Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:12]([F:23])[CH:11]=1)[CH3:9])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:12]([F:23])[CH:11]=1)[CH3:9]
Reactant: C=Cc1cc(C(C)NC(=O)OC(C)(C)C)cc(F)c1NS(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(C(C)N)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 134.2 %

Procedure:
[1-(3-fluoro-4-methanesulfonylamino-5-vinyl phenyl)ethyl]carbamic acid tert-butyl ester (0.06 mmol, 20.2 mg) was dissolved in methylene chloride, 5˜6 drops of CF3COOH were added. A reaction mixture was stirred for 12 hr. A toluene was added. The reaction mixture was concentrated in vacuo to yield brownish syrup (20.8 mg, 100.0%).
Reaction SMILES: [CH2:1]([C:11]1[CH:29]=[CH:28][C:14]([CH2:15][NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([C:11]1[CH:29]=[CH:28][C:14]([CH2:15][NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(CNc2ccc(C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-{[(p-decyl)benzyl]amino}benzoate (prepared as described in Example 58) and 2.84 g. of potassium hydroxide in 90 ml. of 95% ethanol is refluxed for 5 hours. Concentrated hydrochloric acid is added and the mixture diluted with 100 ml. of water. Filtration gives crystals which are washed with water to give a crude product. Recrystallization from ethanol gives white crystals, m.p. 135°-136° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)#[N:29]>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2nc(-c3cccc([N+](=O)[O-])c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and 4-cyanobenzyl bromide according to Method A; LC retention time 2.53 min; MS: m/z (ESI) 478 (M+H).
Reaction SMILES: CN1CC(=O)OB([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][C:12]=2[O:22][C@H:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])OC(=O)C1.[CH2:29]([O:32][C:33]1([CH3:67])[CH2:38][CH2:37][N:36]([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50](Br)[CH:49]=4)[N:47]=[C:43]3[C:42]([CH3:55])=[C:41]([CH3:56])[C:40]=2[C@H:57]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:58]([O:60][CH3:61])=[O:59])[CH2:35][CH2:34]1)[CH:30]=[CH2:31].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:29]([O:32][C:33]1([CH3:67])[CH2:34][CH2:35][N:36]([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:49]=[C:50]([C:11]5[CH:16]=[C:15]([O:17][C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:13][C:12]=5[O:22][C@H:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])[CH:51]=[CH:52][CH:53]=4)[N:47]=[C:43]3[C:42]([CH3:55])=[C:41]([CH3:56])[C:40]=2[C@H:57]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:58]([O:60][CH3:61])=[O:59])[CH2:37][CH2:38]1)[CH:30]=[CH2:31]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1B1OC(=O)CN(C)CC(=O)O1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(OC(F)(F)F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 92 %

Procedure:
Prepared from (S)-6-methyl-2-(2-(pent-4-en-2-yloxy)-5-(trifluoromethoxy)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 92% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 746.85.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:31])=[O:32])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[C:15]([NH2:49])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 1 h

