Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](Br)[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:17][C:18]([F:38])([F:37])[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)=[O:20]>CCOCC.C1COCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)([OH:20])[C:18]([F:37])([F:17])[F:38])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C=CCn1cc(Br)c(C#N)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c(C#N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a chilled (−78° C.) solution of 1-allyl-4-bromo-1H-pyrazole-3-carbonitrile (116.6 mg, 0.550 mmol) in dry ether (2 mL) was added n-BuLi (190 pt, 2.5 M in hexanes, 0.475 mmol). After 2 minutes a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.500 mmol) in THF (2 mL) was added. After 15 minutes, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO2 (0-50% ethyl acetate in hexanes, gradient) to give 152 mg (69%) of the title compound. MS m/z 422.96 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl.CC1C=C(C2OC(C)=NN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[NH2:9]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCCl
Agent: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Agent: Cl
Product: COc1ccc(N)cc1OCCCN(C)C

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 3-dimethyaminopropyl chloride hydrochloride using a similar procedure to Descriptions 1 and 2 (58%).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C3C=C([C:17](O)=[O:18])C=NC=3)=CC=2N=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:17]=[O:18])[CH2:29][CH2:28]1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C=O)CC1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40, mg) was reacted with 1-methylpiperizine via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone (48 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 14.6 mg of 348. MS (Q1) 541.1 (M)+
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)NCc3cccc4ccccc34)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 1-naphthylmethylamine (187 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (170 mg, yield 91%) as a white solid which was recrystallized from dichloromethane-hexane to give white powdery crystals.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[OH:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:3]([CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13][CH2:14][CH2:15][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: O=C(O)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2C(=O)O)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-hydroxy-benzoic acid via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H22O7 [M+H]+: 375.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cccnc1CN1CCCC1
Agent: [Na]
Product: CC1CCCNC1CN1CCCC1
Temperature: 0 °C

Procedure:
g 6 (0.034 moles) of 3-methyl-2-(pyrrolidin-1-yl)methyl pyridine were dissolved in 120 ml of isoamilic alcohol and under nitrogen atmosphere, at 120° C., g 4.8 (0.21 moles) of sodium were added in small portions during 4 hours. The yellow solution obtained was kept at 120° C. for an additional hour, and then cooled and poured in 30 g of ice. The organic layer was separated and the acqueous layer was extracted twice with ether; the combined organic layer was then extracted with two 80 ml portions of HCl 37%; the acqueous layer was washed with ether and evaporated i.v. The residue was taken up in 10 ml of 40% acqueous NaOH and extracted with two 50 ml portions of ether. The combined ether extracts were then dried over anhydrous magnesium sulfate. Removal of the ether yields 3.8 g of crude product as diastereoisomeric mixture. Diast A/Diast B=72/22.4 (GLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=C(C)O[N:34]=3)=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=2)[CH:4]=1.O.[C:40]([OH:43])(=[O:42])[CH3:41].FC(F)(F)C(O)=O.C(C1C=CC(NC(C2C=C(OC)C(OC)=CC=2F)C2NC(=O)N(C3C=CC=CC=3C(O)=O)N=2)=CC=1)(=N)N>CO.[Fe]>[C:40]([OH:43])(=[O:42])[CH3:41].[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH2:37])=[NH:34])=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:18]=2)[CH:4]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Agent: [Fe]
Agent: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 814 mg of 5-{(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 15 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 1g of iron powder, and the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. After adding 7.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent to the reaction mixture, the mixture was further stirred at 60° C. for 5 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (476 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=12.Cl[C:28]1C=CN=C2C=C(C(N(C)N(C)C)=O)SC=12>>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]([CH3:28])[N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=12
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 66 %

