Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[C:11]([OH:22])[CH:12]=[CH:13][C:14]=3[NH:18]C(=O)[O-])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:18][C:14]1[CH:13]=[CH:12][C:11]([OH:22])=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: O=C([O-])Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(2,6-dioxopiperidin-3-yl)-7-hydroxy-1,3-dioxoisoindolin-4-ylcarbamate C3-4 (6.73 g, 17.2 mmol) in DCM (200 mL) was added TFA (20 mL) slowly. The mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction. The mixture was extracted with EA (100 mL×3). The combined organic layers were collected and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, DCM:MeOH:PE) to give 4-amino-2-(2,6-dioxopiperidin-3-yl)-7-hydroxyisoindoline-1,3-dione 3 as a yellow solid (4.05 g, yield: 81%). 1H NMR (DMSOd6, 400 MHz) δ: 1.95-1.98 (m, 1H), 2.52-2.58 (m, 2H), 2.83-2.92 (m, 1H), 4.98 (dd, J=12.6, 5.4 Hz, 1H), 6.06 (s, 2H), 6.95 (d, J=8.8 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 10.17 (s, 1H), 11.05 (s, 1H); MS (ESI+): m/z 290 (M+1); Elem. Anal. Calcd. for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found C, 53.96; H, 3.74; N, 14.45.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])[CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([B:22]([OH:27])[OH:23])=[CH:8][C:9]=1[O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18]
Reactant: FC(F)C(F)(F)COc1cc(Br)ccc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)c(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.99 mL) was added to a solution of 4-bromo-1-chloro-2-(2,2,3,3-tetrafluoro-propoxy)-benzene (434 mg, 1.35 mmol) and triisopropyl borate (382 mg, 2.03 mmol) in anhydrous tetrahydrofuran (2.0 mL) at −78° C., and the mixture was stirred for 10 minutes. The reaction mixture was warmed to room temperature and stirred for 30 minutes. 6 N aqueous hydrochloric acid was then added to the reaction mixture, and the reaction was terminated, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with a mixed solution of dichloromethane and hexane to give 4-chloro-3-(2,2,3,3-tetrafluoro-propoxy)-phenylboronic acid as a white solid (246 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccccc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (1.0 g, 3.98 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) were added a few drops of DMF. The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then aniline (0.36 mL, 3.98 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired (6,7-dimethoxy-5-nitro-quinazolin-4-yl)-phenyl-amine as a yellow solid. (Yield 0.9 g, 70%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CO>C(Cl)Cl.C(OCC)C>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: NC(=O)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CC(N)=O)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with bromo acetamide. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) then trituration in diethyl ether to give 192 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.28 Hz), 7.84 (1H, s), 7.61 (1H, s), 7.07 (1H, dd, J=8.32, 1.84 Hz), 6.95 (1H, d, J=1.79 Hz), 6.89 (1H, s), 5.99-5.90 (1H, m), 5.44 (1H, s), 4.48-4.45 (2H, m), 4.43-4.40 (2H, m), 3.86-3.78 (2H, m), 3.73-3.63 (1H, m), 3.38-3.31 (2H, m), 3.20 (2H, s), 1.56 (6H, d, J=6.64 Hz). LCMS: RT=5.45 min, M+H+=408
Reaction SMILES: [C]=O.FC(F)(F)S(O[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[S:18][CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:21]=3)=[CH:14][C:13]=2[CH:26]=1)(=O)=O.C1(OP(CCCP([O:57][C:58]2C=CC=CC=2)(OC2C=CC=CC=2)=O)(OC2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.CN(C)[CH:73]=[O:74]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:22]([C:20]1[N:21]=[C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:73]([O:57][CH3:58])=[O:74])=[CH:26][C:13]=3[CH:14]=2)[S:18][CH:19]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=P(CCCP(=O)(Oc1ccccc1)Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1csc(-c2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3o2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Carbon monoxide was introduced by bubbling to a mixture of 2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl trifluoromethanesulfonate (6.0 g), palladium acetate (99.7 mg), 1,3-bis(diphenylphosphono)propane (183 mg, 0.44 mmol) and triethylamine (4.13 ml) in a mixed solvent of methanol (15 ml) and N,N-dimethylformamide (30 ml) at room temperature for 1 hour. The mixture was warmed to 70° C. and stirred under carbon monoxide balloon for 3 hours. The resulting mixture was filtered through celite and the residue was washed with ethyl acetate. The filtrate and washing solution was combined and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-n-hexane as eluent to give methyl 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carboxylate (3.92 g) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 90.4 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 4-bromomethyl-benzonitrile (345 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 4-(3-nitro-pyrazol-1-ylmethyl)-benzonitrile (365 mg, 90%) as a white solid. The crude material was used in the following step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.BrC1C=C([CH2:40][S:41](CC2C=CC=C(Br)C=2)(=[O:43])=[O:42])C=CC=1.[CH3:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([C:54]4[CH:53]=[CH:52][CH:57]=[C:56]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:55]=4)[N:17]=[CH:16]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)cc3)n2)cn1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(C)(=O)=O)c3)c2)n1
Reaction time: 1 h
Yield: 92 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.3) (0.47 g, 0.84 mmol), commercially available 3-bromo-phenylmethyl sulfone (0.22 g, 0.92 mmol), tetrakis(triphenyl-phosphine)palladium (0.058 g, 0.05 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h. Hexane (10 mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound (0.33 g, 92%) as an off-white solid. MS (ISN) 423.3 [(M−H)−]; mp 233° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[CH3:38]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:27][C:26]=3[CH3:38])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC2CCC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O.O>ClCCl>[Br:26][C:10]1[N:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: CC(=O)N1CCC(N2CCN(c3ncc4c(C)nccn34)CC2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(N2CCN(c3nc(Br)c4c(C)nccn34)CC2)CC1
Yield: 74.5 %

