Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]2)=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: CCN1CC(N)CN1CC
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=O)Nc2cc(Cl)cc(Cl)c2)CN1CC
Reaction time: 8 h

Procedure:
A solution of 4-amino-1,2-diethylpyrazolidine (1.26 g, 8.8 mmol) in anhydrous toluene (5 ml) was added to a solution of 3,5-dichlorophenyl isocyanate (1.71 g, 9.1 mmol) in dry toluene (20 ml) and the mixture stirred overnight. The precipitated solid was collected, washed with toluene and dried to give the title compound, 1.94 g. This was converted to the 1:1 maleate, mp 165°-167° C.
Reaction SMILES: FC1C=[C:4](C=C(F)C=1)[CH2:5][N:6]1C=CN=C1S.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[SH:29])=[CH:20][CH:19]=1>>[NH2:6][CH2:5][CH2:4][S:29][C:25]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc(-n2ccnc2S)cc1
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Product: COc1ccc(-n2ccnc2SCCN)cc1

Procedure:
The Example 1 procedure wherein 1-(3,5-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(4-methoxyphenyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(4-methoxyphenyl)imidazole.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)=[O:4].Cl[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-])=O)=[CH:24][N:23]=1>>[NH2:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=3[CH:15]=2)[C:2]([F:1])([F:20])[C:16]([F:18])([F:17])[F:19])=[N:23][CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)C(F)(F)C(F)(F)F)ccc2O1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Product: Cc1cc(N)cnc1OC(c1ccc2c(c1)CC(C)(C)O2)C(F)(F)C(F)(F)F

Procedure:
5-Amino-3-methyl-2-[1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-2,2,3,3,3-pentafluoropropoxy]pyridine was prepared from 2,2,3,3,3-pentafluoro-1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)propan-1-one, by the method of Example 42. 2-Chloro-3-methyl-5nitropyridine was used in place of 2-chloro-5-nitropyridine.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH2:67][OH:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH2:66][CH2:67][OH:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CCO)c54)c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[1-(2-hydroxy-ethyl)-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (8 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 20 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (33.5 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (br s, 3H), 8.33 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.37 (m, 5H), 7.32 (d, J=8.4 Hz, 2H), 4.95 (t, J=5.1 Hz, 1H), 4.80 (t, J=5.6 Hz, 2H), 3.89 (q, J=5.5 Hz, 2H), 2.63-2.52 (m, 4H), 2.24-2.13 (m, 1H), 1.87-1.76 (m, 1H). LCMS (Method E): RT=3.00 min, [M+H]+=452.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](=[C:13]([CH2:16][CH2:17]Cl)[CH2:14]Cl)([CH3:12])[CH3:11]>O>[C:10](=[C:13]1[CH2:16][CH2:17][C:6]2([CH:5]=[C:4]([CH3:8])[C:3](=[O:9])[C:2]([CH3:1])=[CH:7]2)[CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)=C(CCl)CCCl
Reactant: Cc1cccc(C)c1O
Solvent: O
Product: CC1=CC2(C=C(C)C1=O)CCC(=C(C)C)C2
Temperature: 15 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
2,6-Dimethylphenol (2.4 g, 0.02 mol) was added to a solution of Ba(OH)2.8H2O (6.6 g, 0.021 mol) in distilled water (12 mL). The mixture was cooled to 15° C. and 2-isopropylidene-1,4-dichlorobutane (3.6 g, 0.022 mol) was added over 1 hour under nitrogen. Stirring at room temperature was continued for 5 hours and then the reaction mixture was extracted with ether. The ether extracts were washed with 10% sodium hydroxide, water, and dried (Na2SO4). Concentration gave 4.7 g of crude material which was mainly the alkylated phenol having the structure: ##STR33## A sample purified by preparative glc had the following spectral characteristics:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=O)=[C:7]2[OH:19])#[N:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(Cl)Cl.CCOCC>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:14]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:19])=[CH:5][C:4]([CH2:3][C:1]#[N:2])=[CH:13][CH:12]=3)=[O:16])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnc2ccc(CC#N)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 180 °C

