Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([NH:28][N:29]1[C:33]([C:34]([O:36]C)=[O:35])=[C:32]2[CH2:38][CH2:39][CH2:40][CH2:41][C:31]2=[C:30]1[C:42]([O:44]C)=[O:43])(=[O:27])[CH3:26].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([NH:28][N:29]1[C:33]([C:34]([OH:36])=[O:35])=[C:32]2[CH2:38][CH2:39][CH2:40][CH2:41][C:31]2=[C:30]1[C:42]([OH:44])=[O:43])(=[O:27])[CH3:26]
Reactant: COC(=O)c1c2c(c(C(=O)OC)n1NC(C)=O)CCCC2
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nn1c(C(=O)O)c2c(c1C(=O)O)CCCC2

Procedure:
A reaction mixture was prepared containing 1.8 g. of dl-5-acetamido-1,3-di(carbomethoxy)-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole, 80 ml. of THF and 20 ml. of 2 N aqueous sodium hydroxide. The reaction mixture was heated to refluxing temperature under a nitrogen atmosphere for about 3 hours after which time it was cooled and the volatile constituents evaporated therefrom in vacuo. The residue was dissolved in 25 ml. of water and the aqueous solution made acidic by the addition of 1 N aqueous hydrochloric acid. The diacid, dl-5-acetamido-1,3-dicarboxy-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole, formed in the above hydrolysis being insoluble in the acidic layer precipitated and was collected by filtration. Recrystallization from a benzene-methanol solvent mixture yielded crystalline diacid melting at 233°-235° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
8-Chloro-3-methyl-3,7-dihydropurine-2,6-dione (200 mg) and potassium carbonate (152 mg) were suspended in N,N-dimethylformamide (10 ml), and benzyl bromide was added dropwise thereto while cooling on ice. The reaction mixture was left standing till reaching room temperature, and was stirred at room temperature for 13 hours. The resulting white suspension was diluted with ethyl acetate and water, and filtered to give 133 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[C:9]=2Cl)=[C:6]([CH3:17])[N:5]=[C:4]([N:18]([CH3:20])[CH3:19])[N:3]=1.[Cl:21]C1C=C(CC#N)C=CC=1Cl>>[CH3:19][N:18]([CH3:20])[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:21])=[C:12]([Cl:14])[CH:13]=2)=[C:6]([CH3:17])[N:5]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(N(C)C)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Product: Cc1nc(N(C)C)nc(N)c1-c1ccc(Cl)c(Cl)c1

Procedure:
This compound was made in an analogous manner to the compound of Example 13 from 3,4-dichlorophenylacetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:19].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[ClH:19].[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Oc1ccc(SC2CCCc3cccnc32)cc1
Yield: 49 %

Procedure:
A mixture of 4.0 g (15.6 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 40 ml of acetic anhydride was heated under reflux for 2 hours. A reagent was then removed under reduced pressure and the residue was subjected to flash chromatography (Kieselgel 60; 5% ethyl acetate in dichloromethane). The thick yellow oil thus obtained was treated with ethereal hydrogen chloride to yield 3.4 g (49%) of 8-(4-acetoxyphenylthio)-5,6,7,8-tetrahydroquinoline hydrochloride.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37](=[O:39])[NH2:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37](=[O:39])[NH2:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(C(N)=O)cc1NC(=O)c1c(N)ncnc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(N)=O)cc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 80 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.44 mmol), 4-amino-N-(5-carbamoyl-2-methoxyphenyl)-6-chloropyrimidine-5-carboxamide (216 mg, 0.67 mmol), DIEA (385 μl, 2.21 mmol) and cesium fluoride (134 mg, 0.88 mmol) were suspended in tert-butanol (7 ml) and the mixture was heated overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue (400 mg, 49% purity, 80% yield) was used in the next synthetic step without further purification.
Reaction SMILES: Br.[NH2:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]3[NH:12][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[C:9]3=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:16][C:14]1([CH3:15])[C:9]2[C:10](=[CH:11][C:5]3[NH:4][C:3]([NH:2][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:7][C:6]=3[CH:8]=2)[NH:12][C:13]1=[O:17]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(N)nc3cc21
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nc3cc4c(cc3[nH]2)NC(=O)C4(C)C)cc1

