Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35]>C(Cl)Cl>[OH:35][CH2:34][CH2:33][N:32]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:36][CH2:37][OH:38]
Reactant: OCCNCCO
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCO)CCO)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added diethanolamine (45 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 537 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3.[OH:22][CH:23]([CH3:27])[CH2:24][NH:25][CH3:26]>C(O)C.C(Cl)(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1=[N:4][N:3]=[C:2]([N:25]([CH2:24][CH:23]([OH:22])[CH3:27])[CH3:26])[N:6]1[N:7]=[C:8]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCC(C)O
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nn1c(Cl)nnc21
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(O)CN(C)c1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12
Yield: 73 %

Procedure:
The compound of the title is prepared by following substantially the same procedure outlined in example 122 but starting from 3,8-dichloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine and (2-hydroxypropyl)methylamine. Yield: 73%. M.p. 236°-38° C. (from ethanol/chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
A suspension of Example A1 (0.125 g, 0.497 mmol), Pd(PPh3)4 (0.029 g, 0.025 mmol), K2CO3 (0.275 g, 1.987 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid (0.104 g, 0.546 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and EtOAc and the solids were removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-((6-nitropyridin-3-yl)oxy)-2′-(trifluoromethyl)-2,4′-bipyridine (139 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=5.2 Hz, 1H), 8.78 (m, 1H), 8.64 (m, 1H), 8.53 (s, 1H), 8.44-8.38 (m, 2H), 8.17 (d, J=2.3 Hz, 1H), 8.03 (m, 1H), 7.36 (dd, J=5.5, 2.3 Hz, 1H); MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 48G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [S:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:12])[NH:5][C:4]=2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:5]1[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=C1CCCCc2sccc2N1
Reactant: ClCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCCc2sccc2N1CCCCCl
Yield: 93.4 %

Procedure:
To a solution of 2.0 g of 6,7,8,9-tetrahydrothieno[3,2-b]azocin-5(4H)-one in 20 ml of dimethylformamide was added 1.3 g of potassium t-butoxide under ice-cooling and stirred at the same temperature. To the mixture was added 2.0 g of 1-bromo-4-chlorobutane and stirred at room temperature for 5 hours. The mixture was poured into water and extracted ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel using a chloroform as an eluent to give 2.8 g of 4-(4-chlorobutyl)-6,7,8,9-tetrahydrothieno[3,2-b]azocin-5(4H)-one as a pale yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].OS(O)(=O)=O>>[F:5][C:6]1[CH:16]=[C:15]([F:17])[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reaction time: 2 h

Procedure:
Conc. HNO3 (8 mL) was added dropwise to a mixture of ethyl 2,4-difluorobenzoate (10.0 g; 53.7 mmol) in cone. H2SO4 (8 mL) at 0° C. After 2 h at 0° C., the mixture was poured onto ice and extracted with EtOAc. The organic extracts were washed with saturated NaHCO3 solution (aq) and concentrated to give the sub-title compound. Yield: 11.8 g (95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[N:15]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccncc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(-c3ccncc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
4-[3-Formyl-1-[(4-pyridin-4-yl)phenyl]-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (68 mg, 0.141 mmol) is dissolved in dichloromethane (1 mL), treated with trifluoroacetic acid (2 mL) and stirred for 2 hr at room temperature. The solvent is removed, the resulting oil is dissolved in water, made basic to pH around 7˜8 with 20% aq sodium hydroxide and extracted with dichloromethane. The combined organic layer is washed with brine and dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane-0 to 10% methanol to afford 2-piperazin-1-yl-1-[(4-pyridin-4-yl)phenyl]-1H-indole-3-carboxaldehyde (46 mg, 85%) as a light tan solid. ESI/MS 383 (M+1).
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[S-:15][C:16]#[N:17].[K+].O>CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:17]=[C:16]=[S:15])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: N#C[S-]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1N=C=S
Yield: 21.6 %

