Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1.Cl[N-:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Na+].[Br-].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.O>C1COCC1>[CH3:1][C:2]12[N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:10])=[O:11])[CH:6]1[CH2:5][CH2:4][CH2:3]2
Reactant: CC1=CCCC1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C3CCCC32C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-methylcyclopent-1-ene (CAS number 693-89-0; 50.0 g, 609.75 mmol) iii and sodium chloro(4-methylbenzenesulfonyl)azanide (CAS number 127-65-1; 192 g, 680.85 mmol) in THF (2500 ml) was added trimethylphenylammonium tribromide (13.3 g, 61.57 mmol). The reaction was stirred vigorously at 25° C. for 12 hours. The reaction mixture was poured into water (1500 ml) and the organics were extracted with ethyl acetate (3×1000 ml). The combined organics were washed with water (500 ml), brine (500 ml), dried over sodium sulfate and concentrated in vacuo. This was then purified by column chromatography (silica, 0-2.5% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NN1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NN3CCOCC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:3][C:2]([CH3:15])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-4-hydroxymethylpiperidine (20.7 g, 96.1 mmol) in dichloromethane (200 mL) was cooled to 0° C. and treated with pyridinium chlorochromate (31.1 g, 144.2 mmol). The suspension was allowed to warm to room temperature and stirred for 3 h. The mixture was then diluted with diethyl ether (250 mL), filtered through a pad of silica gel (50 mm×10 cm), and the solids washed with 4:1 hexane/acetone (3×250 mL). The filtrate was evaporated to leave a pale green oil. This oil was dissolved in ether (200 mL) and washed sequentially with 1N hydrochloric acid (2×100 mL), 1N aqueous sodium hydroxide (100 mL) and brine (100 mL). The aqueous washes were extracted with fresh diethyl ether (2×150 mL). The combined organic extract was dried over sodium sulfate, filtered and evaporated to afford the crude aldehyde (16.3 g, 76.42 mmol), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C@@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(Nc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccccc1

Procedure:
2-Chloro-6-[(α-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R)-α-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CC(C)=O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([O:21][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (406.8 mg, 0.8 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (126.8 mg, 0.88 mmol) and K2CO3 (10 equivalents) in 4A-molecular-sieve-dried acetone (40 mL) was magnetically stirred and heated to reflux under Ar. After the reaction was complete, it was cooled to room temperature. The inorganic salt was removed by filtration and washed with a small quantity of acetone. The combined acetone solution was concentrated on a rotavapor and dried under vacuum pump. The crude product was purified by flash chromatography. The resultant product 2-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine was dissolved in CH2Cl2 (40 mL), and trifluoroacetic acid (˜40 equivalents) was added. The reaction was stirred at room temperature overnight, concentrated, and dried under vacuum pump. The crude compound was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO3 solution, dried under Na2SO4, concentrated, and flash chromatography to provide the desired product 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (195.9 mg, 65%). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 2 H), 8.56 (s, 1 H), 7.87 (dd, J=9.2, 2.4 Hz, 2 H), 7.44 (dd, J=8.4, 4.4 Hz, 2 H), 7.20-7.11 (m, 2 H), 4.30 (t, J=5.8 Hz, 2 H), 2.72 (t, J=5.8 Hz, 2 H), 2.32 (s, 6 H); MS (ESI) m/z 378.1 (M−H)−; MS (ESI) m/z 380.1 (M+H)+
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](SCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.5 %

Procedure:
Under the same conditions as in Example 9, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-methyl-4-triethylsilyloxypentylthio)pregna-5,7,16-triene (55.7 mg, 0.0825 mmol), tetrahydrofuran (2 ml) and IM tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a colorless oil (34.1 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[CH2:19][O:20][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2occc2CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccoc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48.6 %

Procedure:
4-(3-Hydroxymethylfuran-2-yl)piperidine-1-carboxylic acid t-butyl ester (0.3 g, 1.1 mmol, 1.0 eq.) was dissolved in DCM (5.7 mL). The mixture was cooled to 0° C. and DABCO (132 mg, 1.2 mmol, 1.1 eq.) was added, followed by TsCl (224 mg, 1.2 mmol, 1.1 eq.). The mixture was stirred at 0° C. for 90 minutes, then diluted with EtOAc (500 mL) and washed with water (2×250 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (233 mg), which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(CCc2ccccc2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(CCc2ccccc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.81 g) and 2-methylthio-5-phenylethylpyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 26 hr. After stripping, the residue was crystallised twice from ethanol and finally from acetone to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-phenylethylpyrimid-4-one, 0.68 g (46%) mp 134°-136° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7].B(Cl)(Cl)Cl>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7]
Reactant: COc1cc(C)cc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1cc(O)cc(C#N)c1
Temperature: -78 °C
Yield: 90391.6 %

