Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:19](OC)=[O:20])=[C:7]([CH3:18])[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[OH:20][CH2:19][C:6]1[C:5]([CH2:3][OH:2])=[C:17]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N:8]2[C:7]=1[CH3:18]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(CO)c(CO)c2n1Cc1ccccc1C2
Reaction time: 2 h

Procedure:
A solution of 3-methyl-5,10-dihydropyrrolo[1,2-b]-isoquinoline-1,2-dicarboxylic acid dimethyl ester (2.39 g, 8 mmol) in anhydrous dichloromethane (20 mL) was added dropwise into a stirred suspension of LiAlH4 (0.69 g, 18.4 mmol) in anhydrous diethyl ether (30 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (1.2 mL), 15% aqueous NaOH (1.2 mL), and water (3.6 mL) at 0° C. The mixture was filtered, and the inorganic solid was removed by filtration, washed with hot THF (300 mL). The combined filtrate and washings was evaporated in vacuo to dryness. The solid residue was recrystallized from dichloromethane/ether to give (2-hydroxymethyl-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-yl)methanol (DA-1107), 1.47 g (76.2%); mp 99-101° C.; 1H NMR (DMSO-d6) δ 2.22 (3H, s, Me), 3.96 (2H, s, CH2), 4.34 and 4.39 (each 3H, brs, CH2 and exchangeable, OH), 4.93 (2H, s, CH2), 7.26 and 7.34 (each 2H, brs, 4×ArH); m/z 243.0 (M+H)+ Anal. Calcld. for C15H17NO2.0.1H2O): C, 73.50; H, 7.07; N, 5.71. Found: C, 73.42; H, 6.97; N, 5.71.
Reaction SMILES: C([O:3][C:4](=[O:34])/[CH:5]=[C:6](\[CH3:33])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH2:26][CH2:27][CH3:28])=[CH:23][C:22]2[C:21]([CH3:30])([CH3:29])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])C.[OH-].[Na+].CCO>CCOC(C)=O.CCCCCC>[F:12][C:11]([F:13])([F:14])/[C:10](/[C:15]1[C:24]([O:25][CH2:26][CH2:27][CH3:28])=[CH:23][C:22]2[C:21]([CH3:30])([CH3:29])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=2[CH:16]=1)=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:33])=[CH:5]\[C:4]([OH:34])=[O:3]
Reactant: CCCOc1cc2c(cc1/C(=C/C=C/C(C)=C/C(=O)OCC)C(F)(F)F)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOc1cc2c(cc1/C(=C/C=C/C(C)=C/C(=O)O)C(F)(F)F)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure B and using (2E,4E,6Z)-8,8,8-trifluoro-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester (Compound 3, 83 mg, 0.17 mmol), 1M NaOH (0.35 mL), and EtOH (3 mL) at 60° C. for 1.5 h followed by flash column chromatography on silica gel (30% EtOAc-hexane) and HPLC (15% EtOAc-hexane), the title compound was obtained as a white solid (60 mg, 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[O:20]=[C:19]1[C:18]2([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[N:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][N:15]1[CH2:14][C:13]1[CH:12]=[C:11]([CH:41]=[CH:40][CH:39]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCc3ccccc3)c1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C

Procedure:
To tert-butyl 3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.7 g, 4.86 mmol) was added 4M solution of HCl in dioxane (7 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated in vacuo to obtain benzyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:22])=[C:8]([CH2:10][O:11][Si](C(C)C)(C(C)C)C(C)C)[CH:9]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:22])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO[Si](C(C)C)(C(C)C)C(C)C)c(C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)c(C)o1
Reaction time: 16 h

