Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[SH:11][CH2:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:14]1=[O:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([S:11][CH2:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:14]1=[O:15])=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: O=C1OCC(c2ccccc2)C1CS
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(SCC1C(=O)OCC1c1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a solution of 1.2 g of o-fluorobenzoic acid and 1.5 g of α-mercaptomethyl-β-phenyl-γ-butyrolactone in 20 ml of dimethylformamide were added 1.9 ml of diphenylphosphoryl azide (DPPA) and then 1.2 ml of triethylamine under ice-cooling. Then, the mixture was raised to a room temperature and stirred for 18 hours. After completion of the reaciton, the reaction mixture was diluted with 200 ml of ethyl ether, washed with 5% hydrochloric acid, saturated aqueous sodium hydrogencarbonate, and saturated saline, dried over magnesium sulfate and the solvent was then distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 1.6 g (yield 67%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:14]=4[N:15]=3)[C:6]=2[CH:23]=1.Br[C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][C:17]1([CH3:21])[CH2:16][C:14]2[N:15]=[C:11]([N:7]3[C:6]4[CH:23]=[C:2]([O:1][C:25]5[S:26][C:27]([CH3:30])=[N:28][N:29]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)[S:12][C:13]=2[C:19](=[O:20])[CH2:18]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4ccc(O)cc43)nc2C1
Reactant: Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)CC(C)(C)C4)CCO3)s1
Yield: 12.2 %

Procedure:
A mixture of Example 6 (75 mg, 0.23 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (42 mg, 0.23 mmol) and potassium carbonate (64 mg, 0.46 mmol) in DMF (7 mL) was heated to 150° C. for 10 h. The solvent was removed in vacuo and the residue was purified by prep HPLC to give the title compound (12 mg, 12%) as an off-white solid. δH (CDCl3) 1.14 (6H, s), 2.43 (2H, s), 2.67 (3H, s), 2.77 (2H, s), 4.09-4.15 (2H, m), 4.33-4.40 (2H, m), 6.96-7.06 (2H, m), 8.22-8.24 (1H, m). LCMS (ES+) 429 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH:23]1[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=2)[NH:24]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH:23]1[C:32]([CH3:33])([CH3:34])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:36])[CH:29]=2)[NH:24]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(N2CCOCC2)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(N2CCOCC2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (78.7 mg, 0.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (26 mg, 0.65 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.13 mmol) and 1,1′-carbonyldiimidazole (42 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (19 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.6, observed: 488.4.
Reaction SMILES: Br[C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:40]3[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=3)[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1cc(CCc2cnc3c(cc(-c4ccnc(C#N)c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (60.0 mg, 0.119 mmol) (from Example 1, Step 4), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (0.041 g, 0.18 mmol from Combi-Blocks), sodium carbonate (25 mg, 0.24 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (20. mg, 0.024 mmol) in acetonitrile (1 mL)/water (0.2 mL) was evacuated and the refilled with N2 and then stirred at 100° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-60%) to afford the desired product (0.055 g, 85%). LCMS calculated for C28H24N5O4S (M+H)+: m/z=526.2. Found 526.2.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12].C([O-])(=O)C.[NH4+].C[NH:19]C.CN.NC(O)C>C(O)C>[NH2:19][CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12]
Reactant: O=C1C(=CO)Cc2ccccc21
Reactant: CNC
Agent: CC(=O)[O-]
Agent: CC(N)O
Agent: CN
Solvent: CCO
Product: NC=C1Cc2ccccc2C1=O

Procedure:
The 2-hydroxymethylene-1-indanone is then reacted with the appropriate nitrogen compound e.g. ammonium acetate, dimethyl amine, monomethyl amine or aminoethanol, in ethanol or any other suitable solvent to yield a 2-aminomethylene-1-indanone which is then dried and recrystallized from benzene or any other suitable solvent.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[Fe].C(O)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Temperature: 25 °C
Yield: 48.9 %

Procedure:
To a suspension of methanol 38 mL and acetic acid 38 mL of tert-butyl 2-nitro-4-phenylbenzoate 7.5 g was added iron powder 4.2 g at room temperature, and it was heated and refluxed for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. To the obtained residue, saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, solid matter was filtrated to give tert-butyl 2-amino-4-phenylbenzoate 3.3 g of white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:30])[C:12]([CH2:27][CH2:28][CH3:29])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[O:14]2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:30])[C:12]([CH2:27][CH2:28][CH3:29])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[O:14]2)=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(N)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CCl)ccc2c1=O
Yield: 80 %

Procedure:
8 cc of chloroacetyl chloride are added, with stirring, to a mixture consisting of 9.5 g of methyl 7-amino-3-propyl-4'-flavonecarboxylate made according to Example 7a, 1 liter of benzene and 9 g of anhydrous K2CO3. The mixture is heated to reflux of the benzene for 2 hours, then cooled. The benzene phase is washed with water. A precipitate is formed which is filtered and dissolved in chloroform. The benzene and chloroform phases are evaporated. Methyl 7-(2-chloracetamido)-3-propyl-4'-flavonecarboxylate is obtained with a yield of 80%. MP=162° C.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:12]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:20][CH:21]=3)[N:14]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC>[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:12]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]([CH3:28])[CH:21]=3)[N:14]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1
Reactant: COc1ccc(C)n2nc(CCc3c[nH]c(-c4ccccc4)n3)nc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1ccc(C)n2nc(CCc3cn(C)c(-c4ccccc4)n3)nc12
Temperature: 50 °C

