Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cc(F)ccc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound was prepared by hydrolysis of 9b using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63]>CN(C)C=O>[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH2:60][CH2:61][C:62]([O:64][CH3:65])=[O:63])[C:11]([C:7]1[N:6]=[C:5]2[N:4]=[C:3]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)[N:2]([CH3:1])[C:10]2=[CH:9][CH:8]=1)=[O:12]
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21
Reactant: COC(=O)CCNc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1ccc2c(n1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
308 mg (1.0 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-carboxyimidazo[4,5-b]pyridine were suspended in 5 ml of dimethylformamide and mixed with 303 mg (3.0 mmol) of N-methylmorpholine and 321 mg (1.0 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate. After 10 minutes at room temperature, a solution of 215 mg (1.2 mmol) of methyl N-(2-pyridyl)-3-aminopropionate in 2 ml of dimethylformamide was added, whereupon a clear solution was obtained. After 12 hours at room temperature, the reaction solution was stirred into ice-water. After extracting 3 times with ethyl acetate, the combined organic extracts were washed with a saline solution, dried over sodium sulfate, and evaporated down. The residue obtained was chromatographed on silica gel with dichloromethane/ethanol (90:1 to 25:1).
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18]([Cl:22])(=[O:21])[CH2:19][CH3:20]>ClCCl>[ClH:22].[C:8]12([C:2]3[CH:3]=[CH:4][C:5]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:6][CH:7]=3)[CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2
Reactant: CCC(=O)Cl
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(C23CNCC2C3)cc1

Procedure:
A mixture of 5.6 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride, 12.9 g. of aluminum chloride and 6.2 g. of propionyl chloride in 55 ml. of dichloromethane is reacted as described in Example 57, to give 4.5 g. of the desired product, m.p. 191°-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](O)=[O:14])[CH:9]=[CH:10][CH:11]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH2:28])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1COc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (3.08 g, 11.4 mmol) and Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (5.05 g, 11.4 mmol) in DMF (75 ml) was added triethylamine (2.30 g, 22.8 mmol), and the reaction mixture was stirred for 1 h at room temperature. To this reaction mixture was added liquid ammonia (100 ml) at −40 0° C., the resulting mixture was allowed to warm to ambient temperature over 10-12 hours and concentrated. The residue was taken into ethyl acetate and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (ethyl acetate:hexane, 2.5:1 spiked with acetic acid) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].S(Cl)([Cl:15])=O>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([Cl:15])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: Cl
Product: Cc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 100-mL, three-necked, round-bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 5-chloro-2-methylbenzoic acid (10.00 g, 58.62 mmol). The apparatus was cooled in an ice bath, and thionyl chloride (40 mL, 550 mmol) was added in one portion. The ice bath was removed and the reaction mixture was warmed to about 50° for about 45 minutes in order to completely dissolve the 5-chloro-2-methylbenzoic acid. The reaction mixture was allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation. The residue was distilled under vacuum to afford 5-chloro-2-methylbenzoyl chloride as an oil: bp 65° (0.2 torr). This material was transferred immediately into an addition funnel and added dropwise with stirring to a commerical 40% dimethylamine solution (50 mL, 445 mmol) in water (150 mL). After complete addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ether, washed with water, dried, and concentrated. The resulting oil was distilled under vacuum to afford 5-chloro-N,N-2-trimethylbenzamide (10.40 g, 52.65 mmol, 90% yield) as an oil: bp 95°-101° (0.15 torr); IR(neat) 1650 cm-1 ; 1H NMR(CDCl3) δ 7.07-7.53(m,3H), 3.12(s,3H), 2.84(s,3H). Anal. Calcd for C9H12ClNO: C,60.76; N,6.12; Cl,17.94; N,7.12. Found: C,60.57; N,6.06; Cl,17.84; N,6.86.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CCOCC>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: Clc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: NNc1ccc(Cl)cn1
Yield: 82.9 %

