Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH2:27][O:28][CH3:29])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH2:27][O:28][CH3:29])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COCC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(Br)ccc(OC(F)F)c2OC)COC1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 3-(bromomethyl)-3-(methoxymethyl)oxetane (288 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of 3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-(methoxymethyl)oxetane as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([CH3:10])[C:7](=[O:9])[CH3:8].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].CC(C)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:6]([CH3:10])[CH:7]([OH:9])[CH3:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C(C)Cc1cccc(C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Cc1cccc(CC(C)C(C)O)c1
Reaction time: 8 h

Procedure:
A solution of 1 mol of 3-(3-methylbenzyl)-butanone (86% pure) in 300 ml of isopropanol was added drop-wise in the course of 5 hours to 100 g of aluminum triisopropylate heated to boiling with 300 ml of isopropanol, while a mixture of acetone and isopropanol distilled off slowly through a 50-cm long packed column. After reacting for 8 hours, the distillate no longer contained any acetone. The residual isopropanol was then distilled off and 300 ml of toluene, 300 g of ice and 300 g of conc. hydrochloric acid were added to the residue. The layers were separated, the aqueous phase was extracted with 300 ml of toluene, and the combined organic phases were extracted by shaking with a little water, concentrated and distilled through a Vigreux column at 0.2 mbar. A mixture of 1-(3-methylphenyl)-2-methylbutan3-ol isomers was obtained in 85% yield from 78°-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.C(OC([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](O)=[O:35])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1)=[O:35]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F)c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.2 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.58 mmol) produced in Example 16(vi) was dissolved in pyridine (3.0 mL), [(tert-butoxycarbonyl)amino](phenyl)acetic acid (290 mg, 1.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (440 mg, 1.2 mmol) were added, and the mixture was stirred at 60° C. for 7 hr. [(tert-Butoxycarbonyl)amino](phenyl)acetic acid (145 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added to the reaction mixture, and the mixture was further stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 ml), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained oil residue was crystallized from ethyl acetate/heptane to give the title compound (150 mg, 53%) as a pale-yellow powder.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:11]1[CH2:12][CH2:13][C:8]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21

Procedure:
At 0° C., a solution of (B4) (2.2 g, 6.1 mmol) in dichloromethane (20 ml) was treated with TFA (10 ml) for 1 hour, concentrated, co-evaporated with acetonitrile and dissolved in dichloromethane. The resulting solution washed with a mixture of brine (ca. 100 ml) and 6N NaOH (3 ml), dried over Na2SO4 and concentrated to give (S)-N-(3,4-dihydro-2H -spiro[naphthalene-1,4′-piperidine]-4-yl)acetamide (B5) as a white solid. LC-MS: m/e=258.9 (M+H). Rt=0.96 min. The crude was used directly for further reactions.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH2:13](O)[C@@H:14](O)[C@H:15]1[O:20][C:18](=O)[C:17](O)=[C:16]1O>>[C:18]([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6])(=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:2][CH2:3][CH2:5][CH2:7][CH2:9][CH3:11]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Product: CCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Yield: 70 %

Procedure:
Repetition of the preparation substituting ascorbic acid for the erythorbic acid resulted in the isolation of 26.35 g of a white waxy solid assaying 95.1% ascorbic acid 6-laurate (0.070 mole, 70% yield).
Reaction SMILES: [C:1]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]1[O:34][CH:32]1[CH3:33]>>[C:1]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:33][CH2:32][CH2:31][OH:34])=[O:5]
Reactant: CC1CO1
Reactant: CC(C)OC(=O)/C=C\C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)OC(=O)/C=C\C(=O)OCCCO
Temperature: 85 °C
Reaction time: 3 h