Procedure:
Methyl iodide (0.035 mL, 0.57 mmol) was added to a stirred suspension of 8-Methoxy-5-methyl-2-[2-(2-phenyl-1H-imidazol-4-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (145 mg, 0.435 mmol) and Cs2CO3 (360 mg, 1.1 mmol) in 2-Butanone (10 mL). The mixture was heated at 50° C. for 7 hours under an atmosphere of Argon. The mixture was cooled to rt and the solvent was evaporated off. The crude product was dissolved in DCM and purified by silica gel chromatography (Eluent: 0-100% EtOAc in n-heptane, then changed to 0-5% MeOH in EtOAc). Yield: 31 mg (20%) of the title compound as an off white solid. LC-MS: m/z=348.2 (MH+), tR=0.70 min, method E.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].S(Cl)(Cl)=O.O[C:20]1[CH:31]=[CH:30][C:23](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=1[O:32][CH3:33].C(Cl)Cl>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:20]2[CH:31]=[CH:30][C:23](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[O:32][CH3:33])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A mixture of 4.85 g of 4-(3-butenyloxy)benzoic acid and 6 ml of thionyl chloride was treated with 3 drops of dimethylformamide and heated to reflux for 3 hrs. The excess acid chloride was thereupon distilled off firstly at normal pressure and then with increasing vacuum, the residue was held under a high vacuum for 2.5 hrs. and subsequently dissolved in 20 ml of methylene chloride. This solution was added dropwise while cooling with ice to obtain a mixture of 5 g of methyl (E)-4-hydroxy-3-methoxycinnamate, 25 ml of methylene chloride and 3.9 ml of triethylamine and subsequently left to react at room temperature for 60 hrs. Then, the reaction solution was filtered, concentrated slightly and chromatographed over 314 g of silica gel with methylene chloride. Crystallization from cold ethanol gave 7.03 g of 2-methoxy-4-[(E)2-methoxycarbonyl-vinyl]phenyl 4-(3-butenyloxy)benzoate.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O[CH2:18][CH:19]=[CH2:20])(=O)C>>[CH2:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:18][CH2:19][CH3:20]
Reactant: C=CCOC(C)=O
Reactant: CCCCCCCCCCCCBr
Product: C=CCCCCCCCCCCCCC
Yield: 32 %

Procedure:
n-dodecyl bromide was converted analogously to example 1 to its Grignard compound and the latter was reacted with allyl acetate in the manner described. 1-Pentadecene was obtained in 32% yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:29][CH3:30])[CH2:3][NH:4][C:5](=[O:28])[CH2:6][CH:7]([O:21]C1CCCCO1)[CH:8]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH:10]([CH3:12])[CH3:11].Cl>ClCCl>[NH2:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[CH:7]([OH:21])[CH2:6][C:5]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:29][CH3:30])=[O:28]
Reactant: CCC(C)CNC(=O)CC(OC1CCCCO1)C(CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CCC(C)CNC(=O)CC(O)C(N)CC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3 g (7 mmol) of a mixture of [1S-[1R*,2R*(R*),4(R*)]] and [1S-[1R*,2R*(S*),4(R*)]][4-[(2-methylbutyl)amino]-1-(2-methylpropyl)-4-oxo-2-[(tetrahydro-2H-pyran-2-yl)oxy] butyl]carbamic acid, 1,1-dimethylethyl ester in 75 ml of dichloromethane is treated with 25 ml of methanolic hydrogen chloride solution and stirred at room temperature for 2 hours. The mixture is evaporated and the resulting gum is partitioned between diethyl ether and 0.5N hydrochloric acid solution. The aqueous layer is separated, basified to pH 13 with a 2N solution of sodium hydroxide and extracted with diethyl ether (5×100 ml). The combined organic extracts are dried over magnesium sulfate and evaporated to give 1.64 g of [3S-[N(R*),3R*,4R*]]-4-amino-3-hydroxy-6-methyl-N(2-methylbutyl)-heptanamide; [α]D23 =-22.2° (C=1.07%, methanol). Reaction of [3S-[N(R*),3R*,4R*]]-4-amino-3-hydroxy-6-methyl -N(2-methylbutyl)-heptanamide with hydrogen chloride gas in the conventional manner affords [3S-[N(R*),3R*,4R*]]-4-amino-3-hydroxy-6-methyl-N(2-methylbutyl)-heptanamide, hydrochloride (2:3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(O)C1CNC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CC(C(=O)O)C5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 3-azetidinecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (78 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-3-azetidinecarboxylic acid (E67) (18 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.00 (2H, t), 3.47 (2H, t), 3.60 (1H, m), 3.65 (3H, s), 4.22 (4H, m), 4.88 (1H, m), 7.22 (1H, t), 7.31 (1H, s), 7.47 (2H, m), 7.87 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: Cc1ccc(CNC(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C2CCC(CN)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 g of the (4-{[(tert-butoxy)carbonylamino]methyl}cyclohexyl)-N-[(4-methylphenyl)methyl]carboxamide prepared in Example 5A was dissolved in 500 ml of CH2Cl2. 50 ml of trifluoroacetic acid (TFA) was added to the solution and the reaction mixture stirred at room temperature overnight. The volatile components of the reaction mixture were evaporated off leaving a colorless oil which was then dissolved in 500 ml of methanol. 1 Tbs of Bio-Rad AG 1-X8 resin (20-50 mesh) was added and the solution shaken for 48 hours. Additional resin was added until the pH was slightly basic. The resin was then removed by filtration and the methanol evaporated off to give the product [4-(aminomethyl)cyclohexyl]-N-[(4-methylphenyl)methyl]carboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:37]I.[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([CH3:37])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in dry DMF (1 ml) at 0° C. was added sodium hydride (2 mg, 0.05 mmol) and methyl iodide (5 μl, 0.05 mmol) under nitrogen. The resulting mixture was stirred for 30 minutes at 0° C. A saturated solution of NH4Cl was added and the mixture was extracted with DCM (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 20% EtOAc in cyclohexane) to give the title compound (8 mg, 44%). 1H NMR (500 MHz, CDCl3): 7.39-7.19 (9H, m), 6.85 (1H, s), 4.51-4.50 (2H, d), 3.45-3.43 (2H, d), 2.80-2.70 (2H, m), 2.61-2.51 (4H, m), 2.01-1.88 (1H, m), 2.00 (3H, s), 1.40-1.10 (9H, br).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ccncc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2ccncc2Cl)CC1
Yield: 22.1 %