Procedure:
To 1-(4-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (0.102 mmol, 35 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.102 mmol, 18.19 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (32 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CCOCC>[CH:13]1([NH:16][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: NC1CC1
Solvent: CCOCC
Product: COC(=O)C=C(CC(=O)OC)NC1CC1
Yield: 83.5 %

Procedure:
This compound was prepared as described in Step A of Example 94: 190.6 g (1.09 mol) of dimethyl acetonedicarboxylate and 75 g (1.3 mol) of cyclopropyl-amine in 200 ml of ether were reacted affording 194 g of clear oil. Trituration with petroleum ether gave 171.5 g (74%) of the enamine diester as a white solid: mp 64°-70° C. Crystallization from cyclohexane afforded an analytical sample; mp 73°-75° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34]>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>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)=[C:3]3[CH:26]=[CH:25][CH:24]=[N:23][C:4]=23)[C@H:9]([CH3:22])[CH2:10]1)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
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+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C#N)cc2)c2cccnc12
Yield: 21.6 %

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (360 mg, 979 mmol), 2 M sodium carbonate (979 μl, 196 mmol), 4-cyanophenylboronic acid (216 mg, 1.47 mmol), and tetrakis(triphenylphosphine)palladium (57 mg, 49 μmol) afforded (R)-4-(8-(4-benzoyl-2-methylpiperazin-1-yl)pyrido[2,3-d]pyridazin-5-yl)benzonitrile 85 (138 mg, 32% yield) after chromatographic purification. MS 434.2 (calc'd) 435.1 (M+H, found).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(Cl)c(Cl)cc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5,6-dichlorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5,6-dichlorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([CH3:32])([CH2:28][C:29]([OH:31])=[O:30])[C:25]([OH:27])=[O:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][C:24]([CH3:32])([CH3:23])[C:25]([OH:27])=[O:26])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15].[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]([CH3:32])([CH3:23])[CH2:28][C:29]([OH:31])=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(C)(C)C(=O)O
Yield: 55.6 %

Procedure:
174(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (303.0 mg, 1.0 mmol) and 2,2-dimethylbutanedioic acid (146.0 mg, 1.0 mmol) were dissolved in DCM (10 mL), followed by the addition of HOBt (1.0 eq, 153.0 mg) and EDC (1.0 eq, 192.0 mg). The resultant solution was stirred overnight. The solution was purified by reverse phase HPLC using a Gilson to yield 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-4-oxobutanoic acid and 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3,3-dimethyl-4-oxobutanoic acid mixture 120 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:25](B(O)O)=[C:26]2[CH2:31][CH2:30][CH2:29][N:27]2[N:28]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:25]3[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:28][N:27]4[CH2:29][CH2:30][CH2:31][C:26]=34)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cccc21
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)cccc21

Procedure:
The titled intermediate was made via Preparation 33 (General Suzuki Coupling Method D) from 4-bromo-indole-1-carboxylic acid tert-butyl ester and 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5). MS (ESI) m/e 401 (M+1). TLC (SiO2): Rf0.5 (1:1 methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C(OCC)C>[CH2:5]([N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:1]([Cl:4])=[S:2])[CH2:6][CH2:7][CH3:8]
Reactant: S=C(Cl)Cl
Reactant: CCCCNCCCC
Solvent: CCOCC
Product: CCCCN(CCCC)C(=S)Cl
Reaction time: 1 h