Procedure:
7-Benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (2.83 g) was dissolved in chloroform (30 mL). 3-Chloroperoxybenzoic acid (60% pure, 2.21 g, 7.7 mmol) was added in one portion and the mixture was stirred for 1 hour. Ammonium hydroxide (30 mL) was added and the biphasic mixture was stirred for 20 minutes. p-Toluenesulfonyl chloride (1.07 g, 5.6 mmol) was added in one portion and the reaction was stirred for 16 hours. A white precipitate formed. The mixture was diluted with dichloromethane (solid remains in the organic fraction) and the layers were separated. The organic fraction was washed with 5% aqueous sodium bicarbonate (solid moves to the aqueous fraction). The layers were separated, followed by filtration of the solid from the aqueous fraction. The solid was sequentially washed with water and diethyl ether; slurried in acetonitrile; filtered; and dried to yield 1.5 g of 7-benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 225-227° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]#[C:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:9]#[C:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(I)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCCC#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 10.0 gm (35.3 mmol) of 3-iodo-bromobenzene in DMF was treated with 2.95 mL (88 mmol) of 4-butyne-1-ol, 0.2 gm (1.06 mmol) of copper (I) iodide, 1.23 gm of dichlorobis(triphenylphosphine)-palladium(II), and 49 mL (0.35 mol) of triethylamine, stirred at room temperature for 18 h, poured into water and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried over Na2SO4 and concentrated at reduced pressure. Chromatography of the resultant concentrate on silica gel with a gradient of 5% to 30% EtOAc-hexanes afforded 4-(3-bromophenyl)but-3-yn-1-ol as an orange oil, 7.3 gm (92% yield); 1H NMR (400 MHz, CDCl3) δ: 1.79 (s, 1H), 2.67 (t, 2H, J=6.3 Hz), 3.80 (t, 2H, J=6.3 Hz), 7.14 (t, 1H, J=7.9 Hz), 7.30 (d, 1H, J=7.9 Hz), 7.41 (m, 1H), 7.54 (t, 1H, J=1.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C(N(CC)CC)C>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:17])[C:13](=[CH2:14])[CH3:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CC(C)(Br)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=C(C)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 3',4'-dihydroxy-5'-nitro-2-bromoisobutyrophenone (2.6 g) and triethylamine (20 ml) in pyridine (20 ml) was heated for 3 hours at 100° C. Triethylamine and pyridine were evaporated in vacuo. Ether and 2N H2SO4 were added. The organic phase was separated and dried over Na2SO4. The ether solution was treated with charcoal for 2 hours, filtered and evaporated to dryness. The residue was crystallized from dichloromethane-petroleum ether (40°-60° C). Yield 0.48 g, mp 98°-102° C.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][CH:16]([C:21]([CH3:23])=O)[C:17](OC)=[O:18])=[CH:13][CH:12]=1.O>CO>[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][C:16]2[C:17](=[O:18])[NH:4][C:2]([CH3:3])=[N:5][C:21]=2[CH3:23])=[CH:13][CH:12]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of methyl acetoacetate (3.2 mL) 4-methoxy-benzyl chloride (4.1 mL), lithium bromide (2.6 g) and diisopropylethylamine (5.2 mL) in tetrahydrofuran (60 mL) was heated under reflux for 15 hours. After the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 2-(4-methoxybenzyl)acetoacetate. To a suspension of acetoamidine hydrochloride (2.0 g) in methanol (60 mL) was added sodium methoxide (28% solution in methanol, 2.6 mL), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added a solution of methyl 2-(4-methoxy-benzyl)acetoacetate in methanol (6 mL), and the mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitated crystals were collected by filtration and dried to give 5-(4-methoxybenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.54 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CC(=O)CC>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1NCCn2c1cc1cc(OCCCCl)ccc12

Procedure:
The suspension consistent of 0.5 g (2.4 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1, intermediate a), 0.41 g (2.6 mmol) potassium carbonate and 0.29 ml (0.47 g, 3.0 mmol) 1-bromo-3-chloropropane in 12 ml 2-butanone was heated under reflux for 64 hours. The reaction mixture was evaporated to dryness to give a light brown solid containing the desired product together with some starting material (0.58 g, 55%). This mixture was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[CH3:2][N:3]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[CH2:29][C:28]1[CH:31]=[CH:32][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CNCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 94 %

Procedure:
N-methyl-1-naphthylmethylamine hydrochloride (2.1 g; 0.01 mole) was dissolved in 50 ml of dry dimethylformamide, and 3.71 g (0.035 mole) of anhydrous sodium carbonate was added. The mixture was stirred at room temperature, and 2.49 g (0.011 mole) of p-t-butylbenzyl bromide was added. The mixture was reacted at 30° to 40° C. for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 2.98 g (yield 94%) of an oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22].O>CN(C=O)C>[CH3:22][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
(R)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (C13H17N3O3); MS (ESI): 264 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+].[C:17]([Cu])#[N:18].[C-]#N.[K+]>O>[C:17]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6])#[N:18]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
3-Amino-4-chlorobenzoic acid (18.72 g, 109.1 mmol), commercially available, was added to a mixture of water (200 mL) and 37% HCl (35 mL), and the resulting slurry was cooled to 5° C. A solution of NaNO2 (8.65 g, 125 mmol) in water (70 mL) was added dropwise, and the solution stirred at 5° C for 30 min. The solution was then added to a slurry consisting of water (400 mL), CuCN (9.85 g, 109 mmol),and KCN(12.06g, 185 mmol), while maintaining the temperature at5°-10° C. The mixture was stirred at 10° C. for another 30 min, and then heated to 80° C. for 1 hour. The reaction was cooled, and the pH adjusted to ~1 by addition of concentrated HCl. The solution was extracted with 5× CHCl3, and the combined extracts were rinsed with 1M HCl and brine, and dried over MgSO4. The solvent was removed in vacuo, and the crude product was recrystallized from CHCl3 /EtOAc to yield 15.9 g (80%) of the title compound. m.p. 180° C. 1H NMR (300 MHz, CDCl3) δ 10.55 (br s, 1H), 8.42 (d, 1H), 8.26 (dd, 1H), 7.68 (d, 1H). MS (DCI/NH3) m/e 213 (M+NH4)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([Br:16])[C:8]=1[CH:9]=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>CO>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][N:27]=[CH:9][C:8]2[C:7]([Br:6])=[CH:14][C:13]([CH3:15])=[CH:12][C:11]=2[Br:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(NN=Cc2c(Br)cc(C)cc2Br)cc1

