Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ccc(C(F)(F)F)cn3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2-chloro-5-trifluoromethyl-pyridine (22.7 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 160° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.8 mg (8%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].C(Cl)Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:32]2[C:31](=[O:33])[C:30]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]3[C:28]2=[O:38])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A suspension of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.35 g) and potassium phthalimide (0.7 g) in dimethylformamide (10 ml) is warmed at 50° to 60° C. for 3 hours. The reaction mixture is shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is crystallized from ethyl acetate/ether to give 5-chloro-2-[3-(2-phthalimido-acetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone as crystals melting at 251° to 253° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9]1[N:27]=[C:12]2[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: Nc1cccnc1
Product: COc1ccccc1CNc1cccn2nc(Nc3cccnc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-aminopyridine (36.47 mg, 0.3875 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (19.21 mg, 16%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.68 (s, 1H), 8.88 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.33-7.20 (m, 3H), 7.03 (d, J=8.6 Hz, 1H), 6.87 (t, J=15.2, 8.1 Hz, 1H), 6.77 (t, J=13.5, 6.6 Hz, 1H), 6.31 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.87 (s, 3H). MS=347 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ncc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25 mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). The thick mixture was stirred at room temperature for 1 h. To this was added a solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL) and the reaction was stirred at RT overnight under Ar. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic phase was separated and the aqueous was extracted with EtOAc (100 mL). The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine (100 mL) and then dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid (592 mg, 32%). MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: COc1cccc(I)c1
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: O=CO
Product: COc1cccc(/C(=C/C(N)=O)c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1
Temperature: 75 °C
Yield: 29.8 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), 3-iodoanisole (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.4 mL EtOAc (degassed) was heated at 75° C. for 17 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, and dried with anhydrous Na2SO4 to give 20 mL of EtOAc solution of crude material. The EtOAc solution was filtered past a plug of silica gel eluting with EtOAc, evaporated, and the resulting solid chromatographed eluting with CHCl3/MeOH to give the title compound as a light tan solid (12.0 mg, 30%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=5.9 Hz, 1H), 8.46 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 7.33-7.47 (m, 4H), 7.23-7.29 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.91-7.00 (m, 2H), 6.82-6.87 (m, 2H), 6.65 (br. s., 1H), 6.47 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13](=[O:14])[N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH:7]3[C:6]=2[N:15]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl.CCN(C(C)C)C(C)C>[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=1[S:27]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[N:15][C:6]=3[CH:7]2[CH2:12]1)(=[O:29])=[O:28]
Reactant: Cc1ccc2c(n1)C1CNCCN1C2=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(n1)C1CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To the solution of 2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as described in Intermediate 8; 100 mg) in dichloromethane (3.5 ml), DIPEA (0.129 ml) was added under argon atmosphere at room temperature then 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (159 mg) was added at 0° C., and then the ice water bath was removed and the reaction mixture allowed to stir at room temperature for 3 h. The reaction mixture was partitioned between DCM (40 ml) and (20 ml) sodium bicarbonate. The organic phase was washed with sodium bicarbonate (20 ml), HCl (2×20 ml) and water (2×20 ml) and then it was dried using phase separator before the DCM was removed under vacuum to give the title compound (170 mg), which was used in next step without purification.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.O.[O:17]1[CH2:19][CH:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][CH:18]([OH:17])[CH2:19][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CC(O)COc1ccc(C#N)cc1)C2
