Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:34](O)(=[O:36])C>>[OH:1][C:2]1[C:11]([CH:34]=[O:36])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CCC(=O)N1CCC(c2oc3cc(O)ccc3c(=O)c2C)CC1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCC(=O)N1CCC(c2oc3c(C=O)c(O)ccc3c(=O)c2C)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (1.07 g, 3.39 mmol) obtained in Example 31-2 and hexamethylenetetramine (3.33 g, 23.75 mmol) in acetic acid (20 mL) was heated with stirring at 100° C. for 3 hours. The reaction solution was concentrated under reduced pressure. Water (16 mL) and concentrated hydrochloric acid (8 mL) were added to the obtained residue, and the mixture was heated with stirring at a bath temperature of 80° C. for 1 hour. The reaction solution was allowed to cool, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=40/60→0/100) to obtain 584 mg of the title compound (yield: 50%).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:21]([O:20][CH2:19][CH2:18][N:17]1[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1)[CH3:22]
Reactant: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 5 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.25 (silica gel, dichloromethane/methanol, 90/10).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:11]([CH2:12][OH:13])[O:10][C:9]([SiH:14]([CH3:16])[CH3:15])=[CH:8][C@H:7]1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OCC)(=[O:20])[CH3:19]>C(OC=C)(=O)C>[C:18]([O:13][CH2:12][C@H:11]1[O:10][C:9]([SiH:14]([CH3:15])[CH3:16])=[CH:8][C@@H:7]([OH:17])[C@@H:6]1[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CCOC(C)=O
Reactant: C[SiH](C)C1=C[C@@H](O)[C@H](OC(C)(C)C)[C@@H](CO)O1
Solvent: C=COC(C)=O
Product: CC(=O)OC[C@H]1OC([SiH](C)C)=C[C@@H](O)[C@@H]1OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 85 %

Procedure:
1.09 g (5 mmol) of 4-O-tert.-butyldimethylsilyl-glucal are taken up in 10-20 ml of ethyl acetate and 50-80 ml of vinyl acetate, and 1.0 g of lipase from Candida cylindracea (Sigma) is added. After stirring at room temperature for 20-24 hours, the reusable enzyme is filtered off, and the solution is concentrated in vacuo. Subsequent simple filtration through a silica gel column in ether/hexane (~1:1 v:v) yields 1.1-1.2 g of 6-O-acetyl-4-O-tert.-butyldimethylsilyl-glucal (85-90% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:28][CH:27]([OH:29])[CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:28][CH:27]([OH:29])[CH2:26]5)=[CH:21][N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(O)C4)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 147d (140 mg, 0.22 mmol) and lithium hydroxide (132 mg, 5.5 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and diluted with water (10 mL). The resulting mixture was extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 147 (40 mg, 31%) as a yellow solid. MS-ESI: [M+H]+ 598.2. 1H NMR (500 MHz, DMSO-d6) δ 8.57-8.53 (m, 3H), 8.32 (s, 1H), 7.90 (s, 1H), 7.77 (d, J=13.0 Hz, 1H), 7.51-7.49 (m, 2H), 7.43 (s, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.88 (dd, J=3.0, 8.5 Hz, 1H), 5.57-5.56 (m, 1H), 4.89-4.87 (m, 1H), 4.55-4.52 (m, 1H), 4.43-4.41 (m, 2H), 4.05-4.02 (m, 2H), 3.60 (s, 3H), 3.45-3.42 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.CS(Cl)(=O)=O.[N:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[N:53][CH:52]=1>ClCCl.C(OCC)(=O)C.C(#N)C>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:57][C:54]3[CH:55]=[CH:56][N:51]=[CH:52][N:53]=3)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccncn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
1-Methylimidazole (1.78 mL, 22.3 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (4 g, 7.4 mmol) in dichloromethane (50.8 mL). The resulting solution was cooled to 0° C., and then methanesulfonyl chloride (0.6 mL, 7.8 mmol) was added dropwise at 0° C. To the reaction mixture was added 4-pyrimidinamine (849 mg, 8.9 mmol) and stirring continued for 1.5 h at ambient temperature. The reaction solution was filtered to remove unreacted 4-pyrimidinamine, and the filtrate was concentrated to provide a residue. The residue was dissolved in a mixed solution of ethyl acetate and acetonitrile, and was purified by silica gel chromatography (CombiFlash; Column: 220 g; 0-85% ethyl acetate in hexane; 60 min). The solvent was removed under reduced pressure to yield the desired product, phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (4.22 g, 92% yield). (ES+) m/z 615.2 (MH+).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1cccc(Br)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B using 3-bromophenyl(2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 474.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Product: CN(C)CCn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>O>[NH2:14][CH2:12][CH2:13][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCN
Solvent: O
Product: NCCc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine at 70% in water is stirred at ambient temperature for 72 hours. The excess amine is then evaporated off under reduced pressure, and an aqueous solution of acetic acid at 10% is then added until the product precipitates. The beige solid is spin-filter-dried, rinsed with cold water and dried in an oven. 10.5 g of the expected product are obtained. Melting point: 158-160° C. Yield=62%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 64 %

Procedure:
A mixture of 5-nitroindazole (2 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) was stirred for 30 minutes after which 2-(dimethylamino)ethylchloride hydrochloride (2.65 g 18.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and was filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.8 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.73(t, J=6.44, 2H), 3.33 (s, 6H), 4.57 (t, J=6.44, 2H), 7.93 (m, 1H), 8.21 (m, 1H), 8.40 (m, 1H), 8.82 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:13]3=[S:20])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]3=[S:20])=[CH:21][CH:22]=2)=[CH:5][CH:6]=1
Reactant: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=S
Yield: 88.3 %

Procedure:
Reaction of 147i (0.08 g, 0.25 mmol) with 1M BBr3 (0.38 mL) in dry CH2Cl2 (5 mL) within 48 h according to procedure 148a afforded pure 149i (65 mg, 88%) as olive green color solid. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.3 Hz, 2H), 8.55 (s, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.42 (m, 5H), 6.99 (d, J=7.5 Hz, 1H), 6.67 (t, J=7.0 Hz, 1H), 5.85 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 170.05, 155.32, 150.25, 147.44, 138.22, 135.48, 130.91, 128.80, 127.55, 121.48, 113.73, 111.94, 59.91. HRMS (EI) calcd for C17H14N2OS [M]+ 294.0827. found 294.0823.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:11].Br.C1(S[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])C=CC=CC=1>CCOCC>[NH2:11][C:2]1[S:1][C:5]2[CH:6]=[C:7]([NH:10][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CCOCC
Product: N=C(Nc1ccc2nc(N)sc2c1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
A mixture of benzothiazole-2,6-diamine (Example 1, 50 mg, 0.3 mmol) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (91 mg, 0.3 mmol) was stirred at room temperature for 17 hours. After this time a precipitate formed. The mixture was diluted with 4 mL of Et2O and filtered to give the title compound. Yield: 94%, 1H-NMR (DMSO-d6): δ 11.30 (br s, 1H); 9.71 (s, 1H); 8.80 (s, 1H); 8.18 (m, 2H); 7.74 (m, 3H); 7.29 (m, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([NH2:20])=[O:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(N)=O)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
44.5 ml (351 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. to a suspension of 50.0 g (281 mmol) 3-(4-Methoxyphenyl)-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide. Stirring was continued at 0–5° C. for 30 min. and thereafter for 2 h at room temperature. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 48.8 g (98%) 3-(4-Methoxyphenyl)-acrylamide were obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:21])[CH2:12][CH:13]2[C:17](=[O:18])[O:16]C(C)(C)[O:14]2)=[C:6]([O:22][CH3:23])[CH:5]=1)[CH:2]=[CH2:3].Cl>C1COCC1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:21])[CH2:12][CH:13]([OH:14])[C:17]([OH:18])=[O:16])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC(=O)CC2OC(C)(C)OC2=O)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CCc1ccc(OC(=O)CC(O)C(=O)O)c(OC)c1
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid 4-allyl-2-methoxy-phenyl ester (1.0 g, 3.12 mmol) in THF (10.0 mL) was added 1N hydrochloric acid (10 mL) at room temperature (25° C.) and the mixture was stirred at same temperature over a period of 6 h. The solvent was evaporated to half volume, saturated with sodium chloride and the product was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulphate and concentrated to obtain off-white solid (0.81 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: [H][H]
Reactant: Cc1c(O)ccc2occc12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(O)ccc2c1CCO2

Procedure:
A solution of 35 (1.86 g, 12.6 mmol) in absolute ethanol (50 mL) was hydrogenated over 10% palladium on carbon catalyst (0.10 g) at 3 atmospheres pressure. After the required amount of hydrogen had been taken up (overnight) the catalyst was removed by filtration and washed with an additional portion of absolute ethanol (20 mL). The combined filtrate and washings were concentrated to a white crystalline solid (1.88 g). Recrystallization from toluene gave 36.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of ethyl isonipecotate (15.7 g, 0.1 mol) in methylene chloride (100 mL) at 0° C. was treated with pyridine (10 mL) and then benzenesulfonyl chloride (17.6 g, 0.1 mol). The reaction was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was then poured into 1 N HCl (1 L) and extracted with ethyl acetate (2×500 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The solid was recrystallized from ethyl acetate to give 17 g of product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40]>C(Cl)Cl>[C:39]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=2)[C:15]([NH:14][CH2:13][C@H:12]([OH:30])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:29])[CH2:24][CH2:25]1)(=[O:40])[CH3:38]
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccnc(NC2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(piperidin-4-ylamino)isonicotinamide (70 g), and Et3N (40 g) in DCM (2000 mL) was added Ac2O (17 g) dropwise over 1 h at 0° C. After addition, the mixture was warmed to 20° C. and stirring was continued for another 1 h, at which time TLC showed the reaction was completed. The reaction mixture was washed with water (500 mL), and the organic phase dried and concentrated. The residue was then purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give crude product. Five batches were run in parallel and produced a combined crude product weight of 400 g. This crude was further purified by preparative HPLC to give the pure product (310 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 7.94-7.92 (d, 7.0 Hz, 1H), 7.14-7.05 (m, 4H), 6.87 (s, 1H), 6.76-6.74 (m, 1H), 4.44 (m, 1H), 4.10 (m, 1H), 3.96-3.94 (m, 2H), 3.75 (s, 2H), 3.52 (m, 2H), 3.33-3.32 (m, 1H), 2.92-2.86 (m, 5H), 2.67 (m, 2H), 2.13-2.00 (m, 5H), 1.44-1.37 (m, 2H); LCMS (m/z): 452.3 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]2[CH2:31][CH2:32][N:27]([S:24]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[O:15][CH3:14])(=[O:26])=[O:25])[CH2:28][CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(OC)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[(2,4-dimethoxyphenyl)-sulfonyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-[(2,4-dimethoxyphenyl)sulfonyl]piperazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:8]3)=[O:13])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(N1CCC(c2ccncc2)C1)C1(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCC(c2ccncc2)C1)C1(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A mixture of 4-{1-[(3-pyridin-4-ylpyrrolidin-1-yl)-carbonyl]cyclopropyl}phenol (20 mg, 0.00006 mol, example 372), benzyl bromide (7.7 μL, 0.000065 mol), and potassium carbonate (18 mg, 0.00013 mol) in N,N-dimethylformamide (200 μL, 0.002 mol) was stirred at room temperature over night. The crude product was purified with prep-HPLC to afford the product (10.3 mg). LCMS: m/z 399.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([NH2:11])[CH3:10])=[CH:4][CH:3]=1.CO[C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=1[O:33][CH2:34][CH3:35].C[Al](C)C>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]2[NH:19][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C@@:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)([CH3:10])[N:11]=2)=[C:24]([O:33][CH2:34][CH3:35])[CH:25]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(N)(c1ccc(Cl)cc1)C(N)c1ccc(Cl)cc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C(=O)OC
Agent: C[Al](C)C
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, rac-(1R*,2S*)-1,2-bis-(4-chloro-phenyl)-propane-1,2-diamine was reacted with 4-tert-butyl-2-ethoxy-benzoic acid methyl ester (prepared as described in Fotouhi, N. et al. WO 2005110996) in the presence of trimethylaluminum to give the title compound as a racemic mixture.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])[CH3:36]>>[C:35]([C:18]1[C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:37])[CH3:36]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Yield: 69 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide obtained in Example 161, the title compound was synthesized in the same manner as in Example 38. Yield: 69%. Melting point: 218-219° C. (hexane-ethyl acetate).