Procedure:
3 g. (10.1 mmole) 2-Amino-7,7-dimethyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrobromide are stirred with 2.5 g. p-anisoyl chloride in 50 ml. pyridine for 4 hours at 50° C. The pyridine is subsequently distilled off, the residue is worked up with water, decanted, worked up with ligroin and the residue recrystallised twice from ethanol to give 1.4 g. (40% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26](C=2CCl)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1.O=O>>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:20]([C:19]2[CH:28]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: ClCc1c2ccccc2cc2ccccc12
Agent: O=O
Product: c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
N,N'-Bisbenzyl spirodiamide 11 was obtained by diethyl ether extraction from the brine-DMSO reaction mixture in 80-93% yield. Bulkier derivatives N,N'-bis(diphenylmethyl)-spirodiamide 12 and N,N'-bis(9-anthracenylmethyl)-spirodiamide 13 have also been synthesized from diphenymethyl chloride and 9-anthracenylmethyl chloride, respectively. N,N'-bis(9-anthracenylmethyl)spirodiamide 13 was synthesized using the same method as bisbenzyl derivative 11 and isolated by column chromatography in 35% yield. The anthracenyl group in 13 is sensitive to oxygen, so analytically pure crystalline product was collected directly from fractions by cooling the chromatography fractions in a refrigerator under nitrogen. Diphenylmethyl chloride itself reacted with the basic equilibrium mixture of sodium methylsulfinylcarbanion and spirodiamide dianion in DMSO to produce a fluorescent product, tetraphenylethene. By employing a 100% excess of diphenylmethyl chloride, N,N'-bis(diphenylmethyl)-spirodiamide 12 was isolated by column chromatography in 22% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH3:12])[C:8](=[O:11])[NH:9][N:10]=1.Cl[C:14]1C=CC(C2N(CC)C(=O)NN=2)=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:14])[N:10]=1
Reactant: Cn1c(-c2cccs2)n[nH]c1=O
Reactant: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Product: Cn1nc(-c2cccs2)n(C)c1=O

Procedure:
When, in the procedure of Example 7, 5-(2-thienyl)-2,4-dihydro -4-methyl-3H-1,2,4-triazol-3-one is substituted for 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one, the title compound is obtained. Mp 108°-110° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[C:10](I)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH2:1]([CH:3]1[CH2:4][O:5][C:6]2[CH:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:7]=2[O:8]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCC1COc2ccc(I)cc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC1COc2ccc(C#N)cc2O1
Temperature: 80 °C
Yield: 92 %

Procedure:
A solution of 2-ethyl-7-iodo-2,3-dihydro-1,4-benzodioxine (486 mg, 1.68 mmol) in DMF (3 mL) is degassed by repeatedly evacuating the flask and filling with N2. Zn(CN)2 (117 mg, 1.0 mmol), and Pd(PPh3)4 (97 mg, 0.084 mmol) are added, and the resulting solution is degassed, and is then heated to 80° C. for 1.5 h. The reaction is allowed to cool, poured into water and extracted two times with ether. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (step gradient, 25-50% CH2Cl2 in hexanes) to give 3-ethyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile as a clear oil (296 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.16, 7.13, 6.91, 4.31, 4.05, 3.93, 1.7, 1.6, 1.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:22][CH:23]([OH:25])[CH3:24])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[OH:25][CH:23]([CH3:24])[CH2:22][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: CC(O)Cc1cc(Br)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Reactant: O=S([O-])c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(O)Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 120 °C
Yield: 39.3 %

