Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(C)c4)c3)c2cc1OC
Yield: 85 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate from the previous step (115 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (145 mg, 0.26 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.48-7.16 (m, 9H), 6.36 (s, 1H), 3.99 (s, 6H), 2.38 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C@H:11]([CH3:23])[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>C(#N)C>[P:4]([CH2:9][O:10][C@H:11]([CH3:23])[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CO[C@H](C)Cn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O

Procedure:
To a reaction vessel was added stepwise the product (D) of step (4), acetonitrile and Bromotrimethylsilane, the mixture was refluxed while stirring until the completion of the reaction, volatile liquid was removed under vacuum, the resultant residue was then dissolved in a suitable amount of water, and the resulting solution was adjusted to pH 3.0˜3.5 to give the product 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA). Furthermore, dichloromethane or chloroform could be used as reaction solvent and iodotrimethylsilane or chlorotrimethylsilane/potassium iodide as the deprotection agent.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:24])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (210 mg, 0.62 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (148 mg, 0.62 mmol) and DIPEA (0.55 mL, 3.09 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM, MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (120 mg, 43%). LCMS (Method J): RT 2.72 min [M+H]+ 458
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[N:13]([CH3:22])[CH:12]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3F)cn(C)c12
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 95.3 %

Procedure:
A mixture of Example 2B (0.123 g, 0.408 mmol), 2,4-difluorophenol (0.069 g, 0.531 mmol) and cesium carbonate (0.173 g, 0.531 mmol) in dimethylsulfoxide (5 mL) was heated at 110° C. for 1 hour. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20-50% ethyl acetate in hexanes) to provide 0.16 g (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15]([C:16](OCC)=[O:17])=[CH:14][C:13]3[CH:21]=[CH:22][S:23][C:12]=3[S:11]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C1C[O:38][CH2:37]C1>>[OH:38][CH2:37][C:15]1([CH2:16][OH:17])[CH2:14][C:13]2[CH:21]=[CH:22][S:23][C:12]=2[S:11](=[O:24])(=[O:25])[N:10]1[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1Cc1ccc(OC)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (1.80 g, 4.75 mmol) in anhydrous THF (40 mL) at ambient temperature was added DIBAL (1.0M, 11.87 mL, 11.87 mmol) and the mixture was stirred for 1 h. Additional DIBAL (1M, 15 mL,15 mmol) was added (TLC showed starting material remained) and the reaction mixture was stirred for 20 h, cooled (ice bath) and the reaction was quenched by the slow addition of 1N HCl (100 mL). THF was evaporated and the aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give an oil (1.60 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:54][C:55]4[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Reactant: Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2ccc(N3CCc4nc(N)ncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then meta-toluidine (0.022 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (18 mg, 51%). 1H NMR (DMSO-d6) δ: 9.84 (s, 1H), 8.12 (s, 1H), 7.85-7.92 (m, 2H), 7.60 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.03-7.09 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.42 (s, 2H), 4.36 (s, 2H), 3.71 (t, J=6.0 Hz, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.30 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:26](=[O:28])[CH3:27])[C:10](=[O:15])[C:9]=2[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Reactant: CC(=O)OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(CCCCOC(C)=O)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Part A: 1-(4-Methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.0 g, 3.17 mmol) was dissolved in N,N-dimethylformamide (40 mL) and cooled to 0° C. Sodium hydride (60%, 0.317 g, 7.93 mmol) was added followed by 4-bromobutyl acetate (0.918 mL, 6.34 mmol). The reaction was stirred at rt overnight, quenched with 1N hydrochloric acid (200 mL), extracted with ethyl acetate (3×250 mL), washed with water (2×200 mL), washed with brine (1×200 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford 6-(4-acetoxy-butyl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.490 