Procedure:
A suspension of 4-aminobenyl cyanide (6.61 g) and diethyl ethoxymethylene-malonate (10.1 mL) is heated to 95° C. for 1 hour. The reaction is cooled to room temperature and poured into 50 mL hexanes to wash away impurities. The desired enamine intermediate formed upon cooling and is filtered and collected. In a 3-necked roundbottom connected to a Dean-Stark trap, 75 mL of diphenyl ether is added to the enamine and the solution is heated at 250° C. for 2 hours. The crude product is washed with hot MeOH and dried to yield 3.40 g of ethyl 6-cyanomethyl-4-hydroxyquinoline-3-carboxylate as an orange solid. A mixture of this ester (0.50 g) and p-chlorobenzylamine (3.5 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diluted with CH2Cl2 and ether. The solvents are evaporated. The residue is chromatographed on silica, eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to yield 0.162 g of the desired product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][C:7]=3[N:8]2CC(C2C=NC(C)=CC=2)O)=[CH:4][CH:3]=1.ClC1C=C(NN)C=CC=1.COC(OC)CCCNC.ClC1C=C2C(C(CCNC)=CN2)=CC=1.C=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)Cn2c3c(c4ccc(Cl)cc42)CCN(C)C3)cn1
Agent: C=O
Agent: CNCCCC(OC)OC
Agent: CNCCc1c[nH]c2cc(Cl)ccc12
Product: CN1CCc2c([nH]c3cc(Cl)ccc23)C1

Procedure:
Method for the preparation of compound 7 [[2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol]: (3-chlorophenyl)hydrazine is reacted with 4,4-dimethoxy-N-methylbutan-1-amine (put in the references for this) to generate 2-(6-chloro-1H-indol-3-yl)-N-methylethanamine, which upon treatment with formaldehyde, under standard Pictet Spingler reaction conditions (insert the reference for this) gives 7-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The further reaction of this unsubstituted β-carboline with 2-methyl-5-(oxiran-2-yl)pyridine (carboline, aryl/heteroaryl oxide, NaH, DMF, 120° C.) gives the desired compound 2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol, compound 7. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][C:22]=3[C:32]([F:34])([F:35])[F:33])[CH2:31][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 1-(4-methyl-2-trifluoromethylphenyl)piperazine (327 mg) described in Preparation Example 96 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:29])[CH:10]([NH:21]C(OC(C)(C)C)=O)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH2:14]([NH:13][C:11](=[O:12])[CH:10]([NH2:21])[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 2.5 h

Procedure:
Combine N,N′-dibenzyl-2-(t-butoxycarbonylamino)malonamide (0.415 g, 1.04 mmol) and dichloromethane (7 mL). Add trifluoroacetic acid (1.0 mL). After 2.5 hours, evaporate in vacuo dry under high vacuum to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]1([CH2:10][N:11]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:24])[CH2:9][CH2:8]1.II.[Br:27]Br>ClCCl>[Br:27][CH:13]1[CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:17][N:11]([CH2:10][CH:7]2[CH2:8][CH2:9]2)[C:12]1=[O:24]
Reactant: O=C1CCC(c2ccccc2)CCN1CC1CC1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: O=C1C(Br)CC(c2ccccc2)CCN1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (0.3 g, 1.44 mmol) was added slowly to a solution of 1-(cyclopropylmethyl)-5-phenylazepan-2-one (0.35 g, 1.44 mmol) in dichloromethane (8 mL) at 0° C. After 1 h, iodine (3.6 mg, 0.01 mmol) and bromine (0.07 mL, 1.44 mmol) were added, and the mixture was allowed to warm to ambient temperature. After 1 h, another 0.3 g of phosphorus pentachloride was added. After an additional 18 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cl)c1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(Cl)c1F
Yield: 99.3 %

Procedure:
3-Chloro-2-fluorobenzoic acid (10.0 g, 0.06 mol), thionyl chloride (31 ml, 50 g, 0.4 mol) and dry toluene (40 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (11.5 g) as a clear yellow oil.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCC>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC(=O)CC2)CC1
Reactant: Nc1ccccc1
Solvent: CCCCC
Product: CC(C)[C@H]1CC[C@@H](N2CCC(=Nc3ccccc3)CC2)CC1

Procedure:
cis-1-(4-Isopropyl-cyclohexyl)-piperidine-4-on (5.0 g, 23.4 mmol), aniline (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4A) were stirred in 100 ml pentane at room temperature for 6 days. The molecular sieves was filtered off and the solvent was evaporated. The crude product was used without any further purification for the following step.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:58][C:59]([F:71])([F:70])[O:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[CH3:56][C:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:65](=[O:66])[C:64]4[CH:68]=[CH:69][C:61]([O:60][C:59]([F:58])([F:70])[F:71])=[CH:62][CH:63]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])([CH3:57])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 522 was prepared analogous to compound of example 97 by reaction of compound of example 515 with 4-trifluoromethoxy-benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)#[N:16]>>[Cl:34][C:33]1[C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:19][CH2:18][CH2:17][C:15]#[N:16])=[O:36])=[N:29][C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:31][CH:32]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: N#CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCC#N)n3)ccc21

