Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCCCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (10 g) in ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon (5 g, 50% wet) at ordinary temperature under atmospheric pressure. After the absorption of hydrogen has ceased, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield ethyl 6-(4-piperidyl)hexanoate. This ester is dissolved in a mixture of water (100 ml), ethyl acetate (200 ml) and sodium bicarbonate (10 g). Benzyloxycarbonyl chloride (7.2 ml) is added dropwise at room temperature and the resulting mixture is stirred overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluent to give ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.7 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.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>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:10]3[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=3[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CC(=O)c2c(-c3ccc(Cl)cc3)cn(-c3ccccn3)c2C1
Temperature: 100 °C
Yield: 10.7 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (50 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) in ethylene glycol dimethyl ether (2 mL) at 45° C. was degassed with nitrogen for 30 min. A degassed solution of Cs2CO3 (104 mg, 0.16 mmol) in water (1 mL) was added followed by 4-chlorophenylboronic acid (25 mg, 0. 16 mmol). The solution was heated at 100° C. for 18 h then filtered through celite. The filtrate was partitioned between DCM and water. The organic phase was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with isohexane: EtOAc (3:1) to give the title compound (6 mg, 11%) as a colourless solid. 1H NMR (360 MHz, d6-DMSO) δ 1.05 (6H,s), 2.37 (2H,s), 3.01 (2H,s), 7.38 (2H,d, J=8.5 Hz), 7.46-7.50 (1H,m), 7.56 (1H,s), 7.68-7.74 (3H,m), 8.05-8.09 (1H,m), 8.59-8.63 (1H,m). MS (ES+) 351/353 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CN(C)C=O.[H-].[Na+].Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Brc1ccsc1
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.4 G. of 2-amino-4-mercapto-1-nitrobenzene is dissolved in 40 ml. of dimethylformamide under nitrogen and treated at 20°-25° C with 0.5 g. of 100% sodium hydride. After 1 hour, 2.8 g. of cuprous oxide and 4.0 g. of 3-bromothiophene are added. The mixture is heated in an oil bath for 5 hours at 140°-150° C, cooled, diluted with water, and extracted with chloroform. The chloroform solution is passed through a silica gel column and the eluate evaporated to yield 2-amino-4-(3-thienylthio)-1-nitrobenzene.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][O:38][CH3:39])[C@@H:21]1[OH:40])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:59](Cl)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[C:59]([NH:30][C:29]1[C:28]2[N:27]=[CH:26][N:25]([C:34]=2[N:33]=[CH:32][N:31]=1)[C@@H:23]1[O:24][C@H:20]([CH2:19][OH:18])[C@@H:21]([OH:40])[C@H:22]1[O:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21

