Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH:35][CH:36]1[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]([O:35][CH:36]4[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CCOC(=O)C1CCC(O)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min).
Reaction SMILES: N#N.[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[NH:5]1.Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[N:5]1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC1CCC(C)N1
Reactant: N#CCCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCC(C)N1CCCCN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2,5-dimethylpyrrolidine (250 mg, 2.34 mmol) and 4-bromobutyronitrile (0.24 mL, 2.34 mmol) in dry CH3CN (12 mL) was added K2CO3 (1.78 g, 12.89 mmol) at rt followed by KI (39 mg, 0.23 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (19 mL) and treated with LiALH4 (176 mg, 4.50 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (7 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2,5-dimethylpyrrolidin-1-yl)butan-1-amine as a yellow oil. GC-MS-conditions 01: tR=1.75 and 1.83 min; [M+H]+=171.30.
Reaction SMILES: [CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([O:16][CH3:17])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([N:5]2[CH2:6][CH2:7][P:2](=[O:8])([CH3:1])[CH2:3][CH2:4]2)[CH:11]=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: CP1(=O)CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol), 5-fluoro-2-nitroanisole (340 mg, 2.00 mmol), K2CO3 (345 mg, 2.50 mmol), and DMF (5 mL) was heated to 50° C. After 2 h, the reaction mixture was concentrated and purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford 1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as a bright yellow solid (272 mg, 96% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[C@H:17]2[CH2:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])=[CH:4][CH:3]=1.O.NN>CO>[NH2:24][CH2:23][C@@H:17]1[C@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1

Procedure:
A mixture of 2-(((2S,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (130 mg, 272 μmol) and hydrazine hydrate (67 μL, 1.36 mmol) in MeOH (3 mL) was heated at reflux for 2 h. The mixture was cooled and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2×) and brine. The organic solution was dried over anhydrous Na2SO4. The solvent was removed to obtain the title compound which was used without further purification. MS (ESI) 348 (M+H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3]\[CH2:4][OH:5]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:21])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C=O
Reaction time: 16 h

Procedure:
To a solution of (E,E,E)-3,7,11,15 tetramethyl-2,6,10,14-hexadecatetraen-1-ol (320 mg, 1.1 mmol) in dry methylene chloride (10 ml) at room temperature was added manganese dioxide (957 mg, 0.011 mol) and the resulting mixture stirred for 16 hours. The solids were removed by filtration through a pad of celite washing with methylene chloride (50 ml). The resulting solution was evaporated in vacuo to afford the aldehyde (1) as a clear colorless oil.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:21][C:22]1([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:34][C:31]1[CH:32]=[CH:33][C:28]([C:22]2([CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:29][CH:30]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1
Reactant: CC1(c2ccc(O)cc2)CCCCC1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C2(C)CCCCC2)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 79.6 %

Procedure:
In a manner similar to Example 16, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 4.75 g of p-(1-methylcyclohexyl)phenol for 4 hrs. Chilling and filtering gives 7.4 g of product, mp 110°-112° C. Recrystallization from methanol-chloroform gives 6.3 g of white crystals, mp 111°-112.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (133 mg, 54.7%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[F-].[K+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[NH:55][N:54]=[N:53][N:39]=4)=[CH:36][CH:37]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(C#N)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(4-cyanophenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide (1.31 g), tributyltin azide (1.60 g) and toluene (13 ml) is refluxed under argon atmosphere for 24 hours. After cooling, ethyl acetate and 10% aqueous potassium fluoride solution are added to the reaction solution. The insoluble materials are removed by filtration, and the ethyl acetate layer is concentrated to dryness under reduced pressure. To the residue are added 10% aqueous sodium hydroxide solution and diethyl ether, and the mixture is stirred at room temperature for 20 minutes. The aqueous layer is washed with diethyl ether, and acidified with 10% hydrochloric acid under ice-cooling. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent:chloroform:methanol=100:0~20:1), and crystallized from ethyl acetate to give 4-tert-butyl-N-{5-(4-methylphenyl)-6-[2-(4-(5-tetrazolyl)phenoxy)ethoxy]-pyrimidin-4-yl}benzensulfonamide (1.26 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:60]([CH2:62][CH3:63])=[CH2:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:60]([CH2:62][CH3:63])=[CH2:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat) was added and the reagents allows to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organic were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 3"-ether).
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]1([O:32][CH2:31][C@H:30]([CH2:33][N:34]2[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]2)[O:29][CH2:28]1)=[O:27]>[OH-].[Na+]>[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]([OH:32])([CH2:28][O:29][C@H:30]([CH2:31][OH:3])[CH2:33][N:34]1[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]1)=[O:27]
Reactant: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCCCOP(=O)(O)CO[C@H](CO)Cn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As described in U.S. Pat. No. 6,716,825, in Step 1 of the scheme above, cidofovir was suspended in N,N-DMF and N,N′-dicyclohexyl-4-morpholine-carboxamide was added. The mixture was stirred overnight to dissolve the cidofovir. The clear solution was then charged to an addition funnel and slowly added (30 min) to a stirred, hot pyridine (60° C.) solution containing 1,3-dicyclohexyl carbodiimide. The resulting reaction mixture was stirred at 100° C. for 16 h, cooled to room temperature and the solvents were removed under reduced pressure. The reaction mixture was adsorbed on silica gel and the product was purified by flash column chromatography using gradient elution (CH2Cl2 and MeOH) followed by 5:5:1 CH2Cl2/MeOH/H2O. The fractions containing the product were combined and concentrated in vacuo. The product, the DCMC salt of cyclic cidofovir was isolated in a 44% yield. In step 2, a solution of cyclic cidofovir DCMC salt in dry N,N-DMF was charged with 1-bromo-3-hexadecyloxypropane and the mixture was stirred and heated at 80° C. for 6 h. The solution was concentrated in vacuo, the residue adsorbed on silica gel and purified by flash column chromatography using gradient elution (CH2Cl2 and ethanol). The product was eluted with 90:10 CH2Cl2/EtOH. The fractions containing pure product were concentrated in vacuo. Hexadecyloxypropyl-cyclic cidofovir was obtained in a 55% yield. In Step 3, hexadecyloxypropyl-cyclic cidofovir was dissolved in 0.5M NaOH and stirred at room temperature for 1.5 h. 50% aqueous acetic acid was then added dropwise to adjust the pH to 9. The precipitated hexadecyloxypropyl-cidofovir was isolated by filtration, rinsed with water, and dried. The product was crystallized from 3:1p-dioxane/water to give hexadecyloxypropyl-cidofovir (HDP-CDV, i.e., CMX001).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:23]=[N:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH3:37])[CH3:12])[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[N:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:38])=[O:2])[CH3:12])=[C:14]([CH3:37])[CH:15]=2)=[C:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[N:23]1
Reactant: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)Sc1cccc(C(=O)O)c1
Temperature: 50 °C
Yield: 94.3 %