Procedure:
The title compound was prepared from 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one and N-(2-cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-benzamide in an analogous manner to Example 179. Product was isolated as a tan solid (20 mg, 30%). LCMS (m/e) 490 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.53 (s, 1H), 9.14 (m, 1H), 8.72 (d, 1H, J=8.6 Hz), 8.25 (s, 1H), 7.79 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.30 (m, 2H), 7.53 (m, 1H), 7.20 m, 2H), 3.54 (q, 2H, J=6 Hz), 3.21 (s, 3H), 2.81 (t, 2H, J=6 Hz), 2.56 (m, 2H), 2.15 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)OP(=O)(CO[C@H](CI)COCc1ccccc1)OC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO[C@H](C)COCc1ccccc1)OC(C)C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
(S)-1-(Benzyloxy)-2-[(diisopropylphosphono)methoxy]-3-iodopropane (11.1 g, 23.5 mmol) was mixed with triethylamine (2.85 g, 28.2 mmol) in 15 mL of methanol. To this solution, 10% palladium on carbon (2.0 g) was added under nitrogen atmosphere. The reaction was performed in a Parr apparatus at a hydrogen pressure of 40 psi. After 3 hours, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=1:0 to 5:1) to give 7.91 g (98%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[N:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:14]=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:28]([NH2:30])[CH3:29]>>[NH2:30][CH2:28][CH2:29][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[N:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:14]=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCN
Reactant: Clc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2s1
Product: NCCc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2s1

Procedure:
Beginning with 2-chloro-6-(1-(cyclohexyl)-4-(phenyl)-imidazol-5-yl)-benzothiazole and ethyl amine, prepare the title compound essentially as described in General Procedure B. MS(ES+): m/z=403.1 (M+H)+
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][C:11]=1[N+:31]([O-])=O.[Na]>C(O)C>[NH2:31][C:11]1[CH:12]=[C:13]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]3[CH2:29][CH2:30]3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][C:10]=1[NH2:9]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1N
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
Sodium dithionite (3 g) was added to a solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (783 mg) and sodium hydroxyde (0.5 N, 15 ml) in ethanol (30 ml) at 80° C. The reaction mixture was stirred at 80° C. for 10 minutes then filtered then the filtrate was evaporated. The residue was extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 652 mg of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 3,4-diamino-phenyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:17]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:21][CH:18]1[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:17]1
Reactant: C1CCNC1
Reactant: O=C(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetic acid a14-1 (115 mg, 0.348 mmol, 1 eq) and pyrrolidine (32 μl, 0.382 mmol 1.1 eq) in dichloromethane (5 ml) are added dicyclohexylcarbodiimide (79 mg, 0.82 mmol, 1.1 eq), hydroxybenzotriazole (52 mg, 0.382 mmol, 1.1 eq) and diisopropylethylamine (131 μl, 0.731 mmol, 2.1 eq). The reaction mixture is stirred overnight at room temperature, then filtered and concentrated under reduced pressure. The residue is purified by reverse phase chromatography (gradient: CH3CN/H2O/NH4OH from 30/70/0.1 to 60/40/0.1) to afford 9 mg of 1-[2-(2-{3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 86 as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[C:16]([C:32]#[N:33])[CH:15]=[N:14][N:13]2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][C:44](OC(C)=O)=[O:45]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]1[C:11]([CH3:35])=[C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)=[C:16]([C:32]#[N:33])[CH:15]=[N:14][N:13]2[CH:34]=1)[C:44](=[O:45])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CNCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccccc1)Cc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Yield: 83.1 %

Procedure:
To a solution of 414A (28 mg, 0.06 mmol) and Et3N (17 μl, 0.12 mmol) in CH2Cl2 (2 ml) was added Ac2O (11 μl, 0.12 mmol), reaction completed immediately. After regular workup, the residue was purified by prep. TLC to give the 414 (25 mg, 83%) as light yellow powder (2% MeOH—CHCl3). It has a retention time of 7.23 min (standard LCl method, 8 min run). MS Found: (M+H)+=502.0
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:44])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1.S(=O)(=O)(O)O>O.C(O)CCC>[OH:44][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:19])[CH3:20])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Temperature: 65 °C
Yield: 568.8 %

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was added to a mixture of n-butanol 80 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixure was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 2.0 g was added to the mixture. The reaction mixture was then heated to 90° C. in one hour, and the mixture was stirred at 90°~96° C. for four hours to effect reaction, thus almost all of the azobenzene having disappeared. Thereafter, water 50 ml was added to the reaction liquor, and the reaction liquor was neutralized to pH 8~9 with 62% sulfuric acid 13 g to precipitate a crystal. The crystal thus obtained was filtered to separate the crystal, and the separated crystal was then fully washed with water and further with a small amount of methanol. The washed crystal was then dried, thus producing 23.2 g of 2-(2-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide having a melting point of 111° to 113° C. at the yield of 95.0%.