Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3=[N:15][C:16]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:17][CH:18]=[C:13]3[N:12]=[CH:11]2)[C:5]([O:8]C)=[N:6][CH:7]=1>Br>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3=[N:15][C:16]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:17][CH:18]=[C:13]3[N:12]=[CH:11]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1-n1cnc2ccc(N[C@@H](C)c3ccc(F)cn3)nc21
Agent: Br
Product: C[C@H](Nc1ccc2ncn(-c3cc(Cl)c[nH]c3=O)c2n1)c1ccc(F)cn1
Temperature: 100 °C

Procedure:
A suspension of 3-(5-chloro-2-methoxypyridin-3-yl)-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-5-amine (Preparation 24d, 69 mg, 0.17 mmol) in aqueous hydrogen bromide solution (48%, 0.6 mL) was heated to 100° C. for 3 hours. After cooling to ambient temperature, water was removed under reduced pressure and the residue was treated with acetonitrile. The solid was filtered, washed with acetonitrile and dried to give the title compound as a hydrobromide salt (80 mg). The solid was then added to a stirred solution of aqueous saturated potassium carbonate (10 mL) and the resulting suspension was stirred for 2 hours. Ethyl acetate (15 mL) was added and the aqueous layer was separated and washed with ethyl acetate (2×15 mL). The combined organic extracts were dried over sodium sulphate and the solvents evaporated in vacuo to yield the title compound (44 mg, 66%) as a pink solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[C:34]2[CH:35]=[CH:36][C:37]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:38][CH:39]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-Propargylmorpholine (320 mg, 2.4 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled to 0° C. and tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetate contaminated with ca. 20% of 1,6-bis(morpholin-4-yl)-2,4-hexadiyne.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>COC(C)(C)C>[C:28]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1
Reaction time: 0.33 h

Procedure:
9.32 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate are placed in 100 ml of tert.butyl methyl ether with 3.54 g of triethylamine. 4.92 g of benzoyl chloride are added dropwise within about 30 minutes while cooling with an ice bath. The mixture is then left to stir at 0°-5° C. for 20 minutes. The reaction mixture is poured into water and extracted twice with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The crude product is dissolved in ethyl acetate while warming and suction filtered over an about 3 cm deep layer of silica gel. The crystals obtained after evaporation of the filtrate are recrystallized from ethanol, and there is obtained ethyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 116°-117° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)(C)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH2:11][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:19]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=3[N:10]=2)[N:24]=[CH:23][N:22]=1
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1c(N)ncnc1NCc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 48.7 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.123 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 2 h. After cooling the pink solid was removed by filtration and washed with isopropanol (0.5 mL). This material was purified by column chromatography (Si—PCC, gradient 0-4% MeOH in DCM). Product containing fractions were evaporated to a white solid. This was triturated with diethyl ether and dried to give 371 as a white solid, (70 mg, 69%). LCMS (Method C): RT 3.54 min [M+H]+ 360.02. 1H NMR δ (ppm) (DMSO-d): 7.87 (1H, s), 7.69 (1H, t, J=5.2 Hz), 7.65 (1H, dd, J=8.80, 4.87 Hz), 7.64-7.46 (5H, m), 7.22 (2H, s), 7.06 (1H, ddd, J=9.86, 8.79, 2.53 Hz), 6.87 (1H, dd, J=8.97, 2.51 Hz), 4.62 (2H, d, J=5.37 Hz)
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH2:17][O:18][CH:19]([CH:24]=[CH2:25])[C:20]([F:23])([F:22])[F:21]>CO>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[N:2][OH:3])[CH2:17][O:18][CH:19]([CH:24]=[CH2:25])[C:20]([F:23])([F:22])[F:21]
Reactant: C=CC(OCC(=O)c1ccccc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Temperature: 45 °C
Yield: 97.6 %

