Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)[CH3:10].C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: CCOc1ccccc1B(O)O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccccc1-c1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (6.0 g, 0.04 mol) and 2-ethoxyphenylboronic acid (4.81 g, 0.029 mol) in mixture of dimethoxyethane (120 mL) and water (18 mL) were added NaHCO3 (6.72 g, 0.08 mol) and (PPh3)2PdCl2 (0.84 g) and the reaction mixture was allowed to reflux for 8 h, then it was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), the resulting solution was washed with water (20 mL), dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica (eluent CH2Cl2) and recrystallized from hexanes. Yield of 4-chloro-6-(2-ethoxyphenyl)-pyrimidine 4.97 g (73%).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]1[CH2:51][CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]1)=O>>[O:49]1[C:45]2([CH2:50][CH2:51][N:42]([CH2:40][CH2:39][O:10][C:8]3[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=4[CH:12]4[CH2:21][CH2:20][C:19]5[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=5[CH2:13]4)=[CH:6][CH:7]=3)[CH2:43][CH2:44]2)[O:46][CH2:47][CH2:48]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)c1
Yield: 37.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (23 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.6 mg) was obtained.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C(OC(C)C)(C)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CC(C)OC(C)C
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 362.5 %

Procedure:
A solution which contained 4.0 g R-(+)-thioctic acid and 16.0 g S-(-)-thioctic acid in 80 ml diisopropyl ether was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 14.5 g thioctic acid were obtained in the novel modification as first crystallizate. The S-(-)thioctic acid content was 75.8% with a melting range of 50 to 56° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=1>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH:26]=2)[NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:41])=[CH:38][CH:37]=1)#[N:40]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc(C(=O)Nc2cccc(N)c2)cc1
Product: COc1cc2c(Nc3cccc(NC(=O)c4ccc(C#N)cc4)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-aminophenyl)-4-cyanobenzamide. The material so obtained was purified by column chromatography eluting with 85:10:5 methylene chloride/methanol/isopropylamine. The material so obtained was triturated under diethyl ether to give the title compound in 48% yield; NMR: 2.1 (m, 2H), 3.35-3.45 (m, 4H), 3.7-3.8 (m, 8H), 3.98 (s, 3H), 4.22 (m, 2H), 7.2 (s, 1H), 7.38 (m, 1H), 7.51 (m, 1H), 7.58 (m, 1H), 7.93 (s, 1H), 8.04 (d, 2H), 8.13 (d, 2H), 8.31 (s, 1H), 8.46 (s, 1H), 9.59 (s, 1H); Mass: M+H+ 539.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[O:12][CH2:13][CH2:14][C@H:15]1[CH2:19][O:18][C:17]([NH2:20])=[N:16]1)C1C=CC=CC=1>CO.[Pd]>[NH2:20][C:17]1[O:18][CH2:19][C@H:15]([CH2:14][CH2:13][O:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:23]=[CH:22][CH:21]=2)[N:16]=1
Reactant: NC1=N[C@@H](CCOc2cccc(OCc3ccccc3)c2)CO1
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@@H](CCOc2cccc(O)c2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of (S)-4-[2-(3-benzyloxy-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine (0.04 g) at room temperature in methanol (2 ml) under an argon atmosphere was added palladium on charcoal (10%, 15 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The catalyst was filtered off, the filtrate was concentrated and purified by column chromatography to give 3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-phenol (0.018 g) as a light yellow oil. MS (ISP): 223.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:6]([Cl:7])=[N:5][S:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1(C)C=CC=CC=1.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>[Cl:7][C:6]1[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3][S:4][N:5]=1
Reactant: Clc1nsnc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccccc1
Reaction time: 26 h
Yield: 91.5 %