Procedure:
2100 grams of 2-propyl maleate (Example 9), 8.12 grams of triphenylphosphine, and 8.12 grams of tri-2-ethylhexylphosphite were charged to a 4 liter stirred stainless steel pressure autoclave. The reactor was twice pressurized with nitrogen then depressurized, finally leaving 0.36 kPa nitrogen. The reactor contents were heated to 85° C., and 829.74 grams of propylene oxide were added over 3 hours. Then 270 grams of propylene oxide were added. After 3 hours, the pressure was lowered to remove residual propylene oxide. The product was a liquid containing less than 100 parts per million propylene oxide, having a viscosity of 75.7 centipoise at 25° C. and an acid number of 0.61 milligrams KOH/gram of solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:24]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccccc1F)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A sample of 19.53 g of 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 15.8 g of o-fluorobenzoyl chloride are reacted to give the product 3-(o-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a brown gum.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:36][N:14]1[CH:15]=[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:34][CH2:35]3)[N:21]=2)=[O:19])[C:12]([C:10]([N:6]2[CH2:7][C:4]3([CH2:3][O:2][CH2:1]3)[CH2:5]2)=[O:9])=[N:13]1
Reactant: C1NCC12COC2
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CC3(COC3)C2)n1
Yield: 5 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-oxa-6-aza-spiro[3.3]heptane with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (5%) as sticky yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@@H](O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((R)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (420 mg, 1.55 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (225 mg, 85%). 1H NMR (400 MHz, DMSO, d6): δ 4.26-4.22 (1 H, m), 3.47-3.44 (10 H, m), 2.13-2.09 (1 H, m), 1.81 (2 H, m)
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:36])([F:35])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:35][C:6]([F:5])([F:36])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:25][CH:26]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 31 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (35.0 ml, 35.0 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-{6-methoxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone (6.26 g, 14.0 mmol) in anhydrous CH2Cl2 (400 ml) at 0° C. under N2. The reaction mixture was warmed to rt and stirred at rt for 21 hr. MeOH (100 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a red oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2), gave 1.886 g (31% yield) of yellow solid.
Reaction SMILES: [NH:1]([C:3]1[C:4](=[O:16])[N:5]([CH3:15])[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[NH2:2].C(N(CC)CC)C.[CH3:24][CH:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCOCC1>[CH3:15][N:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[N:12]=[C:3]([NH:1][NH:2][C:26](=[O:27])[CH:25]([CH3:29])[CH3:24])[C:4]1=[O:16]
Reactant: COc1ccc2c(c1)nc(NN)c(=O)n2C
Reactant: CC(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)nc(NNC(=O)C(C)C)c(=O)n2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-hydrazino-1-methyl-6-methoxy-1H-quinoxalin-2-one (46.2 mmol) and triethylamine (5.6 g., 55.4 mmol) in 500 ml. of dioxane was added dropwise 2-methylpropanoyl chloride (5.91 g., 55.4 mmol) and the mixture stirred at room temperature for 1.5 hours. The dioxane was then removed under vacuum and the residue washed with water and ether, filtered, and dried at 65° for three hours to yield crude product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]3C[O:27]3)[C:20]=2C=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:38](OO)=[O:39])C=1.CC(C)=O.ClCCl>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH2:25][C@@H:26]([CH2:38][OH:39])[O:27][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](Cn1ncc2ccc(OC[C@@H]3CO3)c(C=O)c21)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@H](CO)CO3)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of the epoxide from Step A (0.86 g, 2.10 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (70%, 0.62 g, 2.52 mmol) in portions under nitrogen atmosphere. After the addition completed the reaction mixture was stirred overnight. The reaction was quenched by a saturated aqueous solution of sodium thiosulfate (20 mL) and dichloromethane was evaporated. To the aqueous residue was added potassium carbonate (1.0 g) and methanol (200 mL), the resulting mixture was stirred for ½ h and organic solvent was evaporated. The residue was extracted with ethyl acetate (50 mL×3), dried and evaporated to dryness to afford an oil. Chromatography on silica eluting with a gradient of 0% to 10% acetone/dichloromethane gave an oil (0.50 g, 60%). LCMS (+APCI) m/z 397 (M+H), 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.33-7.13 (m, 5H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.04-4.97 (m, 3H), 4.65 (ddd, J=6.6, 13.4, 51.6 Hz, 2H), 4.32 (m, 3H), 4.08 (m, 2H), 3.91 (m, 2H), 1.18(d, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]2[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>C1COCC1>[CH:8]1([C:3]2[C:2]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)=[CH:6][N:5]([CH3:7])[N:4]=2)[CH2:10][CH2:9]1
Reactant: Cn1cc(Br)c(C2CC2)n1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a stirred solution of 4-bromo-3-cyclopropyl-1-methyl-1H-pyrazole (500 mg, 2.5 mmol) in THF (10 mL) was added dropwise a 2.5 M solution of n-BuLi (1.4 mL, 3.5 mmol) at −78° C., and the resulting light yellow solution was stirred for 30 min. To the mixture was added a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 mL, 5.5 mmol) in THF (1 mL), and the mixture was warmed to room temperature over 30 min. The reaction was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (50 mL), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography on silica gel (5% MeOH—CH2Cl2, Rf=0.35) to provide 3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (294 mg, 48%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]N2CCC(=O)CC2)[CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:36][C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1CCN(Cc2cccnc2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(Cc2cccnc2)C3)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0995 g, 0.251 mmol) in dry was added 1-(pyridin-3-ylmethyl)piperidin-4-one (0.0486 g, 0.255 mmol). The reaction mixture was then heated at 70° C. for 40 min. The reaction mixture was then cooled at 0° C. and added Sodium triacetoxyborohydride (0.1118 g, 0.5275 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 3 days. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, evaporated, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane followed by 6:2:1:1 EtOAc:acetone:water:MeOH), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.49 (d, J=1.7, 1H), 8.46 (dd, J=4.8, 1.6, 1H), 8.15 (d, J=8.8, 2H), 7.71 (d, J=7.8, 1H), 7.46 (d, J=8.8, 2H), 7.36 (dd, J=7.7, 4.8, 1H), 6.15 (t, J=5.6, 1H), 4.12 (d, J=6.5, 1H), 3.91-3.81 (m, 1H), 3.77-3.53 (m, 6H), 3.50 (s, 2H), 3.45-3.34 (m, 1H), 3.17-3.06 (m, 2H), 2.86 (d, J=11.0, 2H), 2.81-2.71 (m, 1H), 2.70-2.56 (m, 3H), 2.39 (t, J=11.3, 1H), 2.01 (t, J=10.8, 2H), 1.83 (s, 2H), 1.60-1.42 (m, 2H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+571.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>ClCCl.C(N(CC)CC)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[N:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Temperature: 20 °C
Yield: 55.6 %