Procedure:
A mixture of 2,5-dichloropyridine (7.4 g, 50 mmol) and 50 ml of hydrazine hydrate (1 mol) was refluxed for 3 hours and the mixture was diluted with ether. The crystalline solid (1st crop) was filtered, the solid was washed with water; and the aqueous layer was extracted with ether (2×). The organic layer was partially concentrated in vacuo and filtered to yield an additional white solid (2nd crop). The concentration of the filtrate yielded more solid (third crop). The combined solid product was dried in vacuo to afford 5.95 g (82%) of 2-hydrazino-5-chloropyridine as a white solid, m.p. 116°-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]2[CH2:14][CH2:15][CH2:16][S:17]2(=[O:19])=[O:18])[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O

Procedure:
Using methyl 2-amino-4-bromobenzoate (5 g) and 3-chloropropane-1-sulfonyl chloride (3.44 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (5.32 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20](O)=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=[CH:26]1)=O.CN(C)C=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.6 g, 0.0101 mole), and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29M solution, 0.0606 mole) was added. The resulting solution was heated at 45° C. overnight under nitrogen. The solvents were evaporated under reduced pressure. The residue was triturated in water (300 ml), and the resulting solid was collected by filtration, rinsed with water, 5% potassium hydroxide solution and again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. A solid precipitated which was collected by filtration and dried under high vacuum to give 1.26 g (38%) of title compound, mp 204°-207° C.
Reaction SMILES: C(=O)C.[CH3:4][C:5]1[N:6]=[C:7]([C:23](=O)[CH3:24])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([CH3:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=1.[BH3-]C#[N:28].[Na+].CCO.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[CH3:4][C:5]1[N:6]=[C:7]([CH:23]([NH2:28])[CH3:24])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([CH3:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1nc(C)c(-c2ccnc(C(C)(C)C(F)(F)F)c2)s1
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(C(C)N)sc1-c1ccnc(C(C)(C)C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone ethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2 g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 C for 10 minutes in a sealed tube. The mixture was concentrated to remove the EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH was added until aqueous pH was ˜9. Separated layers, and extracted aqueous with EtOAc (50 ml). The combined organic layer was washed with 60 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 1.58 g crude tan oil. This material was taken up in 20 mL dioxane. 2.2 eq HCl (4N in dioxane) was added, and stirred 1 h. Yellow ppt was formed. The suspension was concentrated in vacuo to give 1.97 g 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine dihydrochloride salt as a yellow-green solid, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.23 min. MS m/z 330.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([OH:15])=O)[CH:3]=1.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cc(F)cc2ncccc12
Product: O=C(Cc1cc(F)cc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 0.122 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl-amine (0.20 g, 0.083 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=2.33, method [7], MS(ESI) 434.0 (M+H). 1H NMR (CDCl3) δ 11.79 (s, 1H), 8.94 (d, J=4.0 Hz, 1H), 8.54 (d, J=8.1 Hz, 1H) 8.38 (s, 1H broad), 7.80 (d, J=10.1 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.59-7.55 (m 1H), 7.22 (s, 1H), 4.47 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:14]I>[OH-].[NH4+].O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[I:14]
Reactant: CON(C)C(=O)c1ccc(O)cc1
Reactant: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CON(C)C(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
The product from Example 71C (10.3 g, 56.84 mmol) in concentrated ammonium hydroxide (400 mL) was stirred at 25° C. for 15 minutes and then treated with KI (45.96 g, 276.83 mmol) and I2 (14.43 g, 56.84 mmol) in water (65 mL). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residue was redissolved in DCM (500 mL) and washed with water (350 mL×2). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 90% CH2Cl2, 10% MeOH, to provide the title compound as a white solid (11.6 g, 67% yield). 1HNMR (300 MHz, CD3OD) δ 3.32 (s, 3H), 3.59 (s, 3H), 6.83 (d, 1H, J=8.9 Hz). 7.58 (d, 1H, J=8.9 Hz), 8.06 (s, 1H); MS (DCI) m/z 308 (M+H)+, 325 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].Cl[CH2:12][C:13]([CH3:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH2:12][C:13](=[O:14])[CH3:15]
Reactant: CC(=O)CCl
Reactant: Oc1c(Br)cc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)COc1c(Br)cc(Br)cc1Br
Temperature: 27 °C
Yield: 96.5 %

Procedure:
A mixture of 5 g 2,4,6-tribromophenol (15 mmol), 1.4 g 1-chloroacetone (15 mmol), 4.16 g anhydrous potassium carbonate (30 mmol) and 20 ml DMF is stirred at 27° C. Completion of the reaction is confirmed by TLC. The reaction mass is diluted with water and extracted with ethylacetate The organic layer is washed with water and brine, dried over anhydrous sodium sulphate and concentrated to obtain 5.6 g 1-(2,4,6-tribromo-phenoxy)-propan-2-one (97%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([C:2]2[C:10]3[O:9][C:8]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=4)=[N:7][C:6]=3[CH:5]=[C:4]([OH:19])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Br[Zn]C1CCCC1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(C4CCCC4)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(cyclopentyl)zinc. The desired product was obtained as a white solid, m.p. 220–222° C.; MS m/e 296 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[CH:34][C:35](Br)=[N:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:37][N:36]=1
Reactant: CC1(C)OB(c2cc(NC(=O)c3ccc(S(C)(=O)=O)cc3)ccc2Cl)OC1(C)C
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccc(C(F)(F)F)cn3)c2)cc1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsulfonyl)benzamide (˜1.0 mmol) was used in Procedure A with 5-trifluoromethyl-2-bromopyridine (226 mg, 1 mmol). Purified by silica gel chromatography (0-10% acetone/dichloromethane) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide as a white solid: MS (Q1) 455 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Reactant: C=CCCCBr
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 62%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.17 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.62-1.75 (br, 2H), 2.01-2.22 (m, 7H), 2.35-2.53 (br, 3H), 2.58-2.65 (m, 1H), 2.74 (t, J=6.6 Hz, 2H), 2.75-2.85 (br, 1H), 2.88-3.05 (br, 1H), 3.28-3.41 (m, 3H), 4.97 (d, J=13.5 Hz, 1H), 5.02 (dd, J=17.6, 1.5 Hz, 1H), 5.73-5.83 (m, 1H), 6.93 (s, 1H), 6.98 (s, 1H), 7.15-7.21 (m, 2H), 7.36-7.40 (m, 1H) ppm. MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Yield: 95.4 %

Procedure:
A mixture of 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was treated with a catalytic amount of 10% palladium on activated carbon (30 mg). The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this time, the catalyst was removed by filtration through a plug of celite. The filtrate was concentrated in vacuo to afford 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (262.8 mg, 94.7%) as a pale yellow glass: EI-HRMS m/e calcd for C21H25N3O3 (M+) 367.1895, found 367.1899.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:12])([CH3:1])[CH2:11][CH2:10]2)(=[O:15])[CH3:14]
Reactant: CC1(C)CCc2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 2,2-dimethylchroman (Compound 214, 15 g, 19.4 mmol) in dry CH2Cl2 (100 mL) was added acetyl chloride (1.52 ml, 21.3 mmol) followed by AlCl3 (2.84 g, 21.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then poured into ice water. Extraction (CH2Cl2), drying (Na2SO4), and concentration under reduced pressure afforded a yellow oil. Column chromatography (EtOAc:hexanes 1:9) yielded 2.15 g (54%) of the title compound as a yellow solid. 1H NMR δ 7.73 (2H, m), 6.80 (1H, d, J=8.3 Hz), 2.83 (2H, t, J=6.9 Hz), 2.54 (3H, s), 1.84 (2H, t, J=6.9 Hz), 1.36 (6H, s). Anal. (C13H16O2) C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([Cl:23])=[O:19])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC

Procedure:
A solution of 185 mg (0.70 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrous dimethylformamide-methylene chloride (0.2 ml-2 ml) was cooled in an ice bath. To the solution was added 0.10 ml (1.1 mmol) of oxalyl chloride with stirring. The ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-cyanobenzaldehyde (0.22 g, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.07 g of 4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 19% yield].
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]1[CH2:11][C:12]([OH:14])=O.[Cl:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Cl:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][CH:10]=[C:4]23)[S:19][CH:20]=1
Reactant: O=C(O)Cn1c(=O)ccn2nccc12
Reactant: Nc1scc(Cl)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Cl)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (94 mg, 0.488 mmol) and 4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (49 mg, 0.244 mmol) according to protocol A. Retention time (min)=2.161, method [7], MS (ESI) 376.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 6.85 (s, 1H), 6.27 (d, J=8.1 Hz, 1H), 5.94 (s, 1H), 4.98 (s, 2H).