Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:17][CH:16]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: NCCCN1CCOCC1
Reactant: Cc1cc(-c2cc(-c3ccc(C(=O)O)cc3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3ccc(C(=O)NCCCN4CCOCC4)cc3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
4-(6-(4-Hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (Compound 265, 15.5 mg, 48 umol) and 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 5 mg of product. 1H-NMR (400 MHz, d6-DMSO): δ 8.64-8.69 (m, 1H), 8.19-8.27 (m, 3H), 7.94-8.01 (m, 3H), 7.86-7.91 (d, 1H), 7.50 (s, 1H), 6.88-6.95 (d, 1H), 3.54-3.60 (m, 4H), 3.27-3.36 (m, 4H), 2.29-2.41 (m, 4H), 2.21 (s, 3H), 1.65-1.77 (m, 2H). MS (EI): 449.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][OH:32])[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[N:13]=[C:14]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:15]=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][O:32][C:46](=[O:47])[NH:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCOC(=O)Nc1ccccc1
Reaction time: 16 h

Procedure:
A suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 3), 10 mg of DMAP and 25 μl of phenylisocyanate in 5 ml of chloroform was refluxed for 15 minutes under argon. 1.5 ml of DMF was added and stirring and heating was continued for 16 h. The clear solution was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2×50 ml of water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting first with hexane:ethyl acetate 1:1, then with DCM containing 4% of methanol to give 47 mg of phenylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a slightly yellow solid. LC-MS: tR=4.80 min, [M+1]+=653.37, [M−1]−=651.33.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=O)=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:25])[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:7]=1[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:2][CH2:3][CH3:4].Cl.C[N:41](C)CCCN=C=N.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][C:7]1[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:9](=[O:25])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][C:18]([C:22]([NH2:41])=[O:24])=[C:19]([CH3:21])[N:20]=1)=[CH:12][CH:11]=2)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Yield: 97.2 %

Procedure:
A solution of 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.60 g, 1.1 mmol), 1-ethyl,-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.42 g, 2.2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.33 g, 2.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl{6-[5-(-aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.58 g, 96.7%) as crystals.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)C.CO.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105.2 %

Procedure:
A mixture of 4-[(R)-[[(R)-(1,1-dimethylethyl)sulfinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester (0.59 g), methanol (5 mL) and hydrogen chloride in 1,4-dioxane (4M, 5 mL) was stirred at room temperature for 10 minutes then concentrated in vacuo. The residue was diluted in dichloromethane (2 mL) and triturated with diethyl ether to afford the subtitle compound as a solid (470 mg).
Reaction SMILES: [OH:1][CH2:2][N:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4].[CH2:24](N(CC)CC)[CH3:25].C(Cl)(=O)C>C(Cl)Cl.O>[CH2:24]([O:1][CH2:2][N:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4])[CH3:25]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cn(N(C)CO)c2c(F)c(F)c(F)cc2c1=O
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: O
Product: CCOCN(C)n1cc(C(=O)OCC)c(=O)c2cc(F)c(F)c(F)c21
Yield: 23 %

Procedure:
A solution of ethyl 1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (8.4 g) and triethylamine (3.09 g) in methylene chloride (150 ml) was cooled to 0° C. and treated with acetyl chloride (2.18 g). After 3 hours the reaction was diluted with water and shaken in a separating funnel. The organic layer was dried over magnesium sulfate, evaporated, and the crude product purified by chromatography with silica gel (50% ethyl acetate-hexane elution) to yield ethyl 1-[N-(ethoxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5]1.O.NN>CCO>[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(CCO)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
2-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-ethyl}-isoindole-1,3-dione (370 mg, 1.2 mmol) is dissolved in EtOH (8 mL) and hydrazine hydrate (88 mL, 1.8 mmol) is added at RT. The reaction mixture is then refluxed for 3 h and allowed to cool to RT again. The precipitated product is isolated by filtration, washed subsequently with cold EtOH and dried in HV to give the title compound as a white powder. ES-MS: M+H=174.2. 1HNMR (MeOH-d4) δ 4.24 (bs, 2H), 3.41 (t, 2H), 2.62 (t, 2H), 2.54-2.50 (m, 2H), 2-39-2.201 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=C.C(N(C(C)C)C(C)C)C>C(#N)C1C=CC=CC=1.[Pd](C#N)C#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:6]=[CH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: N#C[Pd]C#N
Solvent: N#Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cc(OC)cc(OC)c1
Yield: 49.4 %

