Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18]/[N:20]=[C:21](/[C:23]3[CH:40]=[CH:39][C:26]([CH2:27][N:28]4[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29]4)=[CH:25][CH:24]=3)\[NH2:22])=[O:17])[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A mixture of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (408 mg, 1.50 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 458 mg, 1.50 mmol), HOBT (345 mg, 2.250 mmol), Hunig's Base (1.05 mL, 6.00 mmol), and EDC (431 mg, 2.25 mmol) in N,N-dimethylformamide (7.5 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (120 mL) and a saturated aqueous solution of sodium bicarbonate (60 mL). The organic layer was washed with water (2×120 mL), washed with brine (120 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded (Z)-tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol, 89% yield) as a light peach colored solid that was used in the next step without further purification. HPLC: ret. time=3.26 minutes (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=560.25.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:21]([O-])([OH:23])=[O:22]>C(OC(=O)C)(=O)C.CCCCCC>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][C:10]=1[N+:21]([O-:23])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCOc1ccc(OCCCCCC)cc1
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCOc1ccc(OCCCCCC)c([N+](=O)[O-])c1
Reaction time: 0.05 h
Yield: 97 %

Procedure:
11.6 g of 1,4-di(n-hexyloxy)benzene was dissolved in a mixed solvent of 50 ml of acetic anhydride and 50 ml of n-hexane, and 4 ml of concentrated nitric acid having a specific gravity of 1.42 was dropwise added thereto at a room temperature of 20° C. over 3 minutes. The internal temperature rose to 46° C., and the reaction was completed to obtain 13.1 g of 2,5-di(n-hexyloxy)nitrobenzene (yield: 97%).
Reaction SMILES: C(C[C:4]1([C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)#N.[OH:16]S(O)(=O)=O.[CH3:21][C:22]([OH:24])=O>>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][C:4]32[CH2:21][C:22](=[O:24])[NH:15][C:14]3=[O:16])=[CH:8][CH:9]=1
Reactant: N#CCC1(C#N)CCc2ccc(Cl)cc21
Reactant: O=S(=O)(O)O
Reactant: CC(=O)O
Product: O=C1CC2(CCc3ccc(Cl)cc32)C(=O)N1
Temperature: 125 °C
Reaction time: 8 h

Procedure:
The mixture of 1-(cyanomethyl)-6-chloro-2,3-dihydro-1H-indene-1-carbonitrile (Prep. 39, 250 mg, 1.16 mmol), and AcOH (2.5 ml), H2SO4 (78%, 0.18 ml) was heated to 125° C. The mixture was stirred overnight at 125° C.
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([NH2:15])[CH:7]=1)=[O:4].[C:18]([C:21]1[C:22](=[O:32])[O:23][C:24]([OH:31])=[C:25]([C:28](=O)[CH3:29])[C:26]=1[OH:27])(=[O:20])[CH3:19]>CO>[C:18]([C:21]1[C:22](=[O:32])[O:23][C:24](=[O:31])[C:25](=[C:28]([NH:15][C:8]2[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH2:16][OH:17])[OH:1])[CH:7]=2)[CH3:29])[C:26]=1[OH:27])(=[O:20])[CH3:19]
Reactant: Nc1cc(NC(=O)C(O)CO)cc([N+](=O)[O-])c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cc(NC(=O)C(O)CO)cc([N+](=O)[O-])c2)C(=O)OC1=O
Yield: 42.9 %

Procedure:
A mixture of 785 mg (3.3 mmole) of N-(2,3-dihydroxypropionyl)-3-amino-5-nitroaniline and 690 mg (3.3 mmole) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 30 ml of methanol was heated under reflux for 30 minutes. After cooling, the crystalline product was filtered and dried in vacuum to give 616 mg of 5-acetyl-4-hydroxy-3-[1-(3-glyceroylamino-5-nitrophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Temperature: 25 °C

