Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[C:10]([N:14]1[CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(Br)CCBr
Reactant: CC(C)(C)N
Solvent: CC#N
Product: COC(=O)C1CCN1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The procedure of Cromwell described in J. Heterocyclic Chem. 6: 435 (1969) and 5: 309 (1968) was followed for the preparation of this ester. To a 200 ml round bottom flask was added 5.20 g (0.02 mol) methyl 2,4-dibromobutyrate, 80 ml acetonitrile and 4.69 g (0.06 mol) of t-butylamine. After stirring at room temperature for 5 minutes, heat was applied and the temperature raised to and maintained at reflux for 24 hours. The yellowish mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, giving a yellow liquid to which dry ether was added. The pot was vigorously shaken and the ether solution decanted. This was repeated three times. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to give a pale yellow liquid. Kugelrohr distillation at 65° (1.8 mm) afforded 2.3 g (70%) of a water-white liquid: IR (liquid film) cm-1 1750, 1725, 1275, 1230, 1200, 1175, 1130, 1060; NMR (CDCl3) delta 3.70 (3H, s), 3.93 (1H, t, J=8 Hz), 3.15 (2H, m), 2.13 (2H, m), 0.93 (9H, s).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[CH:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:22][CH:21]([CH3:23])[CH2:20][CH:19]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)nc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (133 mg, 0.56 mmol), methyl 6-(1-hydroxy-3-methylbutyl)nicotinate (150 mg, 0.67 mmol) and triphenylphosphine (147 mg, 0.56 mmol) in tetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (113 mg, 0.56 mmol). The reaction was stirred at room temperature overnight. The reaction was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yloxy)butyl)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 9.19 (s, 1H), 8.25-8.23 (d, 1H), 7.63-7.61 (d, 2H), 7.58-7.56 (d, 2H), 7.49-7.47 (d, 1H), 7.44-7.43 (d, 2H), 6.93-6.90 (d, 2H), 5.40-5.37 (m, 1H), 3.93 (s, 3H), 2.00-1.93 (m, 2H), 1.75-1.70 (m, 1H), 1.03-0.96 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:38]1[C:46]2[C:41](=[C:42](B3OC(C)(C)C(C)(C)O3)[C:43]([F:47])=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(C(C)(C)C)(C)C>>[F:47][C:43]1[C:42]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:41]2[C:46](=[CH:45][CH:44]=1)[NH:38][CH:39]=[CH:40]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (123 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 114 mg of 121 following reverse phase HPLC purification. MS (Q1) 533.3 (M)+
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].Cl[C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N:25]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 2-chloro-1-methyl-1H-benzimidazole (67.1 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (104 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:7][CH:6]=1.[CH:20](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=[CH:20]2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCOC(OCC)OCC
Product: COC(=O)Cc1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.356 g of [4-(3-amino-pyridin-4-ylamino)-phenyl]-acetic acid methyl ester and 9.2 ml of triethyl orthoformate is stirred and refluxed for 2 hours. The mixture obtained is allowed to cool to rt and is concentrated in vacuo. (4-Imidazo[4,5-c]pyridin-1-yl-phenyl)-acetic acid methyl ester is obtained in the form of a solid: ES-MS: 268.1 [M+H]+; single peak at tR=2.03 min (System 1).
Reaction SMILES: [C:1]([C:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:6](=[O:29])[N:5]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:4]=1[CH3:40])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=[O:23])[C:6](=[O:29])[N:5]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=2)[C:4]=1[CH3:40])#[N:2]
Reactant: CC1=C(C#N)[C@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out under argon. tert-Butyl [(6R)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetate (350 mg, 609 μmol; Example 7) was initially charged in dichloromethane (60 ml), and trifluoroacetic acid (20 ml) was added. The mixture was stirred at RT for 90 min. The volatile components were then removed on a rotary evaporator. The residue was taken up in toluene (50 ml) and again concentrated under reduced pressure. This procedure was repeated once more. The crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a colorless solid (290 mg, 92% of theory).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29].[H-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[N:8]([CH:27]([C:28]([O:30][CH3:31])=[O:29])[CH3:32])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(C(C)C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 84 %