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (5 g) from Example 15 and potassium thiocyanate (4.6 g) were heated in dimethylformamide (30 ml) at 110° C. for 7 hours. The mixture, after cooling, was added to water and the product extracted into diethyl ether. The ether solution was washed with water (twice), dried over magnesium sulphate and run down under vacuum yielding 4 g of crude product. Purification by silica gel chromatography in toluene yielded 1.2 g of title product, mp 52° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl.CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:26])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(S(=O)c2ccc(N)cc2)s1
Yield: 71.4 %

Procedure:
To a solution of 2-acetylamino-5-(4-aminophenylthio)thiazole (6.6 g) in a mixture of dichloromethane (300 ml) and N,N-dimethylformamide (50 ml) was dropwise added the solution of 3-chloroperbenzoic acid (5.9 g) in dichloromethane (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was poured into 10% aqueous sodium bicarbonate. The solution was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g, yield: 71.1%).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:24][O:25]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccc(C=O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 21.06 g of 4-biphenylyl p-toluenesulphonate in 120 ml of dichloromethane was treated at -2° C. while stirring with 23.6 ml of titanium tetrachloride. The mixture was treated dropwise at the same temperature within 30 minutes with 9.63 ml of dichloromethyl methyl ether, stirred at room temperature for a further 1 hour and then poured on to ice. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated sodium hydrogen carbonate solution and then with water, dried over sodium sulphate and concentrated. Recrystallization of the crude product obtained from 50 ml of ethyl acetate gave 11.65 g of 4'-(p-toluenesulphonyloxy)biphenyl-4-carboxaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:19][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[N:14]([CH3:13])[C:15](=[O:20])[CH2:16][CH2:17]1
Reactant: CN1C(=O)CCC1=O
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1C(=O)CCC1(O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 37 g. (0.16 mole) of 3-bromobenzotrifluoride and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°- 139°C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][C:37]=1[O:51][CH3:52])=[O:34])[N:27]2[CH3:32]>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]3[N:3]=[C:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]4)[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=34)=[CH:38][C:37]=1[O:51][CH3:52])=[O:34])[N:27]2[CH3:32]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: CNC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Product: CNC[C@H]1CC[C@H](c2nc(-c3ccc(NC(=O)c4cc5c(OC)cccc5n4C)c(OC)c3)c3c(C)nccn32)CC1

Procedure:
Reaction of the impure 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-methylmethanamine (20 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (26 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol (containing 0.1% ammonium hydroxide)) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-((methylamino)methyl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (5.6 mg)
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:24])[CH:22]=[CH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C=CC(=O)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 12 h

Procedure:
A solution of dicyclohexylamine (19.92 ml, 0.10 mole) and triethylamine (27.88 ml, 0.20 mole) in ethyl ether (100 ml) was cooled to 0° C. A solution of acryloyl chloride (7.93 ml, 0.1 mole) in ethyl ether (20 ml) was added and the solution was stirred for 12 hours, filtered and concentrated to obtain the product as a solid which was dried in vacuo. The stucture was confirmed by NMR.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[F:11])#[N:2].[CH:12]([C:14]1[N:15]=[C:16]([CH3:19])[NH:17][CH:18]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:15]2[C:14]([CH:12]=[O:13])=[CH:18][N:17]=[C:16]2[CH3:19])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1nc(C=O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (1.26 g, 5.9 mmol) in DMF (10 mL), at 0° C., was added 4-formyl-2-methylimidazole (0.650 g, 5.9 mmol) and cesium carbonate (2.9 g, 8.9 mmol). After 2 hours, the reaction mixture was poured into EtOAc—30% hexane, washed with H2O, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the crude product. The crude material was purified by silica gel chromatography, eluting with a gradient of CHCl3—2% to 5% MeOH, to obtain the above-titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:21]#[N:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[CH2:52]([O:54][C:55](=[O:58])[CH:56]=[CH2:57])[CH3:53]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:21]([C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:57]=[CH:56]/[C:55]([O:54][CH2:52][CH3:53])=[O:58])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 96 %

