Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.Cl.[CH3:5][O:6][NH2:7].[C:8]1([CH:14]2[O:18][CH:17](O)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>[CH3:5][O:6][N:7]=[CH:17][CH2:16][CH2:15][CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:18]
Reactant: CON
Reactant: OC1CCC(c2ccccc2)O1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=CCCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
12 mL of acetonitrile, 6 mL of water and 1.0 g of O-methylhydroxylamine hydrochloride were added to 0.98 g of the 5-phenyloxolan-2-ol, and thereafter, 1.08 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 0.5 hours. Thereafter, hexane, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 1.10 g of 4-(methoxyimino)-1-phenylbutan-1-ol in the form of a colorless oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([O-:3])=[O:2].[Cl:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:20][CH2:21][C:22]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](=[O:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: O=C(Nc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Product: O=C(CCl)N(C(=O)Nc1ccccc1[N+](=O)[O-])c1ccccc1

Procedure:
A solution containing N-(2-Nitrophenyl)-N′-phenyl-urea (5.76 g) and chloroacetyl chloride (40 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo, diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N′-(2-chloroacetyl)-N-(2-nitrophenyl)-N′-phenyl-urea as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13](OC)=[N:12][S:11]2(=[O:21])=[O:20])[CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH2:32])[CH3:31]>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13]([NH:32][C@H:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH3:31])=[N:12][S:11]2(=[O:21])=[O:20])[CH:5]=1
Reactant: C[C@H](N)c1ccccc1F
Reactant: COC(=O)c1cccc(C2C(C)(C)OC(OC)=NS2(=O)=O)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(C2C(C)(C)OC(N[C@@H](C)c3ccccc3F)=NS2(=O)=O)c1
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A solution of 3-(2-methoxy-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl)benzoic acid methyl ester (1.3 g) and (S)-1-(2-fluorophenyl)ethylamine (713 mg) in dichloromethane (15 ml) was stirred under an argon stream and thus concentrated. The residue was left to stand for 4 h, dissolved in ethyl acetate, washed with 1 M HCl and sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (1.2 g) with a molecular weight of 434.5 g/mol (C21H23FN2O5S).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][C:17]([NH:26]S(C(C)(C)C)=O)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>CC(O)C>[NH2:26][C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19][CH:14]([O:13][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)S(=O)NC1(c2ccccc2)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Solvent: CC(C)O
Product: NC1(c2ccccc2)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 3 %

Procedure:
4.5 mg of the title compound 71 were prepared as diastereomeric mixture from 190 mg (0.40 mmol) of 2-methyl-propane-2-sulfinic acid [4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-amide (crude, 70) by stirring in a mixture of 2-propanol/0.5N aqueous HCl (2:1) until complete conversion. The reaction mixture was concentrated and purified by preparative HPLC. The resultant trifluoroacetate was taken up in 1N HCl twice and lyophilized. The respective residue was redissolved in water and lyophilized again to give the hydrochloride. Rt=0.91 min, 0.94 min (Method C). Detected mass: 369.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1CCCCC=1>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)CCc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Temperature: 135 °C

