Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH2:10][CH2:9]1.[Br:25][C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]>CCOC(C)=O>[Br:25][C:26]1[N:31]=[C:30]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH2:10][CH2:9]2)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3N)CC21
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3NC(=O)c3ccc(F)c(Br)n3)CC21

Procedure:
Following Method 9, tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 537.1 (MH+); LCMS Rt=0.71 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].Br[C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:17][C:15](=[O:16])[C:14]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)([CH3:23])[CH3:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
(2-Mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester (88.6 g) synthesized in Example 1 and tert-butyl 2-bromo-2-methylpropionate (105.3 g) were dissolved in N,N-dimethylformamide (700 mL), potassium carbonate (66.3 g) was added, and the mixture was stirred at room temperature for 8 hr. Water (1 L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 L). The organic layer was washed with saturated brine, and dried over hydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (150 g) as a slightly brown oil. The present compound was used in the next step without particular purification.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[S:13](N3C=CC=C3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.[K].S(Cl)([Cl:29])(=O)=O>>[Cl:29][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][C:23]2[O:24][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccsc1CCc1ccc2c(c1)OCO2)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [K]
Product: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Yield: 42 %

Procedure:
3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was prepared in the same manner as described in the Example 1 5E using N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium salt of sulfonic acid (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42% yield.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.[Cl:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].C([O-])([O-])=O.[K+].[K+].Cl>C(Cl)Cl.CO>[ClH:40].[Cl:40][CH2:41][S:42]([N:30]1[CH2:31][CH2:32][CH:27]([N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:39])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:28][CH2:29]1)(=[O:44])=[O:43]
Reactant: O=S(=O)(Cl)CCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(S(=O)(=O)CCl)CC2)n1
Yield: 44 %

Procedure:
Reaction of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine (Example 21) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2, followed by conversion to the hydrochloride salt with 1.25 M HCl in methanol gave N1-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-1,3-propanediamine hydrochloride in 44% yield: mp (MeOH) 222-225° C.; 1H NMR (DMSO-d6) δ9.89 (br, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.71 (t, JHF=53.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 5.17 and 5.11 (2s, 2H), 4.74-4.71 and 4.66-4.53 (2m, 1H), 3.98 (s, 3H), 3.92-3.82 (m, 6H), 3.71 (m, 4H), 3.60-3.51 (m, 2H), 3.16-3.04 (m, 4H), 2.75 and 2.70 (2s, 6H), 2.02-1.80 (m, 6H); Anal. Calcd. for C27H39Cl2F2N9O4S.0.5 H2O: C, 46.1; H, 5.7; N, 17.9; Cl, 10.1. Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(#N)C>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.230 mmol) in 5 mL of dichloromethane. Added 0.5 mL of acetic anhydride. After 10 min, reaction is complete and trituration with acetonitrile gave 2-[5-(4-acetyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 91%). MS(ESI) m/z 477.3 (M+H)+
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:35][CH:36]=1)#[N:22]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-valerylamino-3-nitrobenzoate (2.1 g), 4-(2-cyanophenyl)benzyl bromide (2.0 g) and K2CO3 (1.1 g) in DMF (20 ml) was stirred for 4 hours at room temperature. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The resultant solution was dried and concentrated to give a syrup, which was purified by column chromatography on silica gel to afford a yellow syrup (3.5 g, quantitatively).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14].O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCCCO
Solvent: c1ccncc1
Solvent: O
Product: C=CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.2 mol, 23 ml) was added dropwise to a solution of 4penten-1-ol (0.2 mol, 20 ml) in pyridine and stirred overnight at room temperature. The reaction mixture was poured into 100 mlof water and the organic layer separated. The product mixture was washed, sequentially, with dilute HCl, saturated aqueous Na2CO3, and water. The organic layer was dried over anhydrous Na2CO3 and the product distilled: bp 90°-98° (1.0 mmHg); yield 26.9g, (71%); NMR (neat) δ 1.5 (broad m, 4, alkyl), 3.8 (t, 2, --OCH2 --), 4.6 (m, 2, =CH2), 5.2 (m, 1, =CH--), 7.3 (m, 5, ArH).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7](OC)=[O:8].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].Cl>CO>[OH:13][C:11]1[C:6]([O:5][CH3:4])=[C:7]([OH:8])[N:21]=[CH:19][N:20]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(O)ncnc1O
Temperature: 0 °C