Procedure:
To a mixture of 3-bromo-4-chloro-1,2,5-thiadiazole (0.2 g, 1 mmol), phenylboronic acid (0.135 g, 1.1 mol) in toluene (5 ml) is added a 1M aqueous solution of KF (3 cc, 3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol, 5%mol) and the biphasic mixture is refluxed with vigorous stirring for 26 hours. The organic layer is decanted off and the aqueous layer is extracted with toluene (2×10 ml). After drying over magnesium sulfate and concentration under vacuum, the oily material is purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (99/1) to afford 0.18 g (95%) of 3-chloro-4-phenyl-1,2,5-thiadiazole as a colorless oil, which crystallizes on standing (melting point 33° C.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)[nH]n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)[nH]n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of N-tert-butyl-2-(3-methyl-1H-pyrazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 56.4 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (129 mg, 86.8 μL, 1.13 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 1 h. Purification by chromatography (silica, 20-50% [10% methanol/dichloromethane/0.5% ammonium hydroxide]/dichloromethane) gave N-tert-butyl-2-(3-methyl-1H-pyrazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 31.9 μmol, 57%) as a light brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.19 (s, 1H), 10.12 (s, 1H), 9.53 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=3.0, 1 H), 7.81 (s, 1H), 6.33 (s, 1H), 2.19 (s, 3H), 1.45 (s, 9H); MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:28][CH:29]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]([O:32]CC)=[O:31])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:28][CH:29]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]([OH:32])=[O:31])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)c([N+](=O)[O-])c1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1[N+](=O)[O-])c1ccc(-c2ccccn2)cc1
Yield: 64.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[3-nitro-4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-phenoxypropionate (223 mg), which is the product of Example 165, was reacted with aqueous sodium hydroxide solution (1N, 0.80 ml) and the reaction mixture was treated to give the title compound (137 mg) as colorless crystals.
Reaction SMILES: C[C:2]([CH3:29])=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:28])[C:14]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:33]1[CH2:38]CN(CC2CCCCCC2)C[CH2:34]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:28])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[OH:15])[CH2:10][CH2:11]2)[CH2:38][CH2:33][CH2:34][CH2:29][CH2:2][CH2:3]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccc2F)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccc1F)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-(2-fluorophenyl)-2-cyclopentyl-2-hydroxyacetic acid obtained in Example 54 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:34][CH2:35][CH3:36])(=[O:33])[C:30]#[C:31][CH3:32].O>CN(C)C=O>[OH:22][CH2:21][C:17]1[C:16]2[N:15]([N:14]=[C:31]([CH3:32])[C:30]=2[C:29]([O:34][CH2:35][CH3:36])=[O:33])[CH:20]=[CH:19][CH:18]=1
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2cccc(CO)c12
Reaction time: 12 h
Yield: 26.9 %

Procedure:
To a solution of 1-amino-3-(hydroxymethyl)pyridinium 2,4-dinitrobenzenolate (200 g, 0.650 mol) in dimethylformamide (1.3 L) was added potassium carbonate (224 g, 1.62 mol). To the mixture was added ethyl 2-butynoate (72.8 g, 0.650 mol) at room temperature, and the mixture was stirred for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (41.0 g, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (672.6 mg, 1.55 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with saturated Na2CO3 aqueous solution, then extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/5) to give the title compound as a beige solid (410 mg, 79.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-aminoisoquinoline in DMF is added DMAP and benzyl isocyanate and the solution was stirred at room temperature for 4 hours. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 5% MeOH/CH2Cl2) provided 1-benzyl-3-(isoquinolin-6-yl)urea (E88).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][C:16](=[O:18])[CH3:17]>ClCCl>[C:16]([NH:15][CH:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=2)[CH2:6]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NC1Cc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.6 ml of chloro sulfonic acid was dropped to the stirred solution of 1.06 g N-Indan-2-yl-acetamide and 50 ml of dichloromethane and the mixture was stirred for 15 hours at room temperature. The reaction was than quenched with cold water and die organic phase separated, dried over sodium sulfate evaporated. The resulting residue was used for further reaction without further purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].C(N)(=[O:16])C>>[C@H:5]([OH:6])([C@H:3]([OH:4])[C:2]([OH:16])=[O:1])[C@H:7]([OH:8])[C@@H:9]([OH:10])[C:11]([OH:13])=[O:12]
Reactant: CC(N)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Product: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 72 h