Procedure:
A mixture of tert-butyl 8-bromo-6-(2-hydroxypropyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (110 mg, 0.27 mmol), sodium benzenesulfinate (53 mg, 0.32 mmol), di-palladium-tris(dibenzylideneacetone) (24 mg, 0.03 mmol), cesium carbonate (131 mg, 0.40 mmol) and xantphos (31 mg, 0.06 mmol) was suspended in anhydrous toluene (8 mL). The flask was purged with argon, sealed, and heated to 120° C. for 14 h. The reaction mixture was cooled, diluted with dichloromethane, and filtered through a celite bed. The filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 4:1 hexanes/ethyl acetate) to give tert-butyl 6-(2-hydroxypropyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (50 mg, 44%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00-7.92 (m, 3H), 7.71 (s, 1H), 7.58-7.45 (m, 3H), 4.56 (br s, 2H), 4.26-4.17 (m, 1H), 3.83 (s, 2H), 3.04 (t, J=3.9 Hz, 2H), 2.86 (br s, 2H), 1.51 (s, 9H), 1.25 (d, J=4.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)O)=[C:4]([CH2:15][CH3:16])[CH:3]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:11])[CH:13]=[CH:14][CH:10]2[OH:19])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: CCc1cc(Br)ccc1C1C(=O)C=CC1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4-bromo-2-ethylphenyl)furan-2-yl-methanol (13.6 g, 0.039 mol) in acetone (300 ml) and water (30 ml) at 55° C. is added polyphosphoric acid (5.0 g, 0.05 mol). After stirring at this temperature for 20 hours the reaction mixture is cooled to room temperature then concentrated in vacuo. The crude product is then partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic phase is separated. After drying over anhydrous magnesium sulfate, all solvents are removed and the crude product is purified by flash column chromatography (1:1 ethyl acetate/hexane) to afford 5-(4-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone as a brown gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:28])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[CH3:28]
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: Cc1nc(C(C)(C)N)no1
Product: COc1ccc(C(=O)NC(C)(C)c2noc(C)n2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81 c) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>CO>[CH3:17][N:18]([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)c2cncn2C)cn1
Temperature: 75 °C

Procedure:
In a 50-mL round-bottom flask was placed a solution of 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 22, step c), dimethylamine hydrochloride (96 mg, 1.2 mmol), and Et3N (342 mg, 3.39 mmol) in methanol (15 mL). The resulting mixture was heated at 75° C. overnight and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:0-20:1 CH2Cl2/MeOH) to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]#[N:14])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:5])[CH3:2].C(N(CC)CC)C>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([CH2:13][NH2:14])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC1CC(C)C
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1(CN)CC1CC(C)C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
To a solution of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid ethyl ester (0.41 g, 2.10 mmol) in 45 mL EtOH was added triethylamine (5.0 mL) and Raney nickel (1.0 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 18 hours, filtered, and concentrated. Flash chromatography of the residue (5→10% MeOH/CH2Cl2) provided 0.11 g (26%) of 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid ethyl ester as a colorless oil. 1H NMR δ 4.10 (q, J=7.1 Hz, 2H), 2.90 (d, J=14.2 Hz, 1H), 2.76 (d, J=14.2 Hz, 1H), 1.63 (m, 1H), 1.52 (m, 2H), 1.34 (m, 1H), 1.22 (t, J=7.1 Hz, 3H), 1.04 (m, 1H), 0.90 (m, 6H), 0.49 (m, 1H). 13C NMR δ 175.51, 60.75, 42.42, 37.92, 30.61, 29.04, 26.46, 22.91, 22.63, 21.31, 14.49.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](=O)([O:17]C)[O:15][CH3:16]>>[F:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12])[C:2]([CH2:1][C:14]([O:15][CH3:16])=[O:17])=[O:3]
Reactant: COC(=O)OC
Reactant: COc1c(F)cc(C(C)=O)cc1F
Product: COC(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Yield: 97 %

Procedure:
This compound was prepared from 3,5-difluoro-4-methoxyacetophenone and dimethyl carbonate according to method A. Yellow solid; Yield: 97%; mp 64–67° C.; 1H-NMR (300 MHz, CDCl3) δ 3.77 (s, 3H), 3.93 (s, 2H), 4.13 (t, J=1.7 Hz, 3H), 7.52 (m, 2H). Minor tautomer: 3.81 (s, 3H), 4.06 (m, 3H), 5.58 (s, 1H), 7.34 (m, 2H), 12.47 (s, 1H); MS (ESI) m/z 243 ([M−H]−), 245 ([M+H]+); Anal. Calcd for C11H10F2O4: C: 54.10, H: 4.13. Found: C: 54.37, H: 4.08.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[S:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[N:15]=1
Reactant: Cc1nc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: O=Cc1ccccc1Br
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: CN(C)C=O
Product: Cc1nc(-c2ccccc2C=O)cs1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of 2-bromobenzaldehyde (0.063 mL, 0.54 mmol) in DMF (5 mL) and H2O (1 mL) are added 2-methylthiazole-4-boronic acid pinacol ester (122 mg, 0.54 mmol), Pd(PPh3)4 (63 mg, 0.054 mmol) and K2CO3 (112 mg, 0.81 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The reaction is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2-methyl-thiazol-4-yl)-benzaldehyde (58 mg, 53%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][C:5]([N:8]=[C:9]=[O:10])=[N:6][N:7]=1.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[CH2:18][NH:19][CH3:20]>C1C=CC=CC=1>[F:12][C:2]([F:11])([F:1])[C:3]1[S:4][C:5]([NH:8][C:9]([N:19]([CH2:18][CH:14]2[O:15][CH2:16][CH2:17][O:13]2)[CH3:20])=[O:10])=[N:6][N:7]=1
Reactant: CNCC1OCCO1
Reactant: O=C=Nc1nnc(C(F)(F)F)s1
Solvent: c1ccccc1
Product: CN(CC1OCCO1)C(=O)Nc1nnc(C(F)(F)F)s1

