Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14].[OH-].[Na+].CO>O>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 25 °C

Procedure:
A mixture of campholenic aldehyde (456 g, 3.0 mol) and freshly distilled propionaldehyde (348 g, 6.0 mol) was slowly added, over a 1.0 hour period, to a stirred refluxing solution of 18 ml of 40% aqueous sodium hydroxide and 800 ml methanol. The mixture was refluxed an additional two hours, cooled to room temperature and poured into 1,000 ml of water. The resultant solution was extracted three times with 300 ml of hexane. The hexane extracts were combined, washed first with 600 ml of water and then with 600 ml of brine. The solvent was removed by distillation and the oil fractionally distilled to yield the 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal. Yield 323 g (56.1% theory); bp 64°-65° C (0.9 mm); mol wt. 192 (ms); ir, 3035, 2710, 1690 (s), 1640 (s), 800 cm-1 ; nmr, 0.8δ and 1.0 (6 H, 2s, geminal dimethyl groups), 1.7 (3H, broad s, olefinic methyl attached to the cyclopentenyl group), 1.9-2.2 (3H, broad multiplet), 2.3-2.6 (3H, broad multiplet), 5.3 (1H, broad multiplet, olefinic H), 6.6 (1H, t, J~7.5 Hz), 9.4 (1H, sharp s, aldehyde H).
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][NH2:38])[N:32]=[CH:31]1>N1C=CC=CC=1>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)=[N:38][CH2:37][CH2:36][CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C(N=C1NCC(COc2cccc(CN3CCCCC3)c2)O1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
1.97 g (5 mmol) of 2-benzoylimino-5-[(3-piperidinomethylphenoxy)methyl]oxazolidine and 0.69 g (5.5 mmol) of 3-(imidazol-4-yl)propylamine are together heated under reflux in 30 ml of pyridine for 8 hours. The solvent is distilled off under vacuum, and the reaction product is isolated and purified by a method analogous to Method A.
Reaction SMILES: [CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([C:16](OC)=[O:17])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)[O:6][CH2:5][CH2:4][O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([CH2:16][OH:17])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)[O:3][CH2:4][CH2:5][O:6]1
Reactant: COC(=O)C12CC3CC(C1)C(C1(C)OCCO1)(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C23CC4CC2CC(CO)(C4)C3)OCCO1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Methyl 3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]nonane-1-carboxylate (2.3 g, 8.64 mmol) obtained in step III, in THF (15 mL) was added slowly under N2 atmosphere through a dropping funnel to a suspension of LiAlH4 (0.32 g, 8.64 mmol) in ether (15 mL) at ice bath temperature. The reaction mixture was stirred for 30 minutes before being quenched by addition of sat. aq. NH4Cl solution (9 mL), followed by 1N NaOH solution (9 mL) and the reaction mixture was stirred at room temperature for 15 minutes before it was filtered through a pad of celite. The organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure to obtain [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methanol (1.9 g) in 94% yield as viscous liquid. m/z (M+1) 269; IR cm−1 3436, 2936, 1634, 1459, 1373, 1309, 1047, 757. 1H NMR (CDCl3) 300 MHz δ 4.15-3.80 (m, 4H), 3.53 (s 3H), 2.50-2.30 (m 2H), 1.90-1.30 (m, 10H), 1.29 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[CH:17]=[CH:16][C:15]=1[N+:33]([O-])=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O>C(O)C.C(N(CC)CC)C>[N:28]1([C:26]([C@@H:22]2[CH2:23][CH2:24][CH2:25][N:20]([C:18]3[N:19]=[C:14]4[NH:13][C:1]([C:3]5[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=5)[C:6]([O:8][CH3:9])=[O:7])=[N:33][C:15]4=[CH:16][CH:17]=3)[CH2:21]2)=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Into a vial was added methyl 3-formylbenzoate (102 mg, 0.6 mmol) and a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (140 mg, 0.4 mmol) in ethanol (1.5 mL). Sodium dithionate (388 mg, 2.2 mmol) and water (0.5 mL) were added. The vial was sealed and the solution was stirred 110° C. for 18 h. The solution was cooled to room temperature and triethylamine (0.1 mL) was added. The solution was stirred at 100° C. for 18 h. An aliquot of 0.8 mL was removed and concentrated to dryness, and the resulting residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 434.2; HPLC retention time 2.25 min (Method A).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CCCCCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.3 %