Procedure:
A gar1 deletion strain from example 4 was used to express the A. tumefaciens D-galacturonic acid dehydrogenase uro1 from example 1. The BamHI fragment containing the uro1 was released from the TOPO vector described in the Example 1 and the uro1 gene was ligated to the BamHI site of the modified pAN53-1 NotI vector described by Kuorelahti et al., 2006. It was checked that the orientation of the uro1 was suitable for transcription. The resulting plasmid was then cotransformed into the gar1 deletion strain with a selection plasmid pTOC202 that has the A. nidulans amdS gene coding for acetamidase as a marker. Transformants were selected for growth in the presence of acetamide. The transformants were also verified by PCR and by testing the crude extract of the mycelia for D-galacturonic acid dehydrogenase activity. The activity in the transformants were 1.3-1.5 nkat per mg of extracted protein. In the control strain no activity was detected. The transformants were also used for a fermentation experiment to convert D-galacturonic acid to mucic acid. For that purpose mutant and control strains were tested as described in Example 4 except that the medium contained 1% D-xylose in addition to the 1% D-galacturonic acid. The D-xylose was added to allow the strains to grow since the mutant strain is unable to grow on D-galacturonic acid. After 3 days the mutant strains expressing the uro1 had produced between 1 and 1.3 g/l of mucic acid while the control strain, which only contained the gar1 deletion, did not produce detectable amounts of mucic acid.
Reaction SMILES: O.[Na].[N+:3]([CH:6]([CH:9]=O)[CH:7]=O)([O-:5])=[O:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([O:17][CH2:18][CH2:19][OH:20])[CH:13]=1>C(O)(=O)C.O>[N+:3]([C:6]1[CH:7]=[N:11][C:12]2[N:16]([N:15]=[C:14]([O:17][CH2:18][CH2:19][OH:20])[CH:13]=2)[CH:9]=1)([O-:5])=[O:4]
Reactant: Nc1cc(OCCO)n[nH]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(OCCO)nn2c1
Temperature: 90 °C
Yield: 36.9 %

Procedure:
Nitromalonaldehyde sodium salt monohydrate (1.46 g, 9.29 mmol) was added to crude 2-(5-amino-1H-pyrazol-3-yloxy)ethanol (3.28 g) with salts (1.33 g, 9.29 mmol theoretical) in acetic acid (10 mL). This was heated at 90° C. for 2 hours. The cooled reaction mixture was diluted with water, and the mixture was extracted twice with DCM containing 25% IPA. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to yield regioisomer 2-(6-nitropyrazolo[1,5-a]pyrimidin-2-yloxy)ethanol (0.77 g, 3.43 mmol) as a solid. The 2-(6-nitropyrazolo[1,5-a]pyrimidin-2-yloxy)ethanol (460 mg, 2.9 mmol) was suspended in water (40 mL), treated with saturated aqueous sodium bicarbonate (2 mL), and the mixture was refluxed for 2 hours. The cooled reaction mixture was extracted three times with DCM containing 25% IPA. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to an oil. The crude material was purified by column chromatography with ethyl acetate to provide 2-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (60 mg, 0.27 mmol, 2.9% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and morpholine (44 mg, 0.5057 mmol) were dissolved in methylene chloride (20 ml), then WSC-HCl (122 mg, 0.6364 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (102 mg, 0.2073 mmol, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.18 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (60 mg, 0.54 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (80%) of the title compound as a white solid. mp 130°-131°. FDMS: m/e=350.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:37].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.C(O)(C)(C)C>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([OH:37])=[O:12])=[CH:14][CH:15]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The tert-butyl 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate (160 mg, 0.377 mmol) was dissolved in acetonitrile (9 mL) and warm t-butanol (9 mL) followed by the addition of 2-methyl-2-butene (6.00 mL, 56.5 mmol) and cooled to 0° C. followed by the addition of an aqueous solution of sodium chlorite (763 mg, 11.3 mmol) and sodium phosphate (monobasic and monohydrate, 1.56 g, 11.3 mmol) in water (5 mL) dropwise via additional funnel. The ice bath was removed and the mixture was allowed to warm to room temperature. The suspension was stirred overnight. To the suspension was added sodium sulfite (1.43 g, 11.3 mmol) in water (3 mL) and the resultant mixture concentrated to remove the organic solvent followed by extraction three times with ethyl acetate (15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford crude product which was purified by reverse phase HPLC to afford the title compound (140 mg, 84.2% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][NH2:16]>O1CCOCC1>[NH2:13][C:11]1[N:10]([CH3:14])[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:16][CH3:15])[N:7]=2)[CH:12]=1
Reactant: Cn1nc(-c2ccnc(Cl)n2)cc1N
Reactant: CN
Solvent: C1COCCO1
Product: CNc1nccc(-c2cc(N)n(C)n2)n1
Temperature: 50 °C

Procedure:
The reaction mixture of 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazol-5-amine, 9.C (74.0 mg, 353.0 μmol) and methanamine (394.7 mg, 1.0 ml, 40% in water, 1.27 mmol) in 1,4-dioxane (1.5 ml) in a seal tube was heated at 50° C. for 7 h. LCMS results showed the reaction was done. The solvent was removed. The crude product was used for next step. MS ESI (pos.) m/e: 205.0 (M+H)+.