Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[NH:4][N:3]=1
Reactant: OCCCO
Reactant: O=Cc1ccc2[nH]nc(Cl)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1n[nH]c2ccc(C3OCCCO3)cc12

Procedure:
2.2 g (12.2 mmol) 3-chloro-1H-indazole-5-carbaldehyde (Example 43A), 4.64 g (60.9 mmol) propane-1,3-diol and a trace amount of p-toluene sulfonic acid in toluene (60 ml) were heated to reflux for 12 h using a Dean-Stark trap. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (2.76 g, 91% of th.) was used in the next step without further purification.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7]
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCNC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Yield: 91.1 %

Procedure:
A mixture of 4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (150 mg, 0.45 mmol) and 4-amino-butyric acid (688 mg, 6.68 mmol) in 0.5 M NaOMe/MeOH (8.9 mL, 4.45 mmol) was refluxed overnight. Reaction mixture was concentrated and residue was dissolved in water (150 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 151 mg (0.41 mmol) in 92% yield. LC-MS ESI−: 365.08 (M−1)−.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O-])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][N:10]3[CH2:11][C:12]4=[N:13][NH:14][C:15]5[C:20]4=[C:19]([CH:18]=[CH:17][CH:16]=5)[C:21]3=[O:22])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: O=C([O-])c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1c2cccc3[nH]nc(c23)CN1CC12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.1 %

Procedure:
Lithium 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate (3.9 g, 12.1 mmol) from Step B above in THF (20 mL) was cooled in an ice bath while N,N-diisopropylethylamine (9.4 g, 72.8 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (23.0 g, 72.8 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 60:36:4 dichloromethane/methanol/concentrated ammonium hydroxide) to give 4-(quinuclidin-4-ylmethyl)-3,4-dihydropyrazolo[3,4,5-de]isoquinolin-5(1H)-one as a yellow oil (468 mg, 13%): 1H NMR (500 MHz, CD3OD) δ 7.62-7.60 (m, 1H), 7.54-7.53 (m, 2H), 5.15 (s, 2H), 3.53 (s, 2H), 2.93 (t, J=8.0 Hz, 6H), 1.67 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 297 (M+H).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:18])=[O:17])[CH:15]=1)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:40].CO>C(OCC)(=O)C>[ClH:40].[CH3:6][NH:8][CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])(=[O:18])=[O:17])[CH:15]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)O)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)O)c1
Reaction time: 3 h
Yield: 50 %

Procedure:
2-[(4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (256 mg) was dissolved in ethyl acetate (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added at room temperature. After stirring at the same temperature for 3 hr, the reaction mixture was homogenized with methanol, activated carbon was added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate. The obtained crystal was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 110 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15]Cl)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2(CCCN3CCC(c4csc5cc(F)ccc45)CC3)OCCO2)cc1
Yield: 29 %