Procedure:
5′-O-t-Butyldiphenylsilyl-2′-O-(methoxyethyl)adenosine is treated with TBAF as per the procedure of Example 8 and subsequently treated with benzoyl chloride as per the procedure of Example 4 to give the title compound.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@H:34]([O:35]C(=O)C)[C@H:29]([O:30]C(=O)C)[C@H:24]2[O:25]C(=O)C)[C@@H:15]([CH2:46][O:47]C(=O)C)[O:14][C@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[C@@H:23]1([O:22][C@@H:16]2[C@@H:15]([CH2:46][OH:47])[O:14][C@@H:9]([O:10][CH2:11][CH2:12][Br:13])[C@H:8]([OH:7])[C@H:17]2[OH:18])[O:40][C@H:39]([CH2:41][OH:42])[C@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OCCBr)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A solution of NaOMe (0.1 M, 0.6 mL) was added to a solution of 4k (See FIG. 7) (877 mg, 1.18 mmol) in MeOH (6 mL) under N2. After 3 hours, the reaction solution was passed through a Dowex 50W(H+) plug (4×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl 4-O-β-D-galactopyranosyl-β-D-glucopyranoside (4f) (See FIG. 7) (476 mg, 90%) as a white foam which was used directly in the next step. NaSSO2CH3 (185 mg, 1.38 mmol) was added to a solution of 4f (See FIG. 7) (476 mg, 1.06 mmol) in DMF (24 mL) under N2 and warmed to 50° C. After 21 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (CHCl3:MeOH:AcOH:H2O, 60:30:3:5) to give 1f (See FIG. 7) (346 mg, 68%) as a hygroscopic foam; [α]28D=+1.5 (c 1.66, H2O); IR (KBr) 3416 cm−1 (br, OH), 1311, 1131 cm−1 (S—SO2), 1H NMR (400 MHz, D2O, COSY) δ 3.10-3.13 (m, 1H, H-2), 3.30 (t, J 6.0 Hz, 2H —CH2S—), 3.31 (dd, J1′,2 7.8 Hz, J2′,3 10.3 Hz, 1H, H-2′), 3.34 (s, 3H, CH3SO2—), 3.38-3.54(m, 5H), 3.44 (dd, J2′,3′ 10.3 Hz, J3′,4′ 3.3 Hz, 1H, H-3′), 3.57 (dd, J 8.4 Hz, J 11.4 Hz, 1H),3.59 (dd, J 4.9 Hz, J 7.3 Hz, 1H), 3.70 (br d, J3′,4′ 3.3 Hz, 1H, H-4′), 3.77 (dd, J 1.0 Hz, J 11.5 Hz, 1H), 3.79-3.83 (m, 1H, —OCHH′—), 3.97-4.02 (m, 1H, —OCHH′—), 4.22 (d, J1,2 7.8 Hz, 1H, H-1′), 4.33 (d, J1,2 7.8 Hz, 1H, H-1); 13C NMR (125 MHz, D2O) δ 36.7 (—CH2S—), 50.8 (CH3SO2—), 61.0, 62.1, 69.4, 69.6, 71.9, 73.5, 73.7, 75.3, 75.9, 76.4, 79.3 (—OCH2—, C-2, C-3, C-4, C-5, C-6, C-2′, C-3′, C-4′, C-5′, C-6′), 103.3, 103.9 (C-1, C-1′); HRMS m/z (FAB+): Found 503.0886 (M+Na+); C15H28O3S2Na requires 503.0869.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[O:24][CH2:25][C:26]1[N:27]([CH3:31])[N:28]=[CH:29][N:30]=1>>[CH2:12]([N:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[C:16]([O:24][CH2:25][C:26]4[N:27]([CH3:31])[N:28]=[CH:29][N:30]=4)[CH:17]=3)=[CH:3][N:4]=[C:5]2[C:10]1=[O:11])[CH3:13]
Reactant: CCn1ccn2c(Br)cnc2c1=O
Reactant: Cn1ncnc1COc1cc(B(O)O)ccc1F
Product: CCn1ccn2c(-c3ccc(F)c(OCc4ncnn4C)c3)cnc2c1=O
Yield: 23 %

Procedure:
3-Bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one and 4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)benzeneboronic acid were coupled to give the title compound as a white solid (43 mg, 23%): δH (400 MHz, d6-DMSO) 1.26 (3H, t, J 7), 3.94 (3H, s), 3.96 (2H, s), 5.52 (2H, s), 7.22-7.26 (2H, m), 7.44 (1H, dd, J 11 and 8), 7.65 (1H, d, J 6), 7.64 (1H, dd, J 8 and 2), 7.66 (1H, s), 7.98 (1H, s); m/z (ES+) 369 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:47])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Product: Cc1ccc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)cn1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3 and N-methoxy-N, 6-dimethylnicotinamide.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccn(-c2nccc3ccccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2nccc3ccccc23)c1
Yield: 107.7 %