Procedure:
Sodium bicarbonate (0.84 g, 10 mmol) was added to a solution of 2,6-dibromo-4-methylbenzaldehyde (2.62 g, 9.43 mmol) and [4-(methyloxy)phenyl]hydrazine hydrochloride (1.65 g, 9.45 mmol) in methanol (60 mL) and the mixture heated under reflux for 15 min. The mixture was then cooled and evaporated to give the crude title compound which was used without purification.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([O:16][CH3:17])[CH:5]=1.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.FC(F)(F)C(O)=O>C1COCC1.C(Cl)Cl>[CH2:44]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[C:6]([O:16][CH3:17])[CH:5]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1cc(O)ccc1N1CCNCC1
Reactant: BrCc1ccccc1
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(OCc2ccccc2)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
1-(4-Hydroxy-2-methoxyphenyl)piperazine dihydrobromide (1.95 g, 5.27 mmol) was dissolved in 10 mL of THF and 10 mL of saturated sodium bicarbonate solution and then di(tert-butyl)pyrocarbonate (1.35 g, 6.2 mmol) was added. The mixture was stirred vigorously at room temperature for 18 hours and extracted with diethyl ether (3×25 mL). The combined extracts were washed with brine, dried (MgSO4) and filtered. The solvents were removed in vacuo and the residue was dissolved in 20 mL of DMF. The solution was treated with cesium carbonate (1.46 g, 4.5 mmol) and then benzyl bromide (1.1 g, 4.6 mmol) and stirred at room temperature under nitrogen for 3 hours. The mixture was partitioned between 50 mL of water and 50 mL of diethyl ether. The aqueous layer was separated and extracted with diethyl ether (2×50 mL). The combined diethyl ether was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (3:1) to give a pale yellow oil. The oil was dissolved in 20 mL of methylene chloride and the solution was treated with 10 mL of trifluoroacetic acid. After 45 minutes at room temperature the mixture was partitioned between 100 mL of 5M aqueous potassium carbonate and 100 mL of methylene chloride. The aqueous layer was separated and extracted with methylene chloride (2×100 mL). The combined methylene chloride was washed with brine, dried (Na2SO4), filtered and concentrated to give 1-(4-benzyloxy-2-methoxyphenyl)piperazine (1.39 g, 4.7 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1>>[O:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCC1CCCO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCO3)CC1)O2

Procedure:
Compound 117 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)tetrahydrofuran and conditions outlined in procedure V. M.p.=155-159° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.75 (m, 1H), 3.0-2.8 (m, 4H), 2.6-2.4 (m, 4H), 2.2-2.1 (m, 2H), 2.1-1.8 (m, 5H), 1.5 (m, 1H); LCMS: 386 [M+H].
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:10]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(c2cccc(Cl)c2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2)C(c2cccc(Cl)c2)NC(C(=O)O)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 42a (0.45 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.49 g, 98%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[H][H]>CCOC(C)=O.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (27.13 g, 74.04 mmol) was taken up in EtOAc (1000 mL) and 10% Palladium on Carbon was added as a slurry in EtOAc. The reaction was placed under a balloon of hydrogen gas and was allowed to stir at rt for 3 days. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (24.25 g, 97%). MS (M+H, ES+) 337.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([N:7]([CH3:20])[C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(-c2ccccc2)cc1)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
13.00 g (49.0 mmol) N-(Biphenyl-4-yl)-2,2,2-trifluoro-acetamide (II.1.a) is dissolved in 200 mL acetone and 13.5 g (98.0 mmol) potassium carbonate is added. 3.50 mL (55.7 mmol) methyl iodide is added and the mixture is stirred at RT over night. The solvent is evaporated. The residue is taken up in water and extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated.
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=3)[C:22]([CH2:36][CH3:37])=[C:21]([O:38]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:36]([C:22]1[C:21]([OH:38])=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[O:8])[NH:24][C:23]=1[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH3:35])[CH:28]=2)[CH3:37]
Reactant: CCc1c(-c2cc3ccc(OC)cc3[nH]2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(-c2cc3ccc(OC)cc3[nH]2)[nH]c(=O)c(C(=O)O)c1O
Reaction time: 8 h
Yield: 34.3 %

Procedure:
The intermediate obtained in Step 4 (170 mg, 0.24 mmol) was dissolved in a mixed solvent of MeOH (0.5 mL) and ethyl acetate (2.0 mL) and hydrogenated with 10% Pd on charcoal (50 mg) using a balloon at room temperature. LC/MS showed complete conversion was achieved overnight. The catalyst was filtered over Celite and washed with 5% MeOH in DCM. The filtrate was concentrated to dryness and the residue was triturated with DCM and dried to provide the title compound as a pale yellow powder (27 mg) in 34% yield.