Procedure:
A modified procedure of Bretschneider, Richter, and Klotzer, Monatsh. Chem. 96(6), 1661-76 (1965), was used. Absolute methanol (1.0 L) was added with ice bath cooling to sodium methoxide (175 g, 3.24 moles) in a 3 L round bottom flask. When the mixture had cooled to less than 20° C., dimethyl methoxymalonate (162.14 g, 1.00 mole) was added, and then solid formamidine acetate (104.11 g, 1.00 mole) was added. The mixture was stirred i the ice bath for 30 minutes, and then refluxed for 1 hour. The mixture was cooled in a cold water bath and then concentrated HCl (about 350 mL) was added until the mixture was strongly acidic on pH test paper. The precipitate was filtered, suspended in cold water (about 400 mL), and then filtered again. The white powder was dried in vacuo (125.84 g, 88.7%), and carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].Cl>C(O)CCC.CO>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2 H), 7.95 (d, 2 H), 7.70 (m, 5 H), 7.60 (d, 1 H), 7.30 (t, 1 H), 7.15 (t, 2 H), 3.35 (m, 2 H), 3.25 (s, 3 H), 3.20 (m, 2 H), 2.90 (m, 1 H), 1.95–1.75 (m, 2 H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:34])[CH2:13][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:15]2[C:14]([CH2:13][N:12]([CH3:34])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:18][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)=[CH:26][CH:27]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc(N)cc1
Yield: 96.6 %

Procedure:
To a solution of tert-butyl methyl(2-(methyl((3-(4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (0.700 g, 0.00140 mol) in MeOH (25 mL) was added PdC (0.07 g, 10% w/w) under a nitrogen atmosphere. Hydrogen gas was purged into the reaction mass for 2 h. The reaction mixture was filtered through a Celite bed and washed with MeOH. The filtrate was evaporated to give tert-butyl (2-(((3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (0.600 g, yield: 92%). LCMS (ESI): RT=1.79 min, m/z=444.5 [M+H]+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCO>O>[N:33]1([CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCN3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), piperazine (0.035 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C. for 2×10 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.03 g (33%). 1H-NMR (MeOD) δ 7.25 (t, 1H), 6.90–6.95 (m, 2H), 6.85 (d, 1H), 4.12 (t, 2H), 3.82 (s, 2H), 3.3.10–3.15 (m, 6H), 3.00 (t, 3H), 2.10–2.15 (m, 3H). LCMS 445.2 (M+1), HPLC Method B Rt 1.6 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH2:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1

Procedure:
4-Fluorobenzoic acid methyl ester (53 mmol), 1-ethyl-piperazine (44 mmol) and potassium carbonate (44 mmol) are suspended in dimethyl-acetamide (50 ml) and stirred under reflux overnight. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A brownish powder with mp. 102-104° C., Rf=0.22 (CH2Cl2MeOH=95:5) is obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][NH:26][CH3:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][N:26]([CH3:27])[S:33]([CH3:32])(=[O:35])=[O:34])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNC)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one (72 mg, 0.16 mmol; Example 134 Step A) in DMF (0.40 mL) was added methanesulfonyl chloride (61 μL, 0.79 mmol) and pyridine (76 μL, 0.95 mmol) successively at 0° C. After being stirred at 25° C. for overnight, the reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Separation by RP-HPLC (50 to 85% MeCN/H2O (0.1% TFA) a gradient elution) provided the title compound as a pale yellow film.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH3:3].[N+:22]([O-])([OH:24])=[O:23].Cl>C(O)(=O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]1=2)[CH3:3]
Reactant: CN(C)CCCN1c2ccccc2CCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCCN1c2ccccc2CCc2cc([N+](=O)[O-])ccc21
Temperature: 18 °C
Yield: 51.2 %