Procedure:
To a reactor was added hydroxylamine hydrochloride (0.34 kg, 4.95 mol), sodium acetate (0.47 kg, 5.70 mol) and MeOH (2.68 L). To this suspension was charged a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone (0.998 kg, 3.806 mol) in MeOH (1.8 L) and the reaction mixture was heated to 40-50° C. Upon completion (ca. 2 h) the reaction mixture was cooled to rt, and filtered over Celite (0.5 wt) and rinsed with EtOAc (3.0 L). The filtrate was concentrated under vacuum and to the resulting residue was added methyl tert-butyl ether (6.3 L), water (0.94 L) and sat. aq. NaHCO3 (2.5 L). The organic phase was washed once with water (1.6 L) and sat. aq. NaCl (0.1 L). The organic phase was concentrated under vacuum to afford the title compound as an oil (1.03 kg, 95.0%). 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.35 (m, 2H), 7.24-7.06 (m, 2H), 5.78-5.65 (m, 1H), 5.54-5.40 (m, 2H), 4.89-4.81 (m, 1H), 4.53 (d, J=12.6 Hz, 1H), 4.47 (d, J=12.6 Hz, 0.5H), 4.27-4.18 (m, 1H), 4.13-4.05 (m, 0.5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C.CCCCCC>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nn(Cc3ccccc3)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A mixture of 0.10 g of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) and 3.0 g of benzyl bromide was heated at 140° C. for 4 days then at 210° C. for 1 hour. The reaction mixture was dissolved in 10% ethyl acetate-hexane and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC (10% ethyl acetate-hexane). The first fraction was benzyl bromide. The second fraction eluted with 30% ethyl acetate-hexane yielded 1-benzyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole (60 mg, 49%): mp 125.5°-126.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[CH3:25][N:26]1[C:31](=[O:32])[C:30]2=[C:33]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[N:34]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][CH:38]=3)[N:35]=[C:29]2[NH:28][C:27]1=[O:53]>CS(C)=O.CN(C)C=O>[CH3:5][N:4]([CH3:6])[CH2:3][CH2:2][N:28]1[C:29]2=[N:35][N:34]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][CH:38]=3)[C:33]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)=[C:30]2[C:31](=[O:32])[N:26]([CH3:25])[C:27]1=[O:53]
Reactant: CN(C)CCCl
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)CCn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 90 °C
Yield: 158.2 %

Procedure:
N-(2-Chloroethyl)-N,N-dimethylamine hydrichloride (0.058 g), followed by triethylamine (0.092 mL) and DBU (0.103 mL), were added to a solution of 5-methyl-2-(1-naphthylmethyl)-3-(4-pyridinyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.064 g) in 3:1 dimethylformamide and DMSO (1 mL). The mixture was heated at 90° C. for 18 h then cooled to room temperature. Crude reaction was purified on preparative HPLC to give the title compound (0.120 g). Mass 455.03 (M+H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:19][C:18]2=[O:33]>N1C=CC=CC=1>[O:33]=[C:18]1[C:17]2[C:22](=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:14]=[CH:15][CH:16]=2)[O:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:30])[F:31])=[CH:19]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cccc2c(=O)cc(-c3ccccc3C(F)(F)F)oc12
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cc(-c2ccccc2C(F)(F)F)oc2c(NS(=O)(=O)c3cccnc3)cccc12
Temperature: 80 °C
Yield: 31.4 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride 12 (280 mg, 1.3 mmol) was added to a solution of 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-one 11 (100 mg, 0.328 mmol) in pyridine (5 mL). The reaction mixture was heated at 80° C. for 12 h. The pyridine was removed en vacuo. The residue was taken up in CH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) followed by recrystallization from CH3CN to give Compound 326 (46 mg, 31% yield). MS (ESI) calcd for C21H13F3N2O4S: 446.1. found: 447 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.[NH:28]([C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][N:31]=1)[NH2:29]>>[I:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([NH:28][N:29]=[CH:1][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[C:6]([N:13]4[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Reactant: NNc1cc(I)ccn1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=NNc4cc(I)ccn4)nc23)CC1

