Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[I-].[Na+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(NOCC1CC1)c1cc2c(ncn2CCCCCl)c(F)c1Nc1ccc(Br)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCN(CCCCn2cnc3c(F)c(Nc4ccc(Br)cc4Cl)c(C(=O)NOCC4CC4)cc32)CC1
Yield: 73.1 %

Procedure:
A solution of 6-(4-bromo-2-chloro-phenylamino)-3-(4-chloro-butyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 18ee (10 mg, 0.018 mmol), sodium iodide (14 mg, 0.092 mmol), and 1-methyl-piperazine (10 μL, 0.092 mmol) are stirred at 85° C. for three hours. The reaction mixture is diluted with ethyl acetate and washed three times with water, washed twice with saturated aqueous potassium carbonate, dried (Na2SO4) and concentrated under reduced pressure to a yellow oil. Flash column chromatography (1:1 dichloromethane/methanol followed by methanol followed by 20:1 methanol/triethylamine) yields clean product (8 mg, 72%) as an off-white foam. MS ESI (+) m/z 607, 609 (M+, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.71 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.38 (t, 2H), 3.62 (d, 2H), 2.45 (broad, 8H), 2.41 (t, 2H), 2.28 (s, 3H), 1.96 (m, 2H), 1.54 (m, 2H), 1.07 (m, 1H), 0.50 (d, 2H), 0.22 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].NC1C=CC([Cl:41])=CN=1>>[Cl:41][C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Cl)cn1

Procedure:
The product of Example 11, Part D (120 mg, 0.45 mmol) and 2-amino-5-chloropyridine (58 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (85 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.81 (s, 1H); 7.69-7.61 (m, 3H); 7.48-7.43 (m, 1H); 7.35 (m, 2H), 7.26 (t, J=8.8 Hz, 1H); 7.17 (t, J=8.5 Hz, 2H); 5.28 (d, J=15 Hz, 1H), 4.69 (s, 1H), 4.26 (d, J=15 Hz, 1H), 2.59-2.48 (m, 2H); 1.98-1.90 (m, 2H). MS: m/z (MH+) 443.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8](O)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)nn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CO)nn1

Procedure:
6-Amino-3-pyridazinecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 6-amino-3-hydroxymethylpyridazine.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][NH:25][S:26]([C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][NH:25][S:26]([C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:28])=[O:27]
Reactant: CC(C)(C)S(=O)(=O)NCCBr
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)NCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (30.4 mg, 0.07 mmol) in 3 mL of dry DMF was added 2-methyl-propane-2-sulfonic acid (2-bromo-ethyl)-amide (90 mg, 0.37 mmol) and Cs2CO3 (80 mg, 0.25 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS42 as pale yellow solid (17 mg, 41% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([C:6]2[N:10](C(OC(C)(C)C)=O)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]=2)[CH2:3]1>ClCCl.C(O)(C(F)(F)F)=O>[NH:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:6]1[C@H:4]1[CH2:3][C@H:2]([OH:1])[CH2:5]1
Reactant: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Yield: 53.2 %

Procedure:
tert-Butyl 2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.31 g, 1.09 mmol) was stirred in a mixture of dichloromethane (5 mL) and TFA (5 mL) at RT for 4 h, then the mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution and 10:1 DCM/MeOH the layers were separated and the aqueous layer was extracted with 10:1 DCM/MeOH (3×). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol, 54% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].Cl>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: C#Cc1ccc(CCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(Br)cc2F)cc1
Temperature: 5 °C
Yield: 66.1 %

Procedure:
4-Bromo-2-fluoro-1-iodobenzene (33 g) was dissolved in diethylamine (37 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.1 g) and copper(I) iodide (0.1 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (16 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (23 ml) and ice (150 g). After extraction with chloroform, the resultant was washed twice with water, followed by distilling off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 190° to 200° C./4 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-2-fluoro-4'-propyltolane (23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>O1CCCC1>[CH3:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]2[NH:1][C:32](=[O:33])[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-{[2-amino-5-methyl-4-(trifluoromethyl)phenyl]amino}-1-piperidine-carboxylate (D58) (2.92 mmol, 1.1 g) was dissolved in 5 ml of tetrahydrofuran and CDI (1,1′-(oxomethanediyl)bis-1H-imidazole) (1.5 eq., 4.4 mmol, 0.71 g) was added at room temperature; the mixture was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and it was partitioned in ethyl acetate/H2O; the two layers were separated and the aqueous phase was extracted with ethyl acetate (2×); the organic phases were combined and washed with citric acid solution (10% aqueous), brine and they were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-n-hexane)) to yield the title compound, 900 mg, 81%, M+−H=398.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1(C(OC(C)(C)C)=O)[CH2:33][CH2:32][CH2:31][C@@H:9]1[C:10]([NH:12][C@@H:13]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]>ClCCl>[NH:8]1[CH2:33][CH2:32][CH2:31][C@@H:9]1[C:10]([NH:12][C@@H:13]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Distilled TFA (4.60 ml, 59.6 mmol) was added dropwise to a solution of N-Boc-D-Pro-D-Phe-OBn (2.70 g, 5.96 mmol) in dry dichloromethane (5.0 ml), and the mixture was stirred at room temperature for 4 hours. TFA and solvent were then removed by evaporation under reduced pressure, and the resulting residue redissolved in chloroform. Water and solid potassium carbonate were added in amounts sufficient to achieve & pH of 10 in the resulting aqueous solution, and the aqueous layer was then extensively extracted with chloroform. The combined organic layers were dried over MgSO4 and concentrated to yield crude D-Pro-D-Phe-OBn as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.Br.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:25]3[CH2:24][C:23]4[C:27](=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:31])[F:30])[CH:22]=4)[CH2:26]3)[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 25 °C