Procedure:
To a solution of 29.9g (0.26 mole) thiophosgene in 600 ml ethyl ether at 0° was added a solution of 25.8g (0.20 mole) dibutylamine 20.2g (0.20 mole) triethylamine and 250 ml ethyl ether over a period of 35 minutes during which time solids formed. After stirring an additional one hour, the mixture was filtered and the resulting filtrate was removed of volatiles under reduced pressures to yield 35g of crude dibutylthiocarbamoyl chloride.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]3[CH:16]([C:17](=[O:20])[NH:18][N:19]=2)[CH2:15]3)[CH:10]=[CH:11][CH:12]=1)([O-])=O>C(O)C.[Ni]>[NH2:4][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]3[CH:16]([C:17](=[O:20])[NH:18][N:19]=2)[CH2:15]3)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 0.65 g (13.0 millimoles) of hydrazine hydrate in 10 ml of ethanol is added, whilst stirring, to a mixture of 1.5 g (6.5 millimoles) of 2-(m-nitrophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 32b), 20 ml of ethanol and a small amount of an aqueous Raney nickel suspension in the course of 5 minutes, during which the temperature rises from 25° to 35° C. Stirring is continued for 1 hour and the reaction mixture is then slowly raised to the boil. It is refluxed for 5 minutes and filtered hot, and the filtrate is concentrated. After recrystallization from ethyl acetate/methanol, 1.0 g (76% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one is obtained as colorless crystals, identical with the compound from Example 33.
Reaction SMILES: C(NC(C)C)(C)C.[OH:8][C@@H:9]1[CH2:14][O:13][C:11](=[O:12])[CH2:10]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN1CCN(C)C1=O.[Cl-].[NH4+]>C1COCC1>[CH2:15]([C@H:10]1[C@H:9]([OH:8])[CH2:14][O:13][C:11]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C[C@H](O)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OC[C@@H](O)[C@@H]1Cc1ccccc1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
Diisopropylamine (2.7 ml, 19.59 mmol) and 1.6 M of n-butyllithium-hexane solution (12.2 ml, 19.59 mmol) were added to THF (30 ml) under argon gas at 0° C. After stirring for 15 minutes, the solution was cooled to −45° C. Then, (S)-3-hydroxy-γ-butyrolactone (1 g, 9.794 mmol) in THF (20 ml) was added thereto. After stirring for 30 minutes at −45° C., benzyl bromide (1.4 ml, 11.75 mmol) and 1,3-dimethyl2-imidazolidinone (2.9 ml) in THF (20 ml) were added thereto. After stirring for 3 hours at the same temperature, an aqueous saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and condensed in vacuo. The residue was purified by silica gel chromatography to give (2S,3S)-2-benzyl-3-hydroxy-γ-butyrolactone (0.577 g, yield 31%).
Reaction SMILES: C1(C)C=CC=CC=1N[N:8]=[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:10].[CH2:20](O)[CH3:21].OS(O)(=O)=O>O>[CH3:10][C:9]1[NH:8][C:11]2[C:12]([C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[CH:13][C:20]([CH3:21])=[CH:10][CH:9]=2
Reactant: CCO
Reactant: CC(Cc1ccc(F)cc1)=NNc1ccccc1C
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2[nH]c(C)c(-c3ccc(F)cc3)c2c1

Procedure:
The crude hydrazone (100 g), ethanol (700 ml) and conc. aqueous H2SO4 (40 ml) were refluxed for 18 h. After cooling to room temperature water (0.5 l) was added. The thus obtained mixture was extracted with (2×700 ml) ethyl acetate and the combined organic phases were washed with brine, dried and the solvents were evaporated in vacuo. This afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:4) and crystallized from heptane. Yield: 75.5 g, mp:124°-128° C. In a corresponding manner the following indole derivative was prepared: 5-Chloro-3-phenyl-2-methyl-1H-indole 24b, (oil).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:7](=[O:9])[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)NC(CC(=O)O)c1ccccc1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(CC(=O)Nc1ccccc1Oc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31.3 %

Procedure:
To a pre-stirred solution of N-acetyl-3-phenyl-β-alanine (104 mg, 0.50 mmol), EDC (265 mg, 1.38 mmol), triethylamine (70 mg, 0.69 mmol) and DMAP (6 mg, 0.046 mmol) in anhydrous DCM (25 ml), was added 2-(4-chlorophenoxy)phenylamine (100 mg, 0.46 mmol). This mixture was then allowed to stir at room temperature for 14 h. The reaction mixture was washed with 2.5M NaOH (20 ml), 2M HCl (20 ml) and the organics were then dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (eluant; DCM to 9:1 DCM:MeOH) then proceeded to afford the desired product as an off-white solid (58.9 mg, 31%). 1H NMR (270 MHz, CDCl3): δ 2.03 (3H, s, CH3), 2.83-2.99 (2H, m, CH2), 5.30-5.40 (1H, m, CH), 6.73-6.77 (1H, dd, J=1.5, 8.2 Hz, Ar—H), 6.83-6.86 (2H, m, Ar—H), 6.95-7.03 (1H, td, J=1.7, 7.9 Hz, Ar—H), 7.05-7.11 (1H, td, J=1.7, 7.9 Hz, Ar—H), 7.19-7.30 (7H, m, Ar—H), 7.60 (1H, br s, Ar—H), 8.22-8.25 ppm (1H, dd, J=1.5, 8.0 Hz, Ar—H). LCMS: M+H, 409.44 HPLC: 98.66% (2.268 mins, isocratic 90% acetonitrile, 10% water at 1 ml/min).