Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=O)[C:8]3=[CH:18][S:19][CH:20]=[C:7]23)=[O:5])[CH2:3][CH2:2]1.B.[ClH:22].C(O)C>O1CCCC1>[ClH:22].[CH:1]1([C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][C:8]3=[CH:18][S:19][CH:20]=[C:7]23)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C1Nc2ccccc2N(C(=O)C2CC2)c2cscc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(C1CC1)N1c2cscc2CNc2ccccc21

Procedure:
To 5.69 g. of 4-cyclopropylcarbonyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of tetrahydrofuran is added 120 ml. of 1 M borane in tetrahydrofuran under argon, with stirring in an ice bath. The mixture is refluxed for 18 hours, then chilled and 60 ml. of 6 N hydrochloric acid is cautiously added. Most of the solvent is evaporated and 100 ml. of 5 N sodium hydroxide is added. The mixture is extracted with methylene chloride, dried over magnesium sulfate and evaporated giving a gum. Excess hydrochloric acid and ethanol are added to the gum and then evaporated giving a second gum. Ethanol is added to this second gum producing crystals which are recovered giving the desired product as colorless crystals, mp. 157°-159° C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7]1.[Br:21]C1CC(=O)NC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:21][C:5]1[S:1][C:2]([C:6]2([C:10]3[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]4=[N:12][N:11]=3)[CH2:7][CH2:8][CH2:9]2)=[CH:3][CH:4]=1
Reactant: O=C1CC(Br)C(=O)N1
Reactant: c1csc(C2(c3nnc4n3CCCCCC4)CCC2)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(C2(c3nnc4n3CCCCCC4)CCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
3-[1-(2-Thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (60 mg) was dissolved in acetic acid (3 ml) and then bromosuccinimide (38 mg) was added, followed by stirring at room temperature for 8 hours under light-shielding. The reaction solution was diluted with chloroform (30 ml) and then washed with water (10 ml), a 1M aqueous sodium hydroxide solution (10 ml), and brine (10 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 60 mg of 3-[1-(5-bromo-2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Li+].[CH3:14]C([N-]C(C)C)C.CI>C1COCC1>[CH3:14][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-chlorophenyl)propionic acid (1.85 g, 10 mmol) in 10 mL of THF was added to 16 mL of freshly prepared 1.5 M LDA (24 mmol) at dry ice-acetone bath temp. The reaction mixture was stirred 1 hr as it warmed to −30° C. and 1.6 mL (25 mmol) of methyl iodide was added. The resulting mixture was stirred at the same temp. for 0.5 h and the stirring was continued at RT overnight. The reaction was quenched with 1 N HCl, and diluted with ether. The solution was washed with water, 10% sodium thiosulfate and brine. The organic layer was dried over MgSO4. Solvent removal gave a mixture of the desired methylated product and the starting acid. Repetition of the above procedure on this residue gave the desired 2-methyl-3-(4-chlorophenyl) propionic acid contaminated with ˜5% of the starting acid as an oil. NMR: 1.5 (d, 3H), 4.78 (q, 1H). 6.84 & 7.26 (2d, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]=[S:12]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:11]([NH:10][C:13](=[O:14])[O:15][CH2:16][CH3:17])=[S:12])=[N:7][CH:8]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(N)nc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 5-methoxypyridin-2-amine (1.05 g, 8.43 mmol) in dimethyl sulfoxide (5 mL) was added ethyl isothiocyanatoformate (1.44 g, 11.0 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.34 g, 62%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Br-].[CH2:17]([Zn+])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH2:17]([C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was sequentially charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol), and dry THF (2.52 mL). The mixture was then sparged with N2 prior to the addition of benzylzinc(II) bromide (0.5M in THF, 2.12 mL, 1.06 mmol). The reaction was stirred under N2 at 60° C. for 2 h. The reaction was then cooled to rt, slowly poured over saturated aqueous ammonium chloride and ice, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated. The crude product then was triturated with toluene to give 2-benzyl-4-chloro-5,7-difluoro-3-methylquinoline. Mass Spectrum (ESI) m/e=304.0 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[C@@H:12]2[O:25][C@H:11]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].C(O)(=O)C>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[C@H:12]([OH:25])[CH2:11]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2O[C@@H]21