Procedure:
In a 100 mL round bottom flask, 3-methoxy-5-methyl-benzonitrile (500 mg, 3.39 mmol) was dissolved in 15 mL dry DCM, and tetrabutylammonium iodide (1.38 g, 3.73 mmol, 3.5 eq.) was added. The flask was cooled to −78° C. BCl3 (1 M in DCM, 11.87 mL, 33.16 mmol) was added to the reaction dropwise. The reaction mixture was stirred at −78° C. and warmed up to room temperature overnight. The reaction mixture was quenched with ice and neutralized with saturated NaHCO3 solution. DCM was added to extract the reaction mixture. The organic layer was concentrated down and purified (silica gel, 0-10% MeOH/DCM) to give a light yellow solid (408 g, 90%). LC-MS shows 132.0 (M−1). 1H NMR (300 MHz, CDCl3): δ 7.20 (s, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: C(C1C=CC=CC=1[N:9]1[C:13]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]1)#N.FC(F)(F)C(=O)CC(C1OC=CC=1)=[O:28].O.NN>C(O)C>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH:13]1[NH:9][NH:10][C:11]([C:19]([F:22])([F:21])[F:20])([OH:28])[CH2:12]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Agent: NN
Solvent: O
Solvent: CCO
Product: OC1(C(F)(F)F)CC(c2ccco2)NN1

