Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH:16]1([CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.[Al+3].[Cl-].[Cl-].[Cl-]>CCCCCC.C1C=CC=CC=1.O1CCCC1>[CH:16]1([CH2:21][C:22]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:23][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH:16]1([CH2:21][C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)CC(C)=O
Agent: O=C(CC1CCCC1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CC2CCCC2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium in hexane, 25 mmol of 2-cyclopentyl-l-phenyl-ethanone and 70 mL of tetrahydrofuran. 2-Cyclopentyl-1-phenyl-ethanone was prepared by reacting the appropriate acid chloride with AlCl3 in benzene as described by Vogel in Practical Organic Chemistry 1978, 770-775. Upon concentrating the reaction, a solid precipitated out which was recrystallized from ethyl acetate (m.p. 158-160° C.). 1H NMR (DMSO-d6) δ 0.8-0.9 (m, 1 H), 1.0-1.1 (m, 1 H), 1.2-1.8 (m, 7 H), 1.9-2.1 (m, 2 H), 2.9 (ABq, 2 H), 4.8 (s, 1 H), 7.2-7.4 (m, 5 H), 11.3 (s, 1 H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45](C(Cl)=O)=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:19][CH2:18]2)=[O:21])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)c3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (6 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (15 ml), and the solution was added triethylamine (2 ml, 14.35 mmol). To the solution, 4-chlorobenzoyl chloride (150.7 mg, 0.86 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether-ethyl acetate to afford (S)-(4-chlorophenyl)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]methanone (282 mg, yield 85%) as a yellow powder.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=1>C(Cl)Cl>[C:1]([NH:9][C:10]([NH:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH:27]=[CH:26][N:25]=1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCc1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: COc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Benzoyl isocynate (132 mg, 0.896 mmol) is added to a solution of 4-[2-(2-methoxy-phenyl)-ethyl]-pyridin-2-ylamine (93.0 mg, 0.407 mmol) in CH2Cl2 (4 mL), and the mixture is stirred at 60° C. After 20 hours, the mixture is concentrated to give the crude product, which is used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]([CH2:27][CH2:28][O:29]C)[CH2:23][CH2:24][O:25]C)(=[O:21])=[O:20])[C:13]=1[OH:31])=[O:10].[Br-].[Al+3].[Br-].[Br-]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]([CH2:23][CH2:24][OH:25])[CH2:27][CH2:28][OH:29])(=[O:21])=[O:20])[C:13]=1[OH:31])=[O:10]
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Agent: [Al+3]
Agent: [Br-]
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)N(CCO)CCO)c1O
Yield: 43.7 %

Procedure:
A solution of N-(2-bromophenyl)-N′[4-chloro-3-[N″,N″-di-(2-methoxyethyl)-aminosulfonyl]-2-hydroxyphenyl] urea (9.9 mg, 0.018 mmol) and aluminum bromide (4.2 mg, 0.018 mmol) in 2 mL of ethanethio was stirred for 16 hours at room temperature. The mixture was concentrated. The residue was diluted with ethyl acetate, then washed with 1 N aq. HCl, the organic layer was dried over MgSO4 and concentrated. Recrystallization from acetone and methanol gave the desired product (4 mg, 44%). 1H NMR (MeOD-d4): δ 8.30 (d, 1H), 7.92 (d 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.07 (d, 1H), 7.01 (t, 1H), 3.68 (t, 414), 3.51 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:4]=1.[C:24](#[N:26])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[F:10][C:9]([F:12])([F:11])[CH2:8][N:7]1[C:3]([CH2:2][C:24]#[N:26])=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:6]1
Reactant: FC(F)(F)Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: N#CCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 9 b], 5-chloromethyl-1-(2,2,2-trifluoro-ethyl)-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole was reacted with tetrabutylammonium cyanide in acetonitrile to give [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile as yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1>C(O)(=O)C.Br.C(OCC)(=O)C.CO>[OH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Oc2ccc(O)cc2)c1

