Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.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>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C)nc1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyridine (5 g, 29.0 mmol) was dissolved in DMF:THF (3:1, 35 mL): tributylvinyltin (10.2 g, 31.9 mmol) and Pd(PPh3)4 (0.44 g, 0.432 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (350 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (6% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyridine as a light yellow oil (1.6 g, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(COC)OC.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]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc([N+](=O)[O-])cc2)c1C
Yield: 42.6 %

Procedure:
To a mixture of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 1.31 mmol), 4-nitrophenylboronic acid (658.5 mg, 3.94 mmol) and cesium carbonate (865.6 mg, 2.63 mmol) in dimethoxyethane (5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (144.3 mg, 0.2 mmol) at room temperature under nitrogen. The resulting mixture was reacted using a microwave reactor (Personal Chemistry) at 120° C. for 30 minutes. Ethyl acetate (50 mL) was added and the organic layer was washed with water (30 ml) and brine solution (20 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified using an ISCO (90 g) column, eluting with 5-15% ethyl acetate in hexanes, to give [6-fluoro-3-methyl-4-(4-nitro-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (197 mg, 42%) as a light yellow solid. 1H NMR (300 MHz, CDCl3), δ ppm 8.40 (d, J=8.6 Hz, 2 H), 7.82 (dd, J=8.9, 5.7 Hz, 1 H), 7.77 (s, 1 H), 7.46 (d, J=8.6 Hz, 2 H), 7.21 (td, J=8.9, 2.4 Hz, 1 H), 6.76 (dd, J=11.2, 2.4 Hz, 1 H), 3.87 (s, 2 H), 3.74 (s, 3 H), 2.14 (s, 3 H). HRMS calcd. for C20H15FNO4 [(M−H)−] 352.0990, obsd. 352.0990.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:3][CH2:2][F:1])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:15]
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Yield: 43.4 %

Procedure:
1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 499.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
A solution of methyl 4-(5-benzenesulphonamidopyrid-2-yl)-butanoate (1.3 g, 4.2 mmole) in ethanol (25 ml) and 10% w/v sodium hydroxide solution (10 ml) was stirred for 1 hour. The solution was treated with hydrochloric acid and the precipitate was collected by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:14][C:12]([CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])=[O:13]
Reactant: O=Cc1cccc(O)c1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a mixture of 12.21 g of 3-hydroxybenzaldehyde, 14.00 g of 2-chloroacetamide and 60 ml of dimethylformamide was added 20.70 g of potassium carbonate, and this was heated to stir at 90° C. for 2 hours. After cooled to room temperature, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran by heating. Insolubles were filtered and the filtrate was concentration under reduced pressure. The resulting crude crystals were washed with a mixed solution of tetrahydrofuran and t-butyl methyl ether and dried to obtain 13.05 g of 3-(aminocarbonylmethoxy)benzaldehyde [Compound No. (n)] as a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.[CH3:57][C:58]1[CH:75]=[CH:74][C:61]2[N:62]=C(C3C=CC(N=C=O)=CC=3)[S:64][C:60]=2[CH:59]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[S:64][C:60]6[CH:59]=[C:58]([CH3:57])[CH:75]=[CH:74][C:61]=6[N:62]=5)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Cc1ccc2nc(-c3ccc(N=C=O)cc3)sc2c1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(NC(=O)N4CCN(c5ccnc6cc(Cl)ccc56)CC4)cc3)sc2c1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (120 mg, 0.49 mmol), diisopropyl(ethyl)amine (127 mg, 0.98 mmol), and 4-(6-methyl-2-benzothiazolyl)phenyl isocyanate (100 mg, 0.38 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O.CO>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3cccc(C(=O)O)c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C#Cc3cccc(C(=O)O)c3)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carboxyphenylethynyl)cyclohexane (0.11 g, 0.23 mmol) in tetrahydrofuran (6 mL) containing 3N hydrochloric acid (0.7 mL) was heated under an argon atmosphere at 55°-70° C. for 2 h. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between cold water and methylene chloride. The organic phase was washed with saturated brine solution, was dried over magnesium sulfate and was evaporated. The residue was chromatographed (silica), eluting with methylene chloride/methanol/water (90/5/0.25 to 90/10/0.5) and was concentrated in vacuo. The residue was dissolved in methanol and was foamed in vacua to afford a white fractured glass. Anal. (C27H28O5.1/4 H2O.1/4 CH3OH) calcd: C 73.55, H 6.68, found: C 73.51, H 6.66. 1H-NMR (400 MHz, CDCl3) δ 8.22 (t, J=1.5 Hz, 1H), 8.09 (d-d, J=1.3 Hz;J=7.9 Hz, 1H), 7.72 (d-d, J=1.3 Hz, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.22 (d, J=2.2, 1H), 7.13 (d-d, J=2.3 Hz, J=8.4 Hz, 1H), 6.88 (d, J=8.5 Hz,1H), 4.82 (p, 1H), 3.86 (s, 3H), 3.25 (d, J=20 Hz, CH3OH, 0.55H), 3.04 (d-t, J=5.8 Hz, J=14.5, 1.7H), 2.50 (d,br, J=14.8, 1.8H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:21]=O)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[NH2:25][CH2:26][CH2:27][CH2:28][P:29](=[O:32])([OH:31])[OH:30].[BH3-]C#N.[Na+]>CO>[C:15]1([C:14]2[N:13]=[C:12]([CH2:21][NH:25][CH2:26][CH2:27][CH2:28][P:29](=[O:30])([OH:32])[OH:31])[CH:11]=[CH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: NCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=P(O)(O)CCCNCc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure M, 5-(4-trifluoromethylphenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 57, 58 mg, 0.18 mmol), (3-amino-propyl)-phosphonic acid (25 mg, 0.18 mmol), Bu4NOH (0.18 ml, 0.18 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.18 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:4]=1.[CH2:17](Cl)Cl>CO.CCCCCC>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH3:17])=[O:12])[CH:4]=1
Reactant: ClCCl
Reactant: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C(C)Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-trifluoromethyl-2-pyridyloxy)propionic acid (Step A, 15 g, 55 mol) in 100 mL CH2Cl2 and 100 mL MeOH at 0° C. was added trimethylsilydiazomethane (2 M solution in hexane) until a yellow color persisted. After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluted with 0 to 10% EtOAc in hexane to give methyl 2-(4-trifluoromethyl-2-pyridyloxy)propionate (10 g), which was used immediately for methylation following the procedure described in Reference Example 39, Step B substituting ethyl iodide with methyl iodide. 1H NMR (500 MHz, CD3OD): δ 8.25 (d, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 3.65 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([NH:64][C@H:65]([C:67](O)=[O:68])[CH3:66])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]>>[C:54]([NH:64][C@H:65]([C:67]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:68])[CH3:66])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-alanine.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)=[O:9])[CH2:4][CH2:3]1.[NH2:20][C:21]1[S:22][C:23]([CH2:32][CH3:33])=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>ClCCl>[CH2:32]([C:23]1[S:22][C:21]([NH:20][C:16]([C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6]2)=[O:9])=[O:18])=[N:25][C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)N1CCS(=O)(=O)CC1
Reactant: CCc1sc(N)nc1-c1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCc1sc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid (92 mg; 0.317 mmol) and 2-amino-5-ethyl-4-phenyl-1,3-thiazole (64.8 mg; 0.317 mmol) in dichloromethane (4 mL) is added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (79.1 mg; 0.32 mmol). The reaction mixture is left stirring at room temperature for 18 hours. The reaction mixture is directly purified by preparative HPLC provides the title compound, m/z 477 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[CH2:26][NH2:27])[C:6]([NH:8][C@H:9]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=2[O:11][B:10]1[OH:22])=[O:7].CC(O)=O.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=3[O:11][B:10]2[OH:22])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:1][CH:33]([CH3:35])[CH3:32]
Reactant: CC(C)=O
Reactant: NCc1ccc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCc1cc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)ccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 14 (44.1 mg) in methanol (2 mL) was added TEA (0.042 mL), AcOH (0.050 mL), acetone (0.030 mL), and sodium triacetoxyborohydride (70 mg). The resulting reaction mixture was stirred at room temperature for overnight. After removal of the solvents, the product was then purified by reverse phase HPLC and dried using lyophilization. ESI-MS m/z 412 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.[BH4-].[Na+].O>CO>[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Reactant: CC1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCC(NCc2ccc(-c3cccc(C(N)=O)c3)cc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 4′-formylbiphenyl-3-carboxylic acid amide (700 mg, 3.1 mmol) in methanol (15 mL) was added 4 Å molecular sieves (700 mg) and 4-methylcyclohexylamine (421 mg, 3.7 mmol). The mixture was stirred for 16 h before adding sodium borohydride (588 mg, 15.5 mmol). After 1 h water (10 mL) was added, the mixture was filtered through celite and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 6% MeOH: DCM) gave the title compound: RT=2.53 min; m/z (ES+)=323.0 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[C:12](=O)(OC1C=CC=CC=1)[O:13]C1C=CC=CC=1>CN(C)C1C=CN=CC=1.CO>[CH3:1][N:2]1[C:3](=[O:11])[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:10][C:12]1=[O:13]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CNC(=O)c1cccnc1N
Agent: CN(C)c1ccncc1
Solvent: CO
Product: Cn1c(=O)[nH]c2ncccc2c1=O
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
10.0 g (66 mmol) of 2-aminonicotinic acid methyl amide, 21.4 g (100 mmol) diphenyl carbonate and 8.5 g (66 mmol) 4-dimethylaminopyridine were melted at 140 to 150° C. The reaction was allowed to continue for 20 minutes at that temperature. The mixture is allowed to cool down to 50 to 60° C. and 300 ml methanol was added while stirring. The mixture is allowed to cool down to room temperature. 3-methyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium, was isolated by filtration and washed with water, methanol and tert.-butyl methyl ether. 7.80 g (67%) of 3-methyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 272-4° C.).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[CH:5]=C.[BH4-].[Na+]>CO>[OH:1][CH2:5][CH2:4][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11]
Reactant: O=[O+][O-]
Reactant: C=CCOc1ccccc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Ozone was bubbled through a -78° C. dry methanol solution of 2-(allyloxy)benzyl alcohol (LaChapelle et al Tetrahedron, 44(16), 5033-5044 (1988)) (7.0 g, 43 mmol) for 13 minutes, checking the reaction TLC profile every 2 minutes for complete disappearance of the starting olefin (Rf=0.8, 75% EtOAc/hexane). The reaction mixture was purged with nitrogen, NaBH4 (9.7 g, 0.25 mol) was added and the reaction temperature brought to 0° C. After 30 minutes, the reaction was warmed to room temperature, concentrated, diluted with ether, washed with water, brine, dried and concentrated to a residue. The residue was eluted through a pad of silica with EtOAc/hexanes (gradient elution 25%-75% EtOAC). Evaporation of the eluting solvent gave the diol, 2-(2'-hydroxyethoxy)-benzyl alcohol, (4.8 g, 67%) as an oil. MS: MW=168; observed 168, FD, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc2cc[nH]c2c1
Product: Cc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-methyl-1H-indole and iodobenzene: ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1.[S]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=C1CCCc2ccc(OC)cc21
Agent: [S]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc2ccc(OC)cc12
Temperature: 215 °C
Reaction time: 0.5 h

Procedure:
50 g of ethyl 7-methoxy-1,2,3,4-tetrahydro-1-naphthylideneacetate are mixed with 7.35 g of sulphur, and the mixture is heated at 215° C. for 10 hours. It is cooled, 300 cm3 of ethyl acetate are added, and the mixture is stirred for 30 minutes and filtered. It is then dried. The resulting residue is used as such for the hydrolysis step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]23[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[CH:13][C:12]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]2)=[CH:11][CH:10]3[C:9]1=[O:37].[CH3:38]B(O)O>>[CH:36]([C:32]1[N:31]=[C:30]([C:25]2([C:28]#[N:29])[CH2:24][CH2:23][N:22]([CH2:21][C:12]3[CH:13]=[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]54[CH:10]([CH:11]=3)[C:9](=[O:37])[N:8]([C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:16]5)[CH2:27][CH2:26]2)[CH:35]=[CH:34][CH:33]=1)=[CH2:38]
Reactant: Cc1cccc(C2(C#N)CCN(CC3=CC4C(=O)N([C@H]5CCCC[C@@H]5O)CC45C=CC=CC5=C3)CC2)n1
Reactant: CB(O)O
Product: C=Cc1cccc(C2(C#N)CCN(CC3=CC4C(=O)N([C@H]5CCCC[C@@H]5O)CC45C=CC=CC5=C3)CC2)n1

Procedure:
4-(6-Ethenylpyridin-2-yl)-1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)piperidine-4-carbonitrile was prepared employing the procedures described for the construction of 1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)-4-(6-methylpyridin-2-yl)piperidine-4-carbonitrile in Example 4, substituting potassium vinyltrifluoroborate for methylboronic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH:24]2[C:37]3[CH:36]=[CH:35][C:34]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[NH:27][S:26](=[O:39])(=[O:38])[N:25]2[CH3:40])=[CH:20][C:17]=1[CH:18]=O.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45]>ClCCCl>[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH:24]2[C:37]3[CH:36]=[CH:35][C:34]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[NH:27][S:26](=[O:39])(=[O:38])[N:25]2[CH3:40])=[CH:20][C:17]=1[CH2:18][NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41]
Reactant: CN(C)CCN
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CCNCc1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.7 %

Procedure:
Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added to a solution of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (50 mg, 0.13 mmol) and N,N-dimethylethane-1,2-diamine (12.9 μl, 0.16 mmol) in DCE (2 ml) and the mixture was stirred at room temperature for 18 h. The reaction was quenched with sat. NaHCO3 solution (1 ml) and the mixture was extracted with EtOAc (5 ml). The organic phase was concentrated in vacuo. The crude residue was triturated from chloroform/MeOH to give the title compound (20 mg, 34%).