Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][C:3]([CH2:20][CH:19]=[CH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCC(OC)(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Benzoin methyl ether (50 g) and t-butanol (500 g) were added to a 1 liter, 3-neck round bottom flask equipped with magnetic stirrer, and placed in an oil bath at 80° C. To this mixture, 33.7 g of potassium t-butoxide was added and the solution stirred for 15 minutes. Allyl bromide (42.3 g) was added dropwise over a 1 hour period and stirring was continued at 85° C. for 2 more hours followed by cooling to room temperature. After evaporation of t-butanol and filtration of potassium bromide, the product was distilled at 125° C.±2° C. and 0.05 mm Hg to yield 49.2 g of α-allylbenzoin methyl ether which crystallized upon cooling.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C@H:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[C:18]([OH:19])=[N:17][C:5]2=[N:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.0 equiv) in refluxing anhydrous THF (5 volume equivalents) was added carbonyldiimidazole (CDI). Successive portions of CDI were added until the starting material was consumed (approx. 3.6 equiv total) as judged by TLC (50% EtOAc/Hexanes). After complete reaction, the mixture was cooled to room temperature and quenched by the careful addition of water until gas evolution had ceased. The mixture was diluted with 25 volume equivalents of EtOAc and washed with 3×7.5 volume equivalents of water and 1×7.5 volume equivalents of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (66%) as a white solid. LCMS m/z (APCI)=319.0, 321.0 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Si:7]([O:14][C@H:15]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])/[CH:16]=[N:17]/[S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CCOCC>[Si:7]([O:14][C@H:15]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:16]([NH:17][S@:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8]
Reactant: Brc1nccs1
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-bromothiazole (7.9 ml, 89 mmol) in 200 mL ether was cooled to −78° C. and treated with a solution of n-butylithium (36 ml, 89 mmol) (2.5N in hexanes). After stirring for 30 minutes the reaction mixture was slowly added to a cooled (−78° C.) suspension of (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (25.000 g, 59 mmol) in 100 mL ether. The reaction mixture was allowed to stir at −78° C. for one hour. The reaction mixture was quenched with MeOH and saturated NH4Cl solution. The organic solution was washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography gave (S)-N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (24.81 g, 83% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[Cl:13][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CSc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (3-methylsulfanyl-phenyl)-methanol (23.8 g, 0.156 mol) in benzene (250 mL) was added thionyl chloride (26.9 g, 0.234 mol) under cooling with an ice-bath. The ice-bath was removed and the reaction mixture stirred for 48 hours at room temperature. The solution was concentrated and used without further work-up (26.9 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O)(=O)=O.[Na+].[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>O>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[N:7]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)C(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CC1=Nc2ccccc2C1(C)C
Reaction time: 3 h
Yield: 94 %

