Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH:29]=[CH2:30])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])=[O:12])[CH:25]([CH:29]=[CH2:30])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CC1CN(Cc2ccccc2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccccc2)CC1C=C
Temperature: 25 °C

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-4-pentenoic acid (466 mg, 2.17 mmol) and 1-benzyl-3-vinylpiperazine (436 mg, 2.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiinide hydrochloride (HOBT, 622 mg, 3.26 mmol) were combined with anhydrous CH2Cl2 (10 mL) at room temperature. Et3N (0.74 mL, 5.43 mmol) was added in one portion. The resulted solution was maintained at room temperature for 18 h at which time it was concentrated in vacuo to a volume of approximately 5 mL. Then the solution was purified by silica gel chromatography (SGC) eluting with 2:1 hex-EtOAc. The title compound (a pair of diastereomers) was obtained (171 mg, 20%) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.31 (s, 5H), 5.99-5.82 (m, 1H), 5.81-5.65 (m, 1H), 5.50-5.00 (m, 6H), 4.75-4.23 (m, 2H), 3.70-3.37 (m, 3H), 3.11-2.79 (m, 2H), 2.59-2.00 (m, 4H), 1.42 (s, 9H) ppm. MS (CI) 400.6 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=1[Cl:20])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCCCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g (19.0 mmol) of methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate from Example 26 in 10 ml DMF is added 3.0 g (22.8 mmol) of N-chlorosuccinimide in a single portion at room temperature. The resulting solution is allowed to stir 24 hours at room temperature. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered, concentrated and subjected to flash chromatography (20% EtOAc/hexanes) to yield methyl 6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate. This is used in the next step.
Reaction SMILES: Cl.O[CH:3]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH:28][C:29](=[O:34])C(C)(C)C)[CH:4]([CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)C(OC)=O>O>[NH:12]1[CH2:11][CH2:10][CH:9]([C:4]2[C:29](=[O:34])[NH:28][C:27]3[C:22]([CH:3]=2)=[CH:23][N:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cnccc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccncc2cc1C1CCNCC1
Reaction time: 14 h
Yield: 77 %

Procedure:
Concentrated hydrochloric acid (8.0 mL, 97 mmol) was added with stirring to a mixture of tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(4-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate (1.2 g, 2.6 mmol) and water (24 mL). Reaction was heated to reflux and held for 14 hours. Mixture was concentrated in vacuo. Residue was treated with acetonitrile (70 mL) and then concentrated in vacuo. Residue was crystallized from ethanol. Title compound was obtained as white solid in 77% yield. (M+H)+=230.1.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-fluoro-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[O:40]=[C:20]1[C@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: N#Cc1cccc(CBr)c1
Agent: BrCC1CCCCO1
Product: N#Cc1cccc(CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-(bromomethyl)benzonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile was obtained (75%) as a colorless solid: mp 94-96° C. (isopropyl alcohol); 1H NMR (300 MHz, CDCl3) δ 7.65-7.52 (m, 4H), 7.49-7.42 (m, 2H), 7.23-7.15 (m, 1H), 7.08-7.01 (m, 1H), 6.75-6.70 (m, 1H), 6.49 (s, 1H), 6.18 (s, 1H), 5.03 (d, J=15.8 Hz, 1H), 4.95-4.84 (m, 2H), 4.66 (d, J=9.0 Hz, 1H), 4.20-4.07 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4, 29.7; MS (ES+) m/z 411.0 (M+1). Anal. Calcd. for C25H18N2O4: C, 73.16; H, 4.42; N, 6.83. Found: C, 72.92; H, 5.05; N, 6.50.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH2:3][C:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1NC(N)=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g (0.03 mol) of sodium cyanate were added to a solution of 7.91 g (0.02 mol) of N-[(2-aminophenyl)methyl]-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine in a mixture of 5.5 ml glacial acetic acid and 80 ml of water and the mixture was stirred overnight at ambient temperature. The mixture was made slightly alkaline by the addition of saturated sodium hydrogen carbonate solution, then extracted exhaustively with EE. The combined ethyl acetate extracts were washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (99% of theoretical) of colourless crystals were obtained, Rf 0.71 (El D), which were further processed without any additional purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[CH3:24][CH:15]([O:14][C:13]1[CH:25]=[CH:26][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:34](=[O:36])[CH3:35])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH2:16][NH:17][S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 42.2 %

