Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Mg].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CCOCC>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)[N:14]=1)[OH:16]
Reactant: CC(C)CCBr
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (350 mg, 1.39 mmol) in Et2O (14 mL) was cooled to 0° C. To this was slowly added the freshly prepared Grignard reagent (1.26 mL, 1.53 mmol), prepared from magnesium turnings (500 mg, 0.02 mol) and 1-bromo-3-methyl butane (2.34 mL, 0.02 mol) in dry Et2O (16.5 mL). The resulting mixture was stirred under nitrogen at 0° C. After 1.5 hours, more Grignard reagent (0.3 mL, 0.36 mmol) was added and the resulting mixture stirred at 0° C. for a further 1.5 hours. The reaction mixture was then quenched by cautious addition of aqueous HCl (2M, 3 mL) and the solvent removed under vacuum. The residue was partitioned between EtOAc (30 mL) and water (20 mL), the layers separated and the aqueous re-extracted with EtOAc (30 mL). The combined organic layer was washed with brine (50 mL), dried (MgSO4) and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 99:1 to 1:1) followed by EtOAc then MeOH afforded the title compound as a colourless oil (179 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[N:8][C@H:9]([C:11]([O-:13])=[O:12])[CH3:10])=[CH:5][CH:4]=1.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>>[CH2:21]([O:20][C:18]([N:8]1[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12][C@H:7]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C=N[C@@H](C)C(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](C)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-N-Benzyloxycarbonyl-2-(4'-methoxyphenyl)-4-methyl-1,3-oxazolidin-5-one (14) was prepared from sodium N-(para-methoxybenzylidene)-(L)-alaninate (2.29 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a white solid after purification by flash column chromatography, using 33% ethyl acetate/petrol as eluant (1.75g, 51%, single diastereomer): [α]D20 +99.9 (c 1.0, CHCl3); mp 97-99° C.; IR (KBr): 1790, 1695 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.56-7.06 (m, 9H), 6.11 (s, 1H), 4.82 (d, J=12 Hz, 1H), 4.72 (d, J=12 Hz, 1H), 4.13 (q, J=7 Hz, 1H), 3.35 (s, 3H), 1.47 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 172.3, 160.8, 152.0, 135.2, 128.4, 128.0, 127.7, 125.8, 121.3, 114.1, 89.2, 67.5, 55.3, 52.1, 16.5; LRMS (NH3): 342 (MNH4+). Anal. Calcd for C19H19NO5 : C, 66.85; H, 5.61; N, 4.10; found: C, 66.80; H, 5.42; N, 4.15.
Reaction SMILES: [F-].[K+].COC(F)=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8]>COCCOCCOC>[C:7]([CH2:6][C:11]([F:14])([F:13])[F:12])([F:10])([F:9])[F:8]
Reactant: COC(F)=C(C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: FC(F)(F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 34 h
Yield: 39.5 %

Procedure:
Using essentially the same procedure as in Example 1, an isomeric mixture of the perfluorobutyric acid fluorides (2.67 g with summary acyl fluorides content 81%, 10 mmol), potassium fluoride (0.78 g, 13 mmol), the 1-methoxyheptafluoro-1-isobutene (5.10 g, 96% purity, 23 mmol) was combined in 8.54 g diglyme and agitated at room temperature for 34 hours. The reactor was vented and 5.44 g of material collected in the trap. The material consisted of (GC %): 4.0% starting C4 acyl fluoride, 35.3% C4F9OCH3, 58.5% hexafluoropivaloyl fluoride (C5 acid fluoride) and a trace (0.4%) of diglyme. To the diglyme residue was added 8.64 g H2O and 1.76 g triethylamine to yield 1.38 g CF3CH2CF3 (after recondensation), and 95.5 % purity. The products yields were calculated based on the weight of obtained mixtures, their GC % content and purity of starting compounds. Yield of C4F9OCH3 is 77% (from perfluorobutyric acid fluorides and 85% on the consumed fluorides). Yield of CF3CH2CF3 is 39% and C5 acid fluoride -65%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=[C:4]2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:20]1[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]3[N:10]=[C:4]4[CH:3]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:7]=[CH:6][N:5]4[N:8]=3)[CH2:13][CH2:14]2)[S:22][N:21]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nsc(N2CCC(Nc3nc4cc(Br)ccn4n3)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4cc(-c5ccccc5)ccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 66c from (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine and phenyl boronic acid. The title compound was obtained as off-white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.C(O)(=O)C>O>[CH2:12]([N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:19](=[O:20])[C:18]4[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=4[C:16]3=[O:21])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[C:13]#[CH:14]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCN1C(=O)COc2ccc(N)cc21
Solvent: O
Solvent: CC(=O)O
Product: C#CCN1C(=O)COc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 30.1 %

Procedure:
A mixture of 6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.8 g), 3,4,5,6-tetrahydrophthalic anhydride (0.61 g) and acetic acid (20 ml) was heated under reflux for 2 hours. After being allowed to cool, water was added to the mixture, and the precipitated crystals were collected by filtration and washed with water. Recrystallization from ethanol gave 2-[4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.4 g). m.p., 205°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:7]=2[N:26]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:7]=2[N:26]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: CCOC(=O)CC=Cc1c2n(c3ccc(OC)nc13)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(n1)c(CCCC(=O)O)c1n2Cc2ccccc2-1

Procedure:
The ester obtained in Step A is placed in 150 ml of ethanol in the presence of 40 ml of 2N sodium hydroxide solution. The title acid is isolated after stirring at room temperature and then refluxing.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O-])(=[O:12])C.[Na+].C(O)=O>>[CH:10]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8])=[O:12]
Reactant: NC(=O)c1cccn1N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: NC(=O)c1cccn1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Amino-1H-pyrrole-2-carboxamide (1.00 g, 8.0 mmol) and sodium acetate (1.60 g, 20.0 mmol) was added formic acid (11.0 ml, 287 mmol). The mixture was stirred overnight at RT. After removing the excess formic acid in vacuo, water (5 mL) was added and the mixture was cooled to 0° C. The mixture was filtered and the solid washed with water and dried in vacuo to afford 1-formamido-1H-pyrrole-2-carboxamide which was advanced without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].C(N(CC)CC)C.[CH2:17]([C:19]1[S:20][C:21]([C:26](Cl)=[O:27])=[C:22]([CH2:24][CH3:25])[N:23]=1)[CH3:18].Cl.C(N(CC)CC)C>C(OCC)(=O)C.O>[C:7]([CH:6]([NH:9][C:26]([C:21]1[S:20][C:19]([CH2:17][CH3:18])=[N:23][C:22]=1[CH2:24][CH3:25])=[O:27])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)#[N:8]
Reactant: N#CC(N)c1ccco1
Reactant: CCc1nc(CC)c(C(=O)Cl)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc(CC)c(C(=O)NC(C#N)c2ccco2)s1
Yield: 80.8 %

Procedure:
2.80 g of alpha-(2-furyl)-alpha-aminoacetonitrile and 6.0 g of triethylamine were dissolved in 50 ml of ethyl acetate, and with stirring, 2.1 g of the 2,4-diethylthiazole-5-carboxylic acid chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water (150 ml) was added, and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water and dried over sodium sulfate. The dried ethyl acetate layer was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from n-hexane to give 2.41 g (yield 80.0%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.[H][H]>[Ni].O1CCCC1>[O:19]=[S:15]1(=[O:18])[CH2:16][CH2:17][N:12]([C:3]2[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
To an autoclave is added 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine 1,1-dioxide (Step 2, 7.0 kg, 24 moles, 1.0 eq). Raney Nickel (1.4 kg) is activated and suspended in tetrahydrofuran (4 L), and the slurry is added to the autoclave followed by additional tetrahydrofuran (66 L). The mixture is heated at 40° C. under a 40 psi hydrogen atmosphere until the reaction is complete. The mixture is then filtered, and the filtrate is directly used in the next step. A small portion of the filtrate can be concentrated and recrystallized in isopropanol to give the title compound in pure form, 1H NMR (DMSO-d,) δ 6.17 (m, 2H), 5.35 (s, 2H), 3.32 (m, 4H), 3.15 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:22][CH3:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[C:5]([O:22][CH3:23])=[CH:4][N:3]=[C:2]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COc1cnc(Nc2ccc(C(=O)O)cc2)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (120 mg, 0.36 mmol), p-aminobenzoic acid (74.4 mg, 0.542 mmol), and p-toluenesulfonic acid (53 mg, 0.31 mmol) in dry 1,4-dioxane (3 mL) was refluxed overnight. The mixture was cooled to room temperature. The resulting solid was filtered and washed with dioxane to give the desired product as a racemic mixture (120 mg, 76.7%). LCMS (M+H) 433.3.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19]I>C(#N)C>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCCCI
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-chloro-4-iodobutane (1.2 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=7:3 to 1:1) to give the titled compound (1.4 g, 99%) as a brown oil.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[NH:26][CH2:27][CH2:28][CH2:29][N:30]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:35]([O:34][C:32]([NH:31][C@@H:7]([CH2:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[NH:26][CH2:27][CH2:28][CH2:29][N:30]=3)[CH:19]=2)[CH2:16][CH2:17]1)=[O:11])[C:6]([OH:42])=[O:5])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)N1CCC(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CCC(=O)N1CCC(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 147 in dichloromethane (10 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at 25° C. overnight. The solvent is evaporated under reduced pressure, and the residue is purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (200 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]2)=[CH:19][CH:20]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Reaction time: 1 h

Procedure:
Heat a mixture of (±)-(trans)-4-aminocyclohexanol (607 m, 5.3 mmol), Cs2CO3 (4.300 g, 13.2 mmol), and 1-(2-chloroethyl)-4-methoxybenzene (0.8 mL) in DMF (10 mL) at 100° C. for 19 hours. Quench the reaction with saturated aqueous NH4Cl (40 mL). Adjust the pH to alkaline and concentrate to dryness. Suspend the residue in 50:40:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH and stir vigorously for 1 hour. Decant the supernatant. Suspend the residue in 10:90 2.0 M NH3 in MeOH/CH2Cl2 for 30 minutes and filter. Combine the organic layers, concentrate, and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (258.3 mg, 20%): MS ES+ 250.0 (M+H)+, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.96 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](B1OC(C)(C)C(C)(C)O1)=[CH:28][CH:27]=2)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][CH2:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[CH:3]=1)=[CH:28][CH:27]=2)=[O:23])[CH3:20]
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3cnc(N)c(OCc4c(Cl)cccc4Cl)c3)ccc2[nH]1

Procedure:
5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid ethyl ester was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester following procedure 3.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:15]1([C:21]2([C:27]([NH2:29])=O)[CH2:23][CH:22]2[C:24](N)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[OH-].[Na+].[ClH:33]>C1C=CC=CC=1.O.C(O)C.CCOCC>[ClH:33].[C:15]1([C:21]23[CH2:23][CH:22]2[CH2:24][NH:29][CH2:27]3)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)C1CC1(C(N)=O)c1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: c1ccc(C23CNCC2C3)cc1

Procedure:
To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is added dropwise a solution of 6.6 g of 1-phenyl-1,2-cyclopropanedicarboxamide (U.S. Pat. No. 3,166,571-Ex. 8) in 400 ml of benzene, during one hour at room temperature under nitrogen. The reaction mixture is then heated at reflux under nitrogen for 90 minutes. The excess hydride reagent is decomposed by the cautious addition of 25 ml of 10 N sodium hydroxide. The mixture is diluted with 200 ml of water and the benzene phase is separated. The aqueous phase is extracted with chloroform and the combined organic extracts are dried over magnesium sulfate. The solution is concentrated under reduced pressure to give a brown liquid which is dissolved in ethanol and acidified with 5 ml of 2.3 N ethanolic hydrogen chloride. The addition of ether precipitates a solid which is recrystallized from acetonitrile to give white crystals, mp 166°-168° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:25](=[O:34])[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].CC(O[Na])=O.[NH2:40]O.Cl.Cl>C1COCC1.C(O)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:25]1[O:34][N:40]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1c(OCOC)cc(OCOC)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(OCOC)cc(OCOC)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Reaction time: 24 h
Yield: 49.5 %