Procedure:
An amount of 3-(4'-methoxyphenoxy)benzoic acid (40.7 g, 0.167 mole) was dissolved in 200 ml of acetic acid to which 150 ml of a 48 percent solution of hydrogen bromide (HBr) was added (Aldrich Chemical Company). The reaction mixture was heated to reflux under nitrogen for 14.5 hours. The cooled reaction mixture was then diluted with 400 ml of ethyl acetate (EtOAc), washed with saturated NaCl (3×150 ml), dried with MgSO4, filtered, and solvent evaporated to afford a dark brown solid. The crude product was dissolved in methanol, treated with activated carbon, filtered through a celite pad, and evaporated. Recrystallization of the product (1:1 acetic acid/water) gave 3-(4'-hydroxyphenoxy)benzoic acid as tan crystals with a m.p. of 163° C. to 166° C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].[OH:24][CH2:25][CH2:26][NH:27][NH2:28]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:28][N:27]2[CH2:26][CH2:25][OH:24])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNCCO
Agent: CC(=O)[O-]
Agent: [Na+]
Product: OCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 14 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and 2-hydroxyethylhydrazine (0.085 g, 1.0 mmol) to give 0.020 g of product as a white solid
Reaction SMILES: C([Mg]Br)C.C[O:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[C@@H:14]([CH3:21])[CH2:13][C:12]([O:24][CH3:25])([O:22][CH3:23])[C@@H:11]3[OH:26])[CH:8]=1.[H-].[Na+].C(S)C>O1CCCC1.CN(C)C=O>[CH3:25][O:24][C:12]1([O:22][CH3:23])[C@H:11]([OH:26])[C:10]2[C:15](=[CH:16][N:17]=[C:18]3[C:9]=2[CH:8]=[C:7]([OH:6])[CH:20]=[CH:19]3)[C@@H:14]([CH3:21])[CH2:13]1
Reactant: COc1ccc2ncc3c(c2c1)[C@@H](O)C(OC)(OC)C[C@@H]3C
Agent: CC[Mg]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCS
Product: COC1(OC)C[C@H](C)c2cnc3ccc(O)cc3c2[C@H]1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
A solution of ethylmagnesium bromide in tetrahydrofuran (1.0M, 8.90 mL, 8.90 mmol, 1.10 equiv) was added by syringe to a solution of (7S, 10R)-7,8,9,10-tetrahydro-2,9,9-trimethoxy-7-methyl-10-phenanthridinol (15, 2.46 g, 8.10 mmol, 1 equiv) in tetrahydrofuran (5 mL) at -78° C. The reaction flask was transferred to an ice bath for 10 min, then was cooled to -78° C. A 100-mL flame-dried Schlenk-type flask was charged with sodium hydride (1.17 g, 48.7 mmol, 6.00 equiv) and N,N-dimethylformamide (20 mL) was added slowly over 5 min. The resulting slurry was cooled to 0° C. and ethanethiol (1.80 mL, 24.3 mmol, 3.00 equiv) was added dropwise over 15 min by syringe, causing a vigorous exotherm. After the exotherm had subsided, the slurry was warmed to 23° C. and was stirred at that temperature for 10 min. The tetrahydrofuran solution of the magnesium alkoxide prepared above was added to the slurry via cannula over 5 min. Tetrahydrofuran was then removed in vacuo and the reaction mixture was heated at reflux for 1.5 h. The resulting thick brown slurry was cooled to 23° C. and was partitioned between saturated aqueous ammonium chloride solution (500 mL) and ethyl acetate (500 mL). The aqueous layer was separated and extracted further with ethyl acetate (500 mL) and 20% methanol in dichloromethane (500 mL). The aqueous layer was neutralized by the addition of aqueous hydrochloric acid solution (1% v/v, 400 mL) and was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (2.5% methanol-dichloromethane initially, grading to 5% methanol-dichloromethane) to afford (7S, 10R)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-2,10-phenanthridinediol (16) as a yellow solid (1.66 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1cc(CCl)ccc1F
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)ccc1F

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(chloromethyl)-1-fluoro-2-methoxybenzene. MS 442 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.[CH3:13]CCCCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:13])=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Product: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30A was subjected to the conditions outlined in in Example 26E, followed by chromatography (100% hexane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=O>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:21](=[O:23])[C:20]2[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=2)=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnc(Cl)cc1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine (example 5, intermediate a) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the compound as a colorless solid (5%). MS (ESI+): m/z=460.064 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1>C(Cl)(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCn3cccn3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+) and [α]D°=−67.7° (c=0.2955 in chloroform), was prepared in accordance with the general method of example 82b from (2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)-1-methylimidazole (0.25 gm, 0.825 mmol) from Step B in THF (5 mL) cooled to −70° C. in a dry ice/acetone bath was added via syringe n-butyl lithium (1.6 N in hexanes, 0.62 mL, 1.0 mmol). The reaction was stirred at −70° C. for 30 min and then a solution of CBZ-Cl (0.42 mL, 1.65 mmol) in THF (2 mL) was added rapidly. The reaction was warmed to rt over 1 hr. The reaction was poured into an aq. sodium bicarbonate solution and then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:17])[C:4]=2[CH:3]=[CH:2]1
Reactant: [BH3-]C#N
Reactant: O=C1CCCc2occc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2occc21
Reaction time: 48 h
Yield: 37.7 %