Procedure:
A solution of 1,3-dimethoxyestra-1,3,5(10)-trien-17-one (2.0 g, 6.4 mM) in 10 ml of anhydrous tetrahydrofuran is added dropwise to a well-stirred suspension of lithium tri-t-butoxyaluminum hydride (4.86 g, 19 mM) in 40 ml of anhydrous tetrahydrofuran at 0°. The suspension is maintained at 0° for 1 hr, warmed to 40° for 1/2 hr, cooled to room temperature and poured into 200 ml of cold H2O. The basic aqueous solution is extracted with 3 × 50 ml of ether and 3 × 50 ml of methylene chloride. The combined organic extracts are washed with H2O, dried over Na2SO4 and evaporated in vacuo to give an oily residue which is chromatographed on 100 g of neutral silica gel. Elution with chloroform gives 1,3-dimethoxy-17β-hydroxyestra-1,3,5(10)-triene, yield 1.9 g (95%); m.p. 53°-55° (hexane).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])([OH:15])[CH2:14][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(C(F)(F)SCCOCc3ccccc3)CO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCOCc1ccccc1
Yield: 17.6 %

Procedure:
Using 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (3.0 g, 0.008 mol), DMSO (30 ml), 1,2,4-triazole (1.4 g, 0.02 mol) and potassium carbonate (2.8 g, 0.02 mol), 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.62 g, yield: 17.4%) was obtained as a colorless oil by similar procedures to Example 14.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH:36]C(OC(C)(C)C)=O)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH2:36])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NCC(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NCC(N)Cc1ccc(F)cc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 2-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)propyl]amino-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (B) (300 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The mixture was stirred at room temperature for 1 hour and evaporated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (193 mg, 76%).
Reaction SMILES: Br.[CH:2]1([C:5]2[CH:6]=[CH:7][C:8]([CH:13]=[O:14])=[N:9][C:10]=2[O:11]C)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([C:5]2[C:10](=[O:11])[NH:9][C:8]([CH:13]=[O:14])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: COc1nc(C=O)ccc1C1CC1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(C2CC2)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde obtained in Reference Example 1-51(6) (437 mg) in 1,4-dioxane (6 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with chloroform/methanol (2:1). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→0:100) to give 5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde as a yellow powder (278 mg, 69%).
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1.C(C1CN1)#N.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:2])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: N#CC1CN1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
1.52 g. p-Methoxybenzoic acid is dissolved in 20 ml. dioxan and mixed at 10° C. with a solution of 0.68 g. 2-cyanoaziridine in 3 ml. dioxan. A solution of 2.06 g. dicyclohexylcarbodiimide in 4 ml. dioxan is added thereto and the reaction mixture is stirred for 2 hours at 8°-10° C. The crystals formed (2 g. 1,3-dicyclohexylurea; m.p. 225°-230° C.) are filtered off with suction and the filtrate is evaporated in a vacuum. The semi-solid evaporation residue (3.88 g.) is triturated with 3 ml. anhydrous diethyl ether, the crystals obtained (0.6 g.) are filtered off with suction, the filtrate is evaporated in a vacuum and the evaporation residue (2.45 g.) is again triturated with 3-4 ml. diethyl ether and filtered with suction to give 0.59 g. 1-p-methoxybenzoyl-2-cyanoaziridine; m.p. 81°-83° C. A further 0.18 g. of the desired product are obtained from the mother liquor by again evaporating and triturating the evaporation residue with diethyl ether.
Reaction SMILES: [CH:1]1([N:4]([C@@H:18]2[C@H:25]3[C@H:21]([CH2:22][NH:23][CH2:24]3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)=[CH:29][CH:28]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:23]2[CH2:24][C@H:25]3[C@@H:18]([N:4]([CH:1]4[CH2:2][CH2:3]4)[S:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=4)(=[O:6])=[O:7])[CH2:19][CH2:20][C@H:21]3[CH2:22]2)=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CNC[C@H]21
Reactant: O=CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CN(CCCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-Cyclopropyl-N-[(3aS*,4S*,6aR*)-octahydrocyclopenta[c]pyrrol-4-yl]-3-(trifluoromethyl)benzenesulfonamide from Example 201 (140 mg, 0.374 mmol) and 6,6-bis(4-fluorophenyl)hexanal (108 mg, 0.374 mmol) were combined in dichloromethane (2 mL) and then acetic acid (1 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (306 mg, 0.748 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin washed with dichloromethane. The solvent was removed in vacuo and the crude material purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 8.36 (d, J=7.9, 1H), 7.95 (d, J=7.9, 1H), 7.76 (dd, J=6.4, 14.2, 1H), 7.33 (dd, J=5.6, 8.3, 4H), 7.18-7.11 (m, 4H), 3.96 (dd, J=8.0, 16.3, 2H), 3.18-3.10 (m, 1H), 2.82 (dd, J=3.5, 9.5, 1H), 2.50-2.44 (m, 2H), 2.39 (t, J=8.0, 1H), 2.31-2.21 (m, 4H), 2.03 (dd, J=7.8, 15.3, 2H), 1.91 (dt, J=3.5, 10.4, 1H), 1.59 (dt, J=5.6, 11.5, 1H), 1.51 (dd, J=10.6, 16.2, 1H), 1.46-1.33 (m, 6H), 1.28 (dd, J=7.4, 15.1, 2H), 1.08 (td, J=5.0, 10.5, 1H), 0.84 (dt, J=6.9, 12.6, 1H), 0.75-0.66 (m, 1H); MS (ESI+) m/z 647 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O-]S(C(F)(F)[F:18])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>ClCCl>[C:1]([C:3]1[S:4][C:5]2[C:11]([F:18])=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: N#Cc1nc2ccc(O)c(F)c2s1
Reaction time: 22 h