g, 36%). The ester (0.490 g, 0.114 mmol) was dissolved in 5% NH3/ethylene glycol (6 mL) in a pressure tube, heated at 80° C. for 2 hr, cooled, quenched with water (100 mL), extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate gradient and 0–100% methanol/ethyl acetate gradient as the eluents to afford 0.295 g (72%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.97 (d, j=9.1 Hz, 2H), 6.83 (s, 3H), 5.49 (s, 3H), 3.84 (s, 3H), 3.66 (t, j=6.2 Hz, 2H), 3.51 (t, j=7.3 Hz, 2H), 3.23 (t, j=6.8 Hz, 2H), 1.72–1.55 (m, 4H) ppm; Mass Spec 357.3(M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18]C3C=C(C)N=C(C)N=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].ClC1C=C(C=C(Cl)C=1N1C=C2C(Cl)=NC=CC2=N1)C#N.[F:49][CH2:50][C:51]1[CH:56]=[CH:55][N:54]=[C:53](N)[N:52]=1>>[Cl:28][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:18][C:53]3[N:52]=[C:51]([CH2:50][F:49])[CH:56]=[CH:55][N:54]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)nc(C)n1
Reactant: Nc1nccc(CF)n1
Agent: N#Cc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Product: N#Cc1cc(Cl)c(-n2cc3c(Nc4nccc(CF)n4)nccc3n2)c(Cl)c1
Yield: 5 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[4-(2,6-dimethylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile and 4-fluoromethylpyrimidin-2-ylamine were reacted to afford the title compound as a yellow solid (6 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.74-9.73 (m, 1H), 8.98 (d, J=5.2 Hz, 1H), 8.53 (s, 2H), 8.07 (s, 1H), 8.05 (s, 1H), 7.62 (dd, J=7.3, 0.9 Hz, 1H), 7.55-7.52 (m, 1H), 5.78-5.75 (m, 1H), 5.66-5.63 (m, 1H). LCMS (Method B): RT=3.04 min, m/z: 414 [M+H+].
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (61 mg, 56% yield) following Scheme 3 and in analogy to Example 35 using 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (39 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:23])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv), AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl4 (500 mL) was stirred for 1 h at reflux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixture was stirred at reflux for additional 30 min. The reaction mixture was filtered hot and the filtrate was concentrated. Trituration of the residue in CH3CN afforded of 12.88 g of impure (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2 equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol) and Cs2CO3 (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reaction mixture was stirred for 24 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (150 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 212 mg of the title compound as a white solid. Title compound: ESI-MS: 294.3 [M+H]+; tR=1.95 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH:9](OC)=[O:10]>C(N(CC)CC)C>[CH:9]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:10]
Reactant: CCOC(=O)CN
Reactant: COC=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC=O
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 5 L three neck round bottom flask equipped with a mechanic stirrer, a pressure-equalizing funnel and a condenser bearing a calcium chloride drying tube was added glycine ethyl ester hydrochloride (500 g, 3.583 mol) and methyl formate (1.8 L). The suspension was brought to reflux and triethylamine (556 mL) was added to the reaction. The reaction was stirred and refluxed overnight. The reaction was cooled to room temperature and filtered through a Buchner funnel to remove triethylamine hydrochloride salt. The filtrate was concentrated and dried over high vacuum to yield 320 g (93%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]CC)=O)[N:3]=1.[NH3:12]>CO>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:12])=[O:9])[N:3]=1
Reactant: N
Reactant: CCOC(=O)c1n[nH]c(C)n1
Solvent: CO
Product: Cc1nc(C(N)=O)n[nH]1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (3.0 g, 19.3 mmol) is placed in a sealed tube that is then charged with a solution of 7N NH3 in MeOH (40 mL). The reaction is stirred at 50° C. for 24 h. The solvent was then removed under reduced pressure and the crude material was used directly for the next step without further purification. MS (ES+) C4H6N4O requires: 126. found: 127 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cc(-c5ccccc5)ccn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.[C]=S.[Br:20]Br.[OH-].[Na+]>O>[Br:20][C:5]1[CH:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)N1CCN(c2ccccn2)CC1
Agent: [C]=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reaction time: 18 h