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a stirred solution of 9.5 g (38.1 mmol) of 2',3'-anhydroadenosine (Robins, M. J.; Hansske, F; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 367-370) in 114 mL of pyridine was added 11.5 g (76.2 mmol) of t-butyldimethylsilyl chloride. After 3.5 h at room temperature, an additional 5.75 g (38.1 mmol) of t-butyldimethylsilyl chloride was added. After a total of 4.25 h, the reaction mixture was diluted into 2 L of water and extracted with 3×500 mL of dichloromethane. The combined dichloromethane extracts were washed with one liter of saturated aqueous sodium bicarbonate, with 3×500 mL of water, and then dried over magnesium sulfate. Concentration under reduced pressure afforded 13.3 g of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine. To a stirred solution of 2.0 g (5.50 mmol) of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine in 55 mL of THF at 0° C. was added 22 mL (22 mmol) of a 1M solution of lithium triethyl borohydride in THF. The reaction mixture was then allowed to warm to room temperature. After 3 hours, the reaction mixture was recooled to 0° C. and then carefully treated with 4.0 mL of 5% aqueous acetic acid. The resulting mixture was diluted with 150 mL of EtOAc, washed with 3×100 mL of saturated aqueous NaCl, dried over magnesium sulfate, concentrated under reduced pressure, and then coevaporated with three portions of chloroform. Chromatography of the residue on silica gel with a 100:0 to 97:3 chloroform/methanol gradient afforded 1.8 g (90%) of the title compound: colorless glass; Rf =0.10 (silica gel 60 F-254, 0.25 mm, E. Merck (SG), 95:5 CHCl3 :MeOH); [α]D23 -47.8° (c 2.47, CHCl3); IR (CDCl3) 3480, 3415, 3320, 3165, 3125, 2960, 2935, 2860, 1635, 1595, 1575, 1470, 1415, 1330, 1290, 1255, 1210, 1135, 1090, 995 cm-1 ; 1H NMR (300 MHz, CDCl3, TMS=0.00 ppm) δ0.08, 0.09 (2s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3CSi), 2.10 (ddd, 1H, J=13.5 Hz, J'= 6.5 Hz, J"=4.0 Hz, 3'-H), 2.34 (ddd, 1H, J=13.5 Hz, J'=7.5 Hz, J"=6.0 Hz, 3'-H), 3.74 (dd, 1H, J=12.0 Hz, J'=3.0 Hz, 5'-H), 4.05 (dd, 1H, J=12.0 Hz, J'=3.0 Hz), 4.62 (dddd, 1H, J=7.5 Hz, J'=6.5 Hz, J"=J'"=3.0 Hz, 4'-H), 4.70 (ddd, 1H, J=6.0 Hz, J'=4.0 Hz, J"=2.5 Hz, 2'-H), 5.88 (bs, 1H, OH), 6.01 (d, 1H, J=2.5 Hz, 1'-H), 6.15 (bs, 2H, NH2), 8.30, 8.33 (2s, 2H, H-2, H-8); FAB MS, m/z 366 (M+H)+ , 136.
Reaction SMILES: I.[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[N:12][CH3:13])SC.[CH3:20][NH2:21]>C(O)C>[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:21][CH3:20])=[N:12][CH3:13]
Reactant: CN=C(Nc1ccccc1-c1ccccc1)SC
Reactant: CN
Agent: I
Solvent: CCO
Product: CN=C(NC)Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 1-(2-biphenylyl)-2,3-dimethyl-2-thiopseudourea hydriodide (7 g) and a 33% solution of methylamine in ethanol (250 ml) was stirred at ambient temperature for 56 days to give N-(2-biphenylyl)-N',N"-dimethylguanidine (m.p. 101°-102° C.) which was recrystallised from hexane. A sample (2.4 g) was dissolved in methanol (25 ml) and treated with fumaric acid (1.16 g) to give N-(2-biphenylyl)-N',N"-dimethylguanidine fumarate (m.p. 192°-193° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]1[S:9][C:10]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:12]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:2][CH2:3][CH2:5][CH2:6][CH2:7][C:8]1[S:9][C:10]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:12]=1
Reactant: COC(=O)CCCc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CCCCO)sc2-c2cccnc2)cc1
Reaction time: 1 h
Yield: 81 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 770 mg of 2-(3-methoxycarbonylpropyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole prepared by example 4, which was then cooled with ice. To the solution was added little by little 100 mg of lithium aluminium hydride, which was stirred for one hour. To the mixture was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated, followed by purifying by means of a silica-gel chromatography [chloroform-methanol (9:1)] to yield 576 mg (81%) of 2-(4-hydroxybutyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole as an oily substance.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:58](=[NH:60])[NH2:59])[CH:54]=2)[CH:49]=1)(=O)=O>C(OCC)C>[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[C:53]([C:58](=[NH:59])[NH2:60])[CH:54]=3)[CH:49]=2)=[O:24])=[CH:26][CH:27]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)cc3)ccc2c1
Yield: 46.9 %

Procedure:
To 50 ml of dried pyridine, were added 5.1 g of 4-benzyloxycarbonylaminomethylbenzoic acid and 4.4 g of DCC. The mixture was stirred under cooling in ice for 30 minutes, admixed with 5.0 g of 6-amidino-2-naphthol methanesulfonate and stirred for one hour under cooling in ice, then overnight at room temperature. The reaction mixture was filtered* and the filtrate was mixed with ethyl ether. The precipitate which was formed was collected by filtration and recrystallized from a DMF-ethanol mixture to obtain 3.8 g of a white powder of a white powder of 6-amidino-2-naphthyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[O:9])=[C:6]([F:14])[C:5]=1[F:15].O>CO>[Br:3][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: O=Cc1c(F)c(F)c(Br)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Sodium borohydride (1.0 g) was added portionwise over a period of 30 minutes to a stirred solution of 4-bromo-2,3,5,6-tetrafluorobenzaldehyde (8.2 g) in methanol (80 cm3) whilst the temperature was maintained within the range from -5° C. to +5° C., after which the mixture was stirred for 2 hours at the ambient temperature (ca 18° C.). The mixture was poured into water and the precipitated white solid collected by fitration, washed with water and air dried to yield 4-bromo-2,3,5,6-tetrafluorobenzyl alcohol (7.5 g), mp. 60°-62° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:46][N:45]2[CH:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][CH2:38]1)(=O)=O>CN(C)C=O>[Cl:2][C:3]1[C:4]([F:24])=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:36][CH:37]4[CH2:46][N:45]5[CH:40]([CH2:41][CH2:42][CH2:43][CH2:44]5)[CH2:39][CH2:38]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1O
