Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(OCC)C>[F:1][C:2]([F:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (2.0 g; 0.0114 mole) and N,N-dimethylformamide (0.08 g) in 20 ml of dry diethyl ether was cooled to 0° C. A solution of oxalyl chloride (2.17 g; 0.017 mole) in 2 ml of dry diethyl ether was added to the reaction mixture during a 20 minute period. Upon complete addition the mixture was allowed to warm to room temperature and stir for two hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was dissolved in 5 ml of dry diethyl ether and the solvent removed under reduced pressure to yield trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonylchloride as an oil.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:19])[C:15](O)([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].N1C=CC=CC=1.S(Cl)(Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:19])[C:15]([CH3:17])=[CH2:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: CCC#CCOc1cc(OC(C)C(C)(C)O)ncn1
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C(C)C(C)Oc1cc(OCC#CCC)ncn1
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
In 3 ml of chloroform was dissolved 0.5 g of 4-(2-pentynyloxy)-6-(2-hydroxy-1,2-dimethylpropyloxy)pyrimidine, to which 0.18 g of pyridine was added and 0.27 g of thionyl chloride was added dropwise at −13° C., followed by stirring for 1.5 hours. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.3 g of 4-(2-pentynyloxy)-6-(1,2-dimethyl-2-propenyloxy)pyrimidine.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].[Na].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(O)C.C(Cl)(Cl)Cl>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: C=CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOP(=O)(CCC(C)=O)OCC
Temperature: 15 °C

Procedure:
To 243 grams (1.76 moles) of diethyl phosphite stirred under nitrogen and protected by a drying tube was added a solution of sodium ethoxide prepared from 5.07 grams (0.22 mole) of sodium in 100 ml of anhydrous ethanol. Methyl vinyl ketone, 112 grams (1.60 moles), was then added at such a rate as to keep the temperature at 35°-40° C. The addition required about one hour. The reaction mixture was stirred for one-half hour after the addition was completed and was stripped to dryness in vacuo at 60° C/16 mm. The residue was taken up in 600 ml of chloroform, and the solution cooled to 15° C and washed successively with dilute acid, water and saturated sodium chloride solution. After drying, the chloroform solution was distilled to yield 112 grams of diethyl 3-oxobutylphosphonate as a colorless liquid, B.P. 106° C/0.05 mm, nD 25 1.4340. VPC indicated that the product was 90% pure.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCCCl)C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2CCCCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 30.4 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.9 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 158°-160° C. as 3/2oxalate thereof.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)c1C
Yield: 43.5 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (100 mg) to give 80 mg (43%) of the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]Cl>[CH3:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4=[N:19][N:20]([CH:23]5[CH2:28][CH2:27][CH2:26][O:25][CH2:24]5)[C:21](=[O:22])[C:11]4=[N:10]3)=[CH:4][CH:3]=2)=[CH:34][CH:35]=1
Reactant: O=c1c2nn(Cc3ccc(I)cc3)c3ncccc3c-2nn1C1CCCOC1
Reactant: Cc1ccc(B(O)O)cn1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n(C5CCCOC5)nc-4c4cccnc43)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-5-[(4-Iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one [(Example 10, Step 3), 50 mg, 0.10 mmol], 2-methyl-5-pyridinylboronic acid (35 mg, 0.26 mmol, 2.5 equiv), palladium(II) acetate (4.6 mg, 0.21 mmol, 0.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 0.21 mmol, 0.2 equiv), copper(I) chloride (10 mg, 0.10 mmol, 1 equiv) and cesium carbonate (84 mg, 0.26 mmol, 2.5 equiv) were combined in degassed N,N′-dimethylformamide (3 mL) and placed in a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a deep red solid: 1H-NMR (hydrochloride salt, 400 MHz, CDCl3) δ 8.78 (2H, br s), 8.59 (1H, d, J=6.8 Hz), 8.39 (1H, br s), 7.72 (3H, br s), 7.55 (3H, br s), 6.02 (2H, s), 4.67 (1H, br s), 4.03-3.95 (2H, m), 3.79-3.70 (1H, m), 3.51-3.45 (1H, m), 3.02 (3H, br s), 2.36-2.06 (2H, m), 1.90-1.80 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 453.2039 [(M+H)+; calculated for C26H25N6O2: 453.2034].
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[CH2:8]2)[CH3:15]
Reactant: CCI
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C2CCC1c1cc(N)ccc1C2
Reaction time: 1 h

Procedure:
A solution of (+/−)-12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (150 mg, 0.86 mmol) in acetone (4 mL) was treated with ethyl iodide (0.07 mL, 0.86 mmol), potassium carbonate (237 mg, 1.72 mmol) and stirred for 1 h. The mixture was partitioned between dichloromethane and brine and the organic layer dried (MgSO4), filtered and concentrated to give (+/−)-12-Ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine which was used without further purification.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[O:9][C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19]([NH:21][C@H:22]([C:27]([OH:29])=O)[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]>>[CH2:1]([C@@H:7]1[C:8](=[O:18])[O:9][C@H:10]1[CH2:11][C@H:12]([O:17][C:27](=[O:29])[C@@H:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[NH:21][CH:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:8][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@@H](CC(C)C)NC=O