Procedure:
Part B: 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole: To a solution of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2.06 g, 10 mmol) in ethanol (mL) was added hydrazine monohydrate (0.46 g, 10 mmol). The resulting mixture was refluxed for 16 hours and dried under vacuum to give 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline in almost quantitative yield. 1H NMR (CDCl3) δ7.48 (d, J=1.9 Hz, 1H), 6.63 (d, J=3.7 Hz, 1H), 6.47 (dd, J=3.7 Hz, J=1.9 Hz, 1H), 6.16 (s, 1H), 3.48 (d, J=17.9 Hz, 1H), 3.18 (d, J=17.9 Hz, 1H); 19F NMR (CDCl3): δ−81.47; ESMS(+): 221 (M+H, 100).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].Br[C:9]1[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=1.[C:21]([CH2:23][C:24]1([N:40]2[CH:44]=[C:43](B3OC(C)(C)C(C)(C)O3)[C:42]([CH3:54])=[N:41]2)[CH2:27][N:26]([C:28]2[N:29]=[CH:30][C:31]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[N:32][CH:33]=2)[CH2:25]1)#[N:22]>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:21]([CH2:23][C:24]1([N:40]2[CH:44]=[C:43]([C:9]3[CH:10]=[N:11][NH:12][CH:13]=3)[C:42]([CH3:54])=[N:41]2)[CH2:25][N:26]([C:28]2[N:29]=[CH:30][C:31]([C:34]([NH:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[N:32][CH:33]=2)[CH2:27]1)#[N:22]
Reactant: CC(C)(C)OC(=O)n1cc(Br)cn1
Reactant: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1-c1cn[nH]c1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from tert-butyl 4-bromo-1H-pyrazole-1-carboxylate and 5-{3-(cyanomethyl)-3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide. LCMS calculated for C20H24N9O (M+1)+: m/z=406.2. Found: 406.1.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2[N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:28])=[O:27])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[OH:35][NH2:36]>C(O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15]1[CH:16]=[C:11]([N:8]2[C:7]3[CH:32]=[CH:33][C:4](/[C:1](=[N:36]\[OH:35])/[CH3:2])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:12]=[C:13]([NH:25][S:26]([CH:29]2[CH2:31][CH2:30]2)(=[O:27])=[O:28])[CH:14]=1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cc(NS(=O)(=O)C2CC2)cc(-c2ccc(F)cc2F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C/C(=N/O)c1ccc2c(c1)ncn2-c1cc(NS(=O)(=O)C2CC2)cc(-c2ccc(F)cc2F)c1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of N-(5-(5-acetyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (110 mg, 0.235 mmol) in ethanol was added hydroxyl amine hydrochloride (24.7 mg, 0.353 mmol) and the mixture was heated at 80° C. for 2 h. The mixture was concentrated under vacuum and washed with ether to afford the product in 49% yield (55 mg). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.03 (s, 1H), 7.82-7.70 (m, 3H), 7.60-7.58 (d, 2H), 7.52 (s, 1H), 7.46-7.40 (m, 1H), 7.27-7.24 (m, 1H), 2.86-2.83 (m, 1H), 2.25 (s, 3H), 1.01-1.00 (m, 4H); LC-MS (ESI): Calculated mass: 482.5; Observed mass: 483.1 [M+H]+ (rt: 1.475 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[CH3:19][O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0 M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained (~30 ml). After vigorous gas evolution had ceased, cooling was removed and the reaction mixture stirred for 1 h at room temperature. The mixture was then treated dropwise with glacial acetic acid until all yellow color had dissipated. It was then stirred 15 min. and concentrated in vacuo to a pale yellow oil. This material was purified by column chromatography on silica with 20% EtOAc/hexane as eluent. The appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]S(C)=O.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:18]([CH3:35])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: COC(=O)C(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate (250 mg, 0.58 mmol) was dissolved in THF (5 mL) and 60% oil dispersion NaH was added (24 mg, 0.6 mmol). After 1 h, added DMSO (2 mL) followed by MeI (5.8 mmol). After 72 h, the reaction was quenched with MeOH then poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 215 mg (83% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate. MS found: (M+H)+=447.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.89 min, m/z=459.1-460.1 [M+H]+, m/z=458.2-457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 1H) 1.79-1.88 (m, 1H) 2.17-2.26 (m, 1H) 2.93-3.00 (m, 1H) 3.10-3.37 (m, 5H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.48 (dd, J=7.82, 4.89 Hz, 1H) 7.79-7.83 (m, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.57 (dd, J=4.89, 1.47 Hz, 1H) 8.64 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])=[CH:11][N:12]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([C:10]2[O:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[N:12][CH:11]=2)[CH:18]=1
Reactant: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Dissolve 5-[5-(5-chloro-2-hydroxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.26 g, 10.52 mmol) in 50 mL of dioxane and add a solution of LiOH (1.2671 g, 50.91 mmol) in 25 mL of water to it. Allow the reaction to stir at ambient temperature for 18 hours. Acidify the reaction with 5N HCl and concentrate the reaction mixture in vacuo to remove the dioxane. Extract the aqueous residue with EtOAc (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Triturate the residue in cold EtOAc. Collect the product via filtration to afford 1.8837 g of the titled product (60%): mass spectrum: m/z=296.1 (M+H).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([C:14]2[C:15]([C:20]([O:22]CC)=[O:21])=[N:16][O:17][C:18]=2[CH3:19])=[O:13])[CH:5]=1.Cl>O.CO>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([C:14]2[C:15]([C:20]([OH:22])=[O:21])=[N:16][O:17][C:18]=2[CH3:19])=[O:13])[CH:5]=1
Reactant: CCOC(=O)c1noc(C)c1C(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)nc(NC(=O)c2c(C(=O)O)noc2C)c1
Reaction time: 1 h

Procedure:
A solution of 0.27 g (11.5 mmol) of lithium hydroxide in 3 ml of water and 15 ml of methanol is cooled to -15° C. 1.5 g (5.19 mmol) of the product obtained in Example 96 are added slowly thereto with stirring. The stirring is continued for one hour. The mixture is acidified with dilute hydrochloric acid solution. The temperature is allowed to rise to 0° C. and stirring is continued for 30 min. The mixture is filtered and the title product is collected in the form of a white powder which is washed with t-butyl methyl ether.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:22])[CH3:21]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N(C)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), acetyl chloride (0.18 g, 2.22 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 86%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1cc(Nc2cncc(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method B with 212 mg (0.72 mmol) 2a and 135 mg (0.86 mmol) 4-chloro-phenylboronic acid, 190 mg pure title compound (59.7%) were obtained after purification by preparative HPLC (eluent:AcOEt). Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.63 (s, 3H, CH3O(4′)), 3.82 (s, 6H, CH3O(3′+5′)), 6.88 (d, 2H, Harom(2′+6′), J=8.52), 7.24 (s, 2H, Harom(2+6)), 7.97 (d, 1H, Harom (3′+5′)), 8.05 (s, 1H, HP5), 8.40 (s, 1H, HP3), 9.46 (s, 1H, OH), 9.82 (s, 1H, NHamine); MS, (C19H18ClN3O4), m/z: 354.3 [M++1, 100].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCCCC1

Procedure:
The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.