Procedure:
Prepared as described in Example 1, steps D-E, using tert-butyl (1-(2-formylquinolin-8-yl)piperidin-4-yl)methylcarbamate in place of 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde, and 2-hydrazinyl-4-iodopyridine in place of 2-Hydrazinyl-4-(2-methoxyethoxy)pyridine.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2].[CH3:21][NH2:22]>>[CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:22][CH3:21])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCCCCP(=O)(OCC)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCCCCP(=O)(OCC)c1ccc(NC)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 7b from ethyl(4-chloro-3-nitro-phenyl)-n-pentyl-phosphinate and methylamine solution.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:30])([F:29])/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>CN(C)C=O.C(O)C.O.CCCCCC.C(OCC)(=O)C>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]2[CH:9]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]([C:21]([F:20])([F:30])[F:29])[O:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 71.4 %

Procedure:
A one liter three-neck flask was charged with 4-tert-butylsalicylaldehyde (Step 1)(100.0 g, 0.56 mole), dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40° C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110 mL) was added and the mixture heated to 60° C. at which time the reaction temperature rose to 70° C. The reaction was cooled to 60° C., maintained at 60° C. (with added heating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a solid. This solid was dissolved in hot ethanol (600 mL). Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%): mp 91.0–94.9° C. This material was of suitable purity to be used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[O:9].[OH-].[Na+:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[O:9].[Na+:26]
Reactant: COc1cccc(C=CC(=O)Nc2ccccc2C(C)C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C=CC(=O)Nc2ccccc2C(C)C(=O)[O-])c1

Procedure:
162 Milligrams of 2-(3'-methoxycinnamoylamino)phenylpropionic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The mixture was warmed for 30 minutes and then concentrated under reduced pressure. The residue was taken up in a small amount of ethanol and ether was added to the ethanolic solution. The precipitated crystals were collected by filtration to obtain sodium 2-(3'-methoxycinnamoylamino)phenylpropionate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[C:20]([Cu])#[N:21]>CN1CCCC1=O>[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1)#[N:21]
Reactant: CCOC(=O)C1CCc2sc3ccc(Br)cc3c2C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCc2sc3ccc(C#N)cc3c2C1
Temperature: 170 °C
Yield: 88.1 %

Procedure:
To a solution of ethyl 8-bromo-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylate (0.62 g, 1.83 mmol) in 10 mL 1-methylpyrrolidin-2-one was added CuCN (0.328 g, 3.66 mmol). The reaction was heated at 170° C. overnight, then was cooled to room temperature and was partitioned between EtOAc and water. The organic layer was washed with water, then brine, then dried over MgSO4, filtered and concentrated. Purification by chromatography on silica gel (25% EtOAc in hexane) afforded 0.46 g (88%) of the title compound as a white solid: mp 121-122° C.; MS (ES) m/z=285 [M]+.
Reaction SMILES: C(O[C:9](=O)[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][C:20](=[O:28])[N:21]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:22])[CH2:14][CH2:13]1)C)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:21]([CH3:22])[C:20](=[O:28])[CH2:19][O:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:10][CH3:9])[CH2:17][CH2:16]1
Reactant: CN(C)CCN(C)C(=O)CO[C@H]1CC[C@H](N(C)C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN[C@H]1CC[C@H](OCC(=O)N(C)CCN(C)C)CC1