Temperature: 75 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.08 g, 14.5 mmol; from Preparation B above) in 2-propanol (200 mL) was added H2O (20 mL) and 4-(2-oxiranylmethoxy)benzonitrile (2.54 g, 14.5 mmol; prepared as described in international patent application WO 99/31100). The resulting solution was warmed to 75° C., stirred for 18 h, cooled and concentrated in vacuo. Flash chromatography of the residue on silica gel eluting with CH2Cl2:EtOAc (3:1 to 2:1 gradient) gave 3.86 g (69%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@:32]1([C:38]([OH:40])=[O:39])[C@H:36]([CH3:37])[CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(O)(=O)C>O.CO>[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@:32]1([C:38]([OH:40])=[O:39])[C@H:36]([CH3:37])[CH2:35][N:34]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[CH2:33]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2c(Cl)cccc2Cl)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Dichlorobenzaldehyde (646 mg, 3.7 mmol) and sodium triacetoxyborohydride (782 mg, 3.7 mmol) were added to a mixture of (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained by the method of Example 2j (600 mg, 2.47 mmol), acetic acid (0.14 ml, 2.47 mmol) and methanol (10 ml), and the reaction mixture was stirred at room temperature for two hours. 2,6-Dichlorobenzaldehyde (430 mg, 2.5 mmol) and sodium triacetoxyborohydride (522 mg, 2.5 mmol) were further added, followed by stirring at an external temperature of 40° C. for 10.5 hours. Water was added to the reaction mixture, which was extracted with dichloromethane five times, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to give Lot A (32 mg) and Lot B (551 mg) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].CN(C1C=CC=CN=1)C.O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: O=C=NC(=O)CCl
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethylaminopyridine (130 mg). The mixture was stirred at 0° C. for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colorless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([C:16]#[C:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1C#CCO
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-(3-hydroxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.46 g, 1.31 mmol) in MeOH (6 mL) was added palladium, (10 wt. % on activated carbon, 15 mg, 0.014 mmol). The resulting mixture was shaken in a Parr apparatus for 4 h at room temperature under H2 at 60 psi. The mixture was filtered and concentrated to afford the title product as yellow oil (0.41 g, 88% yield). LC-MS (APCl, M+H+): 357.2. HPLC: 96% purity.
Reaction SMILES: [NH2:1][C:2](=[N:43][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:47]([OH:50])(=[O:49])[CH3:48]>[Pd]>[CH3:41][C:39]([CH3:42])([O:38][C:36]([NH:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:43])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:33][CH:32]=1)=[O:37])[CH3:40].[C:47]([O-:50])(=[O:49])[CH3:48]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Product: CC(=O)[O-]
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 75 %

Procedure:
Prepared analogously to Example 4c) from (R)-N5 -[amino(nitroimino)-methyl]-N-[[4-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]phenyl]methyl]-N2 -(diphenylacetyl)-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 75% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)(c2coc(-c3ccc(Cl)cc3)n2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2coc(-c3ccc(Cl)cc3)n2)CC1
Product: Cl
Yield: 5 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 96 step 3 (12 mg, yield 5%). 1H NMR (400 MHz, CDCl3) [free amine] δ 8.56 (s, 1H), 8.28-8.26 (d, J=7.7 Hz, 1H), 8.13-8.11 (d, J=7.6 Hz, 1H), 8.02-8.00 (d, J=8.5 Hz, 2H), 7.79-7.75 (m, 1H), 7.66-7.62 (d, J=7.2 Hz, 1H), 7.57 (s, 1H), 7.42-7.40 (d, J=8.2 Hz, 2H), 3.77-3.76 (d, J=4.7 Hz, 2H), 2.79-2.77 (m, 2H), 2.59 (m, 2H), 2.42 (m, 3H), 2.22-2.21 (m, 2H), 2.08-2.04 (m, 2H). MS (ESI) m/z: Calculated for C26H23ClF3N5O3: 545.14. found: 546.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[O:6]=[CH:7][C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:14][C:13]1[CH:15]=[CH:16][C:8]([CH:7]=[O:6])=[CH:9][C:10]=1[O:11][CH3:12])[C:3]#[C:4][CH3:5]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(C=O)cc1OC