Procedure:
Following the procedure described above for compound 238 (step 2, example 95, scheme 63) but replacing chloride 237 with compound 242, title compound 243 was obtained in 66% yield. MS (m/z): (M+1) 391.1 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].OO.S([O-])([O-])=[O:26].[Na+].[Na+]>C(O)C(F)(F)F>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([S:20]([CH3:21])=[O:26])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(SC)c2F)nc(N)c1Cl
Agent: OO
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: COC(=O)c1nc(-c2ccc(Cl)c(S(C)=O)c2F)nc(N)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylthio-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.4 g, 6.63 mmol) was dissolved with heating in a minimum amount of trifluoroethanol (50 mL). After allowing the reaction mixture to cool to room temperature, 30% hydrogen peroxide (3.0 mL, 26.5 mmol) was added and the reaction mixture was stirred for 2 days. An aqueous solution of sodium sulfite (10% solution) was added to quench excess oxidant (exotherm noted) and the reaction mixture was stirred for 1 hour. Additional water was then added and the reaction mixture was filtered. The precipitate was found to be pure 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methanesulfinylphenyl)pyrimidine-4-carboxylic acid methyl ester (2.13 g, 85% yield): mp 256-258° C.: 1H NMR (CDCl3): δ 8.03 (dd, 1H), 7.54 (dd, 1H), 3.92 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH:12]1[C:20](O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:15][CH2:14][CH2:13][CH:12]1[C:20](=[O:21])[O:18][C:17]2=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Piperidine-1,2,6-tricarboxylic acid 1-benzyl ester (Compound 1, 19.7 g, 64.11 mmol) was suspended in acetic anhydride (80 mL, 848 mmol) in a dry 250-mL round-bottom flask. The mixture was stirred at 70° C. for 30 minutes until a clear solution formed. The remaining acetic anhydride was removed in vacuo, to afford Compound 2 (18.5 g, 100%) as a clear oil. The material was of sufficiently good quality to be used in the next reaction without purification. The product was sensitive to water, so it was prepared for immediate use in the next step. 1H NMR: δ 1.57-2.01 (cm, 6H), 5.14 (s, 2H), 5.17 (s, 2H), 7.32-7.37 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12.[CH:16](OCC)(OCC)OCC>>[CH2:14]([N:11]1[C:4]2[N:5]=[CH:6][C:7]3[C:8](=[O:9])[N:10]=[CH:16][NH:1][C:2]=3[C:3]=2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCn1ncc2c(N)c(C(N)=O)cnc21
Reactant: CCOC(OCC)OCC
Product: CCn1ncc2c3[nH]cnc(=O)c3cnc21
Reaction time: 24 h

Procedure:
20.5 g. of 4-amino-1-ethylpyrazolo[3,4-b]pyridin-5-carboxamide are refluxed with stirring for 24 hours with 100 ml. of triethyl orthoformate. The excess ester is removed in vacuo and the residue recrystallized from dimethylformamide to obtain 7-ethyl-1,7-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one, yield: 19 g. (88%); m.p. 320°-322°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:25]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)=[CH:24][CH:23]=[CH:22][C:21]=3[CH:33]3[CH2:35][CH2:34]3)=[C:14]([CH3:36])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:37]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:37])[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:25]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)=[CH:24][CH:23]=[CH:22][C:21]=3[CH:33]3[CH2:34][CH2:35]3)=[C:14]([CH3:36])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1[nH]nc(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)c1C
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1c(C)c(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)nn1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
At room temperature, to a mixture of 4-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3-methyl-2,4-dioxo-butyric acid ethyl ester (described in Reference Preparation example 115) 5.5 g, tetrahydrofuran 100 ml was added hydrazine one hydrate 0.56 g and the resulting mixture was stirred for twelve hours. The reaction mixture was concentrated under reduced pressure to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g. Next, the mixture of the above-mentioned 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g, toluene 70 ml and dimethyl sulfate 3.8 g was stirred at 100° C. for three hours. To the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester 1.4 g (hereinafter, referred to as “Present compound 48”).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:24]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCCCc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCc1ccc(O)cc1

Procedure:
A mixture of 31.8 gms 9(4-hydroxyphenyl)-nonanoic acid, 15 gm molecular sieves (3A), 320 ml methanol, and 5 ml H2SO4 was refluxed for 48 hrs. The reaction mixture was cooled, filtered through diatomaceous earth, and the methanol removed in vacuo. The residue was dissolved in CHCl3, washed twice with 5% NaHCO3, twice with water, and once with NaCl solution. The aqueous phase was back-washed with ether. The organic layers were filtered, combined, dried over MgSO4, treated with decolorizing carbon, and filtered through diatomaceous earth. The solvents were removed in vacuo and the resulting solid was crystallized from hexanes:CH2Cl2 to give 23.5 gms of product, mp. 52°-4°. A further 4 gms ester was recovered from the mother liquors, after a second crystallization.
Reaction SMILES: N.[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11]C(OC)=O)=[CH:6][C:4]=1[NH2:5]>C(O)C.O>[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:4]=1[NH2:5]
Reactant: COC(=O)Oc1cc(N)c(F)cc1F
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1cc(O)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Concentrated aqueous ammonia (20 ml) was added to a solution of 2,4-difluoro-5-methoxycarbonyloxyaniline (2.0 g, 9.85 mmol) in ethanol (100 ml) and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and most of the organic volatiles were removed by evaporation. The aqueous residue was neutralised to pH7 and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation to give 2,4-difluoro-5-hydroxyaniline (1.2 g, 85%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.B([O-])([O-])[O-].Br[C:31]1[C:35](=[O:36])[N:34]([CH3:37])[C:33](=[O:38])[C:32]=1[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]([CH3:49])[CH:41]=1>[Pd].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]>[C:2]1([C:31]2[C:35](=[O:36])[N:34]([CH3:37])[C:33](=[O:38])[C:32]=2[CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]([CH3:49])[CH:41]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CN1C(=O)C(Br)=C(Cc2cn(C)c3ccccc23)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Product: CN1C(=O)C(Cc2cn(C)c3ccccc23)=C(c2ccccc2)C1=O

