Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2N=N1>C(#N)C.[Cl-].[Na+].O>[CH2:4]([O:3][C:1]([C@@H:6]([NH:10][C@@H:11]([CH3:12])[C:13]([O:15][C:1]([CH:6]1[CH2:7][CH:26]2[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[NH:23]1)=[O:2])=[O:14])[CH2:7][CH2:8][CH3:9])=[O:2])[CH3:5]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC[C@H](N[C@@H](C)C(=O)OC(=O)C1CC2CCCCC2N1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.54 g of (2S,3aS,7aS)-2-carboxyperhydroindole benzyl ester, 7.26 g of N-((S)-1-carbetoxybutyl)-(S)-alanine and 12.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 225 ml of acetonitrile is stirred at room temperature for 30 min, then 560 ml of brine is added. The product is extracted twice with 400 ml of ethyl acetate, combined extracts are washed first with 800 ml of water, acidified with concentrated hydrochloric acid and then with 1.5 l of water. Organic phase is dried over anhydrous sodium sulphate and evaporated at 40° C. in vacuo to yield 13.5 g (88%) of benzyl (2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahydroindole-2-carboxylate (benzyl ester of perindopril).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[Br:14]N1C(=O)CCC1=O>>[Br:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1cc(Br)c(O)c(C=O)c1
Yield: 73 %

Procedure:
Proceeding as in Reference 9, but substituting methyl 3-formyl4-hydroxybenzoate (12.0 g, 66.6 mmol, 1 eq.) and N-bromosuccinimide (12.45 g, 69.9 mmol, 1.05 eq.) gave methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:14]([CH3:15])=[CH:13][C:12]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)nc1
Temperature: 100 °C

Procedure:
A mixture of N-(5-bromopyrid-2-yl)acetamide (31.4 g, Reference Example 23), ethyl crotonate (37.0 mL), triethylamine (33 mL), tetrakis(tri-o-tolylphosphine)palladium(0) and tetrabutylammonium bromide (9.36 g) in dimethylformamide (250 mL) was heated at 100° C. under an argon atmosphere for 48 hours. The reaction mixture was cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with brine, then dried over magnesium sulphate and then evaporated. The resulting light brown solid was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give the title compound (27.3 g) as a pale yellow solid.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4](OCC)(=O)CC(OCC)=O.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:21]([C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Br:15])[CH:24]=1)(=[O:22])[CH3:4]
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
1.24 g of ground magnesium chloride was suspended in 13 ml of toluene and 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added in turn. After stirring at room temperature for 1.5 hours, a suspension of 4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml of toluene was added dropwise over 15 minutes, followed by stirring at room temperature for 2 hours. After neutralizing with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was further subjected to extraction with diethyl ether and the organic layers were combined, and then the solvent was distilled off under reduced pressure. To the resulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) was added, followed by stirring with heating at 150 to 160° C. for 2 hours. The reaction solution was air-cooled, and then water was added. Then, the deposited crystals were collected by filtration. The deposited crystals were dissolved in ethyl acetate, washed in turn with water and an aqueous saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433) was added and, after standing for 10 minutes, activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.89 g of the objective compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C=O.[C:17](O)(=O)C(O)=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)C(=O)O
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 11: 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.125 g, 0.628 mmol), formic acid (1.82 mL), aqueous formaldehyde (40%, 1.63 mL). 65° C.; over night. The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether (0.126 g). M.p. 159-162° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 27), 141 (13), 113 (15), 58 (32), 57 (bp).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[C:14][Si](C)(C)C)=[N:4]1)[CH3:2]>CO.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[CH:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C#C[Si](C)(C)C)nc1N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1nc(N2CCCC2)n(CC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A mixture of 1-ethyl-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole (122 mg, 465 μmol, Eq: 1.00) in methanol (3 ml) and 1N NaOH aq. (0.1 ml) was stirred for 18 hours at 25° C. under argon atmosphere. The mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated affording 1-ethyl-3-ethynyl-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (79 mg, 89.3%) as an orange oil. MS: m/z=191.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl>CO.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NOC1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 138.9 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) in MeOH (32 mL) was added hydrogen chloride methanol reagent 10 (8.0 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 0.5 hour. The reaction mixture was diluted with AcOEt and the precipitate was collected with filtration to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide hydrochloride (1.18 g) as colorless powder.
