Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=O)=[CH:3]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]#[N:13])=[CH:3]1
Reactant: NC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccccc1Oc1cn[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzamide (31.1 g, 0.14 mol) in methylene chloride and triethylamine (65.5 g, 0.65 mol) was treated dropwise with trifluoroacetic anhydride (62.2 g, 0.30 mol). The resulting solution was stirred at 25° C. for 5 min. After this time, the reaction was washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo to afford 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (25.1 g, 87%) as a white solid; ESI-MS 214 [M+H+]; HPLC: >95% (purity). 1H-NMR (300 MHz, CDCl3) δ 11.75 (s, 1H), 7.91 (s, 1H), 7.71-7.81 (m, 2H), 7.44-7.49 (m, 1H), 7.28-7.30 (m, 1H), 5.98 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[F:12][C:13]1[C:18]([CH2:19]Br)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]>>[F:12][C:13]1[C:18]([CH2:19][O:1][C:2]2[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH2:19][C:18]3[C:17]([F:21])=[C:16]([F:22])[C:15]([F:23])=[C:14]([F:24])[C:13]=3[F:12])[CH:7]=2)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CC(=O)c1cc(O)cc(O)c1
Product: CC(=O)c1cc(OCc2c(F)c(F)c(F)c(F)c2F)cc(OCc2c(F)c(F)c(F)c(F)c2F)c1
Yield: 98 %

Procedure:
Synthesized by 1:2 ratio of 3',5'-dihydroxyacetophenone to pentafluorobenzyl bromide. Yield: 98%. m.p. 102°-103° C. 1H NMR, δ: 2.60 (s, 3H, CH3CO), 5.22 (s, 4H, CH2O), 6.83 (bs, 1H, H-C4'), 7.24 (d, 2H, J=1.8 Hz, H-C2' & H-C6') ppm; 13C NMR, δ: 26.0 (CH3CO), 57.4 (CH2O), 106.4 (C4'), 107.4 (C2' & C6'), 109.7 (C1", 2JC-F =17 Hz) 137.4 (C2" & C6", JC-F =249 Hz), 139.2 (C1'), 141.7 (C4", JC-F =256 Hz), 145.7 (C3" & C5", JC-F =251 Hz), 159.2 (C3' & C5'), 196.7 (C=O) ppm. MS(EI): 331 ([M-PFBz]+); MS(ECNI): 331 ([M-PFBz]-, 100%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[NH2:36][C@H:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[OH:41]>C1COCC1.CN(C=O)C.O>[C:46]([O:45][C:43](=[O:44])[CH:37]([NH:36][C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Icosanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (6.01 g, 12.124 mmol) was dissolved in THF (150 mL) and mixed with a slurry of H-Glu-OtBu (2.71 g, 13.33 mmol) in DMF/water (1/1, 40 mL). This resulted in a gel-like solution which was heated to give a clear solution that was stirred at RT for 3 h. Then the solution was evaporated, 100 mL of water was added and the mixture was heated to 60° C. which resulted in a solution which crystallised on cooling. The precipitate was recrystallised from acetonitrile and the crystals were dried in vacuum. Yield 6.82 g (96%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:19]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:26]1[CH:27]=[C:28]([F:30])[CH:29]=[CH:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)cc1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)ethanol (4.34 g, 26.9 mmol) in THF (16 mL) at 0° C. under N2, was added potassium tert-butoxide (K+−OtBu, 26.9 mL, 26.9 mmol, 1.0 M in THF). The reaction mixture was stirred for 20 min at 0° C. during which time a thick slurry formed. The anion solution was then poured into a solution of ethyl 2,4-di-fluorobenzoate (5.00 g, 26.9 mmol) in THF (16 mL) which had been cooled to −65° C. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 h. The mixture was diluted with dichloromethane and washed with water. The water layer was extracted with additional dichloromethane and the dichloromethane layers combined and washed with brine, dried, and concentrated in vacuo to give a yellow oil. Purification on silica gel, eluting with a gradient of 4:1 to 3:1 hexane:EtOAc, yielded 3.82 g (43.5%) of the ether as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[H][H].C(OCC)(=O)C>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Yield: 127.5 %

