Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](=[CH2:33])[CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=[CH2:10])=[O:6].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=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].ClCCl>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[C:2](=[CH2:33])[CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Reactant: OB(O)c1cccc(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)c1cccc(F)c1F)Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (0.726 g, 0.889 mmol) was added to a solution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (9.2 g, 17.8 mmol), 2,3-difluorophenylboronic acid (2.95 g, 18.7 mmol) and sodium carbonate (2 M in water; 19.6 mL, 39.1 mmol) in N,N-dimethylformamide (60 mL) and heated to 75 □C. After 2 h, the mixture was allowed to cool to ambient temperature and extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→55% ethyl acetate/hexanes) gave the title compound (6.8 g). MS 551.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].CN1CCOCC1.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3[NH:22][CH2:23][C@@H:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: COC(=O)c1cccc2nc(-c3c(Cl)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 85 °C
Yield: 71.7 %

Procedure:
In a 40 mL vial, 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester (0.91 g, 3.00 mmol), (S)-2-amino-1-phenylethanol (822 mg, 5.99 mmol) and N-methylmorpholine (909 mg, 988 μL, 8.99 mmol) were combined with DMF (20 mL) to give a black suspension. The vial was sealed and heated in a dry block at 85° C. for 6.5 hr and allowed to cool to room temperature over the weekend. The reaction was diluted with water and the resulting precipitate was washed with water and hexanes yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester (0.87 g, 71.8% yield) as a light purple solid. LC/MS calcd for C22H20N4O4 (m/e) 404.0, obsd 405.2 (M+H); 1H NMR (DMSO-d6) δ: 13.53 (s, 1H), 11.26 (d, J=5.8 Hz, 1H), 10.85 (t, J=5.1 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.76-7.82 (m, 1H), 7.55 (d, J=7.3 Hz, 2H), 7.34-7.42 (m, 3H), 7.26-7.34 (m, 2H), 6.22 (d, J=7.5 Hz, 1H), 5.80 (d, J=4.5 Hz, 1H), 4.85-5.00 (m, 1H), 3.98 (s, 3H), 3.64-3.77 (m, 1H), 3.53-3.63 (m, 1H).
Reaction SMILES: Cl.O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(O)(=O)C.C1([NH:24]N)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.Cl[Pt-2](Cl)(Cl)Cl.[K+].[K+]>[NH2:24][CH2:3][C@H:4]([NH2:5])[C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7]
Reactant: NNc1ccccc1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl[Pt-2](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: NC[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 4 °C
Reaction time: 8 h

Procedure:
A solution of 20 g of glucosamine hydrochloride, 20 ml of glacial acetic acid, 80 ml of water and 9.1 ml of phenylhydrazine was heated on a steam bath for one hour, then cooled and filtered. The filtrate was hydrogenated in a Parr apparatus with Raney nickel catalyst until the uptake of hydrogen ceased. This mixture was then filtered, the filtrate was treated with activated charcoal and refiltered through diatomaceous earth, giving a green solution. A 6.31 ml portion of this green solution was treated with 0.24 g of sodium bicarbonate and a suspension of 1.66 g of potassium tetrachloroplatinate in 8 ml of water. The resulting reddish brown solution was stirred overnight, then cooled to 4° C. for 3 hours and the resulting solid collected. A 100 mg portion of this solid was stirred with 15 ml of hot water and then filtered through diatomaceous earth. The filtrate was cooled giving a solid which was collected, giving 90 mg of 1,2-diamino-1,2-dideoxy-D-glucitol, compound with platinum chloride (1:1) as yellow grains, mp 265° C. (dec.).