Procedure:
0.237 g (5.65 mmol) of lithium hydroxide monohydrate is added at 20° C. to 0.57 g (2.26 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-pyrrole dissolved in 15 mL of tetrahydrofuran and 15 mL of water. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 5 mL of water and then triturated with 5.65 mL of N hydrochloric acid for 1 hour. The aqueous phase is filtered and the solid residue is washed with twice 5 mL of water and then air-dried to give 0.58 g of 3-carboxy-1-(isoquinol-1-yl)-1H-pyrrole in the form of a white solid. Mass spectrum (EI): m/e 238 (M+.), m/e 193.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]#[N:13])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C(=O)([O-])O.[Na+]>C(O)C>[OH:16][N:15]=[C:12]([NH2:13])[C:9]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[CH:10]=1
Reactant: NO
Reactant: COc1cccc2oc(C#N)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2oc(C(N)=NO)cc12
Yield: 102 %

Procedure:
To a solution (40 ml) of 4-methoxybenzo(b)furan-2-carbonitrile (2.8 g) in ethanol were added hydroxylamine hydrochloride (1.2 g) and sodium hydrogencarbonate (3.0 g). The mixture was refluxed under heating for 1.5 hr. The inorganic material was filtered off and the reaction mixture was concentrated under reduced pressure to give the title compound (3.4 g) as brown crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH2:10][CH2:11][F:12]>CN(C=O)C>[F:12][CH2:11][CH2:10][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
A solution of 4-iodo-1H-pyrazole (1.10 g, 5.7 mmol) in anhydrous DMF (25 mL) is treated with NaH (0.23 g, 60% in mineral oil, 5.7 mmol). After stirring for 20 minutes at room temperature, the reaction mixture is treated with 1-iodo-2-fluoroethane (1.0 g, 5.7 mmol) and stirred over night at room temperature. The reaction is quenched with H2O and diluted with EtOAc. The two layers are separated and the aqueous is extracted with EtOAc. The combined organic extracts are washed with H2O, brine, dried (Na2SO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:15/85) to afford the title compound (1.08 g, 79%) as an oil. MS (+) ES 240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([CH3:12])=[C:4]([CH:3]=1)[O:13][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 55 °C
Yield: 80 %

Procedure:
A mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (500 mg, 2.492 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (752 mg, 3.74 mmol) and triphenylphosphine (1307 mg, 4.98 mmol), stirred in THF (10 mL) until completely dissolved, then DIAD (1.530 mL, 7.48 mmol) was slowly added dropwise via syringe over 5 minutes. The reaction heated at 55° C. for 4 h under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The orange oil residue was purified by flash column chromatography (30% EtOAc/hexanes). The desired fractions were combined, concentrated, then triturated with EtOAc to give tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (0.765 g, 1.99 mmol, 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.26 (m, 1 H) 1.41 (s, 9 H) 1.49-1.63 (m, 2 H) 1.79-1.92 (m, 2 H) 2.28 (s, 3 H) 3.15-3.30 (m, 2 H) 3.51-3.66 (m, 2 H) 3.83 (s, 3 H) 4.63-4.81 (m, 1 H) 7.31 (d, J=2.02 Hz, 1 H) 7.37 (d, J=2.02 Hz, 1 H) MS (ES) [M+H]+ 384.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([OH:18])=O)[NH:7]2.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:16]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)=[O:18])[CH2:21][CH2:20]1)=[O:18])[NH:7]2
Reactant: COc1cc2[nH]c(C(=O)O)cc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2[nH]c(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5[nH]4)CC3)cc2c(OC)c1OC

Procedure:
4,5,6-Trimethoxyindole-2-carboxylic acid (290 mg) and homopiperazine (58 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2].C(=O)([O-])[O-].[NH4+:21].[NH4+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH2:21])[C:6]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 75 %