Procedure:
10% Palladium on carbon (200 mg) was added to a solution of 2-(3-fluoro-4-nitro-phenoxy)-2-methyl-propionic acid ethyl ester (1.15 g, 4 mmol) in ethanol (20 ml). The suspension was hydrogenated at a hydrogen gas pressure of 1.7 bar for 8 h at ambient temperature. Ethyl acetate was added (100 ml), the solid was filtered off and the filtrate was brought to dryness under reduced pressure to give the title compound (1.23 g, quant.) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (400 mg) produced in Example 102 was suspended in dimethyl sulfoxide (40 ml). After adding potassium carbonate (540 mg), the mixture was stirred at room temperature for 30 minutes, and 3-bromo-1-propanol (0.3 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[N:15]=[CH:14][C:13]2=[CH:22][CH:23]=[CH:24][N:12]12.[Cl-].[NH4+]>O1CCCC1>[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[NH:15][CH:14]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[C:13]2=[CH:22][CH:23]=[CH:24][N:12]12
Reactant: CN1c2ccncc2N=Cc2cccn21
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2Nc3cnccc3N(C)n3cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a warm Grignard reagent prepared from 7.2 g of 4-chloro-1-methyl piperidine and 1.4 g of magnesium metal in 50 ml of tetrahydrofuran was added a solution of 5.3 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 15 minutes, added to an iced ammonium chloride solution and extracted with ethyl acetate (3×). The combined organics were washed with water (2×) followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% methanol/dichloromethane). Recrystallization from ethyl acetate)methanonl (20:1) afforded 1.65 g of 10,11-dihydro-5-methyl-10-[(1-methyl)piperidin-4-yl]-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp: 235°-238° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCOc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.99-6.93 (m, 2H, partially overlapping 6.91), 6.91 (dd, J=8.9, 2.3 Hz, 1H), 6.80-6.73 (m, 2H), 4.07 (t, J=5.7 Hz, 2H), 3.92 (t, J=5.7 Hz, 2H), 3.40 (s, 2H), 1.01 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH2:29]([CH2:31][NH2:32])[OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([NH:32][CH2:31][CH2:29][OH:30])=[O:6]
Reactant: NCCO
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(NCCO)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (97 mg, 0.248 mmol) and ethanolamine (18 μl, 0.298 mmol). MS (ESI) m/z: Calculated: 433.1; Observed: 434.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31]O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:54]>>[Cl:54][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][S:14][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][C:9]=4[CH3:13])[N:4]=3)=[CH:17][CH:18]=2)=[O:33])=[CH:24][CH:25]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCO)cc4)cc3)n(C)c(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12

Procedure:
To a suspension of 3,5-dimethyl-2-[4-[4-(2-hydroxyethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone (651 mg) in carbon tetrachloride (15 ml) was added triphenylphosphine (476 mg) and the mixture was refluxed for 40 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane) and recrystallized from ethyl acetate to provide the title compound as colorless solid (391 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(Br)c(C=O)c2)O1
Temperature: 150 °C
Reaction time: 10 h
Yield: 52 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (62; 5 g, 0.025 mol) in DMF (100 ml) was added (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (63; 4.87 g, 0.032 mol) and K2CO3 (7.0 g, 0.05 mol). The resulting reaction mixture was stirred at 150° C. for 10 h, cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtOAc=10:1 to afford the desired product, namely (S)-2-bromo-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde 64 (4.1 g, 56%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[CH2:28][CH2:27]3)=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)CCCC4=O)CC2)cc(OC)c1OC
Yield: 75.1 %

Procedure:
Using 1-oxo-1,2,3,4-tetrahydro-6-naphthoic acid [Itoh et al., Chem. Pharm. Bull., 32, 130 (1984)] (0.8 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.25 g), triethylamine (1.7 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (1.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethanol, ethyl acetate and ethyl ether to give 1-(1-oxo-1,2,3,4-tetrahydro-6-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.5 g) as colorless crystals, m.p. 210°-215° C. (decomp.).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.O[N:10]=[C:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O>C(O)(=O)C.[Zn]>[CH2:14]1[C:15]2[CH:11]([NH:10][CH:1]3[C:2]=2[C:3](=[O:7])[CH:4]=[CH:5][CH2:6]3)[CH2:12][CH2:13]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C1CCCC1=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1C=CCC2NC3CCCC3=C12
Temperature: 0 °C

Procedure:
To a solution of 27.6 g (0.25 mole) of 1,3-cyclohexanedione and 27.6 g (0.244 mole) of the crude 2-hydroxyiminocyclopentanone in 435 mL of 70% aqueous acetic acid was added 47.6 g (0.73 g-atom) of zinc powder in about 5 g portions. The reaction was exothermic, but did not reach reflux. The mixture was heated to 80°-85° C. under argon for 2 hours and poured into 1.3 L of ice water and extracted with 3×300 mL of methylene chloride. The methylene chloride extracts were washed to neutrality with 3×500 mL of saturated sodium bicarbonate solution, dried over Na2SO4, and concentrated on a rotary evaporator to 50° C.
Reaction SMILES: C([BH3-])#N.[Na+].C([O:7][C:8](=O)[C:9]([CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][C:20]=1[Cl:34])([CH2:15][CH:16]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.Cl.Cl.[N:38]1[C:42]2[CH2:43][CH2:44][CH:45]([NH2:47])[CH2:46][C:41]=2[NH:40][CH:39]=1.C(O)(=O)C>CO>[CH2:13]([O:12][C:10]([C:9]1([CH2:18][C:19]2[C:20]([Cl:34])=[CH:21][C:22]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][C:24]=2[Cl:25])[CH2:15][CH2:16][N:47]([CH:45]2[CH2:44][CH2:43][C:42]3[N:38]=[CH:39][NH:40][C:41]=3[CH2:46]2)[C:8]1=[O:7])=[O:11])[CH3:14]
Reactant: NC1CCc2nc[nH]c2C1
Reactant: CCOC(=O)C(CC=O)(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN(C2CCc3nc[nH]c3C2)C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
Add sodium cyanoborohydride (3.6 g, 57.4 mmol) portion wise to a solution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester (6.7 g, 14.4 mmol) (Preparation 10) and 4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylamine dihydrochloride salt (6.0 g, 28.7 mmol) (Preparation 1) in 70 ml of Methanol. After 3 h, add 4 ml of acetic acid and warm to 60° C. for 16 h. Most of the Methanol is removed via rotovap. Quench the resulting mixture with saturated bicarbonate and extract with ethyl acetate. Dry extracts over sodium sulfate, concentrate, and purify by normal phase column chromatography (0-10% methanol in ethyl acetate) to afford 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl ester as a white solid (3 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7]([C:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[N:13]=1)=[CH2:8].O1C=CNC1=O.C(C1C=C(O)C=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:11](=[O:16])[C:12]([CH3:15])([NH:13][C:9](=[O:10])[CH:7]=[CH2:8])[CH3:14]
Reactant: CN(C)CCN
Reactant: C=CC1=NC(C)(C)C(=O)O1
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: O=c1[nH]cco1
Solvent: c1ccccc1
Product: C=CC(=O)NC(C)(C)C(=O)NCCN(C)C
Reaction time: 2 h