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.BrCCCC1C=CC(F)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)N)=[CH:25][CH:24]=1.C(OC(OCC)CCCNC)C.ClC1C=C2[C:60](=CC=1)[N:59]([CH2:63][CH2:64][CH2:65][C:66]1[CH:71]=CC(F)=CC=1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:22][C:23]1[CH:28]=[C:27]2[C:26](=[CH:25][CH:24]=1)[N:29]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:66]1[CH2:71][N:59]([CH3:60])[CH2:63][CH2:64][C:65]2=1
Reactant: CNCCc1cn(CCCc2ccc(F)cc2)c2ccc(Cl)cc12
Reactant: NN(CCCc1ccc(F)cc1)c1ccc(Cl)cc1
Agent: C=O
Agent: CCOC(CCCNC)OCC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(n(CCCc3ccc(F)cc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 1-(3-bromopropyl)-4-fluorobenzene, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(3-(4-fluorophenyl)propyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(3-(4-fluorophenyl)propyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29](=O)[C:28]3[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=3[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:42][NH2:43]>CO>[CH3:12][N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:29]3=[N:42][NH:43][C:31](=[O:32])[C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=43)[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:19]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, 0.94 mmol) in hydrazine monohydrate (50 mL) and methanol (5 mL) was stirred at 40° C. for 24 hr. The mixture was cooled to room temperature and filtered to give the crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give benzyl methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate (80 mg, yield 16%). LC-MS (ESI) m/z: 517 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.CC([O-])=O.[Na+].[NH2:16][OH:17].Cl>CCO>[Cl:1][C:2]1[C:7]([CH:8]=[N:16][OH:17])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,6-dichloropyrimidine-5-carbaldehyde (8.00 g, 44.8 mmol), NaOAc (3.7 g, 1.0 eq) and NH2OH.HCl (3.1 g, 1.0 eq) in EtOH (320 mL) was stirred at rt for 2 h. The reaction mixture was filtered, concd and purified by column chromatography on silica gel (dry loading, first DCM then DCM/EtOAc, 1/9) to give 4,6-dichloropyrimidine-5-carbaldehyde oxime as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]([N:14]2[N:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][C:15]2=[O:23])=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[Cl:3][C:4]1[C:13]([N:14]2[N:18]=[C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:16][C:15]2=[O:23])=[CH:12][C:7]2[N:8]([CH2:26][CH:25]=[CH2:24])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: C#CCBr
Reactant: CC(C)(C)c1nn(-c2cc3[nH]c(=O)sc3cc2Cl)c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)sc2cc(Cl)c(-n3nc(C(C)(C)C)oc3=O)cc21
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A dispersion of sodium hydride (50% oil; 0.16 g) in dry N,N-dimethylformamide (3 ml) was cooled to 0° C., and a solution of 3-[6-chloro-2(3H)-benzothiazolon-5-yl]-5-(1,1-dimethylethyl) -1,3,4-oxadiazol-2(3H)-one (1.00 g) in dry N,N-dimethylformamide (3 ml) was dropwise added thereto at the same temperature, followed by stirring at the same temperature for 30 minutes. Upon addition of propargyl bromide (0.44 g), the resultant mixture was heated to 50° C. and stirred for 5 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ether and hexane (1 : 1) as an eluent to give 3-[6-chloro-3-(2-propenyl)-2(3H)-benzothiazolon-5-yl] -5-(1,1-dimethylethyl)-1,3,4-oxadiazol -2(3H)-one (0.28 g). nD25.5 1.5703.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:28]C)[CH2:24][CH2:25][CH2:26]Cl)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[N:7]([CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:21])[C:6]=2[N:18]=1
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Reactant: CCN(CC)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN(C)C)c1ccccc1N(C)C2=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 70 ml of dimethyl formamide and 1.9 gm of 50% sodium hydride in mineral oil was stirred at 30°-50° C. in a nitrogen atmosphere for 30 minutes. Then, a solution of 6.1 gm of 3-diethylamino-propyl chloride in 30 ml of dimethyl formamide was added dropwise, and the mixture was heated on an oil bath at 120° C. for 3 hours and then evaporated in vacuo. The residue was mixed with an aqueous potassium carbonate solution, and the mixture was extracted with ether. The ethereal phase was dried with sodium sulfate and evaporated, and the residue was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 76% of theory of the compound named in the heading, which had a melting point of 130°-131° C.