Procedure:
To a solution of 6,7-dihydro-1-benzofuran-4(5H)-one (2.0 g) in methanol (50 ml) was added 3 Å sieves (15 g), ammonium acetate (11.3 g) and sodium cyanoborohydride (1.22 g). After 48 h of stirring, the reaction mixture was filtered through celite, concentrated, dissolved in 1 N HCl (100 ml) and washed with ethyl ether (3×100 ml). The Aqueous layer was basified to pH 10 (NaOH), extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated to yield (760 mg, 38%) of the title compound as an oil:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: Nc1ccccc1Cl
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2cccc(Cl)c2n1
Yield: 40 %

Procedure:
A mixture consisting of 128 g (1.0 mole) of o-chloroaniline, 304 g of conc. hydrochloric acid and 61 g of water was maintained at 90°-95° C., and with sufficient stirring, 70 g (1.0 mole) of crotonaldehyde was added dropwise over the course of 2 hours. After the addition, the mixture was reacted further at 90°-95° C. for 1 hour. The reaction mixture was cooled, and then rendered alkaline by adding a conc. aqueous solution containing 132 g of sodium hydroxide with ice cooling. The alkaline mixture was separated into layers, and the oily layer was distilled at 2-3 mmHg to afford 72 g (0.4 mole) of 8-chloroquinaldine.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.N1CC[O:27][CH2:26][CH2:25]1.C(Cl)(=O)C>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:26](=[O:27])[CH3:25])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 3 h

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone [Enantiomer C] (CC-039) (0.150 g, 0.45 mmol) in DCM (2 mL) was added polymer supported morpholine (2.5 equivalents) and acetyl chloride (0.51 mmol). The reaction mixture was stirred for 3 hours, filtered and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.095 g). LCMS m/z 375.27 [M+H]+ RT=9.71 min (Analytical Method 2).
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[Se]=O.CC(O)=O.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)([CH3:29])[CH3:28]>O1CCOCC1>[OH:20][C:2]1([C:33]2[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][C:32]=2[O:36][CH3:37])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)C(O)(O)C2=O
Reactant: COc1cccc(C(C)C)c1
Agent: O=[Se]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc([N+](=O)[O-])c(NC(C)=O)c2C1=O
Reaction time: 12 h
Yield: 14 %

Procedure:
N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (2.60 g, 11.1 mmol) was completely dissolved in anhydrous dioxane (20 ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 7 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). Trifluoroacetic solution of the resulting product was added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followed by stirring for 12 hrs. The remainder was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography (ethylacetate 100%) to afford the title compound (0.64 g, 14%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>C1COCC1.ClCCl>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:28][CH3:29]
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 55 °C
Yield: 64.3 %

Procedure:
2.0 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide, 2.45 g (12.05 mmol) of (S)-2-(tert-butoxycarbonylamino)butanoic acid (purchased from Aldrich®, cat. no. 15533) and 1.90 g (12.24 mmol) of EDC.HCl were dissolved in a mixture of 90 mL of THF and 30 mL of dichloromethane. The resulting solution was heated at 55° C. overnight. Then the solvents were evaporated and the crude residue was taken up in dichloromethane and washed with an aqueous solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulphate, filtered and the solvent was evaporated. The solid obtained was triturated in diethyl ether to furnish 2.47 g (64% yield) of the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][N:6]=1.Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>[F:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc2nc(-c3ccc(NCCF)nc3)oc2c1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Product: Oc1ccc2nc(-c3ccc(NCCF)nc3)oc2c1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
To N-(2-fluoroethyl)-5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (0.18 mmol), in a microwave vial with a stir bar, was added tetrabutylammonium bromide (0.02 mmol) and hydrobromic acid 48%, w/w aq soln (5.0 mL). The reaction vessel was sealed and heated at 120° C. for 10 min. LCMS showed remaining starting material and the reaction was run an additional 10 min. The reaction mixture was neutralized with sat NaHCO3 (100 mL), extracted with (3×50 mL) CH2Cl2, the combined organic layers were dried (Na2SO4) and evaporated to give 33.1 mg as a brown oil. Purified on prep HPLC to give 10.4 mg of the title compound as a tan solid after lyophilization. 1H NMR (400 MHz, Chloroform-d/MeOH-d4 1:1) δ ppm 8.75 (d, 1H) 8.05 (dd, 1H) 7.42 (d, 1H) 7.00 (d, 1H) 6.82 (dd, 1H) 6.63 (d, 1H) 4.62-4.66 (m, 1H) 4.50-4.54 (m, 1H) 3.71-3.76 (m, 1H) 3.64-3.69 (m, 1H); 19F (1H decoupled) NMR (400 MHz, Chloroform-d/MeOH-d4) δ ppm −224.8; MS m/z 274 (M+H).