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][N:9]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:38])([F:37])[C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].O>ClCCl.[Pd]>[C:1]1([C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][NH:9][S:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([C:22](=[O:23])[C:21]([F:38])([F:20])[F:37])[CH2:25][CH2:26]3)(=[O:34])=[O:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CNS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C(F)(F)F)c1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-phenyl-2-tert-butoxycarbonylaminoethylazide (10.50 g, 0.04 mol) dissolved in 250 mL dichloromethane and 2.5 g of 10% Pd/C was hydrogenated for 5 hrs at 70 psi of H2. The catalyst was separated by filtration. To the filtrate triethylamine (8 mL) was added, the mixture was cooled to −20° C. followed by slow addition of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (12.56 g, 0.04 mol) dissolved in 150 mL dichloromethane. The reaction mixture was then stirred overnight at room temperature. Water (500 mL) was added and the mixture was shaken well, organic layer was separated, shaken with 200 mL 2% citric acid, separated and dried with MgSO4. The drying agent was separated by filtration. The filtrate was concentrated and the title product was precipitated by addition of hexane. Yield: 17.67 g, (86%); (MH)+=514; 1H NMR (DMSO-d6): 1.33 (s, 9H), 2.85-2.99 (m, 2H), 3.26-3.30 (t, J=8.0 Hz, 2H), 4.31-4.35 (t, J=8.0 Hz, 2H), 4.53-4.59 (m, 1H), 7.19-7.35 (m, 6H), 7.66-7.68 (m, 2H), 7.72-7.75 (t, J=6.0 Hz, 1H), 8.13-8.15 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:27]([F:39])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:39][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCCC(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCCC(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (30 mg, 0.167 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (89 mg, 0.200 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 18 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 2.73-2.84 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.32-4.38 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.66 (s, 1H), 7.69 (s, 1H), 7.80 (s, 1H), 12.70 (br s, 1H); APCI-MS (m/z): 542.20 [M−H].
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2Cl)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[H-].[Na+:36].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:41][OH:42]>CN(C=O)C>[Na+:36].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:41][O:42][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:34])=[O:2])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Reactant: OCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1ccc(C=Cc2cnccc2OCc2cc(F)cc(F)c2)cc1-c1ccccc1C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(2-(4-chloropyridin-3-yl)ethenyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 1040, (27 mg, 0.05 mmol) was dissolved in DMF (1 mL) with 3,5-difluorobenzyl alcohol (0.1 mL) and treated with NaH (60% in mineral oil, 6.5 mg, 0.16 mmol). After stirring 18 hours at ambient temperature, the reaction was evaporated and lyophilized from water to provide 29 mg of the title compound. MS m/e 589 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:28][NH2:29])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:29][CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1cnc(CN)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(CNc2nc(N)nc(-n3cccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-(3,5-dimethyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:6]1[C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(N)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1cccc(Cl)c1-c1nnn[nH]1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
To a mixture of 2-amino-6-chlorobenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed with water (3×20 mL). The aqueous extractions were combined and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 137 mg of 3-chloro-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C7H6ClN5: 196 (M+H). Step 2: N-[3-Chloro-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of the tetrazole intermediate 3-chloro-2-(1H-tetrazol-5-yl)aniline (137 mg, 0.7 mmol) in 3 mL of DCM, DIPEA (1.4 mmol, 2.0 eq.) was added followed by thiophene-2-carbonyl chloride (1.0 mmol, 1.5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This was then washed with acetonitrile, and dried under vacuum to afford 80 mg of desired N-[3-chloro-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide. 1H-NMR (400 MHz, d6-DMSO): 10.25 (s, 1H), 7.83 (dd, 1H), 7.73 (dd, 1H), 7.68-7.64 (m, 2H), 7.62-7.59 (m, 1H), 7.17 (t, 1H). MS (EI) for C12H8ClN5OS: 306 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][CH:24]([N:26]([CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][CH3:45])C(OC(C)(C)C)=O)[CH3:25])=[CH:17][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:13][CH2:12]1)(=[O:10])[CH3:9].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][CH:24]([NH:26][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][CH3:45])[CH3:25])=[CH:17][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:13][CH2:12]1)(=[O:10])[CH3:9]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(C(C)=O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccccc1OCCNC(C)Cc1cc2c(c(C(N)=O)c1)N(C(C)=O)CC2
Yield: 101.9 %

Procedure:
To a mixture of trifluoroacetic acid (0.2 ml) and methylene chloride (0.2! ml) was added a solution of 1-acetyl-5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (40 mg) in methylene chloride (0.2 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of methylene chloride and methanol (10/1) as eluent to give 33 mg of 1-acetyl-5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)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.[NH2:45][CH2:46][C:47]1[N:48]=[CH:49][NH:50][CH:51]=1>CN(C=O)C>[NH:50]1[CH:51]=[C:47]([CH2:46][NH:45][C:8]([C:4]2[N:5]([CH3:7])[CH:6]=[C:2]([Cl:1])[CH:3]=2)=[O:10])[N:48]=[CH:49]1
Reactant: NCc1c[nH]cn1
Reactant: Cn1cc(Cl)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(Cl)cc1C(=O)NCc1c[nH]cn1
Reaction time: 0.08 h

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (55 mg, 0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in DMF (2 mL), BOP (217 mg, 0.49 mmol) was added. After 5 min of stirring, a solution of 4-aminomethylimidazole II-2 (100 mg, 1.03 mmol) in DMF (2 mL) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide (81 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=O)[CH3:2]>C1COCC1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]2)[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH3:2]
Reactant: CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a mixture of tert-butyl 4-[3-(acetylamino)-4-(phenylsulfonyl)phenyl]-1-piperazinecarboxylate (0.44 g, 0.96 mmol) in 7 mL of dry THF is added borane-methyl sulfide complex (0.28 mL, 2.8 mmol, 10.0 M). The mixture is stirred at rt overnight. The reaction is quenched upon dropwise addition of 10% HCl. Water (3.0 mL) and KOH (2.0 g) are added, the mixture heated at reflux for 6 h. At that time methanol (2 mL) is added and the mixture stirred at reflux overnight. After cooling to rt, the organics are removed under reduced pressure, the aqueous layer is saturated with NaCl, and extracted with CH2Cl2 (3×10 mL). The combined organic layers are dried over MgSO4, filtratered, and concentrated to give the crude product. Purification by column chromatography (15% EtOAc/hexane) gave 0.18 g (43%) of the pure title compound as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[C:22](Cl)(=[O:24])[CH3:23].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH:1]([C:4]1[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:6][C:7]([C:22](=[O:24])[CH3:23])=[C:8]([O:10][CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a clear solution of 2-Isopropyl4-methoxy-1-(toluene-4-sulfonyl)-benzene (5.3 g, 16.56 mmol) in DCE (50 ml) was added acetyl chloride (2.0 g, 24.84 mmol) and AlCl3 (3.3 g, 24.84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hrs and quenched by H2O (10 ml). Ten minutes after quenching, the aqueous solution was extracted into CH2Cl2. The combined extracts was washed with H2O, dried wover Na2SO4, filtered and concentrated. Flashed chromatography on silica gel (0 to 30% EtOAc in Hex) gave 1-[4-Isopropyl-2-methoxy-5-(toluene4-sulfonyl)-phenyl]-ethanone (4.7 g, 79%) as white solid.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:28]1([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)Nc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and phenyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23]C(OC(C)(C)C)=O)=[CH:18][C:17]=2[O:31][CH2:32][CH3:33])=[CH:10][CH:9]=1>>[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][C:17]=2[O:31][CH2:32][CH3:33])=[CH:10][CH:9]=1
Reactant: CCOc1cc(CNC(=O)OC(C)(C)C)ccc1C(=O)Nc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(CN)ccc1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N Hydrochloric acid-dioxane (1 ml) was added to N-(4-pyridyl)-4-tert-butoxycarbonylaminomethyl-2-ethoxybenzamide (60 mg), and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate to give 40 mg of N-(4-pyridyl)-4-aminomethyl-2-ethoxybenzamide dihydrochloride 1/2 hydrate having a melting point of 251° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([F:13])[CH:6]=[CH:7][C:8]=2[F:12])[CH2:3]1.OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([F:13])[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]=2[F:12])[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2c(F)ccc(F)c2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCc2c(F)cc([N+](=O)[O-])c(F)c2C1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
An ice-cooled mixture of 0.94 g (5.1 mmol) 2-methyl-5,8-difluoro-1,2,3,4-tetrahydro-isoquinoline and 2.8 ml conc. H2SO4 is slowly combined with 0.36 ml 65% nitric acid. Then the mixture is stirred for 2.5 h while cooling with ice and it is then poured onto ice water. It is made alkaline with NaOH, extracted 3× with EtOAc, the organic phases are dried with Na2SO4, filtered and concentrated.