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.102 g, 0.430 mmol; Example 216A) and 5-(trifluoromethyl)isoindoline hydrobromide (0.127 g, 0.473 mmol) in dichloromethane (0.75 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.114 mL, 0.645 mmol) and the reaction was stirred at room temperature. After stirring for 18 hours, the reaction was loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=8.5, 12.6, 2H), 7.42 (dd, J=8.1, 15.3, 1H), 7.36-7.21 (m, 2H), 7.12-6.93 (m, 2H), 4.91 (d, J=17.7, 4H), 4.29 (d, J=16.1, 1H), 4.17 (d, J=16.2, 1H), 3.85-3.54 (m, 3H), 2.72-2.50 (m, 1H), 2.19 (ddd, J=8.5, 12.9, 16.3, 1H); MS (ESI+) m/z 407.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
9.15 g of methyl 2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 6 are solubilized in CH2Cl2 (50 ml). TFA (50 ml) is added at 0° C., and the mixture is stirred at RT for 6 h. After evaporation of the solvent, the residue is triturated in diethyl ether and cooled at 5° C. The solid product 33 is obtained by filtration.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.N.[CH:11](O)=O>>[Cl:8][C:5]1[N:4]=[C:3]2[S:9][CH:11]=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nc1S
Reactant: O=CO
Agent: N
Product: Clc1ccc2ncsc2n1

Procedure:
3-Amino-6-chloropyridine-2-thiol (Q-3) (16.4 g, 103 mmol) in formic acid (80 mL) was refluxed at 110° C. for 2 h. The reaction mixture was cooled and neutralized with concentrated ammonia to pH 7. A precipitate was collected by filtration as the title compound (14.5 g). MS (m/z): 171 (M+1)+.
Reaction SMILES: [Na].[Br:2][C:3]1[N:11]([CH3:12])[C:10]2[C:9](=[O:13])[NH:8][C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1.Cl[CH2:17][P:18](=[O:21])([CH3:20])[CH3:19]>>[Br:2][C:3]1[N:11]([CH3:12])[C:10]2[C:9](=[O:13])[N:8]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1
Reactant: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CP(C)(=O)CCl
Agent: [Na]
Product: Cn1c(Br)nc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 28 g (0.1 mol) of 8-bromo-3,7-dimethylxanthine sodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and chromatographed on silica gel.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ncns2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ncns3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
BCl3 (1 M in DCM, 3.0 mL, 3.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,2,4-thiadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (190 mg, 0.60 mmol) in dry DCM (20 mL) at −78° C. The mixture was stirred at 0° C. for 6 hrs., then, MeOH (3 mL) was added slowly at −78° C. The solvents were evaporated under vacuum to give (2S,5R)-6-hydroxy-2-(1,2,4-thiadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (110 mg, 80%) as a yellow solid, which was directly used in the next step. ESI-MS (EI+, m/z): 227.1 [M−H]−.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@H:44]1[C@H:48]([O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:47]([O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:46]([C:67]2[N:68]=[N:69][N:70]([CH2:72][CH3:73])[CH:71]=2)[O:45]1)(=O)C1C=CC=CC=1>>[C:59]([O:58][C@H:47]1[C@@H:48]([O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:44]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=3[NH:10][CH2:9][CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:45][C@@H:46]1[C:67]1[N:68]=[N:69][N:70]([CH2:72][CH3:73])[CH:71]=1)(=[O:66])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCn1cc([C@H]2O[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nn1
Agent: Cl
Product: CCn1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nn1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and (2S,3R,4R, 5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,3-triazol-4-yl)tetrahydro-2-furanyl benzoate (Preparation 25).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14]C#N)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17].Cl.[C:23](=[O:26])([O-])[OH:24].[Na+]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([CH2:14][C:23]([OH:24])=[O:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:17]
Reactant: O=C([O-])O
Reactant: Cc1nc2ccc(CC#N)cc2n1Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Product: Cc1nc2ccc(CC(=O)O)cc2n1Cc1ccccc1Cl