Procedure:
A mixture of 1.5 g of 2-(4-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane, 1.5 g of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride, 3.3 ml of diisopropylethylamine and 2.5 ml of methanol was stirred with heating under reflux for 25 hours. The reaction mixture was separated with chloroform and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230- to 400-mesh, eluent: hexane-ethyl acetate=1:2) to obtain 0.71 g of 2-(4-fluorophenyl)-2-[3-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]propyl]-1,3-dioxolane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]1[CH:28]2[CH2:29][NH:30][CH2:31][CH:27]2[CH2:26][N:25]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]3[CH2:13][N:14]([C:17]4[CH:22]=[CH:21][C:20]([N:30]5[CH2:29][CH:28]6[CH2:24][N:25]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH:27]6[CH2:31]5)=[N:19][CH:18]=4)[C:15](=[O:16])[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C1c2nn(-c3ccc(Cl)cc3)cc2CN1c1ccc(F)nc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc(N4Cc5cn(-c6ccc(Cl)cc6)nc5C4=O)cn3)CC2C1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
To a mixture of Example 34A (20 mg, 0.061 mmol) in DMSO (0.8 mL) was added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (63 mg, 0.297 mmol). The resulting mixture was irradiated in microwave reactor at 140° C. for 30 min. The sealed tube was heated at 140° C. for 3 h and allowed to cool down to room temperature. The reaction mixture was subjected to filtration. The solid collected was further washed with MeOH (5 mL) and dried under vacuum to give product (19.5 mg) as light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.60 (s, 9H), 2.90-3.05 (m, 2H), 3.20-3.50 (m, 4H), 3.60-3.80 (m, 4H), 4.77 (s, 2H), 6.42 (d, J=8.8 Hz, 1H), 7.43-7.50 (m, 2H), 7.72-7.76 (m, 2H), 7.89 (s, 1H), 8.07 (dd, J=8.8, 2.7 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H). LCMS, [M+H]+=521.4.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:22])[NH:18][C:19](=[O:21])[CH:20]=2)=[C:12]([F:23])[CH:11]=1>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:2][CH:20]2[C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:12]([F:23])[CH:11]=1
Reactant: O=C1C=C(c2ccc(Br)cc2F)C(=O)N1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C1NC(=O)C2(c3ccc(Br)cc3F)CC12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsulfoxonium iodide (3.18 g, 14.5 mmol) in DMSO (15 mL) was added KOH (1.08 g, 19.3 mmol) at r.t. The reaction mixture was stirred at r.t. for 30 min followed by addition of 3-(4-bromo-2-fluoro-phenyl)-pyrrole-2,5-dione (2.60 g, 9.6 mmol). The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The title compound was obtained as brown solid in crude form (2.51 g, 92%) and was as such used in the next step.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[N:15]([CH2:21][C:22](O)=[O:23])[C:16]([Br:20])=[C:17]([Br:19])[N:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>O>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:22](=[O:23])[CH2:21][N:15]2[C:16]([Br:20])=[C:17]([Br:19])[N:18]=[C:14]2[Br:13])[CH2:3][CH2:2]1
Reactant: O=C(O)Cn1c(Br)nc(Br)c1Br
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1c(Br)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 mL 2-piperazin-1-yl-pyrimidine was added to a mixture of 17 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid, 16.6 g TBTU, 7.3 mL TEA and 100 mL DMF. The reaction mixture was stirred for 2 h at RT and subsequently added to water. The precipitate was filtered to give 23 g desired product. Rt: 0.93 (method B), ESI+: 507
Reaction SMILES: C[C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([OH:28])=O.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>CO>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:26]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][CH2:15][C@H:16]([OH:25])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:7][C:6]=2[CH:2]=1)=[O:28]
Reactant: COCCN
Reactant: Cc1c(C(=O)O)oc2ccc(OCCNC[C@H](O)COc3ccccc3)cc12
Solvent: CO
Product: COCCNC(=O)c1cc2cc(OCCNC[C@H](O)COc3ccccc3)ccc2o1

Procedure:
A solution of methyl 5-(2-(2(S)-hydroxy-3-phenoxy-propyl-amino)ethoxy)benzofuran-2-carboxylic acid (0.10 g, 0.26 mmol) and 2-methoxyethyl-amine (0.6 mL) in methanol (3 mL) were maintained at reflux temperature for 18 h. The reaction solution was concentrated in vacuo and flash chromatographed on silica gel (5% methanol:chloroform) to afford the title compound as a colorless solid. (92 mg; m.p. 95°-96° C. Analytical calculated for C23H28N2O6.0.25H2O: C, 63.79; H, 6.63; N, 6.47. Found: C, 63.59; H, 6.39; N, 6.34.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[I:17]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO>[I:17][C:12]1[CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: ClI
Reactant: COc1ccc(CN2C=CCCC2=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2C=C(I)CCC2=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(4-methoxybenzyl)-3,4-dihydropyridin-2(1H)-one (2 g, 9.21 mmol) was dissolved in MeOH (90 mL) and cooled to −78° C. ICl (13.81 ml, 13.81 mmol) was added slowly and the mixture agitated for 1 h and then Sat′d Na2S2O3 was added and the mixture was agitated until room temperature was observed. The solvent was evaporated in vacuo. The residue was dissolved in DCM and washed with Sat′d Na2S2O3 and then with water and dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in toluene (40 mL) and treated with Trifluoroacetic acid (100 uL) and heated immediately to 145° C. for 15 min and then cooled to 0° C. and ET3N (5 mL) was added. The mixture was agitated for 1 h and concentrated in vacuo and then the residue purified by flash chromatography (0-20% EtOAc/heptane) to afford the desired product as a gummy syrup. LCMS (m/z): (MH+), 344.1, 0.88 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[S:28])[NH2:27])[CH2:22][CH2:21]1>>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:18])[C:7]2[CH:6]=[C:5]([C:3]3[N:27]=[C:26]([N:23]4[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]4)[S:28][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: NC(=S)N1CCC(O)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(O)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 397 mg (0.94 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 100 mg (0.62 mmol) of 4-hydroxypiperidine-1-carbothioic acid amide from step a. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:32]Br>ClCCl>[Br:32][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:18]=[C:19]([Cl:25])[C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:14])([F:16])[F:15])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Cc1cccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a dichloromethane (200 ml) solution of 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoro-methyl)pyrrolidin-1-yl]pyridine (3.4 g), an aqueous solution (100 ml) of sodium carbonate (1.2 g) was added. Under ice cooling, a dichloromethane solution of bromine (1.4 g) was added dropwise. Upon the completion of the dropwise addition, the stirring was continued for 1 hour at 0° C. The dichloromethane layer was separated and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 3-bromo-2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([O:26]C)=[O:25])=[C:7]([C:11]([C:13]3[N:14]=[CH:15][C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([OH:26])=[O:25])=[C:7]([C:11]([C:13]3[N:14]=[CH:15][C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Yield: 60.7 %