Procedure:
A mixture of 3-(2-ethoxycarbonylvinyl)-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl ester (150 mg, 0.26 mmol, see step (c) above), Pd—C (10%), cyclohexene (1.2 mL) in absolute EtOH was heated under microwave irradiation at 135° C. for 1 h. The mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were concentrated to give the sub-title compound. Yield 150 mg (100%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH2:38])=[O:37])[C:17]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:46]N>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH:38][CH3:46])=[O:37])[C:17]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(C)=O)CC2
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(C)=O)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
The remaining half of the reaction mixture from the preparation of 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide was diluted with THF (100 mL) and a solution of methylamine (2M, 9 mL), 18 mmol). The reaction mixture was stirred overnight, then concentrated to dryness. The residue was sonicated in CH2Cl2 (15 mL) and filtered. The filtrate was purified by silica gel chromatography using 10% THF/CH2Cl2 to obtain 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide as a yellow solid (236 mg, 41% for 2 steps). 1H NMR (400 MHz, DMSO-d5) δ ppm 2.16 (s, 3H), 2.34 (s, 3H), 2.75 (d, J=4.4 Hz, 3H), 3.19 (d, J=8.24 Hz, 2H), 3.73 (s, 3H), 4.15 (d, J=8.33 Hz, 2H), 6.55 (d, J=3.85 Hz, 1H), 6.94 (t, J=9.25 Hz, 1H), 7.04 (s, 1H), 7.17-7.41 (m, 4H), 7.93 (d, J=8.24 Hz, 2H), 7.98 (J=8.42 Hz, 1H), 8.16 (s, 1H), 8.19 (s, 1H), 8.36-8.52 (m, 1H), 10.16 (s, 1H); ESIMS (M+H)+=644.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]1[C:16]2[CH:25]=[CH:24][NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([F:1])[CH:3]=2)=[C:7]([C:15]2[C:16]3[CH:25]=[CH:24][NH:23][C:17]=3[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)[CH:8]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)c(F)c2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)c(F)c2)c2cc[nH]c2c1=O

Procedure:
Example 48b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 48a for the product of Example 2b, to provide the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2.[I-].[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([Zn+])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[C:15]1([S:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH:31]2[CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:32]2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)C1
Temperature: 80 °C
Reaction time: 150 h
Yield: 24.9 %

Procedure:
To a solution of 8-iodo-3-(phenylsulfonyl)quinoline (200 mg, 0.51 mmol, prepared according to WO2003080580) in DMA (1 ml) was added PdCl2(dppf) (8.3 mg, 0.10 mmol; dppf=1,1′-bis(diphenylphosphino)ferrocene) and CuI (11.6 mg, 0.06 mmol), followed by dropwise addition of (1-(tert-butoxycarbonyl)azetidin-3-yl)-zinc(II) iodide (317 mg, 0.91 mmol) in DMA (1 ml) over 10 min. The mixture was then heated at 80° C. for 6 h, then stirred at room temperature for 150 h and quenched with a saturated aqueous solution of NaCl. The reaction mixture was extracted with tert.-butyl-methyl-ether (MTBE). The organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (54 mg, 25%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:14][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)c(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1cc(CBr)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 49.1 %

Procedure:
5-Methyl-2-(trifluoromethyl)benzonitrile (200 mg, 1.08 mmol) in 1,2-dichloroethane (3 mL) was stirred with N-bromosuccinimide (192 mg, 1.08 mmol) and azobisisobutyronitrile (36.1 mg, 0.22 mmol) at 80° C. for 2 hours. The reaction mixture allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane→ethyl acetate/hexane=1/3 (v/v)) to give the title compound as a colorless solid (140 mg, yield 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]([CH3:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[BH4-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@H:14]([CH3:18])[CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 156.2 %