Procedure:
Imipramine (26a, 1.925 g, 6.87 mmol) was dissolved in 32 mL acetic acid and cooled to 18° C. Conc. nitric acid (0.79 mL, 13 mmol) in 1.1 mL acetic acid was added dropwise, with stirring, keeping reaction at 17°-18° C., then reaction stirred at that temperature for an additional 20 minutes. The reaction was then poured into 130 mL of 0.15M HCl and washed with Et2O (2×85 mL), then pH adjusted to 13 with conc. NaOH and extracted with CHCl3 (4×100 mL). The CHCl3 extracts were combined, washed with 85 mL brine, dried over Na2SO4, and solvent removed in vacuo. The residue was purified by column chromatography, eluting with THF/Hex/NH4OH (70/30/0.4) to yield 1.145 g (51%) of the desired 2-nitroimipramine (26b) as a red oil. 1H NMR (200 MHz, CDCl3) d 8.0-7.9 (m, 2H), 7.3-7.0 (m, 5H), 3.9 (t, 2H), 3.2 (s, 4H), 2.3 (t, 2H), 2.1 (s, 6H), 1.7 (p, 2H); mass spec (FAB) (M+H)+ 326.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound. ESI-MS (m/z): 358 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[C:31]([OH:36])(=[O:35])[CH:32]([CH3:34])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH:32]([C:31]([OH:36])=[O:35])[CH3:34])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 3.3 g. lactic acid, 500 mg. toluene sulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]-benzoate separates as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][S:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl>[Br:18][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[C:9]([CH3:12])[CH:10]=1)[S:7][CH2:6][CH2:5][C:4]2=[O:13]
Reactant: Cc1ccc(C)c2c1SCCC2=O
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Reaction time: 0.25 h

Procedure:
66.5 g (0.35 mol) of 5,8-dimethyl-4-thiochromanone, together with 118 g (0.87 mol) of aluminum chloride, were dissolved or suspended in 600 ml of methylene chloride. After 15 min of stirring, 62.2 g (0.39 mol) of bromine were slowly added dropwise, and the reaction mixture was subsequently boiled under reflux for 10 min. The reaction mixture, which was still warm, was poured into 220 ml of conc. hydrochloric acid in crushed ice. The mixture was stirred for 10 min, the methylene chloride phase was separated off and the aqueous phase was extracted with diethyl ether (3×400 ml). The combined organic phases were washed with water, dried over MgSO4 and concentrated using a rotary evaporator.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].CC(O)=O.[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]([C:19](O)=[O:20])[C:17]=1[C:26](O)=[O:27]>C(N(CC)CC)C>[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]2[C:17]=1[C:26](=[O:27])[N:2]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10])[C:19]2=[O:20]
Reactant: Nc1c(O)ccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Nc1c(O)ccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
3-Aminopiperidine-2,6-dione hydrochloride (9.58 g, 58.4 mmol) was dissolved in triethylamine (TEA) (14.7 g) and the mixture was stirred at room temperature for 4 hrs. HOAc (150 mL) and 3-amino-4-hydroxyphthalic acid C1-5 (9.6 g, 48.7 mmol) were added. The mixture was stirred at 120° C. for 20 mins. TEA was added until the white solid was dissolved completely. The mixture was stirred at 120° C. for 2 hrs. After cooling, the solution was extracted with ethyl acetate (500 mL×4). The combined organic layers were dried over Na2SO4, filtered, and concentrated to a dark solid. The dark solid was washed with EA (300 mL) and dried to give compound 1 as a dark solid (7.2 g, yield: 51%). 1H NMR (DMSO-d6, 400 MHz) δ: 11.05 (s, 1H), 10.82 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 5.95 (s, 2H), 5.03-4.98 (m, 1H), 2.91-2.83 (m, 1H), 2.60-2.44 (m, 2H), 2.01-1.98 (m, 1H); MS (ESI+): m/z 290 (M+1); Elem. Anal. Calcd. for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found: C, 53.67; H, 3.80; N, 14.44.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8]N(S(C)(=O)=O)C[CH2:5]1.[CH2:14]1C2(CNC2)[CH2:16][O:15]1>>[Cl:1][CH2:2][CH2:3][N:4]1[CH2:5][C:8]2([CH2:16][O:15][CH2:14]2)[CH2:9]1
Reactant: C1NCC12COC2
Reactant: CS(=O)(=O)N1CCN(CCCl)CC1
Product: ClCCN1CC2(COC2)C1

Procedure:
The title compound was prepared following the method described above for the synthesis of 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine using 2-oxa-6-azaspiro[3.3]heptane as the starting reagent. The product was isolated as colorless oil (10 mg, 12%). LCMS: m/e 162.15 (M+H)+, 0.87 min (method 10).