethane (150 mL) at 0° C. was added methanesulfonyl chloride (12.8 g, 111 mmol) and the resulting slurry was stirred at 0° C. for 15 min and allowed to warm to room temperature. The solution was stirred for an additional 3 h at room temperature and diluted with water (130 mL) and ethyl acetate (350 mL). The layers were separated and the aqueous was extracted with ethyl acetate (150 mL). The combined organic extracts were washed with a saturated sodium bicarbonate (200 mL), a 50% sodium chloride solution (2×200 mL), dried over sodium sulfate and concentrated to afford 29.5 g (97%) of methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 4.29 (d, 2H, J=5.7 Hz), 3.61–3.68 (m, 4H), 2.99 (s, 3H), 2.04–2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C17H40O5SSi2: 413.2213 (M+H)+; Found: 413.2226.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of methyl 2,4-dichloro-3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoate (2-16-1, 1.868 mmol, 1. eq.) were dissolved in 19 ml of dry THF and 2.2 ml of methanol. 4.67 ml of 2 M aqueous sodium hydroxide solution (9.34 mmol, 5 eq.) were added. The mixture was stirred for three hours at room temperature. The reaction mixture was partitioned between citric acid (pH 3) and ethyl acetate. This process dropped out a white precipitate which was filtered off and dried for three days to yield 992 mg (1.86 mmol, 99.8%) of the analytically pure target compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[N+:18]([O-:20])=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(C(=O)O)n[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)Cc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5-Isobutyl-1H-pyrazol-3-carboxylic acid (5 g, 29.7 mmol) was added portionwise to concentrated sulfuric acid (25 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 5.15 ml) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. The resultant white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid (6.4 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=2.71-2.76 (2H, d), 1.88-2.00 (1H, m), 0.80-0.87 (6H, d) ppm. LRMS (thermospray): m/z [M+NH4]+ 231, [M−H]+ 212. LRMS (electrospray): m/z [M−H]+ 212, [2M−H]+ 425. Anal. Found C, 42.54; H, 5.18; N, 18.63. C8H11N3O4. 0.7 mol H2O requires C, 42.55; H, 5.54; N, 18.61%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCC(C)C2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(C)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-1-yl)ethanamine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N+:4]([O-:16])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N+:4]([O-:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Yield: 66 %

Procedure:
A mixture of (7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal) (327 mg, 1.286 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (283 mg, 1.1 eq.) in chloroform:methanol (9:1 v:v) (5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (481 mg, 2 eq.). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (5 ml). The reaction was then diluted with DCM (80 mL) and the organic phase was separated using a hydrophobic frit. The aqueous phase was extracted with DCM (2×50 mL) The combined organic extracts were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% (2M NH3 in MeOH)/DCM gradient to provide the desired compound (345 mg, 66%) as a tan foam.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(N2C(S([CH2:25][C@@H:26]3[NH:30][C:29](=[O:31])[CH2:28][CH2:27]3)(=O)=O)=NN=N2)C=CC=CC=1.[CH:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:43]([C:45]3[CH:50]=[CH:49][C:48]([S:51][CH3:52])=[CH:47][CH:46]=3)=O)=[N:39][C:40]=2[O:41][CH3:42])[CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1>[CH:32]1([C:35]2[CH:36]=[CH:37][C:38](/[C:43](/[C:45]3[CH:46]=[CH:47][C:48]([S:51][CH3:52])=[CH:49][CH:50]=3)=[CH:25]/[C@@H:26]3[NH:30][C:29](=[O:31])[CH2:28][CH2:27]3)=[N:39][C:40]=2[O:41][CH3:42])[CH2:34][CH2:33]1
Reactant: O=C1CC[C@H](CS(=O)(=O)c2nnnn2-c2ccccc2)N1
Reactant: COc1nc(C(=O)c2ccc(SC)cc2)ccc1C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(SC)cc2)ccc1C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
A 1 M solution of lithiumhexamethyldisilazide in tetrahydrofuran (6.68 mL) was added to a solution of (5R)-5-{[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]methyl}pyrrolidin-2-one obtained in Reference Example 3-2 (1.07 g) in tetrahydrofuran (10 mL) at −78° C. in a nitrogen gas stream, and the mixture was stirred at −78° C. for 30 minutes. A solution of (5-cyclopropyl-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in Reference Example 1-51 (500 mg) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at −78° C. for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=1:2) to give (5R)-5-{(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(methylsulfanyl)phenyl]ethenyl}pyrrolidin-2-one as a colorless oil (50.6 mg, 8%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20](OC)=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([CH2:20][OH:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@@H]2CNC[C@H]2CO)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (500 mg, 1.57 mmol) in 7 mL of THF at 0° C. was added LiAlH4 (60 mg, 1.57 mmol). The resulting mixture was stirred for 15 min at 0° C. and then allowed to stir at room temperature for 20 min. The mixture was then successively treated dropwise with H2O (0.06 mL), 15% NaOH (0.06 mL), and H2O (0.18 mL). The resulting suspension was then stirred for 1 hr, filtered through Celite, and concentrated under reduced pressure to an oil. Silica gel chromatography (1:1 CHCl3 :methanol) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(hydroxymethyl)pyrrolidine as a pale yellow oil (329 mg, 72%). 1H-NMR (300 MHz): δ 2.35 (m, 1), 2.90-3.08 (m, 3), 3.30-3.76 (m, 4), 3.82 (s, 3).