Procedure:
2-Trifluoromethyl-1,3,4-thiadiazol-5-yl isocyanate dimer (3.1 grams) was added to a solution of N-(1,3-dioxolan-2-ylmethyl)-N-methylamine (2grams) in benzene (10 ml) contained in a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was heated on a steam bath for a period of about 1 hour. The mixture was then stripped of solvent under reduced pressure to yield a solid residue. The residue was recrystallized from an ether-pentane mixture to yield the desired product N-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)-N'-(1,3-dioxolan-2-ylmethyl)-N'-methylurea having a melting point of 114° to 115°C.
Reaction SMILES: [P:1]([CH2:5][N:6](CC(O)=O)[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].OO>O>[P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: OO
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 65 °C

Procedure:
To 100 mL of water, 5 g of an activated carbon shown in Table 1 and 20.0 g of N-(phosphonomethyl)iminodiacetic acid were added. Into the mixture, 20.0 g of a hydrogen peroxide aqueous solution having a concentration of 30% by mass was added dropwise over 3 hours at 65° C. under stirring while maintaining the temperature of 65° C. After the completion of the dropping, the resulting mixture was maintained for 1 hour, and N-(phosphonomethyl)glycine was then isolated as a crystal. The isolated crystal was quantitatively determined by a high-speed liquid chromatography, and the weight yield and purity were measured.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].O.Cl[CH2:15][CH2:16][OH:17]>C(O)CCC>[OH:17][CH2:16][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCO
Temperature: 100 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
10 g (71.88 mmol) 2-nitrophenol A1 and 3.59 g (89.86 mmol) sodium hydroxide were dissolved in 55 ml n-butanol and 5 ml water at 70° C., 6.26 ml (7.52 g, 93.44 mmol) 2-chloroethanol were slowly added drop by drop. This was followed by three days of vigorous stirring at 100° C. After cooling, the reaction mixture was filtrated, the precipitate washed with chloroform and the filtrate reduced. The residue was taken up in chloroform and washed three times with aqueous 10% sodium hydroxide solution. Then the organic phase was dried over sodium sulfate and was concentrated in vacuo. 10.8 g of bright yellow crystals were obtained; yield 82%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>C(O)C.O>[CH2:20]([NH:27][C:28](=[S:29])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:18]=[CH:19][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)NCc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (1.5 g, 0.005 mole) was dissolved in hot ethanol (30 ml) under a nitrogen atmosphere. Benzyl isothiocyanate (0.82 g, 0.0055 mole) and potassium acetate (0.6 g, 0.006 mole) were added and the mixture was refluxed under nitrogen for two hours. The reaction mixture was cooled to room temperature, diluted with water (10-15ml.) and chilled in ice. The product was filtered off, washed with ethanol and dried. Recrystallization of the product from acetonitrile gave an off-white solid. Yield 1.25 g (62%), m.p. 197°-199° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10].C(O[C:14]([S-])=[S:15])C.[K+].[OH-].[K+]>C(O)C>[SH:15][C:14]1[O:10][C:4]2[CH:5]=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1ccc(O)cc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc2nc(S)oc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
A suspension of 4-aminobenzene-1,3-diol hydrochloride (25.6 g), potassium ethylxanthate (76.1 g) and potassium hydroxide (13.3 g) in ethanol (450 mL) was stirred for 16 hr with heating under reflux. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure, water (400 mL) was added thereto and the insoluble material was filtered through celite. To the filtrate were added 6 M hydrochloric acid (40 mL), and then 1 M hydrochloric acid (300 mL). The precipitate was collected, and washed successively with water, acetonitrile and diisopropyl ether to give the title compound (16.8 g).