Procedure:
A stirred solution of 5-methyl-4-triisopropylsilanyloxymethyl-furan-2-carboxylic acid methyl ester (15) (5.2 g) in tetrahydrofuran (200 mL) was treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 3.2 mL) and stirring continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (350 mL) and washed with water (150 mL). The aqueous phase was re-extracted with ethyl acetate (2×100 mL). The combined extracts were dried, concentrated in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate/pentane (1:1 by volume) to give compound 16 as a yellow oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH2:36]([O:38][C:39]([C:41]1([C:44]2[N:45]=[N:46][C:47](Cl)=[CH:48][CH:49]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1([C:44]2[N:45]=[N:46][C:47]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCOC(=O)C1(c2ccc(Cl)nn2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)nn2)CC1
Yield: 44 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridazin-3-yl)-cyclopropanecarboxylic acid ethyl ester following a procedure analogous to that described in Example 1. Yield: 44% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[NH:10][CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=4)[N:13]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[N:18][CH:19]=4)[N:13]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(-c2c[nH]c(-c3cc(C4CC4)on3)n2)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(C(C)(C)O)nc2)nc1-c1cc(C2CC2)on1
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
To a solution of product from Step 4 (60 mg, 0.193 mmol) in THF (1 ml) was added cesium carbonate (126 mg, 0.387 mmol). After being stirred for 10 min, CH3I (0.013 ml, 0.213 mmol) was added and the reaction was stirred for 4 hrs. The reaction mixture was diluted with EtOAc, washed with NaHCO3 (sat), dried, concentrated, and separated by prep TLC (hex:EtOAc:CH3OH=6:5:1) to give 2-{5-[2-(5-cyclopropylisoxazol-3-yl)-1-methyl-1H-imidazol-4-yl]pyridin-2-yl}propan-2-ol (45 mg) LCMS: [M+H]+=325.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:9]O)[C:6](=O)[CH3:7])[CH3:2].[C:12]([S-:14])#[N:13].[K+]>Cl.O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:9][C:12](=[S:14])[NH:13][C:6]=1[CH3:7])=[O:11])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(=S)[nH]c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Pd/C (10%, 1.00 g) is added to a solution of 2-hydroxyimino-3-oxo-butyric acid ethyl ester (62.8 mmol) in HCl (1.25 M in EtOH, 75 mL) and the mixture is stirred at RT under a hydrogen atmosphere (4 bar) for 48 h. After filtration through celite and removal of the solvents crude 2-amino-3-oxo-butyric acid ethyl ester hydrochloride is obtained which is dissolved in a mixture of water (220 mL), EtOH (30 mL) and conc HCl (37%, 2.5 mL). A solution of KSCN (49.9 mmol) in water (25 mL) is added and the mixture is stirred for 2 h at reflux. By cooling in an ice bath the desired product precipitates and is collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:3]=1[C:4]([O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[NH:9])=O>N1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[N:9]=[C:4]([C:3]2[C:16]([F:21])=[C:17]([F:20])[CH:18]=[CH:19][C:2]=2[F:1])[O:6][N:7]=1
Reactant: N=C(NOC(=O)c1c(F)ccc(F)c1F)c1ccccn1
Solvent: c1ccncc1
Product: Fc1ccc(F)c(-c2nc(-c3ccccn3)no2)c1F
Yield: 20.3 %

Procedure:
A solution of N-[(2,5,6-trifluorobenzoyl)oxy]pyridine-2-carboximidamide (50 mg, 0.169 mmol) in pyridine (0.3 mL) was heated at 115° C. for 17 hours. Standard work up, and silica gel chromatography, afforded 9.5 mg (20%) of 3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[Cl:30][C:31]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[CH:35][C:34]([OH:44])=[C:33]([C:45]2[CH:50]=[CH:49][N:48]=[N:47][CH:46]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([O:44][C:34]2[CH:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[C:31]([Cl:30])=[CH:32][C:33]=2[C:45]2[CH:50]=[CH:49][N:48]=[N:47][CH:46]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Oc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4cccc(F)c4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.9 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 136 mg, 0.29 mmol) was added to a solution of 6-chloro-3′-fluoro-4-(pyridazin-4-yl)biphenyl-3-ol (Preparation 98, 133 mg, 0.29 mmol) and potassium carbonate (183 mg, 0.88 mmol) in dimethylsulfoxide (5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with sodium hydroxide (1M, 5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in dimethylsulfoxide:acetonitrile (2.5 mL: 1.5 mL) and then purified on the reverse phase HPLC eluting with acetonitrile:water (from 5:95 to 95:5, 30 minutes gradient then 5 minutes isocratic) to give the title compound (60 mg, 18%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)O1.[C:17]([O:21][C:22](=[O:43])[CH:23]([NH:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=1)[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC>COCCOC.O.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:17]([O:21][C:22](=[O:43])[CH:23]([NH:33][C:34]([C:35]1[CH:36]=[CH:37][C:38]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:39][CH:40]=1)=[O:42])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Yield: 82.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.34 g, 6.104 mmol, 1 equiv.) and 2-(4-Bromo-benzoylamino)-pentanedioic acid di-tert-butyl ester (2.7 g, 6.104 mmol, 1 equiv.) were dissolved in DME (120 mL). A solution of K2CO3 (1.68 g, 12.21 mmol, 2 equiv.) in 30 mL of water was injected into the mixture, followed by the addition of Pd(PPh3)4 (352 mg, 0.31 mmol, 5%). The mixture was heated to reflux overnight. Reaction was complete as determined by TLC. Regular work-up and column chromatography (silica gel, 30-40% EtOAc/n-Hexane) afforded 2.3 g of 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester in 83% yield. MS (ESI) m/z 453.
Reaction SMILES: Br[C:2]1[C:14](=O)[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.CO.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][OH:21])[CH:28]=3)[CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNc1nc(C)c2c(n1)N(C1CCCC1)CC(c1cccc(CO)c1)=C2
Yield: 84.5 %