Yield: 95.2 %

Procedure:
1-Bromobut-2-yne (0.36 mL, 4.0 mmol) was added to a suspension of vanillin (0.55 g, 3.6 mmol) and potassium carbonate (1.79 g, 10.9 mmol) in acetone (10 mL) and treated according to Procedure 3. 4-(But-2-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 95%) was obtained as a pale yellow crystalline solid; mp 90-92° C.; δH (400 MHz, CDCl3) 1.84 (t, J=2.2 Hz, 3H, CH3), 3.93 (s, 3H, OCH3), 4.81 (q, J=2.2 Hz, 2H, OCH2), 7.12 (d, J5,6=8.4 Hz, 1H, H5), 7.42 (d, J2,6=2.0 Hz, 1H, H2), 7.45 (dd, J5,6=8.4, J2,6=2.0 Hz, 1H, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 4.0, 56.2, 57.5, 73.2, 85.2, 109.4, 112.4, 126.7, 130.7, 150.1, 152.7, 191.2; vmax 991, 1259, 1504, 1586, 1679, 2226, 2302, 2833, 2921 cm−1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]1>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: Cc1nnc(NCCCN2CCN(C)CC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-methyl-1-(3-aminopropyl)piperazine at 150° C. gave the title compound as the free base (yellow solid, 16% of theory) after purification by HPLC and trituration with i-propylether, mp 60° C. (foams). The free base was converted to the trihydrochloride salt mp. 280° C., 275° C. shrink (hydroscopic).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][OH:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:13][CH2:12][C@@H:8]2[O:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 10 using [[(2S)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.97 g, 3.7 mmol), DCM (20 ml), p-toluenesulfonyl chloride (1.06 g, 5.6 mmol), TEA (0.78 ml, 5.6 mmol) and 4-DMAP (0.46 g, 3.7 mmol). Yield: 1.47 g. MS m/z (rel. intensity, 70 eV) 416 (M+, 40), 244 (bp), 243 (26), 231 (19), 91 (50).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[C:3]=1[F:38].CC[N:41]([CH:45]([CH3:47])[CH3:46])[CH:42](C)C.ClC(Cl)([O:51]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C1COCC1>[CH:45]1([NH:41][C:42](=[O:51])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[C:3]=2[F:38])[CH2:46][CH2:47]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)c(F)c4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NC1CC1
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: -25 °C

Procedure:
To a stirred solution of aniline 23 (500 mg, 0.92 mmol) and DIPEA (0.8 mL, 4.61 mmol) in THF (18 mL) at −25° C. under nitrogen was added dropwise a solution of triphosgene (273 mg, 0.920 mmol) in THF (2 mL). The reaction mixture was stirred at −25° C. and cyclopropylamine (0.32 mL, 4.61 mmol) was slowly added. The reaction mixture was allowed to warm to RT over 1.5 h and stirred at RT overnight. The reaction mixture was then partitioned between AcOEt and water. The organic layer was successively washed with a saturated aqueous solution of ammonium chloride, 1N NaOH and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound 24 as an off-white solid. The crude material was used in the next step without any further purification. MS (m/z): 626.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[Br-:31].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][Br:31])[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of the product from Example 25A (0.87 g, 2.2 mmol) in chloroform (10 mL) was cooled to −10° C., treated with pyridine (0.21 mL, 2.6 mmol), then treated with pyridinium tribromide (0.84 g, 2.6 mmol), stirred for 1 hour, diluted with methylene chloride (150 mL) and washed with 1N HCl (25 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (1% and then 2% methanol/methylene chloride) to provide the title compound (0.68 g) as an oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15](C)[C:16](=O)OC(C)(C)C)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO.Cl>[CH3:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCCCCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC)cc1
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of the product of Step A (0.14 g; 0.44 mmol) in 60% TFA in CH2Cl2 (5 ml) was stirred for 30 min at room temperature and the mixture was diluted to 5 ml with EtOH and a few drops of concentrated HCl was added. This was evaporated to dryness under reduced pressure, kept in vacuo for 1 h and the residue was partitioned between saturated NaHCO3 (5 ml) and Et2O (15 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the title compound (0.055 g; 57%), as a creamy solid. 1H-NMR (CDCl3) 7.01 (d, 2H, J=8.2 Hz); 6.55 (d, 2H, J=8.2 Hz); 3.55 (broad s, 1H); 2.81 (s, 3H); 2.49 (t, 2H, J=7.9 Hz); 1.56 (m, 2H); 1.28 (m, 10H); 0.88 (t, 3H, J=6.8 Hz).