Procedure:
A solution of trimethylacetyl chloride (17.5 g, 146 mmol) in dichloromethane (25 ml) was added to a solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in dichloromethane (100 ml) and triethylamine (24 ml) dropwise with stirring at 20° C. The reaction mixture was then stirred for 40 minutes, filtered, washed with water, dried and concentrated. Recrystallization from hexanes afforded 20.6 g (70%) of the title product as a white flaky solid. mp 63-64° C. 1H NMR (CDCl3): δ=8.82 (br, 1 H); 8.30 (d, 1 H); 8.19 (m, 2 H); 1.36 (s, 3 H). MS (EI): m/z=256, 258 (M+, Br isotopes).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[CH3:30][C@@H:31]1[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@@H:35]([OH:36])[C@H:31]3[CH3:30])[CH2:26][CH2:27]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: C[C@H]1NCC[C@H]1O
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@@H](O)[C@H]2C)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (2R,3R)-2-methyl-pyrrolidin-3-ol hydrochloride (example 188A) in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)NCCC(=O)O)cc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl]amino}propanoate (63.0 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (57.5 mg, 97%) as a pale-brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@@:8]2([CH3:28])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:9]2=[O:27])=[CH:5][CH:4]=1)#[N:2].ClC1C=C(N2C3=NC=C(C(O)=O)N3[C@](C)([CH2:50][C:51]3[CH:56]=[CH:55][C:54](OC(F)(F)F)=[CH:53][CH:52]=3)C2=O)C=C(Cl)C=1>>[CH2:50]([NH:10][C:9]([C@@H:8]([NH:12][C:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:28])[C:9](=[O:27])[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:11]2=[N:15][CH:14]=1)=[O:17])[CH3:7])=[O:27])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NCc1ccccc1

Procedure:
The following compounds were prepared using procedures similar to those described above using either (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid or (R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid as a starting material: