Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+].Cl>C(O)C>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH:33]=[CH:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (965 mg), benzo[b]furan-5-carbaldehyde (350 mg) and ethanol (10 ml) is added dropwise a 50% aqueous potassium hydroxide solution (2 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent under reduced pressure, and to the residue are added water and diisopropyl ether. The mixture is stirred, and the aqueous layer is obtained by separation. The aqueous layer is neutralized by using a 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The resulting organic layer is washed with water, dried, and evaporated to remove the solvent to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61]Br)=[N:53]1)=O)(C)(C)C>CN(C=O)C.C1COCC1>[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:4]2=[O:34])=[N:53]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of 0.35 g (0.77 mmol, 1.0 equiv) of 2-(2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 36, in 7 mL of DMF is cooled in an ice/water bath. 0.85 mL (0.84 mmol, 1.1 equiv) of 1M NaN(TMS)2 in THF is added and the solution stirred at 0° C. for 10 min. A solution of 0.26 g (0.84 mmol, 1.1 equiv) of N-tert-butoxycarbonyl-3-bromomethyl-indazole in 3 mL of DMF is added and the resulting yellow solution stirred at RT for 1 h. The reaction is quenched with H2O, extracted with EtOAc (×3), washed with H2O (×2) and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc/hexane 1/1 as eluent followed by Si60 MPLC using EtOAc/hexane 1/1 as eluent gave 0.23 g of a white powder; low resolution MS (FAB) 689 (MH+). A portion of this compound is dissolved in 4N HCl in dioxane and stirred at 0° C. for 30 min, and then concentrated to a white foam. Purification by RP-18 MPLC using MeCN/H2O 3/2 containing 0.1% HCl as eluent gave 33 mg of the title compound HCl salt as an amorphous white powder: 1H NMR (d6 -DMSO, 400 MHz) δ8.47 (d, 1H, J=3.5), 8.0-7.0 (m, 15H), 4.79 (m,1H), 4.20 (m, 2H), 3.79 (s, 3H), 3.51 (dd, 1H, J=7, 15), 3.39 (dd, 1H, J=5, 15), 0.97 (dd, 6H, J=7, 14); low resolution MS (FAB)m/e 589 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]#[N:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]1[NH:37][N:36]=[N:35][N:32]=1)[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc(Cn2c(-c3ccccc3)ccc2-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)cc1
Yield: 30.8 %

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 48 mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). The solids were isolated by vacuum filtration and dissolved in methylene chloride. The organic solution was dried (MgSO4), filtered and the solvent removed under reduced pressure to give 5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H -tetraazole as an amorphous beige solid (0.203 g, 92%), mp 190–200° C. (dec). Elemental Analysis for C29H23N5O.0.49 H2O.0.21 C3H7NO Calc'd: C, 73.90; H, 5.32; N, 15.15. Found: C, 73.05, H, 5.25; N, 15.03.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].Br[CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31])=[O:13])[CH3:3]
Reactant: Cc1oc(=O)oc1CBr
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCc3oc(=O)oc3C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g) in dry DMF (2.0 ml) was ice-cooled. After 4-bromomethyl-5-methyl-1,3-dioxol-2-one (115 mg) was dropped thereto, the mixture was stirred for 30 minutes. After removal of the bath the mixture was further stirred for 30 minutes. Thereto was ethyl acetate, and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (ethyl acetate only) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.11 g, yield 60%).
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:18])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 4-aminopyridine (52 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 30-90 EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(pyridin-4-yl)benzamide as an off-white solid. Yield: 86 mg (43%). 1H-NMR: 10.81 (s, 1H), 8.50 (d, J=6.0 Hz, 2H), 8.35 (t, J=1.5 Hz, 1H), 8.24 (dt, J=8.0, 1.0, 1.0, 1H), 8.01 (dt, J=8.0, 1.0, 1.0, 1H), 7.77-7.72 (m, 3H), 7.50 (d, J=8.0 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:35]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
1.7 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 0.55 g of triethylamine are introduced into 25 ml of methylene chloride. A solution of 0.6 g of chloroacetyl chloride is added dropwise thereto. The dark solution is left to stand overnight, diluted with 50 ml of methylene chloride, washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated by evaporation. The crystallisate so obtained is recrystallised from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.00 g of 5-{4-(6-bromo-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 60) and 40 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.75 g of the title compound, melting at 204-205° C.
Reaction SMILES: [CH3:1][C@@:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CO.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>[CH3:1][C@@:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:31][CH:30]=2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: Brc1ccc(-c2ncco2)cc1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate (0.2 g, 0.5 mmol) in MeOH (2.5 mL) in a microwave reactor vial was added 2-(4-bromophenyl)-1,3-oxazole (0.118 g, 0.525 mmol, 1.05 eq), potassium carbonate (0.214 g, 1.5 mmol, 3 eq), and palladium tetrakis (0.117 g, 0.1 mmol, 0.2 eq). The reaction mixture was irradiated at 120° C. in a microwave reactor for five minutes. The vial was allowed to cool to RT, and a solution of lithium hydroxide (0.036 g, 1.5 mmol, 3 eq) in water (2 mL) was added. The reaction mixture was allowed to stir at room temperature for one hour. The mixture was then washed with ethyl acetate (100 mL) and 1M sodium hydroxide (50 mL). The aqueous layer was separated and acidified to pH 1 with 6M HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}butanoic acid (0.125 g, 64% yield) as a white solid. LC-MS M+H+390.1.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([Cl:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([Cl:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)=[O:6]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: Fc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)c1cc(I)ccc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 48.94 g 2-chloro-5-iodo-benzoic acid in 180 mL of fluorobenzene and 0.3 mL of N,N-dimethylformamide is added 16.2 mL of oxalyl chloride at 0 to 10° C. The solution is stirred at about 20° C. for 2 hours. The excess amount of oxalyl chloride is evaporated. The residue is diluted in 166 mL of fluorobenzene and 25.93 g of aluminum chloride is added at 0° C. in five portions. The solution is stirred at 75° C. for 1.5 hours and quenched with 300 mL of water at 0 to 25° C. The product is extracted in 300 mL of isopropylacetate and washed with two times of 200 mL brine (3 weight-%). The residue water and solvent is removed upon evaporation.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=O>C(O)C.[Pd].Cl>[CH2:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCc1ccc(O)c(OC)c1
Yield: 102.5 %

Procedure:
Acetovanillone (Aldrich, 11.0 g, 66 mmol) was dissolved in absolute ethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A few drops of concentrated hydrochloric acid were added and the mixture hydrogenated on a shaker at 42 psi. The reaction mixture was filtered through Celite, and the filtrate was concentrated to afford 10.3 g of a golden liquid. This was diluted with water, extracted with diethyl ether and the organic phase was washed with water and sodium bicarbonate. The solvent was dried (MgSO4) and concentrated to afford 9.3 g of a slightly yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-].[CH2:31](Cl)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC#N.C1COCC1.CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester) (76.8 mg; 0.25 mmol), Cs2CO3 (241 mg; 0.74 mmol), and NaI (3.7 mg, 25 μmol) in CH3CN/THF (6:4; 2.5 mL) was stirred for three hours at RT. Subsequently, benzyl chloride (35 μL; 0.3 mmol) in CH3CN (1 mL) was added and the resulting mixture was heated at 60° C., for 20 h. After cooling to RT the solvents were removed in vacuo. The residue was partitioned between CH2Cl2 and 1M aqueous K2CO3. The layers were separated and the aqueous layer washed with CH2Cl2. The combined organic layers were concentrated in vacuo, and the residue dried under vacuum, at 40° C., overnight. The obtained product was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([O:10]C)=O)[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][N:2]1[S:3](=[O:18])(=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]([OH:12])=[C:7]1[C:8]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:10]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Temperature: 140 °C
Reaction time: 28 h