Procedure:
To a stirred and cooled (<10° C.) mixture of 150 g of ethyl 4-(2-pyridinyl)-1-piperazinecarboxylate and 1535 ml of carbon sulfide were added dropwise 32.8 ml of bromine. Upon completion, stirring was continued for 18 hours, while meantime the mixture was allowed to reach room temperature. At a temperature below 20° C., there was added a solution of 70 g of sodium hydroxide solution 10N in 300 ml of water. After stirring for 3 hours at room temperature, the layers were separated. The aqueous phase was extracted twice with trichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. 46 ml of benzene were added to the residue and the whole was evaporated again. Upon standing for 48 hours, the product was solidified. The oily phase was decanted and the solid product was crystallized twice from 2,2'-oxybispropane at 10° C. It was filtered off and dried, yielding 100 g of ethyl 4-(5-bromo-2-pyridinyl)-1-piperazinecarboxylate; mp. 68° C. (interm. 11).
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:16]>ClC(Cl)C>[Cl:16][C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC1(C)Cn2c(nc(O)cc2=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Temperature: 60 °C
Yield: 83 %

Procedure:
18.5 g of 7-hydroxy-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are suspended in 200 mL of dichloroethane. 48 mL of POCl3 are added and the mixture is heated to 60° C. for 3 h. After returning to RT, the solvents are dry evaporated. The residue is taken up in water and AcOET, 30% NaOH is added until pH=12. The product precipitates, it is filtered and then dried. 16.9 g (yield=83%) of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a yellow solid and including the following characteristics:
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#N)=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:37].[Na+].[Na+]>C(OCC)(=O)C>[C:4]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[CH2:24][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[O:37])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C=O)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine dichloromethane (15 ml) and (R)-[7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester (2 g, 6.73 mmol) and stir for 10 min under nitrogen at room temperature. Add diisobutylaluminum hydride (1 M solution in methylene chloride, 14.1 ml; 14.1 mmol) dropwise over 15 min. Add ethyl acetate (30 mL) to the reaction mixture and stir at room temperature for 1 h. Add a 20% aqueous solution of sodium tartrate (30 mL) and stir for 1 h at room temperature. Separate the organic layer and extract the aqueous layer with ethyl acetate (2×15 mL). Combine and dry (Na2SO4) organic layers, filter and concentrate to give 2.2 g [(R)-7-formyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester. Purify by chromatography on silica gel using methylene chloride/acetone (95/5) to give 1.3 g (64%). MS (m/z): 301 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([O:25]CC)=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>O1CCOCC1.O>[N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 24 h

Procedure:
Ethyl 5-[(3-(piperadin-1-yl)propyl)sulfonamido]indole-2-carboxylate (PREPARATION 83, 1.63 g) is dissolved in 10 ml of dioxane and 5 ml of water. Then 0.59 g of solid potassium hydroxide pellets are added and the reaction is stirred at 20°-25° for 24 hr. Then 8.91 ml of 1N hydrochloric acid is added after diluting the reaction with 100 ml of water. The mixture is extracted with n-butanol (3×50 ml) and the organic layer is separated and evaporated under reduced pressure to provide the title compound, NMR (300 MHz, d6-DMSO) 7.37, 7.27, 7.00, 6.90, 2.91, 2.25, 1.75, 1.31, (peak at 4.3 ppm obscured by DMSO).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClC(Cl)C>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3

Procedure:
A 5.80 gm (0.0211 mole) quantity of the compound of Example 15 was dissolved in 100 ml of dichloroethane, and 380 mg (0.003 mole) of dimethylaminopyridine and 3.1 gm (0.03 mole) of triethylamine were added, followed by 2.38 gm (0.030 mole) of acetyl chloride. This mixture was refluxed overnight and evaporated. The resulting mixture was partioned between dilute aqueous NaHCO3 and CH2Cl2. The organic layer was dried and evaporated. The residue was triturated with ether and the resulting solid was collected to give 4.40 g of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1, 2,4-triazolo[3,4-a]phthalazin-3yl)acetamide; mp 147-149° C. (toluene-hexane).