Procedure:
2-Aminoindane (1.07 g, 8.03 mmol) was dissolved in dichloromethane (20 ml), and acetic anhydride (0.76 ml, 8.04 mmol) and triethylamine (1.7 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 50 min. The reaction mixture was diluted with ethyl acetate-hexane=1:1 mixed solvent (80 ml), and the organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane-1:5 mixed solvent, and dried under reduced pressure to give the title compound (961 mg, yield 68%) as a pale-yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C.O.[I-].[K+]>[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:24][CH:25]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
Carbazole (1.0 g, 6.0 mmol) and sodium hydride (60 wt. % in mineral oil, 0.14 g, 6.0 mmol) were placed under argon and dissolved in DMF (5 mL). The mixture was stirred at room temperature for 30 min, followed by treatment with (4-bromomethylphenyl)acetic acid methyl ester (1.5 g, 6.0 mmol) and 5 mg of potassium iodide. The reaction was heated to 80° C. for 2 h. The reaction was then diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.71 g, 36%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 8.20 (d, 2H, J=7.7 Hz), 7.49 (m, 2H), 7.40 (d, 2H, J=8.1 Hz), 7.32 (m, 2H), 7.17 (d, 2H, J=8.1 Hz), 7.12 (d, 2H, J=8.1 Hz), 5.52 (s, 2H), 3.71 (s, 3H), 3.61 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 171.6, 140.3, 135.7, 132.8, 129.3, 126.5, 125.5, 122.8, 120.1, 118.9, 108.5, 51.7, 45.9, 40.4. ESI-HRMS (m/z): [M+H]+ calcd. for C22H19NO2, 330.1489. found, 330.1494.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: N#CC(Br)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(Sc1nc2ccccc2[nH]1)c1ccccn1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
A mixture of 2-mercaptobenzimidazole (0.30 g, 3.0 mmole), bromo(2-pyridyl)acetonitrile (0.59 g, 3.0 mmole) and potassium carbonate (0.37 g 3.0 mmole) in 50 ml of dry N,N-dimethylformamide was heated at 60° C. for 6 h. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water and then saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated to give a solid. The crude product was further purified by column chromatography on silica gel (100% ethyl acetate) to give 66 mg (10%) of the title compound as a solid; mp 166-167° C.; 1H NMR (DMSO-d6) δ 9.3 (m, 1H), 8.65 (m, 2H), 8.32 (m, 1H), 7.78 (br s, 4H), 4.81 (br s, 2H) ppm; IR ν 2206, 1512, 1465, 1432, 1357, 1179, 740 cm-1.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromopyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([CH3:26])=[CH2:25]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:25][C:24]([CH3:26])=[CH2:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(OCc2ccccc2)cc1
Temperature: 58 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
A mixture of 4-(benzyloxy)phenol (2.01 g, 10.1 mmol), K2CO3 (1.60 g, 11.6 mmol) and 3-chloro-2-methylpropene (93) (2.00 mL, 20.4 mmol) in anhydrous acetone (2.5 mL) was stirred in a sealed vial at 58° C. for 24 h. The resulting mixture was filtered, washing with CH2Cl2, and then the filtrate was evaporated to dryness and the residue was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, and then further elution with 25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-[(2-methyl-2-propenyl)oxy]benzene (94) (Karrer, F. DE 2312518) (1.74 g, 68%) as a white solid: mp (CH2Cl2/hexane) 62-64° C.; 1H NMR (CDCl3) δ 7.45-7.29 (m, 5H), 6.90 (dt, J=9.3, 2.8 Hz, 2H), 6.85 (dt, J=9.3, 2.8 Hz, 2H), 5.08 (m, 1H), 5.01 (s, 2H), 4.79 (m, 1H), 4.38 (s, 2H), 1.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][S:8][CH:9]([CH2:25][CH2:26][CH3:27])[C:10]([NH:12][C@H:13]([C:22](O)=[O:23])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[C:31]([O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:38])([CH3:34])([CH3:33])[CH3:32].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.OC1C2N=NNC=2C=CC=1>ClCCl.CCCCCC.C(OCC)(=O)C>[C:31]([O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:38][C:22](=[O:23])[C@H:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:12][C:10](=[O:11])[CH:9]([S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=1)[CH2:25][CH2:26][CH3:27])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Combine 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanine (0.14 g, 0.34 mmol), (L)-phenylalanine t-butyl ester hydrochloride salt (0.174 g, 68 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.67 mmol) in dichloromethane (5 mL). Add N-methylmorpholine (0.1 mL, 1.01 mmol) and hydroxybenzotriazole (0.091 g, 0.67 mmol). After 3 hours, after 1 hour, partition the reaction mixture between methyl t-butyl ether and an aqueous 5% sulfuric acid solution. Separate the layers, extract the organic layer with a saturated sodium bicarbonate solution and then brine. Dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/1 hexane/ethyl acetate and then 1/1 hexane/ethyl acetate to give the title compound: Rf=0.45 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][C:15]([P:18]([CH3:23])(=[O:22])[O:19]CC)=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:3]=1.[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][C:15]([P:18]([CH3:23])(=[O:19])[OH:22])=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cc1
Yield: 64.4 %