Procedure:
6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one (5.00 g, 14.83 mmol), 3-(hydroxymethyl)phenylboronic acid (3.38 g, 22.24 mmol) and Pd(PPh3)4 (0.685 g, 0.593 mmol) were suspended in Toluene (20 mL), MeOH (10 mL) and sat. NaHCO3 (10 mL) and then heated to 100° C. overnight. The reaction was deemed complete by MS and TLC. The organic layer was injected directly onto a column, eluting with CH2Cl2 then 4% MeOH in CH2Cl2. The fractions containing the desired material, as deemed by MS, were combined and evaporated in vacuo to give a greenish beige solid. This was triturated with MeCN and filtered to give crop one, 4.7 g. A second crop was obtained of 0.25 g. A third crop was obtained of 0.10 g. The three crops were deemed to be of sufficient purity based on NMR's and were combined and washed again with MeCN to give a solid (4.39 g, 81.24%).
Reaction SMILES: N.P(OCC)(OCC)(O[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[C:12]([CH3:15])([CH3:14])[CH3:13])=O.[Li]>CCOCC>[C:12]([C:6]1[CH:5]=[CH:10][CH:9]=[C:8]([CH3:11])[CH:7]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOP(=O)(OCC)Oc1ccc(C)cc1C(C)(C)C
Agent: N
Agent: [Li]
Solvent: CCOCC
Product: Cc1cccc(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To NH3 (liquid, 1000 mL) was added a solution of 2-tert-butyl-4-methylphenyl diethyl phosphate (60 g, crude from last step, about 0.2 mol) in Et2O (anhydrous, 500 mL) at −78° C. under N2 atmosphere. Lithium metal was added to the solution in small pieces until the blue color persisted. The reaction mixture was stirred at −78° C. for 15 min and then was quenched with sat. NH4Cl until the mixture turned colorless. Liquid NH3 was evaporated and the residue was dissolved in water. The mixture was extracted with Et2O (400 mL×2). The combined organics were dried over Na2SO4 and evaporated to give 1-tert-butyl-3-methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%), which was used directly in next step.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1

Procedure:
Using cyclohexyl{3-ethyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.55 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.37 g) synthesized in Example 1(2) and in the same manner as in Example 1 (7), the title object compound (0.32 g, 38%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]3[CH2:32][CH2:31]3)=[CH:24][C:23]=2[F:33])[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH:30]4[CH2:32][CH2:31]4)=[CH:24][C:23]=3[F:33])[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Yield: 83.4 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-106 by using N-(4-chloro-3-(1-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.300 g), KOH (0.300 g), water (2.0 mL), THF (10.0 mL) to afford 0.200 g of desired product. MS (m/z): 383.16 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][O:25][C:26]([CH2:28][C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=O)=[O:27]>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[O:20][CH3:21])[N:1]=[C:29]([CH2:28][C:26]([O:25][CH3:24])=[O:27])[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
Three drops of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (1.55 g), dimethyl acetonedicarboxylate (0.936 g) and acetic acid (30 ml), and the resulting mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crystals were recrystallized from acetone to give methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-methoxycarbonylquinoline-2-acetate (1.41 g, 64%). Colorless prisms. mp. 170°-171° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:11](=O)[CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C)[CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[CH3:15][NH:14][CH2:13][CH2:12][CH2:11][N:7]1[CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNCCCN1CCC1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
Lithium aluminum hydride (2.98 g) was gradually added to a solution of tert-butyl (3-azetidin-1-yl-3-oxopropyl)carbamate (5.99 g) in tetrahydrofuran (150 ml) while stirring in an ice bath. The mixture was stirred under a nitrogen atmosphere, for 15 minutes in an ice bath and for 45 minutes at room temperature. It was then heated and stirred for 8 hours at 80° C. under a nitrogen atmosphere. The reaction mixture was further heated to reflux for 34 hours at 100° C. under a nitrogen atmosphere. It was then cooled in an ice bath. Water (2.98 ml), 5N aqueous sodium hydroxide (2.98 ml) and water (8.94 ml) were added thereto in that order while stirring, and the mixture was stirred at room temperature for 3 days. The insoluble portion was then filtered. The filtrate was concentrated under reduced pressure to provide the title compound (2.78 g, 82.8%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[C:20]1([NH:30][CH2:31][CH2:32][NH2:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:33][CH2:32][CH2:31][NH:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: NCCNc1cccc2ccccc12
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2cccc3ccccc23)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(1-naphthyl)ethylendiamine dihydrochioride and DBU in DME. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH:13]=O)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:3][CH:2]([F:15])[F:1])[CH:11]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: N#Cc1ccc(CC=O)cc1OC(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(C#N)c(OC(F)F)c2)CC1
Yield: 27.3 %

Procedure:
A solution of crude compound 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile (100 mg, 0.48 mmol), N-Boc Piperazine (100 mg, 0.54 mmol) and NaBH(OAc)3 (0.4 g, 2 mmol) in 20 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford tert-butyl-4-{2-[4-cyano-3-(difluoromethoxy)phenyl]ethyl}piperazine-1-carboxylate (50 mg, 27% yield). The material was further treated with TFA to remove the Boc group. The crude product was used directly in the next step. MS: m/e 282 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2cccc(F)c2)cc1
Yield: 84.4 %

Procedure:
A mixture of 4-[[2-(3-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.62 g) in methanol (5 mL) and 0.5N sodium hydroxide (6 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.5 g of colorless 4-[[2-(3-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 108°-109° C.