Procedure:
The final title compound (98 mg, 42%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (200 mg, 0.5739 mmol, prepared in example 32) methylene chloride (3.8 mL, anhydrous) triethylamine (0.12 mL, 0.6620 mmol) and acetyl chloride (0.08 mL, 0.6069 mmol), in a manner analogous to Example 29.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][N:15]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=2)[CH2:4][CH2:3]1>Cl>[NH:14]([C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:13]=[CH:12][N:11]=1)[NH2:15]
Reactant: CN1CCN(c2cc(NN=C(c3ccccc3)c3ccccc3)ncn2)CC1
Agent: Cl
Product: CN1CCN(c2cc(NN)ncn2)CC1
Temperature: 25 °C

Procedure:
300 mg (808 μmol) of the compound from Example 5A in 15 ml conc. hydrochloric acid are heated at 65° C. for 4 h. After cooling, the reaction mixture is washed with dichloromethane and the aqueous phase is concentrated. This gives 162 mg of the crude product as the hydrochloride. This is stirred with polymer-bound tris-(2-aminoethyl)amine in dichloromethane at RT. After filtration, the filtrate is concentrated and the residue is dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:54]1([CH2:57][NH:58][CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH2:56][CH2:55]1>CN(C=O)C>[CH:54]1([CH2:57][N:58]([CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:56][CH2:55]1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (306 mg, 0.85 mmol) in DMF (3 mL) was added with HATU (485 mg, 1.28 mmol) and DIEA (0.37 mL, 275 mg, 2.12 mmol). This was sonicated, stirred for 30 min and then 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (200 mg, 0.85 mmol) in 1 mL DMF was added to the mixture. Then it was stirred at room temperature for 16 hours and the mixture was concentrated to dryness. This was purified by silica gel column (eluted with 0-10% methanol in dichloromethane) followed by trituration with methanol to give a white solid as the title compound (93 mg, 0.19 mmol, 22% yield). m/z=495.3 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].C(Cl)Cl.[C-:20]#[N:21].[K+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[C:20]([CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16])#[N:21]
Reactant: [C-]#N
Reactant: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCC1CC(=O)N(c2ccc(F)cc2)C1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
A mixture was prepared of 48.3 g (0.2 moles) 3-chloromethyl-1-(4-fluorophenyl)-pyrrolidine-2,5-dione (according to Example 1), 300 ml methylene chloride and 7 g hexadecyltrimethylammonium chloride, dissolved in 80 ml water. To this mixture, a solution of 28.6 g (0.43 moles) potassium cyanide in 90 ml water was added dropwise at 0° C., and then stirred for 4 hours at 0° C. and another 12 hours at 20° C. The resulting phases were then separated with the organic phase being washed with water and dried with sodium sulfate. Finally, methylene chloride was distilled off and the residue dissolved in 250 ml toluene. Upon standing, the desired product crystallized. The actual yield was 44.1% of the theoretical yield. Melting point 97° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Si:36]([O:35][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:16]=[CH:17][N:18]=[CH:19][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:26][CH:25]=2)[CH2:28][CH2:29]1)([C:39]([CH3:42])([CH3:40])[CH3:41])([CH3:37])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 24.6 %

Procedure:
A 10 mL reaction vessel was charged with compound 4 (153 mg, 604 μmol), compound 247 (215 mg, 604 μmol), tris(dibenzylideneacetone)-dipalladium (0) (41.5 mg, 45.3 μmol), sodium t-butoxide (69.7 mg, 725 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (52.4 mg, 90.6 μmol), and dioxane (3 mL). The reaction was purged with argon and heated with microwave energy at 120° C. for 3.5 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes+2.5%/0-100% ethyl acetate+2.5% TEA, then ethyl acetate+2.5% TEA/0-5% methanol) afforded compound 296 as a yellow solid (85 mg, 25%).
Reaction SMILES: BrC1C=C(NC2C=CC(N3CCN([CH:23]4[CH2:26][O:25][CH2:24]4)CC3)=CN=2)C(=O)N(C)C=1.[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[N:42]=[CH:41][C:40]([N:43]3[C@@H:48]([CH3:49])[CH2:47][N:46](C(OC(C)(C)C)=O)[C@H:45]([CH3:57])[CH2:44]3)=[CH:39][CH:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>>[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:44][C@@H:45]([CH3:57])[N:46]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:47][C@@H:48]3[CH3:49])=[CH:41][N:42]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Yield: 91 %