Procedure:
General procedure C was followed using isonipecotamide (43 mg, 0.34 mmol), 3,4,dichloropyridine (50 mg, 0.34 mmol), triethylamine (0.14 mL, 1.0 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (18 mg, 22%), m.p. 210-212° C.; umax (CHCl3)/cm−1 2360, 2342, 1653, 1581 1382, 1223, 1135, 1041; m/z (ESI) C11H15ClN3O requires 240.0898, found [M+H]+ 240.0899.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.O.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(I)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
mb) 4.2 g of magnesium shavings are suspended in 8.3 ml of anhydrous ethanol and treated with 0.83 ml of carbon tetrachloride. A solution of 27.63 g of diethyl malonate in 17 ml of ethanol and 62 ml of toluene is added dropwise in such a manner that the temperature remains at 50°-60°. Subsequently, the mixture is heated at 60° for a further 1 hr. The reaction mixture is cooled to -30° and a solution of 51.9 g 2-chloro-4-iodo-benzoyl chloride in 70 ml of anhydrous toluene is added dropwise within 30 min. The reaction mixture is stirred while slowly warming to room temperature within 1.30 hrs., then cooled to 0° and treated dropwise with a solution of 4 ml of conc. sulphuric acid in 60 ml of water. After 20 min. the phases are separated and the aqueous solution is back-extracted twice with 100 ml of toluene each time. The combined organic phases are washed with 100 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. 70.3 g (96%) of diethyl 2-(2-chloro-4-iodo-benzoyl)-malonate are obtained as a yellowish oil. Mass spectrum: peaks inter alia at 424 (M+, 0.4%), 389 (48%), 343 (63%), 265 (100%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.C([Li])(CC)C.Br[C:36]1[S:40][C:39]([C:41]([O:43][CH3:44])=[O:42])=[CH:38][CH:37]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[NH4+]>COC(C)(C)C.C1CCCCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:44][O:43][C:41]([C:39]1[S:40][C:36]([C@H:12]2[CH2:11][CH2:10][CH2:9][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:37][CH:38]=1)=[O:42]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Pd+2]
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CCOCC
Solvent: C1CCCCC1
Product: COC(=O)c1ccc([C@H]2CCCN2C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-Boc-pyrrolidine (3 mL) and (−)-sparteine (3.9 mL) in tert-butyl methyl ether (36 mL) at −78° C. was added 1.4M sec-butyl lithium in cyclohexane (12.21 mL). The solution was stirred for 3 hours and 1M zinc chloride in ether (10.2 mL) was added. The mixture was stirred for 30 minutes and warmed to ambient temperature for 30 minutes. Methyl 5-bromothiophene-2-carboxylate (3.15 g), tri-tert-butylphosphine tetrafluoroborate (249 mg) and palladium(II) acetate (153 mg) were added, and the mixture was stirred at ambient temperature overnight, treated with concentrated ammonium hydroxide (1 mL) and stirred for 30 minutes, and filtered through diatomaceous earth (Celite®). The filtrate was washed with 0.5M hydrochloric acid solution and water and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate/hexane.