Procedure:
Tert-butyl 4-(2-bromophenyl)-4-cyanopiperidine-1-carboxylate (20, 100 mg, 0.28 mmol) and Pd(OAc)2 (7.0 mg, 0.030 mmol) were added to a vial, followed by tri(o-tolyl)phosphine (14 mg, 0.047 mmol). The reaction vial was purged with Ar (3×). Dry CH3CN (1.4 mL) and Et3N (103 μL, 0.74 mmol) were added, followed by ethylacrylate (36 μL, 0.33 mmol). The reaction mixture was heated at 85° C. overnight. The reaction was concentrated. Et2O (2 mL) was added to the mixture and was then filtered through Celite. The crude residue was purified by silica gel chromatography (gradient, 10% to 20% EtOAc/hexanes) to yield (E)-tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxoprop-1-enyl)phenyl)piperidine-1-carboxylate as a pale yellow oil (21, 102 mg, 96% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1H), 7.58 (dd, 1H), 7.41 (td, 1H), 7.38-7.34 (m, 1H), 6.31 (d, 1H), 4.29 (q, 1H), 3.29 (bt, 2H), 2.35-2.31 (m, 2H), 1.90 (dt, 2H), 1.47 (s, 9H), 1.35 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC1C=C(C2C3CN(C([O:51][C:52](C)([CH3:54])[CH3:53])=O)CCC=3NN=2)C=CC=1F>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:30])([CH3:31])[CH3:1])[C:4]([N:6]3[CH2:7][CH2:54][C@H:52]([OH:51])[CH2:53]3)=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N[C@H](C(=O)N2CC[C@H](O)C2)C(C)(C)C)C1

Procedure:
Compound 47 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with intermediate 25. LCMS (+ESI) m/z=476.3 [M+H]+.
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: C1COCCO1
Reactant: COCC(=O)c1ccccc1
Agent: O=[Se]=O
Solvent: O
Product: COc1ccccc1C(=O)C=O

Procedure:
A mixture of 3 g of 2-methoxyacetophenone, 2.9 g of selenium dioxide, 20 ml of dioxane and 2 ml of water is treated in the same manner as described in Example 5-(1). 2.9 g of 2-methoxyphenylglyoxal hydrate are thereby obtained as a crude oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:4]1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH:34]=O)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21].Cl.Cl.N1CC(N2CCSCC2)C1.FC1C=CC(C(CC=O)CN(C)C(=O)OC(C)(C)C)=CC=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH2:34][N:3]2[CH2:6][CH:5]([N:7]3[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]3)[CH2:4]2)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: OC1CCN(C2CNC2)CC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: C1CN(C2CNC2)CCS1
Agent: CN(CC(CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: CN(C[C@@H](CCN1CC(N2CCC(O)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C

Procedure:
The compound was synthesized in an analogous way to that of Method 3d but using 1-azetidin-3-ylpiperidin-4-ol dihydrochloride (see Meth 15) and tert-butyl [(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]methylcarbamate (see WO 95/05377) rather than 4-azetidin-3-ylthiomorpholine dihydrochloride and tert-butyl [2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (yield, 35%). 1H NMR (500 MHz, CDCl3): 1.3 (m, 2H), 1.4 (s, 9H), 1.5-3.8 (cm, 23H), 7.0 (dd, 1H), 7.2-7.4 (m, 2H), LCMS: m/z 487 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:56][O:57][C:58]1[CH:59]=[C:60]([CH:63]=[C:64]([O:68][CH3:69])[C:65]=1[O:66][CH3:67])[CH2:61][NH2:62]>CN(C)C=O>[CH3:69][O:68][C:64]1[CH:63]=[C:60]([CH:59]=[C:58]([O:57][CH3:56])[C:65]=1[O:66][CH3:67])[CH2:61][NH:62][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:23]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Reactant: COc1cc(CN)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)C2CCCC(n3c(=O)c4c(C)onc4c4ccncc43)C2)cc(OC)c1OC
Yield: 86.9 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol) and 3,4,5-trimethoxy benzylamine (33 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and chromatograph over silica gel to give 66 mg (85%) of the desired product as a white solid. MS(ES): (M+1)+ 507.2, 508.2, 509.2 m/z.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)C(=O)NC1CCCCC1O
Product: CC(C)C(=O)NC1CCCCC1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from N-(2-hydroxycyclohexyl)isobutyramide (Example 39c) and 2-amino-6-fluorobenzonitrile as a brown solid (70%). MS 302 (MH+).