Reaction SMILES: [Na+].[Cl-].[CH:3]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:4][CH2:3][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOC(=O)C(CO)Cc1ccc2c(c1)OCO2
Temperature: 37 °C
Reaction time: 18 h

Procedure:
Each type of the Recombinant Escherichia coli shown in Table 6 was inoculated in 50 ml of 2×YT medium (containing 1.6% of tripeptone, 1.0% of yeast extract, and 0.5% of NaCl, pH=7.0) sterilized in a 500-ml Sakaguchi Flask, and incubated while shaking at 37° C. for 18 hours. To 1 ml of the resultant culture solution, 10 mg of ethyl 2-formyl-3-(3,4-methylenedioxyphenyl)-propionate, 1 mg of NAD (or NADP), and 10 mg of glucose were added and the mixture was stirred at 30° C. for 2 hours. After completion of the reaction, the conversion rate and optical purity of the product were analyzed in the same manner as in Example 9. The results are shown in Table 6 (The conversion rates are all 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Temperature: 80 °C
Yield: 64 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(9-phenylnonoxy) quinoline (11 g, 0.025 mol), degreased 40 mesh Fe filings (30 g), H2O (100 ml), HOAc (20 ml) and n-Bu2O (20 ml) was heated at 80° C. for 2 h, cooled and filtered. The solid residue and the filtrate were thoroughly extracted with warm Et2O and the combined extracts were dried (Na2SO4), treated with Darco, and concentrated. The resulting solid was dissolved in pet ether (Darco) and cooled in dry ice - Me2CO to give 6.5 g (64%) of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline as pale yellow crystals, mp 32°-32.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH3:35])[CH:3]=1)([CH3:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 85 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in anhydrous acetonitrile (10.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed for 12 hr at 85° C. After concentration under reduced pressure, the solution was separated through the silica gel chromatography (30% EtOAc) so that ivoty solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (43.5 mg, 42.2%).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[CH:18]=[N:17]2)=[CH:13][CH:12]=1>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][C:25]=3[Cl:8])[CH:18]=[N:17]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2cc(-c3csc(N)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3nc(N)sc3Cl)cn2)cc1
Yield: 28.9 %

Procedure:
According to Scheme 6, Step 2: NCS (8.14 mmol, 1.09 g) was added to a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14 mmol, 2.33 g) in acetonitrile (20 mL) and the reaction mixture was stirred under reflux for 1.5 hour. After evaporation of the solvent, the crude residue was diluted in EtOAc. The organic phase was washed with water and brine, was dried over Na2SO4, was filtered and was concentrated. The crude mixture was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 90:10) as eluent to yield 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-amine (2.35 mmol, 755 mg, 29%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:24](Cl)(=O)=O.I(Cl)(=O)=O.C[NH+](C)C>CO.C1COCC1>[I:24][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:18])[C:4]3[CH2:5][CH2:6][N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Agent: C[NH+](C)C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (4.17 g, 17.0 mmol) was dissolved in methanol-THF solution (34 ml, 1:1). To the mixture was added calcium carbonate (2.21 g, 22.1 mmol) and then trimethylammonium dichloroiodate (6.51 g, 18.7 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was combined a 10% aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 5.52 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 6-aminonicotinic acid methyl ester (4 g) in pyridine (40 ml) is added with stirring 2-methylbenzoyl chloride (6.73 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dried to give 6-(2-methylbenzoylamino)nicotinic acid methyl ester (5.7 g) as white powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:15]3[N:14]=[C:13]([Cl:18])[N:12]=[C:11]([Cl:10])[N:16]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 5-Cyclopropyl-2H-pyrazol-3-ylamine (334 mg, 2.71 mmol) in 2 ml of THF was added dropwise to a solution of 2,4,6-Trichloro-[1,3,5]triazine (500 mg, 2.71 mmol) in 5 ml of THF at room temperature. After 1 hour, the precipitate was collected to afford 370 mg (50.4% yield) of the desired product.
Reaction SMILES: [Si]([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4=[N:26][S:27](=[O:31])(=[O:30])[CH2:28][CH2:29][N:24]4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1>[O:31]=[S:27]1(=[O:30])[CH2:28][CH2:29][N:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]4[CH:32]=[CH:33][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:15][CH:16]=3)[C:25]2=[N:26]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(O)cc4)cc3)C2=N1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 9-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (1.82 g) in THF (dry) (55 mL) was added to tetrabutylammonium fluoride (1 M in THF) (6.79 mL) at room temperature. After stirring for 0.5 hr, the mixture was added with sat. NH4Cl aq. and silica gel, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane then MeOH in EtOAc), recrystallized from THF-IPE, then preparative HPLC (C18, eluent; H2O/MeCN with 0.1% TFA). The collected fraction was concentrated in vacuo. The residue was recrystallized from MeCN—H2O to give the title compound (492 mg) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[CH:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>O1CCCC1>[CH:26]1([N:25]([CH:23]([CH:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)[CH3:24])[C:8]([C:7]2[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=2[F:11])=[O:9])[CH2:28][CH2:27]1
Reactant: CC(NC1CC1)C1Cc2ccccc2C1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C1Cc2ccccc2C1)N(C(=O)c1c(C(F)F)nn(C)c1F)C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
At ambient temperature, a solution of 217 mg (1.02 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 202 mg (0.93 mmol) of N-[1-(indan-2-yl)ethyl]cyclopropanamine and 103 mg (1.02 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 1 hr at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×150 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and filtered over a chemelut™ cardridge to yield after concentration 190 mg of a beige oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 120 mg (30% yield) of N-cyclopropyl-3-(difluoromethyl)-N-[1-(indan-2-yl)ethyl]-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a colourless oil (M+H=378).