Procedure:
6.24 g (13.38 mmol) of trans-(4-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methoxy}-cyclohexyl)-methyl-carbamic acid benzyl ester in 34 mL of EtOAc were hydrogenated in the presence of 0.51 g of 10% Pd/C. After removal of the catalyst and evaporation of the solvent, the residue was redissolved in 50 mL of MeOH and hydrogenated in the presence of 0.4 g of 10% Pd/C. The catalyst was removed by filtration over decalite and the filtrate was concentrated. To the residue ether and aqueous HCl were added and the layers were separated. The inorganic one was washed with ether, 1M NaOH was added and the compound was extracted with CH2Cl2, and mixtures of CH2Cl2/THF (1:1). The combined organic layers were washed with brine and dried over Na2SO4. Evaporation of the solvent yielded 2.7 g (75%) of trans-N-(2-dimethylamino-ethyl)-N-methyl-2-(4-methylamino-cyclohexyloxy)-acetamide as colorless oil, MS: 272 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(N)=O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)CNc1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.0 g, 0.0063 mole), glycinamide hydrochloride (3.11 g, 0.028 mole), triethylamine (3.1 g, 0.031 mole) in 35 ml of acetonitrile was heated at reflux for 161/2 hrs. The yellow precipitate was filtered off. The precipitate was slurried and filtered successively with water, absolute alcohol and acetone. The yellow solid was dried under high vacuum at room temperature to give 0.9 g (73.2%), of title compound, m.p. 250°-51° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:16]3[N:20]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[N:19]=[C:18]([CH3:25])[CH:17]=3)[C@H:13]([C:26]([NH:28][C:29]3([C:32]#[N:33])[CH2:31][CH2:30]3)=[O:27])[CH2:12]2)(=[O:10])=[O:9])=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.CC1(C)C(C)(C)[O:42][B:41](B2OC(C)(C)C(C)(C)O2)[O:40]1.ClCCl.C([O-])(=O)C.[K+]>CS(C)=O.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]>[C:32]([C:29]1([NH:28][C:26]([C@H:13]2[N:14]([C:16]3[N:20]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[N:19]=[C:18]([CH3:25])[CH:17]=3)[CH2:15][C@H:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([B:41]([OH:42])[OH:40])=[CH:3][C:4]=3[C:34]([F:37])([F:36])[F:35])(=[O:10])=[O:9])[CH2:12]2)=[O:27])[CH2:31][CH2:30]1)#[N:33]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(B(O)O)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C

Procedure:
A solution of (2S,4R)-4-(4-bromo-2-(trifluoromethyl)phenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (40 mg, 66.6 umol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (33.8 mg, 133 umol; CAS Reg. No. 73183-34-3), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (10.9 mg, 13.3 umol) and potassium acetate (32.7 mg, 333 umol) in DMSO (0.8 ml) was heated to 80° C. for 20 h. The reaction mixture was cooled to ambient temperature and poured onto 20 ml 0.1 N HCl/ice/brine and extracted with iPrOAc (2×25 ml). The combined organic layers were washed with 0.1 N HCl/ice/brine (3×), icewater/brine (3×), dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the crude title compound (66 mg; quant.) which was used in the next reaction step without further purification. MS (ESI): m/z=566.2 [M+H]+.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[N:18])[CH2:12][CH2:11]1)[CH3:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[ClH:27]>CCOCC.O>[ClH:27].[CH2:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]1)[CH3:9]
Reactant: CCC1CCN(CC#N)CC1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Product: CCC1CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 28 %

Procedure:
The title compound was prepared according to general procedure H described in Scheme 3. The crude triethylsilane solution of 2-(4-ethylpiperidin-1-yl)acetonitrile was added carefully to a slurry of LiAlH4 (8.3 equiv., 1.2 g, 31 mmol) in ether (5 mL) and stirred at RT under Ar for 14 h. The crude reaction mixture containing a white precipitate was cooled to 0° C. and treated dropwise with 10% aqueous NaOH (1 mL) and stirred for 30 min. The cooled mixture was treated with H2O (2.1 mL) to provide a thick precipitate. The mixture was then treated with ether (10 mL), stirred and filtered. The filter cake was washed with ether (5×10 mL). The combined ether layer was concentrated under reduced pressure to provide a concentrated solution in ether/H2O that was acidified to pH 2 with 1 N HCl. The mixture was concentrated under reduced pressure to provide 2-(4-ethylpiperidin-1-yl)ethanamine hydrochloride as a brown oil (200 mg, 28% yield).