Procedure:
To a suspension of 2-cyano-6-hydroxybenzothiazole (2.0 g, 11.4 mmol) in dichloromethane (50 ml) in a 250-ml round-bottomed flask was added 3,5-dichloro-1-fluoropyridinium triflate (6.1 g, 19.3 mmol). The reaction flask was fitted with a reflux condenser and the mixture was brought to reflux under argon atmosphere for 53 hr. Additional 3,5-dichloro-1-fluoropydidinium toiflate was added (1.0 g, 3.2 mmol) and reaction continued for another 22 hr. Additional 3,5-dichloro-1-fluoropylidinium triflate was added (1.0 g, 3.2 mmol)and reaction continued for another 27 hr. Additional 3,5-dichloro-1-fluoropyridinium triflate was again added (1.0 g, 3.2 mmol) and reaction continued for another 72 hr. The reaction mixture was concentrated by rotoevaporation to give a brown residue that was purified by flash chromatography with 100 g of silica gel and methylene chloride as eluting solvent. The title compound was obtained as a white solid. Yield: 0.97 g (44%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:37][N:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[N:19]2[C:20]([CH:21]=[N:22][C:17]([NH:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)=[N:18]2)=[CH:23][CH:24]=1)[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3cccc(N4CCOCC4)c3)nn12)S(C)(=O)=O
Yield: 21.6 %