Procedure:
A mixture of 1.29 g (5.0 mmol) of 2-(S)-((t-butoxycarbonyl) piperidin-4-yl)propanoic acid (from EXAMPLE 30, Step C) and 0.70 mL (5.0 mmol) of TEA in 30 mL of THF at 0° C. was treated with 0.43 mL (5.0 mmol) of ethyl chloroformate and the resulting mixture was stirred cold for 30 min. The solids were filtered. The filtrate was added to a cooled (0° C.) mixture of 0.50 g (13.0 mmol) of NaBH4 in 10 mL of H2O, maintaining the internal temperature at less than 10° C. The resulting mixture was warmed to rt and stirred for 1 h. The reaction was layered with 75 mL of ether and quenched with 25 mL of 1.0 N HCl. The layers were separated. The organic layer was washed with 25 mL of 1.0 N NaOH, 25 mL of sat'd NaCl, dried over MgSO4 and concentrated to afforded 1.90 g (88%) of the title compound: 1H NMR (500 MHz) δ 0.90 (d, J=6.5, 3H), 1.17-1.66 (5H), 1.45 (s, 9H), 2.65 (br s, 2H), 3.56 (dABq, J=5.5, 10.5), 4.13 (br s, 2H1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([C:15]1[S:16][C:17]2[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]>>[CH:12]([C:15]1[S:16][C:17]2[CH2:23][CH2:22][CH:21]([CH2:24][O:25][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1nc2c(s1)CCC(CO)C2
Product: Cc1ccc(S(=O)(=O)OCC2CCc3sc(C(C)C)nc3C2)cc1
Yield: 71 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. M.p.=82°-83° C. Yield: 71%
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.C1(C)C=CC=CC=1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([OH:6])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous sodium bicarbonate (1 g, 12 mmol) was added to a solution of 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in 50 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (1.2 mL, 10 mmol) was added and the mixture was refluxed for 6 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated and it was recrystallized from methanol (ca. 40 mL) to obtain (1.82 g, 80 of P1 as a white powder: mp 78-80° C.; TLC Rf 0.88 in toluene:methanol (10:1); 1H NMR (600 MHz, acetone-d6) δ 11.41 (s, 1H, OH), 9.81 (s, 1H, CHO), 7.67 (d, 1H, J=8.4 Hz, Ar—H6), 7.45-7.35 (m, 5H, C6H5), 6.70 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 6.56 (d, 1H, J=1.8 Hz, Ar—H3), 5.24 (s, 2H, PhCH2).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.O.ClC(Cl)(Cl)[C:15]([N:17]=C=O)=[O:16]>C(Cl)Cl.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[NH2:17][C:15]([O:1][CH2:2][C@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1)=[O:16]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(=O)S[C@@H]1CO[C@H](CO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@H](COC(N)=O)C1

Procedure:
The title compound is prepared by the procedure of Example 7 using 0.28 g of product from Example 9 in 20 ml of methylene chloride, 0.208 ml of trichloroacetyl isocyanate, 0.80 ml of acetic acid, 6.79 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran and 0.37 ml of water to give 0.320 g of the desired product.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl[CH2:38][C:39]([NH2:41])=[O:40].Cl>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:38][C:39](=[O:40])[NH2:41])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: NC(=O)CCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Yield: 94.4 %

Procedure:
The pH of a solution of 1.40 g of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in about 4 ml water was adjusted to 9.5 using 40% aqueous benzyltrimethylammonium hydroxide. To the resulting solution was added 412 mg α-chloroacetamide. The temperature was increased to 80° C. and base was added as necessary to maintain the pH at 9.5-10. After 3 hours the solution was cooled to room temperature and acidified to pH 3 with concentrated HCl. The resulting solution was evaporated under reduced pressure to a colorless sludge. The mixture was taken up in about 25 ml MeOH and re-evaporated. The thick residue was triturated with a 1:1 mixture of acetone and ethanol to provide a granular solid and colorless solution. The solid was collected by filtration, washed with acetone/ethanol followed by acetone and finally ether, then dried in a vacuum oven at 50° for 2 hours. Obtained was 1.54 g of the title compound as a colorless powder. The product was twice crystallized from ethanol/water.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:38][CH2:39][N:34]([C:40]([O:42][CH3:43])=[O:41])[CH2:35][CH2:36]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: COC(=O)N1CCNCC1
Product: COC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of methyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]2SC)=[O:5].[Sn].Cl>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11]2)=[O:5]
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccccc3F)cccc21
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C1Cc2cccc(C(=O)c3ccccc3F)c2N1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A mixture of 60 g (0.2 mole) of 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one and 60 g (0.5 mole) of tin powder in one liter of 95% ethanol was heated to reflux and 150 ml of concentrated hydrochloric acid was added. Heating was continued for 18 hrs, then the mixture was cooled and the precipitate was collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol to give 31 g (60%) white needles, m.p. 209°-210° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(=S)=S>[C:19]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.17 h