Procedure:
Following the procedures as described for compound 101k, reaction of 122d (700 mg, 1.79 mmol), afforded 122e as a yellow solid (723 mg, 91%). LCMS: [M+H]+ 448
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>CCO.C1COCC1.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Cl)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of example 85A (0.214 g, 0.505 mmol) in EtOH (2.52 mL) and THF (2.52 mL) was added platinum(IV) oxide (0.115 g, 0.505 mmol), and the resulting mixture was stirred at rt under 1 atm H2 overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give a mixture of the title compound and some dechlorinated product (4,4′-(trans-1-phenylpyrrolidine-2,5-diyl)dianiline).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O.O>C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
to a solution of 0.82 g of 2-mercapto-5-methyl benzimidazole (5 mmoles) in 10 ml of dry THF is added 200 mg of sodium hydride suspension (60% suspension in mineral oil) (5 mmoles). The reaction mixture is heated at reflux temperature for ½ hour. The mixture is then cooled to room temperature and 0.71 g of 5-nitrofuraldehyde (5 mmoles) in 5 ml of THF is added dropwise. The reaction mixture is stirred for ½ hour and then poured into 200 ml of water. The mixture is extracted twice with 75 ml of EtOAc. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH 97/3 as eluent. 1.07 g of 5-(5-Methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is isolated as a black glassy solid (yield=83%). Analytical LC/MS method A: ([M+H]+): 259, RT: 3.64 min (gradient 0 to 50% acetonitrile in 7 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[O:5][C:6]2=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.[Pd]>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[O:5][CH:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=C1OC(=O)c2c(N)cccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1OC(=O)c2c(N)cccc21
Reaction time: 3 h

Procedure:
120 mg (0.51 mmol) ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate are dissolved in 50 ml of methanol and combined with 50 mg palladium on activated charcoal (10% Pd). The reaction mixture is hydrogenated for 3 h at 2 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2)#[N:2]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: N#Cc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]ncc2c1
Temperature: 0 °C

Procedure:
To a solution of LiAl H4 (0.76 g, 20.1 mmol) in THF (10 mL) cooled to 0° C. was added a solution of 5-cyanoindazole (0.64 g, 4.47 mmol) in THF (10 mL) dropwise. After 0.5 h the reaction mixture was warmed to reflux for 2 h, then cooled to 0° C. and quenched by the careful addition of water (0.76 mL), 1.0 N sodium hydroxide (0.76 mL), and water (2.28 mL). This mixture was filtered through a pad of celite and washed with THF/MeOH (3:1, 300 mL). Removal of the solvent in vacuo provided a solid which was purified via flash column chromatography (25×150 mm column; elution with MeOH:CH2Cl2:CH2Cl2 saturated with NH3, 10:60:30). This afforded the title compound as a light yellow solid:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]([F:33])([F:32])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][O:28][CH2:29][CH2:30]O)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>C(Cl)Cl>[F:7][CH2:30][CH2:29][O:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([C:11]([F:33])([F:32])[F:10])=[N:13][N:14]=3)[N:17]=2)[CH2:22][CH2:23]1
Reactant: OCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.1 %

Procedure:
(Diethylamino)sulfur trifluoride (0.059 mL, 0.45 mmol) was added dropwise to a stirred solution of 2-[[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl)methoxy]ethanol (104 mg, 0.3 mmol) in DCM (3 mL) at −70° C. The solution was allowed to warm to ambient temperature and stir for 18 hours. The solution was diluted with DCM and washed with 2M aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[(2-fluoroethoxy)methyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (22.0 mg, 21%) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]([OH:25])[CH2:10][NH:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:38][C:39]1[O:43][N:42]=[C:41]([C:44]2[S:45][CH:46]=[C:47]([CH:49]=O)[N:48]=2)[CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]([OH:25])[CH2:10][N:11]([CH2:49][C:47]1[N:48]=[C:44]([C:41]2[CH:40]=[C:39]([CH3:38])[O:43][N:42]=2)[S:45][CH:46]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: Cc1cc(-c2nc(C=O)cs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)NN(Cc1csc(-c2cc(C)on2)n1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A solution of Example 19A (0.4 g, 0.86 mmol) in dichloroethane (5.7 mL) was treated with acetic acid (99 μL, 2 equivalents), 2-(5-methyl-3-isoxazolyl)thiazole 4-carboxaldehyde (0.199 g, 1.2 equivalents), and sodium triacetoxyborohydride (0.545 g, 3 equivalents) and stirred at 25° C. for 16 hrs. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated. The crude residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 0.55 g (60%) of the title compound.