Reactant: CS(=O)(=O)OCC1CCC2CCCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1OCC1CCC2CCCCN2C1
Temperature: 70 °C
Reaction time: 38 h
Yield: 13.8 %

Procedure:
4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by octahydro-2H-quinolizin-3-ylmethyl methanesulfonate (466 mg, 1.89 mmol) in dimethylformamide (1 mL). The mixture was stirred at 70° C. for 38 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (15-20% methanol in dichloromethane). The purified material was crystallized from methanol to afford N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amine as a cream colored solid (83.4 mg, 0.165 mmol, 14% yield). 1H NMR (400 MHz, CDCl3): 8.69 (s, 1H), 8.53 (t, 1H), 7.34 (dd, 1H), 7.28-7.22 (m, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 4.06-3.95 (m, 2H), 4.02 (s, 3H), 3.09 (d, 1H), 2.87 (d, 1H), 2.43-2.27 (m, 1H), 2.10-1.97 (m, 1H), 1.95-1.84 (m, 2H), 1.80-1.52 (m, 5H), 1.46-0.95 (m, 5H); MS (EI) for C25H27N4O2FCl2: 505 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:44][CH3:45]>C1COCC1>[CH2:42]([O:46][CH2:47][CH2:48][CH2:49][NH:50][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCOCCCN
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCOCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-butoxypropylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 556.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=O)CCl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 47.2 mg, 0.139 mmol) was added dichloromethane (697 μL) and triethylamine (35.0 μL, 0.251 mmol). Chloroacetyl chloride (12.20 μL, 0.153 mmol) was added dropwise. The reaction mixture was stirred at rt for 16 h. Additional chloroacetyl chloride (12.20 μL, 0.153 mmol) was added. The reaction mixture was diluted with dichloromethane. The organics were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-(2-Chloroacetamido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (58.5 mg, 101% yield) was isolated as an orange paste. Material was used in subsequent reactions with no further purification.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])[CH2:17][C@H:16]2[CH3:32])(=[O:14])=[O:13])=[C:8]([F:33])[CH:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:8]1[CH:7]=[C:6]([OH:5])[CH:11]=[CH:10][C:9]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[CH2:17][C@H:16]1[CH3:32])(=[O:14])=[O:13]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(OC(C)(C)C)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(O)cc1F
Reaction time: 1 h

Procedure:
A solution of (2R)-1-[(4-tert-butoxy-2-fluorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (375 mg, 0.76 mmol) in DCM (25 mL) was added TFA (5 mL). The reaction was allowed to stir for 1 hour, after which it was judged complete by LCMS. The reaction was concentrated in vacuo to remove excess TFA, and the crude oil was dissolved in DCM (20 mL) and washed with saturated NaHCO3(aq) (3×25 mL). The organic phase was dried over Na2SO4, and decanted, then concentrated in vacuo affording the desired phenol in >95% purity, which was used in subsequent synthetic steps without purification. HRMS: calcd for C18H17F5N2O3S+H+, 437.09528. found ([M+H]+), 437.09527.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([NH:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31](=[O:35])[NH:32]2)=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccc(NC(=O)c3ccccc3)cc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-benzamido-2-oxindole to give 0.4 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzamide as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[C:40]([O:41][CH3:42])=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([F:43])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[C:40]([O:41][CH3:42])=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:43])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:44])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a 25 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluoro-5-methoxybenzoate (80 mg, 123 μmol, Eq: 1.00) was combined with THF (2 ml) and MeOH (4 ml) at 45° C. to give a colorless solution. 1 N NaOH (0.5 ml, 1.00 mmol, Eq: 8.11) was added. The reaction mixture was stirred at 40° C. for 2 hr.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=1)=[O:19]
Reactant: CON(C)C(=O)C=Cc1cccc(F)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(3-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (18 g) as an oil.