Procedure:
226 g (2 mol) of phenylhy-drazine (95.7% pure) were initially introduced at 90° C. in a solution of 5 mol of sodium hydrogen sulphate in 1900 ml of water. 225 ml (2.1 mol) of methyl isopropyl ketone were added dropwise in the course of 30 min. The mixture was stirred for 3 h at 90° to 100° C. After cooling, the batch was neutralised and the organic phase was separated off and distilled. 299.3 g of 97.5% pure 2,3,3-trimethylindolenine were obtained Yield: 91.6% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylate (3.94 g, 11.7 mmol), lithium hydroxide (0.65 g, 27.1 mmol), MeOH (250 mL), and water (40 mL) was stirred at rt for 20 hr. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=2-3. The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, brine, dried and concentrated to yield the product as a white solid. LC-MS: 310.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 13.29 (s, 1H), 8.21 (t, 1H, J=1.6 Hz), 7.99 (t, 1H, J=1.6 Hz), 7.98 (t, 1H, J=1.5 Hz), 7.64 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=7.9 Hz), 3.50 (t, 2H, J=6.7 Hz), 3.43 (t, 2H, J=6.5 Hz), 2.36 (s, 3H), 1.98-1.78 (m, 4H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[C:25]([O:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:37]=[CH:36][C:35]([O:34][C:25]3[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:27][N:26]=3)=[CH:42][CH:41]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A mixture of 1.30 g of N-methyl-N-phenylsulfonyl-2-chloro-6-fluorobenzohydrazonoyl chloride, 1.00 g of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)benzonitrile, 0.50 g of anhydrous aluminum chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.70 g of the given compound (measurement of nD20 was impossible). NMR data (60 MHz, CDCl3 solvent, δ value)
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si](C(C)(C)C)(C)C)=[C:8]([C:10](O)=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)[O:64]N1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[C:13](=[O:64])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=4)[C:16]=3[CH2:36][OH:37])[CH2:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cccc(N3Cc4nc(C(C)(C)C)sc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
To a solution of 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylic acid (125e) (500 mg, 0.78 mmol) in methylene chloride (40 mL) was added N,N-Diisopropylethylamine (503 mg, 3.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (900 mg, 2.37 mmol). The mixture was stirred at 25° C. for 2 h. After flash column purification with PE:EA (1:3 to 1:6) as eluent, 125 was obtained as white solid (32 mg, 10%). LCMS: (M+H)+ 503. 1H NMR (500 MHz, MeOD) ppm 8.84 (d, J=2 Hz, 1H), 8.66 (s, 1 H), 8.29 (d, J=5.5 Hz, 1H), 7.49-7.56 (m, 4 H), 7.09 (d, J=5.5 Hz, 2 H), 5.04 (s, 2 H), 4.57 (s, 2 H), 3.73 (s, 3 H), 1.54 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A solution of 6-chloro-2-nitrophenol (1.7 g.) and ethyl chloroacetate (2.1 ml.) in dimethylformamide (12 ml.) with potassium carbonate (1.5 g.) was stirred at 75°-80° C. for 3 hours. The mixture as poured into water (120 ml.) and extracted with ethyl acetate (4 × 50 ml.) . The organic layer on evaporation yielded 6-chloro-2-nitrophenoxyacetic acid ethyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[CH2:10][C:5]2=[CH:4][CH:3]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2ccc(Cl)nc2N1
Product: CCOC=C1C(=O)Nc2nc(Cl)ccc21

Procedure:
This compound was synthesized from 6-chloro-1H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 11.06 (s, 1H); 7.84 (s, 1H); 7.63 (d, 1H); 6.98 (d, 1H); 4.39 (m, 2H); 1.32 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[C:20]([CH3:21])=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH3:22])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[C:20]([CH3:21])=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH3:22])=[CH:14][CH:13]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1c(N)ccc2c1N(C)C(=O)C2(C)C
Product: Cc1c(NC(=O)c2ccnc(Cl)c2)ccc2c1N(C)C(=O)C2(C)C

Procedure:
Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1,3,3,7-tetramethyl-1,3-dihydro-indol-2-one. The title compound was obtained as light yellow crystals.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:14])([CH3:13])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 72 %

Procedure:
The crude ethyl 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate was saponified by treating with 100 mL of ethanol and 100 mL of 4.0 M NaOH solution. The suspension was stirred for 3 hours, after which a clear solution formed The solution was concentrated, diluted with 150 mL of H2O, washed with 2×50 mL of ether, and acidified to pH 1 with 10% HCl solution. The aqueous phase was extracted with 3×100 mL portions of ether and the combined ether extracts were washed with 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated leaving 18.3 g (72% yield) of racemic 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionic acid as a white solid after was recrystallization from CHCl3 and hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:1][C:2]2[C:3]([C:13]=1[OH:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1O

Procedure:
3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) was heated at reflux, under argon for 1 h. The cooled reaction mixture was poured onto pentane (1 litre). The precipiated solid was collected by filration, washing with pentane. Drying afforded the title compound (24.78 g, crude).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:16]=1)[CH3:2].[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:30][C:7]1[C:6]2[N:16]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (14.3 g, 35.8 mmol) in 90 mL of CH2Cl2 was treated with 90 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 90 mL of CH2Cl2 and 90 mL of water. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4 and concentrated. The resulting solid was triturated in ether and filtered to yield 9.35 g of tert-butyl 2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9]I.C(=O)([O-])[O-].[Ca+2].CCOCC>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(F)cc1I