Procedure:
To an ambient temperature solution of 3-(1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoic acid methyl ester (53 mg, 0.0934 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (140 μL, 0.280 mmol, 2.0N in water). The reaction is heated to 50° C. for 2 h. The reaction mixture is concentrated and the residue is diluted with Et2O and water. The aqueous layer is adjusted to pH ˜4 and is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (49 mg, 94%). LC-ES/MS m/e 556.3 (M+1), HPLC purity: 100%.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16](O)=[O:17])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.C[N:26]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:26])=[O:17])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: -50 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To the solution of 2-biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid (0.35 g, 1.1 mmol) in THF (20 mL) was added N-methyl morpholine (0.2 mL, 1.6 mmol) and the mixture was cooled to −50° C. Isobutyl chloroformate (0.22 mL, 1.6 mmol) was then added drop wise, the reaction mixture was warmed to −10° C. and stirred for 2 h. The reaction mixture was again cooled to −50° C. and purged with ammonia gas for 10 minutes. Reaction mixture warmed to room temperature and stirred for 1 hour. TLC showed completion of the reaction. The crude mixture was filtered and the filtrate concentrated. The resulting residue was stirred with hexane and the free solid formed filtered and dried to obtain title compound (0.24 g, 70%).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]2)=[CH:11][CH:10]=1.[SiH](CC)(CC)CC>>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:16][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:18]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C1CC(O)(c2ccc(Br)cc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CC(c2ccc(Br)cc2)C1
Temperature: 17.5 °C
Yield: 98.9 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed trifluoroacetic acid (12 L), methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate (2330 g, 8.17 mol, 1.00 equiv), followed by the addition of Et3SiH (3556 g, 30.58 mol, 5.00 equiv) dropwise with stirring at 10-25° C. The resulting solution was stirred at room temperature for 0.5 h, concentrated under vacuum, diluted with 8 L of H2O and extracted with 1×8 L of ethyl acetate. The organic layers were combined, washed with 1×3 L of saturated aqueous sodium bicarbonate and 1×2 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2175 g (crude) of methyl 3-(4-bromophenyl)cyclobutane-1-carboxylate as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Yield: 29.5 %

Procedure:
To a stirred mixture of (E)-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (9.87 g, 0.034 mol) in carbon tetrachloride (60 mL) under a nitrogen atmosphere was added N-bromosuccinimide (9.08 g, 0.051 mol) and benzoyl peroxide in water (75%, 1.09 g, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (3.70 g, 29%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ncc(CN2CCSCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 9.2 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (60 mg. 0.18 mmol), acetic acid (11 μL, 0.18 mmol), thiomorpholine (21 μL, 0.22 mmol) and sodium triacetoxyborohydride (38 mg, 0.20 mmol) to afford 7 mg (9%) of the desired product after purification.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)([CH3:5])[CH2:3][CH3:4].O.[Cl-].[Ca+2].[Cl-]>CCO.[Fe]>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCC(C)(C)c1ccc(N)c(N)c1
Yield: 66.9 %

Procedure:
To a stirred solution of 4-(1,1-dimethylpropyl)-2-nitroaniline (Preparation 94, 11 g, 0.052 mol) in EtOH:water (240 mL:60 mL) was added iron powder (14.8 g, 0.254 mol) and calcium chloride (11.7 g, 0.105 mol). The reaction was heated to reflux for 6 hours before cooling and concentrating in vacuo. The residue was extracted with EtOAc, dried over Na2SO4, concentrated in vacuo and purified using silica gel column chromatography eluting with 50% EtOAc in hexane to afford the title compound (6.2 g, 65%).
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[C:25]1([S:31]([N:34]2[C:38]3=[N:39][CH:40]=[CH:41][C:42](B4OC(C)(C)C(C)(C)O4)=[C:37]3[CH:36]=[C:35]2[CH:52]=[O:53])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:52]([C:35]1[N:34]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:32])=[O:33])[C:38]2=[N:39][CH:40]=[CH:41][C:42]([C:2]3[C:3]([C:9]4[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:17])=[CH:11][CH:10]=4)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=3)=[C:37]2[CH:36]=1)=[O:53]
Reactant: CC1(C)OB(c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)OC1(C)C
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Procedure:
Following the procedure described in Intermediate 100 with N-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N′-phenylurea and 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde provided the title compound. ESMS [M+H]+: 591.4