Procedure:
The alkylation of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 9, Step C) with methyl 2-bromopropionate was carried out as described in Example 3, Step A, except that no excess sodium hydride was used. After work-up, the residue was flash chromatographed over silica gel (eluted with 0.5% MeOH/CH2Cl2) to give the desired material in 84% yield as a colorless oil, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 419 (M+1)+.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>CCO>[NH2:15][C:14]1[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1N
Temperature: 60 °C
Yield: 81.9 %

Procedure:
A mixture of ethyl 2-hydrazinylacetate hydrochloride (0.309 g, 2 mmol), NaHC O3 (0.185 g, 2.2 mmol), and 4,4-dimethyl-3-oxopentanenitrile (0.250 g, 2 mmol) in EtOH (10 mL) was heated at 60° C. overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford ethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate as solid (0.369 g, 82%). 1H NMR (300 MHz, CDCl3) δ 5.50 (s, 1H), 4.75 (s, 2H), 4.23 (q, 2H), 3.57 (br, 2H), 1.29 (t, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:23][OH:24])=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 126 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14]C)=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[BrH:16]>>[BrH:16].[BrH:16].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: Br
Product: Oc1ccc(Cl)cc1N1CCNCC1
Temperature: 25 °C

Procedure:
A suspension of 5.5 g of 1-(5-chloro-2-methoxyphenyl)piperazine in 40 mL of 62% hydrobromic acid was stirred at reflux for 30 hours. After cooling to room temperature, the mixture was filtered by suction and the solid was washed on the funnel with acetone affording 6.02 g of the title compound. M.p.>270° C. (ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10](OS(C1C=CC(C)=CC=1)(=O)=O)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClC1C=CC=CC=1Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc(=O)c2ccc(OS(=O)(=O)c3ccc(C)cc3)c([N+](=O)[O-])c2o1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2o1
Temperature: 170 °C
Yield: 66.8 %

Procedure:
To a solution of 8-nitro-4-oxo-7-(toluene-4-sulfonyloxy)-4H-chromene-2-carboxylic acid ethyl ester (433 mg, 1 mmol) in o-dichlorobenzene was added benzylamine (214 mg, 2 mmol). The reaction mixture was heated at 170° C. for 1 hour, and the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate and washed sequentially with aqueous HCl (2N 50 ml), NaOH (2N, 50 mL) and water, dried over anhydrous Na2SO4, and filtered. The solvent was evaporated in vacuo to give a solid residue. Recrystallization of the residue from ethyl acetate-hexane (2:1) provided 246 mg (67%) of the title compound: mp 168° C.; 1H NMR (400 MHz, CDCl3): 1.43 (t, J=7 Hz, 3H), 4.45 (q, J =7.0 Hz, 2H), 4.61 (d, J=5.0 Hz, 2H), 6.90 (d, J=9.2 Hz), 7.09 (s, 1H), 7.42-7.32 (m, 5H), 8.04 (t, J=5 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H); IR: 3350, 2980, 1730,1660, 1600,1420,1250 cm−1; MS 369 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][C:2]1[C:3](/[CH:4]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccc(C=O)c1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cccc(/C=C/[N+](=O)[O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-3-(methyloxy)benzaldehyde (available from Allichem Product List; 20 g; 133 mmol) in nitromethane (400 ml) was added ammonium acetate (6.16 g; 80 mmol) and the resulting orange mixture was stirred for 1 h at 100° C. then cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (×2) and brine, and the organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Trituration with dichloromethane/ether gave the title compound as a yellow solid (6.6 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:26]
Reactant: C1COCCN1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(O)c1c(CC(=O)N2CCOCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with morpholine at 22° C. to give the title compound as a white solid. MS: 447.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:6][NH:7][CH3:8].C(N(CC)CC)C.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:6][N:7]([CH3:8])[C:26]([Cl:25])=[O:28]
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)Cl
Reaction time: 0.17 h