Procedure:
A mixture of 22 g. of 4-fluoroaniline, 50 g. of iodine, 25 g. of calcium carbonate, 75 ml. of ether and 75 ml. of water is heated at reflux for 48 hours. The ether is removed by distillation and the excess iodine is destroyed by addition of sodium thiosulfate. Steam distillation and recrystallization from petroleum ether gives 4-fluoro-2-iodoaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[CH:6][CH:7]=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[Br:16]Br>C(O)(=O)C.O>[Br:16][C:7]1[CH:6]=[C:5]([CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(C)c(OCC)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(OCC)c(C)cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5-ethoxy-4-methylbenzoate (500 mg, 2.40 mmol) in acetic acid (10 mL) and water (10 mL) at room temperature was added bromine (385 mg, 2.40 mmol). The resulting reaction mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with hexanes/ether (80/20). Layers were separated and the organic layer was washed with saturated Na2CO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to yield the title intermediate (660 mg, 2.23 mmol) as light yellow solid.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>>[C:45]([O:44][C:42](=[O:43])[CH2:41][N:14]([C@H:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=2)[C:10]1=[O:39])[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])([CH3:48])([CH3:47])[CH3:46]
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN([C@H]1CCN(Cc2csc(C#N)c2)C1=O)S(=O)(=O)c1ccc2ccc(NC(=O)OCc3ccccc3)cc2c1

Procedure:
The title compound is prepared from N-Cbz-7-aminonaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 10% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.B(F)(F)F.O>C(Cl)Cl>[S:16]1[C:15]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:1][C:2]3([CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[C:14]=2[CH:18]=[CH:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2-c2ccccc2O)C1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)Oc1ccccc1-c1sccc12
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(2-(2-hydroxyphenyl)thiophen-3-yl)pyrrolidine-1-carboxylate (4.4 g, 12.1 mmol) in DCM (25 mL) at 0° C. was added BF3 (1.6 g, 24.2 mmol) dropwise. After stirring overnight, the reacton mixture was treated with water and extracted with EtOAc several times. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (3.8 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.[O:16]([C:23]([N:25]=[C:26]=[S:27])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:26]([SH:27])[NH:25][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: COc1ccc(CSC(=N)CC#N)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of of 2-cyano-thioacetimidic acid 4-methoxy-benzyl ester (42 g, 0.19 mol) in 191 mL of ethyl acetate at 0° C. was added phenoxycarbonylisothiocyanate (34 g, 0.19 mol), and the mixture was stirred at 0° C. for 24 hours. The mixture was diluted with ether and filtered. The solids were washed with ether, collected and dried in vacuo, affording 56 g (73%) of 2-cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester as a yellow solid. 1H NMR (400 MHz, CDCl3) δ12.81(s, 1H), 9.01 (s, 1H), 8.68 (s, 1H) 7.28-6.99 (m, 7H), 6.69 (d, 2H, J=8.8 Hz), 4.17 (s, 2H), 3.64 (s, 3H) ppm; MS (APCI, m/z): 400 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:30]([N:12]3[C@H:13]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C@H:14]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[N:15]=[C:11]3[C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=3[O:33][CH2:34][CH3:35])=[O:31])[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCCC2)CC1

Procedure:
[1,4′]Bipiperidinyl-1′-yl-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-methanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-piperidinopiperidine (Aldrich) in an analogous manner as described in example 25. HR-MS (ES, m/z): observed 661.3071, calculated for C38H47Cl2N4O3 [(M+H)+] 661.3071.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[Si:22]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-methyl 4-(hydroxymethyl)cyclohexanecarboxylate was dissolved in dichloromethane (30 mL), then imidazole (1.0 g) and tert-butylchlorodimethylsilane (1.6 g) were added. The reaction was stirred at room temperature overnight. The reaction mixture was then concentrated, dissolved in ethyl acetate and washed with 1N aqueous HCl, water, and brine. The organic layer was dried over Na2SO4. The title compound was obtained after filtration and concentration.