Procedure:
To a mixture of methyl [6-chloro-2-[(5,6,7,8-tetrahydroisoquinolin-3-yl)carbonyl]-1H-indol-3-yl]acetate (Example 1) in MeOH (20 ml)-THF (20 ml) was added 2N aqueous NaOH (0.6 ml, 1.2 mmol) at room temperature and the resulting mixture was heated at reflux temperature for 8 h. The mixture was cooled and concentrated. The residue was dissolved in water (20 ml) and washed with diethyl ether (20 ml×3). The aqueous layer was acidified with 2N aqueous HCl and extracted with ethyl acetate (40 ml×3). The combined organic layers were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to afford 23.3 mg (60.7%) of the title compound as yellow solids.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30].C(N(CC)CC)C>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1ccc(NS(=O)(=O)CCC)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are treated with 116 mg (0.816 mmol) of 1-propanesulfonyl chloride and 87 mg (0.816 mmol) of triethylamine in 15 ml of tetrahydrofuran for 1 hour.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1cccc(CC(=O)OC)c1
Product: COC(=O)Cc1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2o produced 3at. MS found M+H=467. The oxalate salt of 3at was recrystallized from ethyl acetate; mp 77-82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][N:11]1[C@@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:35]
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Yield: 109 %

Procedure:
Deprotection of (S)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (183 mg, 0.382 mmol, 1 equiv) was accomplwashed in 3 hours in the presence of 4M hydrochloric acid in dioxane at ambient temperature. The resulting mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a white solid (158 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.82 (d, 2H, J=14.4 Hz), 2.67-2.77 (m, 2H); 2.93 (bs, 1H); 3.35-3.39 (m, 2H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.8 Hz); 4.84 (d, 1H, J=4.4 Hz); 5.93 (s, 1H); 6.84 (t, 1H, J=7.2 Hz); 6.96 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.41-7.47 (m, 4H); 7.53 (s, 1H); 9.06 (bs, 1H); 9.14 (bs, 1H); MS for C22H25N3O3 m/z 380.01 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH3:22]>>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH3:36]
Reactant: CCN(CC)CCOCCC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Product: CCN(CC)CCOCCC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 44 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6- one and 2-[2-[2-(diethylamino)ethoxy]ethyl]piperidine (Bp.0.4 mmHg 95°-99° C.) in a yield of 44% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([C:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 87.3 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 56, 470 mg, 0.96 mmol), iron (320 mg, 5.73 mmol) and NH4Cl (35.8 mg, 0.67 mmol) in ethanol (19 mL) and water (6.33 mL) was heated at reflux for 4 h. Then the mixture was cooled and concentrated in vacuo to give a thick slurry which was triturated with 10% CH3OH in CH2Cl2 (50 mL) for 15 minutes. The mixture was then filtered and a small amount of sat. NaHCO3 was added to the filtrate. The resulting phases were separated and the aqueous solution was extracted with 10% CH3OH in CH2Cl2 (50 mL). The combined organic solutions were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (387 mg, 88%) as a yellow foam; 1H NMR: 2.31 (3H, s), 2.38-2.44 (2H, m), 2.61 (2H, t), 3.02 (2H, dd), 3.68 (3H, s), 4.33 (2H, d), 5.72-5.76 (1H, m), 6.66 (1H, s), 7.08 (1H, s), 7.14 (1H, td), 7.35-7.43 (1H, m), 8.41 (1H, s), 8.44 (1H, s), 8.49 (1H, d), 8.84 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 462.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reaction time: 4 h
Yield: 54.7 %

Procedure:
The a solution of 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladium on carbon (0.060 g). The hydrogenation was finished under 30 psi after 4 h. The mixture was passed through Celite to a flask containing HCl in ethanol. Concentration of the filtrate gave the final product (0.15 g, 88% yield). MS/ES+: m/z=334.