Procedure:
To 120 ml. of carbon disulfide is added 54 g. of anhydrous aluminum chloride powder on an ice bath, followed by the dropwise addition of a solution of 11.4 g. of ethyl indan-1-carboxylate in 60 ml. of carbon disulfide. The mixture is stirred for 10 minutes, after which a solution of 42 g. of benzoyl chloride in 60 ml. of carbon disulfide is added dropwise. After the dropwise addition has been completed, the temperature is gradually increased and the solution is stirred on reflux for 3 hours and thirty minutes to complete the reaction. Ice and hydrochloric acid are added to the reaction mixture followed by extraction with ether. The extract is washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in the order mentioned and, then, dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is column-chromatographed on silica gel (conditions: 2 Kg. of silica gel; eluant solvent-benzene containing 2.5% of ethyl acetate). The first-emerging fractions rich in ethyl 4-benzoylindan-1-carboxylate are pooled separate from the ensuing fractions rich in ethyl 6-benzoylindan-1-carboxylate. The former fractions are further purified by rechromatography on a column of silica gel, whereby ethyl 4-benzoylindan-1-carboxylate is obtained as an oily product.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([OH:21])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1>[Br-].C([N+](CC)(CC)CC)C.ClCCl>[O:1]([CH2:8][CH2:9][O:10][C:11]1[C:12]([O:21][CH2:25][CH2:24][OH:23])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc2ccccc2cc1OCCOc1ccccc1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: ClCCl
Product: OCCOc1cc2ccccc2cc1OCCOc1ccccc1
Yield: 73.1 %

Procedure:
A stirred mixture of 3-(2-phenoxyethoxy)-2-naphthol (3.9 g), ethylene carbonate (1.4 g) and tetraethylammonium bromide (0.8 g) was heated at 155°-160° C. for 2 hours. The cooled reaction was diluted with dichloromethane and washed with 1N sodium hydroxide and with water. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude material which was purified by HPLC (dichloromethane-ethyl acetate; 20:1 ) and crystallized from dichloromethane-diethyl ether to give 3.3 g of 2-[[3-(2-phenoxyethoxy)2-naphthalenyl]oxy]ethanol as a colorless solid, mp 119°-120° C.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O>CCO.[Fe]>[Cl-:1].[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:6]3[CH:5]=[CH:4][N+:3]([CH3:2])=[CH:8][CH:7]=3)=[CH:11][CH:12]=2)=[O:17])=[CH:20][CH:21]=1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Yield: 79.8 %

Procedure:
Compound D4 (295 mg, 0.77 mmol) was dissolved in ˜5:1 EtOH:H2O (12 mL), and Fe dust (209 mg)was added. The mixture was vigorously stirred and refluxed for 4 h, and then filtered hot through a pad of Celite. The Celite was washed with boiling EtOH, and EtOH fractions were combined and evaporated to dryness. The residue was extracted into hot water, and filtered through Celite, and then evaporated to dryness. The residue was azeotroped with MeOH (3×20 mL), and then dissolved in MeOH (10 mL). Methanolic HCl (1.25 M, 5 mL) was added, and the solution stirred for 10 min. Solvent was removed under reduced pressure, and the residue was crystallized from MeOH/EtOAc to give D5 (218 mg, 80%); mp (MeOH/EtOAc); 1H NMR [(CD3)2SO] δ11.13 (s, 1 H, NH), 10.44 (s, 1 H, NH), 9.88 (br, 2 H, NH2), 8.36 (d, J=7.5 Hz, 2 H, ArH), 8.12 (d, J=8.6 Hz, 2 H, ArH), 7.86 (d, J=8.8 Hz, 2 H, ArH), 7.50 (d, J=8.8 Hz, 2 H, ArH), 7.32 (d, J=8.6 Hz, 2 H, ArH), 7.32 (d, J=7.5 Hz, 2 H, ArH), 7.30 (d, J=8.7 Hz, 2 H, ArH), 4.00 (s, 3 H, N+CH3); LCMS 319+ve