Procedure:
4.64 g (20 mmol) of 3,5-difluoro-2-nitro-benzoic acid ethyl ester in DMF and 2.1 g (22 mmol) of ammonium carbonate was heated at 60° C. for 6 h. The reaction mixture was treated with water. The resulting solid was collected by filtration and washed with water to produce 3.4 g (15.0 mmol, 75%) of 3-amino-5-fluoro-2-nitro-benzoic acid ethyl ester. LCMS: 229 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccc([N+](=O)[O-])cc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
tert-Butyl 4-((2-fluoro-4-nitrophenyl)(methyl)amino)piperidine-1-carboxylate (2.83 mmol, 1 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the intermediate N-(2-fluoro-4-nitrophenyl)-N-methylpiperidin-4-amine (600 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([N:35]([CH3:37])[CH3:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([N:35]([CH3:36])[CH3:37])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-dimethylamino-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (139 mg, 66%). LCMS (m/e) 524 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.15 (s, 1H), 8.34 (d, 1H, J=9.2 Hz), 8.03 (s, 1H), 7.39 (s, 1H), 7.21 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.91-6.80 (m, 2H), 6.78 (s, 1H), 6.21-6.12 (m, 1H), 3.55 (t, 2H, J=5.5 Hz), 3.38 (s, 3H), 3.02 (d, 3H, J=4.9 Hz), 3.00 (s, 6H), 2.96-2.85 (m, 4H), 2.80-2.68 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Intermediate 88 (13.4 g, 38.42 mmol) was dissolved in 200 ml DCM and N-methyl piperazine (8.52 ml, 76.83 mmol) was added followed by DIPEA (26.77 ml, 153.67 mmol) and TBTU (18.5 g, 57.63 mmol). After 16 h stirring at RT, the solution was evaporated to dryness and purified by silica gel chromatography. Yield: 13.05 g, 79%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([CH3:27])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[K+].O>CO>[CH3:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]([CH3:27])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2ccccc2)c(C)cc1OCCCC(C)(C)C(=O)O
Yield: 921.8 %

Procedure:
A solution of 7.8 g (2.1 mmol) of 5-[2,5-dimethyl-4-(phenylmethoxy)phenoxy]-2,2-dimethylpentanoic acid, methyl ester (Example 13), 3.5 g (3×21 mmol) of potassium hydroxide, 10 mL of water and 100 mL of methanol is stirred at reflux for 12 hours. The methanol is removed and the residual aqueous solution is diluted with 150 mL of water then back-extracted with diethyl ether. The aqueous layer is acidified with 15 mL of 6N hydrochloric acid solution and the product is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving 6.9 g of a dark brown crystalline residue. Recrystallization from 30 mL of acetonitrile in the presence of charcoal affords 4.0 g of the title compound as tan, dense crystals; mp 104°-106° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][C:18]1[N:2]2[N:1]=[C:5]3[N:6]=[CH:7][CH:8]=[CH:9][C:4]3=[C:3]2[N:10]=[C:14]([C:13]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=2[Cl:11])[C:15]=1[C:16]#[N:17]
Reactant: Nc1n[nH]c2ncccc12
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)nc2c3cccnc3nn2c1N

Procedure:
Commercial 1H-pyrazolo[3,4-b]pyridin-3-amine and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted according to the procedure of Example 1, Step A, and the crude product was purified by preparative HPLC (C18 reverse phase column, gradient elution with 10-80% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a yellow solid. LC-MS 355 (M+1).
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH3:23])[C:19]([OH:22])=[CH:20][CH:21]=1>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: Cc1cc(N)ccc1O
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2)c1C

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol) and 4-amino-o-cresol (250 mg, 2.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 286 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:6]=1.[CH3:16]COCC>CO>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][CH:4]=2)[CH:8]=1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)co1
Reactant: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(-c2coc(C)n2)c1

Procedure:
A solution of 3-(2-methyl-oxazol-4-yl)-benzoic acid (1.42 g) in a mixture of MeOH (30 mL) and 4NHCl/Et2O (6 mL) was heated to 40° C. for 4 h. The solution was evaporated in vacuum and the residual oil was stirred with H2O (30 mL), the pH of the mixture being set to about 6 by the addition of sat. NaHCO3 solution. The precipitate was isolated by filtration to give 3-(2-methyl-oxazol-4-yl)-benzoic acid methyl ester (1.18 g) as light-brown solid,