Procedure:
by esterifying (S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl-L-leucine there was obtained
Reaction SMILES: [IH:1].[CH3:2][C:3]1([CH3:14])[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[NH:6][C:5](SC)=[N:4]1.[NH2:15][NH2:16]>C(O)C.CCOCC>[IH:1].[NH:15]([C:5]1[NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][CH2:9][C:3]([CH3:14])([CH3:2])[N:4]=1)[NH2:16]
Reactant: NN
Reactant: CSC1=NC(C)(C)CCC(C)(C)N1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)NC(NN)=N1

Procedure:
A 10.0 g portion of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-methylthio-1H-1,3-diazepine, hydroiodide was dissolved in 150 ml of ethanol and 2.5 g of hydrazine was added. The mixture was refluxed 6 hours, diluted with 300 ml of ether and stored at -10° C. The solid was removed by filtration. The filtrate was concentrated to about 25 ml in vacuo, diluted with 50 ml of 2-propanol, then 200 ml of ether and stored at -10° C. The solid was collected, washed with ether and dried in vacuo at 60° C., giving 3.5 g of the desired intermediate, mp 154°-155° C.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)CC>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:27][CH2:26]1
Reactant: Clc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N
Solvent: O
Solvent: CCC(C)O
Product: Nc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
A solution of NH3 in H2O (20 M, 2 mL) was added to a suspension of 8-chloro-3-cyclopropyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (33 mg, 0.091 mmol) in 2-butanol (0.4 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC (4% MeOH in DCM as eluent) afforded the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 0.95-1.22 (m, 4H), 1.93-2.09 (m, 1H), 5.10 (br. s., 2H), 7.02-7.18 (m, 6H), 7.32-7.44 (m, 3H), 7.55-7.62 (m, 2H). MS (ES+): m/z 343.15 (100)[MH+]. HPLC: tR=2.52 min (Open Lynx polar—5 min).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH3:8]COCC.[NH2:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:22]=[C:23]([C:43](=[O:45])[CH3:44])[CH:24]=[N:25][C:26]=2[NH:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:33]=2)[N:15]=1>C1COCC1.CCOC(C)=O>[NH2:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]2[CH:22]=[C:23]([C:43]([OH:45])([CH3:8])[CH3:44])[CH:24]=[N:25][C:26]=2[NH:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:33]=2)[N:15]=1
Reactant: CCOCC
Reactant: CC(=O)c1cnc(Nc2cncc(S(=O)(=O)c3ccccc3)c2)c(-c2nc(C)nc(N)n2)c1
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)(C)O)cnc2Nc2cncc(S(=O)(=O)c3ccccc3)c2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To cerium(III) chloride (304 mg, 1.235 mmol) was added THF (4.1 mL) and the resulting mixture was heated to 40° C. for 1 h. The reaction mixture was then cooled to −78° C. and methylmagnesium bromide in ether (3.0 M, Aldrich; 1372 μL, 4.12 mmol) was added. The resulting mixture was stirred at −78° C. for 15 min. 1-(5-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-(phenylsulfonyl)pyridin-3-ylamino)pyridin-3-yl)ethanone (190 mg, 0.412 mmol) in THF (4.1 mL) was then added, and the resulting mixture was stirred at −78° C. for 4 h. The reaction mixture was subsequently diluted with 100 mL of EtOAc, added to a separatory funnel, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was separated, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2 M ammonia in MeOH)/DCM) provided the title compound (36% yield) as a light yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.38 (s, 1H) 9.18-9.23 (m, 1H) 9.06 (d, J=2.35 Hz, 1H) 9.00 (d, J=2.35 Hz, 1H) 8.67 (d, J=2.15 Hz, 1H) 8.53 (d, J=2.54 Hz, 1H) 8.02-8.08 (m, 2H) 7.98 (br. s., 1H) 7.79 (br. s., 1H) 7.71-7.77 (m, 1H) 7.64-7.71 (m, 2H) 5.22-5.26 (m, 1H) 2.46 (s, 3H) 1.51 (s, 6H). m/z (ESI, +ve ion) 478.1 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:24])[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][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:24][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][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)CBr
Yield: 70 %