Procedure:
The ethyl methylphosphinate 2-4 (130 mg, 0.27 mmol) was dissolved in 5 ml of dioxane and treated with 2 ml of 5N NaOH. The mixture was heated at reflux overnight. The mixture was then concentrated under vacuum and the residue was treated with 2 ml of trifluoroacetic acid. The mixture was re-evaporated and the residue was purified by prep-HPLC to provide the product, 2-5 (80 mg, 64%). 1H NMR (CD3OD, 300 MHz,): δ 8.76 (m, 2H), 8.48 (m, 2H), 8.01 (m, 1H), 7.77 (m, 2H), 7.61 (m, 1H), 7.51 (m, 2H), 7.29 (m, 5H), 6.39 (s, 1H), 1.61 (d, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([C:21]#[N:22])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1.[BH4-].[Na+].O>C1COCC1>[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH:21]([NH2:22])[CH3:1])=[C:11]([N:14]3[CH2:20][C:16]4([CH2:19][O:18][CH2:17]4)[CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1
Reactant: C[Mg]Br
Reactant: Cn1ccc2nc(C#N)c(N3CC4(COC4)C3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
Methylmagnesium bromide (1.56 mL, 2.18 mmol) was added slowly to a stirred solution of 1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (222 mg, 0.873 mmol) in THF (20 mL). The reaction was stirred at 40° C. for 1.5 hours, then cooled to 0° C. and quenched with MeOH (10 mL). After 10 minutes, sodium tetrahydroborate (83 mg, 2.18 mmol) was added. The reaction mixture was stirred for 20 minutes. Water (1 mL) was added and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was dried over MgSO4, filtered through Celite, and concentrated. The crude product was purified by basic silica column chromatography (3-5% MeOH in DCM) to give the title compound as a clear oil (111 mg, 47%). 1H NMR (500 MHz, CD3OD) δ ppm 7.28 (d, 1H, J=3.5 Hz), 7.14 (s, 1H), 6.47 (d, 1H, J=3.5 Hz), 4.89 (s, 4H), 4.33 (q, 1H, J=7.0 Hz), 4.10 (qAB, 4H, J=35.5, 7.5 Hz), 3.36 (s, 3H), 1.43 (d, 3H, J=7.0 Hz). ESI-MS m/z [M+H]+ calc'd for C15H20F4O, 273; found 273.
Reaction SMILES: [CH3:1]C(O)C=C.BrCC1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:19]([O:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)[CH2:20][CH:21]=C>>[CH3:1][CH:24]([O:23][CH2:19][CH:20]=[CH2:21])[C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=1
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Reactant: C=CC(C)O
Agent: O=C(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(C)c1ccc(C(=O)O)cc1