Procedure:
Treatment of an iodobenzene of formula 11 with bis(pinacolato)diborane in the presence of a palladium catalyst such as PdCl2(dppf), followed by coupling of the resulting borate with a 4-bromo-3-(1-methylindol-3-ylmethyl)-1-methyl-pyrrole-2,5-dione 12 under Suzuki reaction conditions provides a 4-phenyl-3-(1-methylindol-3-ylmethyl)-1-methylpyrrole-2,5-dione 13. Compounds of formula 12 can be prepared by methods well known in the art. For example, 4-bromo-3-(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione can be prepared by method described in Brenner, M. et al., Tet. Lett., 44, 2887, (1988).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([NH2:16])([CH3:15])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:4]1([CH3:15])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([OH:18])[CH:20]=2)[NH:16]1)=[O:17]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)Cc2c([nH]c3ccccc23)C(c2cccc(O)c2)N1
Yield: 14 %

Procedure:
1.00 g (4.30 mmol) of the commercially available 2-amino-3-(1H-indol-3-yl)-2-methyl-propionic acid methyl ester are reacted with 600 mg (4.73 mmol) 3-hydroxy-benzaldehyde in the presence of trifluoroacetic acid according to the Pictet-Spengler reaction. The resulting mixture of diastereomers is separated by column chromatography (toluene, ethyl acetate 4:1). 1.17 g (68%) of the title compound and 320 mg (14%) of (1SR,3SR)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester (compound A2) are obtained as white solids.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([OH:17])[C:15]#[N:16])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH3:19][OH:20].[ClH:21]>C(Cl)Cl.O1CCOCC1>[ClH:21].[F:1][CH:2]([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([OH:17])[C:15](=[NH:16])[O:20][CH3:19])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: CO
Reactant: N#CC(O)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=N)C(O)c1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 132B (308 mg, 1.16 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added MeOH (0.3 mL) and 4.0 N HCl in dioxane (1.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. The solvent was removed to give methyl 2-(3,4-bis(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (5.0 mL) was added H2O (5.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 132C (160 mg, 46% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.23 (s, 1H) 6.81 (t, J=73.60 Hz, 2H) 7.26-7.38 (m, 2H) 7.40 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[O:10][C@@H:9]1[CH2:11][OH:12].[N+:13]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C1OC1CO>ClCCl>[CH2:8]1[O:10][C@@H:9]1[CH2:11][O:12][S:22]([C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=[CH:20][CH:19]=1)(=[O:23])=[O:24]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: OCC1CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 ml rounded bottom flask was charged with triethylamine (3.3 g, 4.5 ml, 32 mmol), R-glycidol (2.0 g, 27 mmol)(Arco Company, Newton Square, PA) and dichloromethane (50 ml) then cooled to 0° C. A solution of 3-nitrobenzenesulfonyl chloride (6.0 g, 27 mmol) in dichloromethane (40 ml) was added dropwise over a 5-minute period to the glycidol solution and the reaction mixture was stirred at 0° C. under N2 for 3 hrs. The reaction mixture was poured into a separatory funnel and washed successively with 1N aqueous hydrochloric acid (90 ml), 5% aqueous sodium bicarbonate solution (90 ml), and saturated aqueous sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to yield (2S)-(+)-glycidyl-3-nitrobenzenesulfonate as a pale colored solid. Recrystallization from hexanes/EtOAc (1:1, 50 ml) provided 5.89 g (83%) of pure (2S)-(+)-glycidyl- 3-nitrobenzenesulfonate, m.p. 61°-63° C., [α]D +22.3° (c 0.41, chloroform), >95% optical purity.
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([OH:14])[CH:7]=1)=[CH:4][CH3:5])[CH3:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CC(C)=O.CN(C=O)C>[CH2:20]([O:19][C:17]([C:16]1[O:14][C:8]2[CH:7]=[C:6]([C:3]([CH2:1][CH3:2])=[CH:4][CH3:5])[CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:18])[CH3:21]
Reactant: CC=C(CC)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC=C(CC)c1ccc2cc(C(=O)OCC)oc2c1
Yield: 76.9 %

Procedure:
4-(1-Ethyl-propenyl)-2-hydroxy-benzaldehyde (9.00 g, 47.3 mmol) and ethyl bromoacetate (9.88 g, 59.1 mmol) and K2CO3 (13.1 g, 94.6 mmol) in acetone (100 mL) followed by DBU (mL) and DMF (40 mL) are reacted analogous to Example 30-B to give the title compound (9.40 g, 77%).