Procedure:
0.0792 g (5 millimols) of palladium(II) cyanide, 10.03 g (50 millimols) of 3,5-dimethoxybenzoyl chloride, 6.26 g (62.5 millimols) of ethyl acrylate and 6.46 g (50 millimols) of N-ethyldiisopropylamine, in 100 ml of benzonitrile, are stirred for 70 minutes at 140° C. The crude product is distilled in vacuo. Working up affords 5.83 g (49% of theory) of ethyl 3,5-dimethoxycinnamate as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[NH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:13]1[C:14]2[C:19](=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[C:12]1[CH3:21])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2[nH]c(C)c(S(=O)(=O)c3ccc(Cl)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 0.5 h

Procedure:
The product of step (b) (1.27 g) was dissolved in THE (20 ml) at ° C. and NaH (0.115 g, 60% dispersion in oil) was added and stirred for 30 min. Ethylbromoacetate (0.66 ml) was then added and stirred for 1 h at room temperature. Ethanol was added to quench the reaction, the solvent was removed and the product washed with water and extracted with EtOAc. Purification by Flash column chromatography (30% EtOAc/hexane as eluent) gave the sub-title compound (0.716 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:30])[C:23]2[C:18](=[CH:19][C:20]([C:25](=O)C)=[C:21](C)[CH:22]=2)[C:17]([CH3:29])([CH3:28])[CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.CCCCCC>[CH3:28][C:17]1([CH3:29])[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:14]([CH3:30])([CH3:13])[CH2:15][CH2:16]1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
To a stirred solution of 794.2 mg (7.8486 mmol) diisopropylamine in 7 ml dry tetrahydrofuran under argon at -78° C. was added dropwise 4.9 ml of 1.6M (7.84 mmol) n-butyllithium in hexane. This solution was stirred at -78° C. for 1.25 hours and then treated via a double ended needle with a solution of 1.9 g (7.7749 mmol) of 1,1,4,4,7-pentamethyl-6-acetyl-1,2,3,4-tetrahydronapthalene in 4 ml dry tetrahydrofuran. After stirring at -78° C. for 1 hour, the mixture was treated with 1.3134 g (7.6117 mmol) of diethyl chlorophosphate. The cooling bath was removed and mixture stirred at room temperature for 3 hours. This material was then transferred using a double ended needle into a solution of lithium diisopropylamide [prepared as above using 1.5884 g (15.6972 mmol) of diisopropylamine and 10 ml of 1.6M (16 mmol) n-butyllithium in hexane] in 15 ml dry tetrahydrofuran at -78° C. The cooling bath was removed and mixture stirred at room temperature for 15 hours, then quenched with 50 ml water, and acidified to pH 1 with 3N hydrogen chloride. The mixture was extracted with 3×75 ml petroleum ether and the organic extracts were combined, washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 3% ethyl acetate in hexane) followed by kugelrohr distillation (50° C., 0.05 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ1.28 (12H, s), 1.67 (4H, s), 1.42 (3H, s), 3.20 (1H, s), 7.15 (1H, s), 7.44 (1H, s).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]([CH:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCCC1>[C:1]1([C@@H:7]([N:9]([CH:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)N(C(=O)C(F)(F)F)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C(=O)C(F)(F)F)C1CCC(=O)CC1
Temperature: 55 °C
Yield: 40.9 %

Procedure:
N-((1S)-1-Phenylethyl)-N-(1,4-dioxaspiro[4.5]dec-8-yl)-2,2,2-trifluoroacetamide (15.31 g, 42.84 mmol) was dissolved in tetrahydrofuran (30 mL). The solution was treated with 30 mL of 3.0 N aqueous HCl. The reaction was heated to 50-60° C. over 48 h. The reaction was cooled to room temperature. THF was removed under reduced pressure. The crude product was extracted with dichloromethane and was purified by silica gel column (eluent 15-20% ethyl acetate in hexanes). The product was isolated as a yellow oil (5.49 g, 41% yield) M+1: 314.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:16]([CH:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][CH2:8]2.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:85]1(B(O)O)[CH2:87][CH2:86]1>C1(C)C=CC=CC=1.O>[CH:85]1([C:2]2[CH:18]=[CH:17][C:16]([CH:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[O:20]3)=[CH:15][C:3]=2[CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[O:11][CH2:10][CH2:9][CH2:8]3)[CH2:87][CH2:86]1
Reactant: Brc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCCO2
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COC[C@H]2OC(c3ccc(C4CC4)c(Cc4ccc5c(c4)CCCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
To a stirred solution of 6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (300 mg, 0.363 mmol) in toluene (1.6 mL) was added tricyclohexylphosphine (10 mg), potassium phosphate (346 mg, 1.63 mmol), water (81 μl), cyclopropylboronic acid (93 mg, 1.09 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (4 mg) was added. After heating overnight at 100° C., the reaction mixture was cooled to room temperature and was filtered through celite. The celite was washed with an additional ethyl acetate (30 mL) and the organic layer of the filtrate was separated and washed with water (20 mL) followed by brine (20 mL), then dried over sodium sulfate and concentrated to give crude product which was further purified by column chromatography to furnish 6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=4)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:34]/[C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[CH:23]=[N:24][C:19]([N:16]4[CH2:17][CH2:18][O:13][CH2:14][CH2:15]4)=[CH:20][CH:21]=3)=[N:26][N:27]2[CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])=[CH:32][CH:31]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Temperature: 60 °C
Yield: 62.9 %

Procedure:
A round bottom flask was charged with 5-methoxyoxindole (100 mg, 0.61 mmol), 3-(6-Morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (266 mg, 0.61 mmol), piperidine (6 uL, 0.06 mmol) and MeOH (4 mL). The reaction was then heated to 60° C. for 4 h. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange powder was then filtered and washed with MeOH to give the title compound (224 mg, 63%). 1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 8.79 (d, J=1.5 Hz, 1H), 8.20 (d, J=8.5, 1H), 8.17-8.13 (m, 2H), 7.77 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.82 (s, 2H), 3.73 (t, J=4.3 Hz, 4H), 3.62-3.53 (m, 9H), 0.82 (t, J=8.2 Hz, 2H), −0.12 (s, 9H); MS ESI 584.3 [M+H]+, calcd for [C32H37N5O4Si+H]+ 584.26.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[N:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[N+:18]=[N-:19]>C(O)(C)C>[ClH:1].[N:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(N=[N+]=[N-])cc3)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 4-azidoaniline hydrochloride (200 mg, 1.11 mmol) were refluxed in 10 mL of isopropyl alcohol for 0.5 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 392 mg (98%); mp 200°-205° C. (dec).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[N:13][C:12]=2[N:22]2[CH2:27][CH2:26][CH:25]([F:28])[CH2:24][CH2:23]2)[CH2:5][CH2:4]1>[Pd].C1COCC1>[F:31][C:2]([F:1])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[N:13][C:12]=2[N:22]2[CH2:27][CH2:26][CH:25]([F:28])[CH2:24][CH2:23]2)[CH2:5][CH2:4]1
Reactant: CNc1nc(N2CCC(F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CNc1nc(N2CCC(F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reaction time: 3 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-5-nitro-2-(4-fluoro-piperidinyl)-nicotinic acid amide (100 mg, 0.22 mmol), Pd/C (50 mg) and THF (15 mL) is stirred under 50 psi H2-atmosphere for 3 h. The mixture is filtered, and the filtrate is concentrated. HPLC Rt=1.28 min (method B). MS m/z: 418 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:5](O)=O)[CH2:4][CH2:3]1.[NH2:8][NH:9][C:10]([NH2:12])=[S:11].O(Cl)Cl.[P+3]>O1CCOCC1>[CH3:1][C:2]1([C:5]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CC1
Reactant: NNC(N)=S
Agent: ClOCl
Agent: [P+3]
Solvent: C1COCCO1
Product: CC1(c2nnc(N)s2)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 16.4 %