Procedure:
To a stirred solution of ethyl 4-[2,4-bis(methoxymethoxy)-6-(4-nitrophenoxy)phenyl]-2,4-dioxobutanoate (71 g, 149 mmol) in THF (250 mL) and ethanol (500 mL) is added CH3COONa (24.4 g, 298 mmol) and NH2OH.HCl (22.8 g, 328 mmol) at room temperature. After the conversion to the oximes is complete, 6 M HCl solution was added dropwise to reach pH 2 to promote the cyclization. After stirring for 24 hours, Na2HPO4 was added to reach pH 6 and the suspension taken up in ethyl acetate was thoroughly washed with brine and dried over Na2SO4. The solvent was removed and the residue was crystallized from a mixture of MTBE (240 mL) and hexane (180 mL), to provide the title compound (35 g, 49% yield).
Reaction SMILES: Cl.C([Si](C)(C)[O:7][CH:8]1[CH2:13][CH2:12][C:11]([NH:20]S(C(C)(C)C)=O)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.NC1(C2CC2)CCC(O)CC1>>[NH2:20][C:11]1([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13][CH:8]([OH:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)S(=O)NC1(C2CCCCC2)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Agent: NC1(C2CC2)CCC(O)CC1
Product: NC1(C2CCCCC2)CCC(O)CC1
Yield: 79.2 %

Procedure:
425 mg of diastereomeric 1-amino-bicyclohexyl-4-ol (29) was synthesized as hydrochloride from 1.13 g (2.72 mmol) of 2-methyl-propane-2-sulfinic acid [4-(tert-butyl-dimethyl-silanyloxy)-bicyclohexyl-1-yl]-amide (27) following the procedure for 4-amino-4-cyclopropyl-cyclohexanol (28). Rt=0.61 min, 0.76 min (Method C). Detected mass: 198.3 (M+H+), 163.0 (M-NH3+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1.C([O-])(=O)C.[K+].Br[C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]2)=[CH:28][C:27]=1[F:42]>CCO>[F:42][C:27]1[CH:28]=[C:29]([CH2:30][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]2)[CH:40]=[CH:41][C:26]=1[C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:19][C:12]=2[CH:13]=1
Reactant: OB(O)c1cc2cc(Cc3ccccn3)ccc2o1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccn5)ccc4o3)c(F)c2)C1
Temperature: 80 °C

Procedure:
In a sealed flask, a mixture of 5-(pyridin-2-ylmethyl)benzofuran-2-ylboronic acid (214 mg, 846 μmol) and potassium acetate (166 mg, 1691 μmol) was set under argon, treated with bis{di(tbutyl)phenyl}palladium(II) dichloride (32 mg, 51 μmol), followed by a solution of ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (267 mg, 846 μmol) in EtOH (5 mL). The resulting suspension was degassed again and heated to 80° C. for 2.5 h. The mixture was cooled to ˜10° C. and dropwise treated with H2O (15 mL). The mixture was extracted 2× with EtOAc. The combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography (DCM to DCM/MeOH=4:1) gave ethyl 1-((3-fluoro-4-(5-(pyridin-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[CH3:9])N.N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:21]>O>[Br:21][C:4]1[CH:6]=[C:7]([Cl:10])[C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Br
Reactant: Cc1c(Cl)cc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 45 %

Procedure:
Suspend the 3,5-dichloro-4-methylaniline in 48% HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 0° C. with an ice/brine bath. Add a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL) dropwise. After the addition is complete, stir the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48% HBr (2 mL) and heat the rapidly stirring reaction to 50° C. for 1 hour. Cool the reaction to room temperature, dilute the reaction with ethyl acetate and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45%) of the product as a yellow solid.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][CH3:15])[N:3]=1.C(O)(=[O:18])C>[OH-].[Na+]>[CH2:14]([O:13][CH2:12][C:4]1[NH:3][C:2](=[O:18])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[CH3:15]
Reactant: CC(=O)O
Reactant: CCOCc1nc(N)c2nccnc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A solution of 30.0 g (0.146 mole) of 4-amino-2-(ethoxymethyl)pteridine in 800 ml of 5% aqueous sodium hydroxide is brought slowly to 75° C. and maintained at this temperature for 2 hours. After cooling, the solution obtained is acidified with acetic acid to pH 6 and is then extracted with chloroform. The organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from ethanol in the presence of Norit. Yld: 19.5 g (65%), m.p.=168°-169° C. The product is identical to that obtained in Example 1.