Procedure:
A solution of bromoacetyl bromide (44.4 g; 0.22 mol) in CH2Cl2 (50 mL) was added dropwise in 2.5 h at 20° C. to a mixture of octadecylamine (59.3 g; 0.22 mol) and K2CO3 (30.4 g; 0.22 mol) in CH2Cl2 (600 mL) and H2O (600 mL). After 16 h at room temperature the organic layer was separated, washed with H2O, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (CH2Cl2/MeOH=100/1 (v/v)) to give the desired product (60 g; 0.154 mol). Yield 70%. GC: 96% (area %), K.F.: <0.1%; 1H-NMR, 13C-NMR and MS spectra were consistent with the postulated structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:26](OC4C=CC=CC=4)=[O:27])[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[NH2:35][C@@H:36]([CH3:39])[CH2:37][OH:38]>C1COCC1>[OH:38][CH2:37][C@@H:36]([NH:35][C:26]([C:19]1[C:18]2[CH2:17][N:16]([CH:14]([C:4]3[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:15])[C:24](=[O:25])[C:23]=2[CH:22]=[CH:21][N:20]=1)=[O:27])[CH3:39]
Reactant: C[C@H](N)CO
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)N[C@@H](C)CO)C2=O)cnc1OCC(F)(F)F
Temperature: 90 °C
Yield: 52 %

Procedure:
A mixture of phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (20 mg, 0.042 mmol, Intermediate-91, single enantiomer) and (S)-2-aminopropan-1-ol in THF (1.0 mL) is heated at 90° C. overnight. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 9.9 mg (52% yield) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccccc1Oc1ccc(C=O)cc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a mixture of 4-fluoro-benzaldehyde (1.5 g, 12.08 mmol) and 2-isopropyl-phenol (1.64 g, 12.08 mmol) in anhydrous N,N-dimethyl acetamide (20 mL) was added granulated potassium carbonate (3.7 g, 26.58 mmol). The reaction mixture was stirred at 150° C. for 18 hours and was partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with saturated aqueous hydrogenocarbonate solution, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (15% ethyl acetate in n-heptane) to yield 4-(2-Isopropyl-phenoxy)-benzaldehyde as a gum (2.25 g, 77%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[C:12]1([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cocn1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a solution of oxazole (0.5 g, 7 mmol) in anhydrous THF (10 mL) was added n-BuLi (3.5 mL, 8.8 mmol) dropwise at −65° C. After stirring for 10 min, anhydrous ZnCl2 (2 g, 14.7 mmol) was added. The reaction mixture was allowed to warm to room temperature. Then Pd(PPh3)4 (0.3 g, 0.26 mmol) and iodobenzene (2 g, 9.8 mmol) were added. The reaction mixture was heated at 60° C. for 1 h. After quenching with water (20 mL), the solution was extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by column chromatography to give 600 mg of the desired product. LC-MS: m/z 146 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][OH:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:51](OC(=O)C)(=[O:53])[CH3:52].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:51]([O:32][CH2:31][CH2:30][C@:22]([OH:33])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])(=[O:53])[CH3:52]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate, Compound D (13.7 g, 19.6 mmol) was dissolved in dichloromethane (274 mL), and then acetic anhydride (4.64 mL, 49.1=mop, triethylamine (2.74 mL, 19.7 mmol), and dimethylaminopyridine (240 mg, 1.96 mmol) were added at 0° C. After stirring for 1.5 hours, the mixture was quenched with water (195 mL) and then separated. The aqueous layer was extracted with dichloromethane (195 mL). The dichloromethane layers were combined, then washed with a saturated aqueous solution (140 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 11.0 g (14.8 mmol, yield 76%) of No. 5318799 (Compound R).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 5 °C

Procedure:
To a suspension of 2,4-difluorobenzaldehyde (608.9 mg, 4.28 mmol), 1,1-dimethylnitroethane (881.9 mg, 8.55 mmol) and zinc (840.0 mg, 12.8 mmol) in ethanol (15 ml) was added acetic acid (1.54 g, 25.6 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. After the mixture was cooled to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)[CH:13]=[N:14][C:10]=2[CH:9]=1)#[N:7].[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[C:6]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:30]=[O:31])[CH:13]=[N:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Yield: 90 %

Procedure:
Phosphorus oxychloride (0.54 mL, 5.81 mmol, 1.5 eq) was added to dimethylformamide (10 mL) at room temperature, and to this solution was added 5-cyano-1-(indol-5-yl)benzimidazole (1.00 g, 3.87 mmol). The resulting reaction solution was heated at 40° C. under nitrogen for 2 hours. An aqueous solution of 10% sodium hydroxide (10 mL) was then added, followed by enough solid sodium hydroxide to adjust the pH to above 13. This mixture was heated at reflux under nitrogen for 1 hour, cooled, and the precipitated solid was filtered to afford the title compound (1.00 g, 90%) as an off-white solid. Mp, greater than 200° C.; IR (KBr) 2225, 1675 cm-1 ; 1H NMR (DMSO-d6) δ10.00 (s, 1H), 8.82 (s, 1H), 8.49 (s, 1H), 8.38 (d, J=0.7 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.5 and 1.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.6 and 2.2 Hz, 1H); LRMS (m/z, relative intensity) 287 (18), 286 (M+, 100), 258 (18), 230 (11). HRMS calculated for C17H10N4O: 286.0853. Found: 286.0870.