Procedure:
Combine 1-methylcyclopropane-1-carboxylic acid (10.00 g, 99.88 mmol), and thiosemicarbazide (9.10 g, 99.88 mmol) in dioxane (110 mL). Heat the mixture to 90° C. under N2, then add phosphorus(III) oxychloride (9.14 mL, 99.88 mmol) dropwise over 25 minutes. The reaction mixture is stirred for 6 hours at 90° C., then 8 hours at room temperature. Decant onto 200 g ice and add ammonium hydroxide to make basic. Filter to remove solids; the filtrate is extracted with ethyl acetate. The organic layer is washed with water. Dry the resulting organics over magnesium sulfate, filter, and concentrate to give product (2.54 g, 16%). MS (ES), m/z 156 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](C)[C:7]=1[C:13](O)=O.S(=O)(=O)(O)O.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>O>[C:6]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:23]=1[C:22]([OH:25])=[O:24])#[N:5]
Reactant: CC(=O)O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cccc(C#N)c1C(=O)O

Procedure:
Under ice cooling and stirring, 1.5 g of sodium nitrite dissolved in 2 ml of water was added dropwise over 1.5 hours to 3 g of 3-amino-o-toluic acid dissolved in a mixed solution of 8 ml of acetic acid, 8.3 g of sulfuric acid and 6.5 ml of water. After 3.2 ml of acetic acid, 0.4 g of sulfuric acid and 5.6 ml of water were added to the reaction mixture, the mixture was filtered and the reaction filtrate was adjusted. On the other hand, 6.5 g of potassium cyanide dissolved in 12.7 ml of water was added dropwise to 5.9 g of copper sulfate.pentahydrate dissolved in 12.7 ml of water at room temperature under stirring and 21.5 g of sodium hydrogen carbonate and 70 ml of toluene were added to the mixture. Under ice cooling and stirring, the above reaction filtrate was added dropwise to this 10 reaction mixture over 1 hour and then the mixture was stirred at 80° C. for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to about pH 3 with 1N-hydrochloric acid, crystals precipitated were extracted with ethyl acetate and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium carbonate. The solvent was removed to obtain 3.8 g of the title compound. Mass (CI); m/z=162 (M+ +1)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: Oc1cccc(I)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Ic1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
The solution of 3-iodophenol (70.31 g), PPTS (750 mg) and 3,4-dihydro-2H-pyran (55.68 g) in CH2Cl2 (400 mL) was refluxed under N2 for 3 h. TLC of the reaction solution indicated the presence of starting material, 3-iodophenol. Consequently, more 3,4-dihydro-2H-pyran (30 mL) and PPTS (350 mg) were added to the reaction solution. The reaction was refluxed for another 3 h. After being cooled to room temperature, the reaction solution was washed by saturated NaHCO3 (100 mL×2), H2O (120 mL×3) and brine (120 mL×1), dried by Na2SO4 and concentrated to give crude product, which was purified to give pure 2-(3-Iodo-phenoxy)-tetrahydro-pyran (89.5 g; 92%). 1H NMR (300 MHz, CDCl3) □ 7.42 (m, 1H), 7.31 (m, 1H), 7.00 (m, 2H), 5.39 (dd, 1H, J=3.0, 3.0 Hz), 3.87 (m, 1H), 3.61 (m, 1H), 1.97 (m, 1H), 1.84 (m, 2H), 1.65 (m, 3H).