Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(6-bromonaphth-2-ylsulphonyl)piperazine-3-carboxylate to give 4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 42% yield, m.p. 117-121° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CO[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]>C(O)C>[CH3:17][O:16][C:14](=[O:15])[C:13](=[CH:12][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COC(=O)C(=CNc1ccc(OC)cc1)C(=O)OC
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a solution of 12.3 g (0.1 Mol) of p-Anisidine in 50 ml of ethanol, a solution of 17.4 g (0.1 Mol) of Dimethyl methoxymethylenemalonate in 70 ml of ethanol was added dropwise with stirring at room temperature. After an additional hour of stirring at that temperature, the reaction mixture was cooled with an ice bath and the product cristallised spontanously. The crude solid material was isolated by filtration and washed with ethanol and gave 12.9 g of the title product which is a white solid melting at 89-91° C., UV 328 nm (E=899).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2csc(C(=O)O)c2)cc1

Procedure:
At 10° C., p-tolyl-acetaldehyde (11.0 g, 82 mmol) is added to a mixture of POCl3 (20 mL, 230 mmol) and DMF (20 mL). The mixture is stirred at rt for 2 h before the reaction is quenched by adding water/ice and NaOAc and extracted with DCM (2×200 mL). The solvent of the organic extract is evaporated and the product is purified by CC on silica gel eluting with heptane:EA 9:1. The resulting oil (1.95 g) is dissolved in ethanol (5 mL) and then added dropwise to a freshly prepared solution of Na (370 mg, 16.2 mmol) and ethyl-2-mercaptoacetate (1.95 g, 16.2 mmol) in ethanol (20 mL). The reaction mixture is stirred at it for 72 h, diluted with water (100 mL) and extracted with EA (2×150 mL). The organic extracts are dried over MgSO4 and evaporated. CC on silica gel eluting with heptane:EA 5:1 gives 4-p-tolyl-thiopene-2-carboxylic acid ethyl ester (850 mg). This ester is dissolved in ethanol (10 mL) and 3 M aq. NaOH (5 mL) and the mixture is refluxed for 2 h. The reaction mixture is acidified and extracted with DCM. The organic extract is dried over MgSO4 and the solvent is evaporated to give 4-p-tolyl-thiophene-2-carboxylic acid (580 mg) as a solid; LC-MS: tR=0.91 min, [M+1+CH3CN]+=260.16, 1H NMR (CDCl3): δ 8.14 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.05 (s br, 1H), 2.39 (s, 3H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[F:38][CH:39]([F:43])[C:40](O)=[O:41]>C(Cl)(Cl)Cl>[F:38][CH:39]([F:43])[C:40]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:41]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Yield: 62.6 %

Procedure:
A mixture of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (0.42 g), triethylamine (2.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.8 g) and difluoroacetic acid (0.75 g) in chloroform (10 ml) was refluxed for 8 hours. The residue was washed with aqueous hydrochloric acid and aqueous potassium carbonate and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 63) (0.3 g). m.p., 117.9° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Reactant: CN(C)CCN
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCCN(C)C)cc3)no2)cc1C
Yield: 20.4 %

Procedure:
The title compound (9 mg) is prepared in analogy to Example 189 step b) starting from 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (37 mg, 100 μmol) and N1,N1-dimethyl-ethane-1,2-diamine (10 mg, 110 μmol); LC-MS: tR=0.42 min; [M+1]+=442.23. 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.32 (s, 6H), 2.58 (t, J=6.0 Hz, 2H), 2.64 (q, J=7.0 Hz, 4H), 3.55-3.62 (m, 2H), 3.73 (s, 2H), 6.95 (t br, J=4.8 Hz, 1H), 7.68 (s, 1H), 7.92-7.96 (m, 2H), 8.21-8.25 (m, 2H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C@H:16]([NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[NH:35])=[CH:32][CH:31]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:10]=[C:11](COC)[CH:12]=1.[F:39][CH2:40][CH2:41][N:42]1C2C=C(C(NC3C=CC(C4N=C(C)ON=4)=CC=3)C#N)C=C(OC)C=2[O:45][CH2:44][C:43]1=[O:70]>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:39][CH2:40][CH2:41][N:42]1[C:11]2[CH:10]=[C:9]([C@H:16]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[NH:35])=[CH:32][CH:31]=3)[C:17]3[NH:21][C:20](=[O:22])[N:19]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:18]=3)[CH:8]=[C:7]([O:6][CH3:5])[C:12]=2[O:45][CH2:44][C:43]1=[O:70]
Reactant: COCc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCC(=O)N2CCF
Solvent: CC(=O)O
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC(=O)N2CCF

Procedure:
The same procedure was carried out as in Examples (10c) to (10e), except that [4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile was used instead of (3-methoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in Example (10c), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:36])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=4)[C:16]([CH:33]=[O:34])=[C:15]3[CH3:35])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:36])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:24]([F:25])([F:26])[F:27])=[CH:20][CH:21]=4)[C:16]([CH2:33][OH:34])=[C:15]3[CH3:35])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)c(C=O)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)c(CO)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 50 mg of 1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-3-carbaldehyde in 1 mL of THF was treated at 0° C. with 5 mg (0.14 mmol) of LiAlH4 and allowed to reach RT within 1 h. Ice cubes were added and the mixture distributed between Et2O and H2O. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent yielded 36 mg of 2-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-hydroxymethyl-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, off white solid, 533 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Yield: 111.9 %

Procedure:
A mixture of 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (515 mg, 1.13 mmol), 10% Pd/C (116 mg), and ammonium formate (1.43 g, 22.62 mmol) in EtOAc was refluxed overnight; then filtered, the filtrate was washed with saturated sodium chloride aqueous solution, then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a pure titled product (476 mg); ESI MS (m/z): 377 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1.ClCCl>[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:17][C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:18])=[O:28])=[C:25]([O:32][CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-2-amino-4-chlorobenzamide (0.74 g, 26.5 mmol) in pyridine (1 mL) and dichloromethane (20 mL) at 0° C. was added a solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (1.05 g, 26.5 mmol) in dichloromethane (10.5 mL). The cold bath was then removed and after 72 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water, followed by satd aq NaHCO3 and then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a solution of 20% ethyl acetate in hexanes.
Reaction SMILES: [CH:1]1([CH2:5]O)[CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1(C=O)CCC1.[CH3:35][C:36]([S@@:39]([NH2:41])=[O:40])([CH3:38])[CH3:37]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]1(/[CH:5]=[N:41]/[S@:39]([C:36]([CH3:38])([CH3:37])[CH3:35])=[O:40])[CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=CC1CCC1
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 20-L 4-necked round-bottom flask was placed a solution of cyclobutylmethanol (1000 g, 11.61 mol) in dichloromethane (10 L). This was followed by the addition of Dess-Martin periodinane (4683 g, 11.04 mol) in several batches at 10-15° C. over 120 min. The resulting solution was stirred for 2 h at room temperature and then quenched by the addition of 20 L of cold, saturated aqueous sodium bicarbonate solution. Solids were removed by filtration and washed with 5 L of dichloromethane. The filtrate was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with DCM:PE (2:1). This resulted in 100 L of cyclobutanecarbaldehyde in dichloromethane and petroleum ether solution. Step 2: Into a 50-L barrel was placed cyclobutanecarbaldehyde in dichloromethane and petroleum ether (33 L of the solution described at the end of Step 1), (S)-2-methylpropane-2-sulfinamide (500 g, 4.13 mol) and copper sulfate (2 kg, 13.33 mol). The resulting solution was stirred for 2 days at room temperature. Solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5) to afford (S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.O>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.4 mL, 15.0 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 15.0 mL, 15.0 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanone (2.02 g crude, 7.5 mmol) in THF (15 mL) and refluxed for 30 min. The reaction mixture was poured into water (50 if L), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellow solid (1.44 g, 66% yield): mp, 112-114° C.; 1H NMR (DMSO-d6) δ 3.79 and 3.83 (2s, 3H, OCH3), 4.25-4.33 (m, 4H, CH2CH2), 6.07 and 6.08 (2s, 1H, CH), 6.77-7.32 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.3, 64.0, 64.0, 64.2, 64.3, 92.7, 93.0, 113.9, 114.1, 117.0, 117.2, 118.0, 118.6, 118.7, 121.9, 122.5, 129.1, 130.0, 130.1, 130.4, 130.8, 131.4, 143.1, 143.2, 144.7, 145.5, 160.3, 160.7, 160.8, 161.1. Anal. Calcd for C18H15NO3+0.1H2O: C, 73.26; H, 5.19; N, 4.75. Found: C, 72.96; H, 5.22; N, 4.67.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].[BH4-].[Na+].C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[Pd]>[C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Reaction time: 18 h
Yield: 52.2 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is drooped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then a solution of sodium borohydride (228 mmoles 8.6 g) and tetrabutylammonium chloride (5.0 g) in 50 ml of 0.1 M NaOH is added and the mixture is stirred at room temperature for 18 h. The aqueous phase is separated, 50 ml of acetic acid are added to the organic phase and the mixture is left under stirring for 30′, then added with 10% Pd—C (26 g, 22 mmoles) and ammonium formate (456 mmoles, 33.3 g) and left under stirring for 4 h. Afterwards, the catalyst is filtered off through Celite and 100 ml of water is added. The resulting precipitate is filtered, washed with 20 ml of isopropanol and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (53.9 g, yield: 48%).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH2:18]1[O:20][CH2:19]1>C1COCC1.CCCCCC>[OH:20][CH2:19][CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C1CO1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccc2[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (0° C.) mixture of 1.56 g (38.9 mmol) of a 60% dispersion of sodium hydride in 10 mL THF is slowly added a solution of 5.05 g (25.9 mmol) 5-bromoindole (Acros) in 20 mL THF. After H2 evolution stopped (˜10 min) the mixture is cooled to −78° C., and 25.9 mL (64.8 mmol) of a 2.5 M hexane solution of n-butyllithium is added dropwise. After five minutes, added 16.8 mL (38.9 mmol) of a 2.3 M THF stock solution of ethylene oxide and removed cooling bath. After 90 minutes, quenched with 5 mL distilled water. The organic layer is then poured away from the inorganic salts and concentrated. The resulting residue is chromatographed (1:1 hexane:ethyl acetate) to provide 2.24 g of the product as a yellow oil in 54% yield. 1H NMR (CDCl3): δ 2.96 (2H, t, J=6.5 Hz), 3.88 (2H, m), 6.51 (1H, m), 7.06 (1H, dd, J1=8.5 Hz, J2=1.5 Hz), 7.19 (1H, m), 7.33 (1H, d, J=8.5 Hz), 7.49 (1H, s), 8.19 (1H, br). MS (EI) m/z 161 M+, 130 (M−CH2OH)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14]CC)=O)=[C:10]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].Cl.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC.[F:56][C:57]([F:67])([F:66])[C:58]1[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=1)[CH2:61][NH2:62]>CCO.O>[CH3:1][C:2]1[C:11]([C:12]([NH:62][CH2:61][C:60]2[CH:63]=[CH:64][CH:65]=[C:58]([C:57]([F:56])([F:66])[F:67])[CH:59]=2)=[O:14])=[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(C)nc2ncccc2c1N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2ncccc2c(N2CCCCC2)c1C(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
Ethyl 2-methyl-4-(piperidin-1-yl)-1,8-naphthyridine-3-carboxylate (120.0 mg, 0.4 mmol) was dissolved in EtOH. NaOH (4.0 ml of a 1.0 M aq. solution) was added and the mixture refluxed for 3.0 days. The mixture was cooled, acidified with aq. HCl (1.0 M) and concentrated to dryness. The residue was suspended in anhydrous THF, N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (84.34 mg, 0.44 mmol), 1-hydroxybenzotriazole hydrate (30.74 mg, 0.2 mmol.) and Et3N (54.8 μl, 0.4 mmol) were added. The mixture was stirred at room temperature for 30 min. 3-(trifluoromethyl)benzyl amine (57.33 μl, 0.4 mmol) was added to the mixture and stirring continued for 18 h. H2O was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. Purification was done by flash chromatography (CH2Cl2/MeOH 98:2→96:4) giving 20.0 mg (12%) of the title compound.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(=O)[CH2:52][C:53]([CH2:58][C:59](O)=O)([C:55]([OH:57])=O)[OH:54]>ClCCl>[C:11]([O:10][C:8]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:55]([C:53]2([OH:54])[CH2:52][CH2:59][CH2:58]2)=[O:57])[CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2(O)CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 10a (340 mg), tert-butyl 1,4-diazepane-1-carboxylate (694 μl), DIPEA (2.4 ml) and BOP (1.9 g) in dichloromethane (15 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into an aqueous citric acid solution (5%) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in toluene/acetone [1/0→7/3 (v/v)] as eluent.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]1[N:44]=[C:43]([NH:45][C:46]2[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[CH:48][N:47]=2)[CH:42]=[C:41]([CH:56]2[CH2:60][CH2:59][NH:58][CH2:57]2)[CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:58]2[CH2:59][CH2:60][CH:56]([C:41]3[CH:42]=[C:43]([NH:45][C:46]4[CH:51]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:49]=[CH:48][N:47]=4)[N:44]=[C:39]([N:35]4[CH2:36][CH2:37][CH2:38][CH:34]4[CH3:33])[CH:40]=3)[CH2:57]2)=[O:9])[N:4]=[CH:3]1
Reactant: C[C@@H]1CCCN1c1cc(C2CCNC2)cc(Nc2cc(C(F)(F)F)ccn2)n1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCN1c1cc(C2CCN(C(=O)c3cn(C)cn3)C2)cc(Nc2cc(C(F)(F)F)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
To a mixture of 1-methylimidazole-4-carboxylic acid (39.79 mg, 0.315 mmol, 1.5 equiv.), HOBT (57.42 mg, 0.420 mmol, 2.0 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81.46 mg; 0.420 mmol, 2.0 equiv.) in chloroform (3.0 mL) was added 6-[(2R)-2-methylpyrrolidin-1-yl]-4-pyrrolidin-3-yl-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine hydrochloride (90 mg, 0.210 mmol) followed by DIPEA (0.148 mL, 0.841 mmol, 4.0 equiv.). The resulting mixture was stirred at rt for 2 h. It was diluted with DCM (10 mL), washed with 10% citric acid and 1 N NaHCO3, dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC to afford 16.1 mg (15.3%) of product as yellow solid. 1H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.80 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 7.68-7.60 (m, 2H), 7.10 (d, J=5.1 Hz, 1H), 6.39 (s, 1H), 5.90 (s, 1H), 4.48-4.09 (m, 3H), 3.94-3.73 (m, 2H), 3.69 (d, J=5.2 Hz, 3H), 3.56-3.43 (m, 2H), 3.25-3.18 (m, 1H), 2.31-2.13 (m, 1H), 2.12-1.86 (m, 4H), 1.73-1.63 (m, 1H), 1.17 (d, J=6.0 Hz, 3H). LC-MS: m/z=500 (M+H+).