Procedure:
To a five liter flask equipped with thermometer, packed distillation column, condenser, and stirrer, under a nitrogen atmosphere is added 3300 ml mixed xylenes, 80 g (0.297 mole) methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mole) 2-aminopyridine and 8 g of activated carbon (Darco G-60* or Darco KBB*). The mixture is heated at reflux (ca. 140° C.) for 28 hours while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours, then at a rate of 5-10 ml per hour for the remaining reflux period, while adding fresh xylene to maintain a reaction volume of about 3500 ml. After 28 hours, the reaction mixture is cooled slightly (~100° C.) and filtered to remove carbon. The carbon cake was washed with warm xylene (100 ml), the filtrate and washings cooled slowly under a nitrogen atmosphere with rapid stirring to 25°-50° C. Stirring was continued for one hour to allow for complete crystallization. The crystals were collected by filtration, the mother liquor concentrated to about 1500 ml, cooled under nitrogen to 0°-5° C., filtered, the cake washed with 100 ml cold xylene and the crystals dried under vacuum below 60° C. for several hours. The yield is 76.7-84.6 g (78-86% of theory). Average throughput 24.4 g/liter of solvent.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1)[NH2:2].[C:25]([C:27](=[C:37](SC)[S:38][CH3:39])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])#[N:26]>CO>[NH2:26][C:25]1[N:1]([C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=2)[N:2]=[C:37]([S:38][CH3:39])[C:27]=1[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]
Reactant: CSC(SC)=C(C#N)C(=O)Nc1ccccc1
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Solvent: CO
Product: CSc1nn(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)c(N)c1C(=O)Nc1ccccc1

Procedure:
A solution of 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.63 mmol) in methanol (6 ml) was heated with 2-cyano-3,3-bis(methylthio)-N-phenylacrylamide (0.5 g, 1.89 mmol), overnight, at 60-65° C. The solid that separated out was filtered and washed with isopropyl alcohol (3 ml) to yield the required product. 1H-NMR (CDCl3) δ: 1.98 (s, 3H), 6.96-7.57 (m, 15H), 7.25-7.30 (2H, D2O exchangeable), 8.86 (br, 1H, D2O exchangeable); MS m/z: 547.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8]C2CCNCC2)=[CH:4][C:3]=1[N+:17]([O-])=O.O.O.[Sn](Cl)Cl.[CH3:25][CH2:26]O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:17]2[CH2:26][CH2:25][CH2:16][CH2:2][CH2:3]2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(OCCC2CCNCC2)ccc1Cl
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 19 h
Yield: 92 %

Procedure:
4-(2-(4-chloro-3-nitrophenoxy)ethyl)piperidine (2.3 g, 8.1 mmol, 1 eq.) and tin (II) chloride dihydrate (9.1 g, 40.4 mmol, 5 eq.) were placed in EtOH (81 mL). The reaction mixture was heated at 60° C. and stirred for 19 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1N NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 2-chloro-5-(2-piperidinoethoxy)aniline (1.9 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]/[O:29]C)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CO/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-3-[(E)-2-(methyloxy)ethenyl]-1H-indole (D61) (1.2 g) in 1,4-dioxane (20 mL) stirred was added a solution of HCl (20 mL) in water. The reaction mixture was stirred at 20° C. for 30 mins. The reaction mixture was quenched with NaHCO3, partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated to give the crude product as a brown oil, which was purified by Mass Directed Auto Prep (basic) to afford [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (220 mg) as a white solid. δH (CDCl3, 400 MHz): 1.39 (6H, d), 3.70 (3H, s), 3.77 (2H, d), 4.66 (1H, m), 7.00 (2H, m), 7.17 (1H, t), 7.53 (1H, dd), 7.62 (1H, dd), 8.01 (1H, dd), 8.19 (1H, dd), 9.70 (1H, t). MS (ES): C22H20ClN3O3 requires 409. found 410.2 (M+H+).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:22](OCC)(OCC)OCC>>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:16])([F:18])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]2[CH:22]=[N:21][N:20]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(OCC)OCC
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2cnnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 227.3 %

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoformate (2 mL, 0.01 mol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder (0.1 g, 48%). LCMS calculated for C12H13F3N6O: (M+H) 315.1; found: 315.1.