Procedure:
A solution of 100 g. of N,N-dimethylethylenediamine in 40 cc. of benzene was added dropwise to a stirring solution of 16.4 g. of 2-vinyl-4,4-dimethyl-5-oxazolone in 50 cc. of benzene. The oxazolone solution contained a few milligrams of t-butylhydroquinone as a polymerization inhibitor. An external water bath was used to maintain the resultant solution at about 25° C. The solution was stirred about 2 hours, filtered through Celite, and evaporated. The residue after evaporation was triturated with hexane and the mixture filtered to provide N-(N',N'-dimethyl-β-aminoethyl)-2-methyl-2-acrylamidopropanoic acid amide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CS(C)=O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:12]#[N:13]
Reactant: BrCCCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccccn2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Yield: 81.5 %

Procedure:
The title compound is prepared by the procedure of Example 113 using 1.3 g of product from Example 117, 0.218 g of 50% sodium hydride, 2.15 g of 1,5-dibromopentane and 16 ml of dimethyl sulfoxide to give after chromatography 1.61 g of the desired product as a yellow oil. Calcd for C20H23N2SBrO2 : C=55.18; H=5.32; N=6.43; S=7.36; Br=18.35 Found C=55.39; H=5.33; N=6.32; S=7.16; Br=18.17
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O>[Pd].C(O)C.O>[NH2:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@H](N)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2

Procedure:
A solution of N-carbobenzoxy-L-alanyl-N-(5-indanyl)glycine (4.5 g) and 10% palladium on carbon (1.0 g) in 250 ml ethanol was hydrogenated at 25 psi for 2 h and filtered. Concentration of the volatiles in vacuo provided a residue which was dissolved in H2O and filtered over Celite. Lyophilization of the filtrate provided the crystalline (m.p. 119°-120° C.) product.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]1[NH:4][CH2:5][CH2:6][CH2:7]2.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH:16]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]2([CH3:1])[CH2:14][C:13]3[C:8]([CH:3]12)=[CH:9][CH:10]=[CH:11][CH:12]=3)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CC12CCCNC1c1ccccc1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)N1CCCC2(C)Cc3ccccc3C12
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
To a solution of (4aRS,9bRS)-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (140 mg) and acetone (217 mg) in 1,2-dichloroethane was added sodium triacetoxyborohydride (792 mg), followed by stirring at room temperature for 3 days. A 1 M aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain (4aRS,9bRS)-1-isopropyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (138 mg) as an oily substance. This was made into a salt using an equivalent amount of methanesulfonic acid by a conventional method, washed with ethyl acetate, and collected by filtration to obtain (4aRS,9bRS)-1-isopropyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine methanesulfonate (95 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[C:26]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[N:25][N:24]=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([C:26]4[NH:25][N:24]=[N:23][N:22]=4)=[CH:28][CH:29]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 83%, 0.18 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 1.2 eq. of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 17 mg (22% of theory)
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CS(O[CH2:16][C:17]#[CH:18])(=O)=O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N:1][CH2:16][C:17]#[CH:18]
Reactant: O=Cc1ccccc1Cl
Reactant: N
Reactant: C#CCOS(C)(=O)=O
Solvent: Cc1ccccc1
Product: C#CCN=Cc1ccccc1Cl
Reaction time: 10 h

Procedure:
An aqueous 28% ammonia solution (12.1 g, 200 mmol) and o-chlorobenzaldehyde (3.65 g, 26 mmol) were mixed and a solution prepared by dissolving propargyl methanesulfonate (2.68 g, 20 mmol) in 10.7 g of toluene was added dropwise at 20° C. over 0.6 hour to the solution, followed by stirring at the same temperature for 10 hours. After separating, the resulting organic phase was concentrated to obtain a crude product of N-(2-chlorobenzylidene)-2-propynylamine.