Procedure:
To 0.500 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile was added 10% hydrochloric acid, and the mixture was heat-refluxed for 15 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and was extracted with chloroform. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 9:1 to 4:1) to give 0.170 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (160).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH3:31][NH:32][CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:32]([CH3:33])[CH3:31])=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 42.3 %

Procedure:
Using General Procedure B: Reaction of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (157 mg, 0.40 mmol) and dimethylamine (2.0 M in THF, 0.4 mL, 0.80 mmol) with NaBH(OAc)3 (0.179 g, 0.84 mmol) in CH2Cl2 (4 mL) overnight followed by purification of the crude material by radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2—CH3OH-NH4OH) provided the free base of the title compound (72 mg, 43%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=C(C=Cc1ccc(C#N)cc1)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(N)c1
Reaction time: 0.75 h
Yield: 63.9 %

Procedure:
Part C. Methyl 3-(3-nitrophenyl)-5-(4-cyanophenyl)-2,4-pentadienoate (0.869 gm, 2.6 mmol) was dissolved in THF and degassed with N2. A catalytic amount of 10% Pd/C was added and the solution was placed on a Parr shaker for 45 min. at 45 p.s.i. The solution was filtered through Celite and the solvent was removed under vacuum. The residue was chromatographed on silica gel eluting ethyl acetate:methylene chloride (20:80, v:v) to give methyl 3-(3-aminophenyl)-5-(4-cyanophenyl)pentanoate as an oil 0.512 gm (64%). 1H NMR (CDCl3): 1.9 (m, 2H), 2.55 (t, 2H), 3.0 (m, 1H), 3.25 (m, 2H), 3.6 (s, 3H), 6.5 (s, 1H), 6.55 (m, 2H), 7.1 (t, 1H), 7.3 (m, 2H), 7.55 (m, 3H).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[CH3:20]>>[Cl:12][C:8]1[CH:7]=[C:6]([CH:2]([O:21][C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH3:13])[CH:15]=2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(Br)c1cccc(Cl)c1
Reactant: Cc1ccc(O)cc1C
Product: Cc1ccc(OC(C(=O)O)c2cccc(Cl)c2)cc1C
Yield: 90.1 %

Procedure:
3-Chlorophenylacetic acid (20.90 g, 122.51 mmol) and NBS (23.50 g, 132.03 mmol) were dissolved in carbon tetrachloride (300 mL), then BPO (300 mg) was added, the resulting reaction was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid. 1.40 g of this α-bromo-3-chlorophenylacetic acid was reacted with 3,4-dimethylphenol (686 mg) according to the General procedure C to give 1.47 g of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.17 (s, 3 H) 2.21 (s, 3 H) 5.58 (s, 1 H) 6.65 (dd, J=8.20, 2.64 Hz, 1 H) 6.78 (d, J=2.64 Hz, 1 H) 7.01 (d, J=8.20 Hz, 1 H) 7.29-7.40 (m, 2 H) 7.42-7.52 (m, 1 H) 7.59 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C@H:8]([NH2:7])[CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution of 1.41 g (3.3 mmol) [2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethyl]-carbamic acid tert-butyl ester in 5 mL dichloromethane was treated with 1.5 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 16 hours at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was added 50 mL saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure affording a soft solid, that was recrystallized from 2,2,4-trimethylpentane containing about 5% ethyl acetate to afford 804 mg (77%) of (S)-2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine as light tan crystals; mp 180-182° C.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:28])=[N:19][C:20]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[I:56]I>C(#N)C>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:28])=[N:19][C:20]([N:23]2[CH:27]=[C:26]([I:56])[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cccn2)nc1O
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cc(I)cn2)nc1O
Temperature: 85 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The product of step B, compound 1-1-b, (3.2 g, 8.6 mmol) was dissolved in acetonitrile (100 mL), and treated with CAN (6.62 g, 12.1 mmol) and I2 (1.42 g, 5.6 mmol). The reaction mixture was stirred for 16 h at 85° C. The resulting mixture was concentrated, diluted with 50 mL of water, stirred for 20 min and filtered. The solid filtrate was dried under vacuum to provide the product, 1-1-c (3.6 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 6.22-6.24 (d, J=6.6, 1H), 7.22-7.39 (m, 11H), 7.55-7.74 (m, 1H), 8.07 (m, 1H), 8.47 (m, 1H), 8.71 (s, 1H), 10.49 (s, 1H). LC-MS 498[MH]+.