Procedure:
In 3.0 ml of dichloromethane was dissolved 831 ml of triphosgene, and added dropwise thereto were a solution of 1.08 g of N-(3,5-bistrifluoromethylbenzyl)-N-methylamine and 1.76 ml of triethylamine in 5.0 ml of dichloromethane, spending 10 minutes, under nitrogen atmosphere under ice-cooling. The reaction mixture was stirred at 0° C. to 5° C. for 30 minutes. The solvent was removed by distillation, and the residue was dried. To the residue were added water and dichloromethane and the mixture was extracted twice with dichloromethane. The organic layers were combined and washed with saturated brine, and dried. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane→hexane:ethyl acetate=10:1), to give 760 mg of N-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonyl chloride as shown in Table 134 below.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14])=[CH:11][CH:10]=1)=[O:8]>CO>[NH:15]([C:13]([C:12]1[CH:24]=[CH:25][C:9]([C:7]([O:6][CH3:5])=[O:8])=[CH:10][CH:11]=1)=[O:14])[NH2:16]
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
Acetyl chloride (11.8 g, 150 mmol) was added at 0° C. to methanol (200 mL) followed by the tert-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine carboxylate (12.7 g, 43 mmol) (added as a solid). The reaction mixture was stirred at room temperature for 20 hours. The volatiles were removed in vacuo, affording methyl 4-(hydrazinecarbonyl)benzoate (8 g, 96%). The product was used without further purification. LCMS [M+H]: 195.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[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.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1.N1C=CC=CC=1>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])=[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)[CH3:26]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(NS(=O)(=O)c2cn(C)cn2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.424 mmol) of the compound from example 42A are reacted with 307 mg (1.70 mmol) of 1-methylimidazole-4-sulfonyl chloride and 0.34 ml (4.24 mmol) of pyridine in 5 ml of tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and tert-butyl 3-aminopropylcarbamate according to general procedure 1 providing the intermediate (300 mg, 63%) as a yellow oil: Rf=0.65 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=9.6 Hz, 1H), 7.46 (s, 1H), 6.46 (d, J=9.6 Hz, 1H), 5.13-5.10 (m, 2H), 3.53 (quart, J=6.2 Hz, 2H), 3.27-3.23 (m, 2H), 1.84-1.79 (m, 2H), 1.46 (s, 9H); ES-MS: (M+H)=370, 372 m/z.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[N:7]([C@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:17])[CH:14]=2)[CH2:9]1)[CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)[C@@H]1Cc2ccc(Br)cc2C1
Yield: 110.7 %

Procedure:
3 g of ((R)-5-Bromo-indan-2-yl)-carbamic acid tert-butyl ester (9.61 mmol) were dissolved in 20 ml of dimethylformamide and 0.442 g of sodium hydride (60% in mineral oil) (11.05 mmol) added. Stirring continued for 14 minutes before 1.3 g of propylbromide (10.57 mmol) were added. The reaction mixture was stirred at room temperature for 15 h and at 40° C. for 3 h. An additional equivalent of sodium hydride and 0.7 ml propylbromide were added followed by stirring for 2 h at 40° C. and 15 h at room temperature. The solvent was evaporated under reduced pressure, the residue treated with water and extracted three times with diethyl ether. The combined organic layers were washed once with water, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 3.77 g of crude product which was used in the subsequent reaction without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:37]1
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 4-(2,4-difluorobenzyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=478.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.30 (m, 4H), 2.36 (m, 4H), 2.67 (t, 2H, J=6.8 Hz), 3.47 (s, 2H), 4.22 (t, 2H, J=6.8 Hz), 6.58 (d, 1H, J=3.6 Hz), 6.72 (m, 1H), 7.06 (dt, 1H, J=8.4 Hz and 2.0 Hz), 7.14 (d, 1H, J=3.2 Hz), 7.20 (m, 2H), 7.42 (dd, 1H, J=15.2 Hz and 8.0 Hz), 754 (br s, NH2), 7.93 (s, 1H). Anal. calculated for (C24H24F2N80+0.5 H2O): C, 59.13; H, 5.17; F, 7.79; N, 22.98; O, 4.92. Found C, 58.84; H, 4.97; N, 22.63.