Procedure:
3-Morpholin-4-yl-phenylamine (122.3 mg, 0.6860 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (125.0 mg, 0.3430 mmol) and N,N-Diisopropylethylamine (0.1792 mL, 1.029 mmol) were dissolved in 1-Methoxy-2-propanol (1.25 mL, 12.8 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 35.51 mg of N-Methyl-N-{2-[2-(3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a lyophilized powder. (M+H)=479.1. 1H NMR (400 MHz, DMSO, d6) δ 9.26 (s, 1H), 8.97 (s, 1H), 7.73 (m, 1H), 7.66 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.02 (t, 1H, J=8.09 Hz), 6.93 (d, 1H, J=4.64 Hz), 6.87 (m, 2H), 6.45 (m, 1H), 3.57 (m, 4H), 3.08 (s, 3H), 2.71 (s, 3H), 2.67 (m, 4H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][Li].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C(OCC)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:6]2[CH:7]([CH3:15])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: [Li]C
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
A stirred solution of phenanthridine (3.58 g, 20 mmol) in anhydrous diethyl ether (20 mL) was cooled to −30° C. and treated drop-wise under nitrogen via syringe with a solution of 1.4 M methyllithium in diethyl ether (14.5 mL, 20.3 mmol). The yellow solution was warmed to room temperature and stirred for 15 minutes. The mixture was cooled to −78° C. and treated with 4-methoxybenzenesulfonyl chloride (4.12 g, 20 mmol), as a solid, in a single aliquot. The reaction mixture was warmed slowly to room temperature over one hour, poured into 1 N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed sequentially with water, a 1 N hydrochloric acid solution, and a saturated, aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic phase was filtered through a short column of silica gel, and the filtrate evaporated in vacuo to yield a crude yellow oil (5.3 g, 73%). The crude oil was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of methyl tert-butyl ether-hexane (15:85) at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (2.02 g, 5.6 mmol, 28%) as a homogeneous, colorless, crystalline solid, m.p. 167-169° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14]O)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.[F:16][C:17]([F:25])=[CH:18][CH:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14][N:22]3[CH2:23][CH:19]([CH:18]=[C:17]([F:25])[F:16])[CH2:20][C:21]3=[O:24])=[C:9]([CH:11]3[CH2:12][CH2:13]3)[N:10]=2)[N:7]=1
Reactant: OCc1c(C2CC2)nc2ccc(Cl)nn12
Reactant: O=C1CC(C=C(F)F)CN1
Solvent: Cc1ccccc1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 28 %

Procedure:
A solution of (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889 mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37 mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) in toluene (20 ml) is heated under reflux for 16 h. After cooling, the solvent is removed under reduced pressure, the crude product is dissolved in dichloromethane (100 ml). The organic layer is washed by water (150 ml). The aqueous layer is extracted by dichloromethane (100 ml). The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography over silicagel (benzine/AcOEt:60/40) to afford 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 62 after recrystallization in diisopropylether.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1.Cl[C:14]1[CH:34]=[CH:33][CH:32]=[C:31](C)[C:15]=1[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[C:19]([CH3:30])=[N:18]1>>[Cl:12][C:10]1[CH:9]=[CH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=4)[C:19]([CH3:30])=[N:18]3)[C:4]=2[CH:11]=1.[CH2:16]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:30]1)[C:15]1[CH:14]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Cc1nn(Cc2csc3ccc(Cl)cc23)c2cc(CC(=O)O)ccc12
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
The titled compound (4.3 mg) as a brown solid was prepared from the compound [102-4] obtained in the process (4) of Example 102 (24.7 mg) and 3-bromomethyl-5-chlorobenzo[b]thiophene according to the method of the process (5) of Example 102.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1

Procedure:
The title compound was prepared according to EXAMPLE 231 but using Boc-3-(4-fluorophenyl)-(R)-alanine and 4-hydroxypiperidine. m/z (ES+)=367.34 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.8 g) and 4-amino-1-benzyl-3,3-diethylpiperidine (8.0 g, 32.52 mmol) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,3-diethylpiperidine. Yield 4.8 g (94.60%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26-2.86 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]([N:15]1[C:24](=[O:25])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=2)[C:16]1=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[CH2:8]([N:15]1[C:24](=[O:25])[CH:23]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=2)[C:16]1=[O:27])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1Cc2cc(Cl)ccc2C(=O)N1Cc1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)C1C(=O)N(Cc2ccccc2)C(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Isopropylsulfonyl chloride (140 mg, 0.962mmol) was added to a solution of 250 mg (0.875 mmol) 2-benzyl-6-chloro-4H-isoquinoline-1,3-dione and 270 mg (1.75 mmol) DBU in 2.5 mL methylene chloride under Argon, which was cooled in ice-EtOH to -10° C. After 30 min, the reaction was allowed to warm to room temperature and was stirred overnight. The reaction was diluted with EtOAc, washed three times with 2N HCl dried (Na2 SO4) and concentrated. The residue was triturated with EtOH, petroleum ether was added and the resulting crystals were filtered. Recrystallization from MeOH-petroleum ether gave 186 mg of the title compound, mp 150°-152° C.