Procedure:
The reaction of But-3-en-2-ol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-(1-Methyl-allyloxymethyl)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.89 (S, COOH); 7.90 (d, J=8.3, 2 arom. H); 7.42 (d, J=8.3, 2 arom.H); 5.77 (m, —CH═CH2); 5.21, 5.16 (2 d-like, —CH═CH2); 4.54, 4.44 (AB, J=8.9, —OCH2—C6H4); 3.95 (m, CH(CH3)O); 1.22 (d, CH(CH3)O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 144.00; 140.10; 129.65; 129.27 (2 arom.C); 1267.00 (2 arom.C); 116.06; 75.83; 68.56; 20.97.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:5]=1[OH:12])[CH:2]=C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:10][C:8]1[C:7]([Br:11])=[CH:6][C:5]2[O:12][CH:2]=[CH:1][C:4]=2[CH:9]=1
Reactant: C=CCc1cc(F)c(Br)cc1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1cc2ccoc2cc1Br
Yield: 90 %

Procedure:
Beginning with 3.5 gm (15 mMol) 2-allyl-4-fluoro-5-bromophenol, the title compound was prepared in 90% yield essentially by the procedure described in Preparation XXXI with the exception that the cyclization/dehydration step was performed using sulfuric acid in toluene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:24][C:25]1[N:35]=[C:28]2[CH:29]=[CH:30][C:31]([CH2:33]Cl)=[CH:32][N:27]2[N:26]=1>CN(C=O)C>[Br:24][C:25]1[N:35]=[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:32][N:27]2[N:26]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: ClCc1ccc2nc(Br)nn2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (1.4 g, 6.09 mmol) in DMF, is added cesium carbonate (5.9 g, 18.1 mmol) and 2-bromo-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 6.09 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with ice cold water and extracted with EtOAc (2×200 mL). The organic extract is washed with brine (2×30 mL), dried over sodium sulphate, and concentrated. The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane to give the title compound as a yellow sticky oil (1.4 g, 54%). LCMS m/z 442 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:30])[CH2:18][O:19][C:20]1[C:21]([CH3:29])=[CH:22][C:23]([CH:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:22]=[C:21]([CH3:29])[C:20]([O:19][CH2:18][CH:17]([F:30])[F:16])=[CH:25][N:24]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCC(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (360 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (350 mg, 1.4 mmol, Amine-59, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:33]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24]
Reactant: CN(C)CCOc1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OCCN(C)C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 63.6 %

Procedure:
A mixture of 5-bromo-3-(5-(2-(dimethylamino)ethoxy)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 268c (244 mg, 0.67 mmol), (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b (342 mg, 0.67 mmol), PdCl2(dppf) (59 mg, 0.08 mmol), K3PO4 (150 mg), and NaOAc (50 mg) in MeCN (6 mL) and water (2 mL) was heated at 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 296a (287 mg, 60%). MS: [M+H]+ 674.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7](=[CH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]=1)[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]=1)[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(CC(CC(=O)O)C(=O)OC(C)(C)C)ccn1
Yield: 65.7 %

Procedure:
2-(2-tert-Butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (2.81 g, 7.60 mmol) and Pd/C (10%, 400 mg) were suspended in EtOH and hydrogenated at 41 atm. and 28° C. for 3 days. The catalyst was removed from the reaction mixture by filtration. The catalyst was washed with EtOH (96%). 1 M K2CO3 (30 mL) was added to the filtrate followed by addition of water (50 mL). After 2 days the reaction mixture was evaporated to ca 80 mL, then brine (10 mL) was added and the reaction mixture extracted with ether. The aqueous phase was acidified to pH=3 and extracted with chloroform. Methanol (25 mL) was added and the reaction mixture was dried (Na2SO4+CaSO4) and filtered to give 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-succinic acid 1-tert-butyl ester (1.90 g, 83%).