Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:28]=2[C:29]([NH:31][CH2:32][C:33]#[CH:34])=[O:30])[C:23]([Cl:40])=[CH:22][N:21]=1>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[C:28]([C:29](=[O:30])[NH:31][CH2:32][C:33]#[CH:34])=[CH:35][CH:36]=[CH:37][C:38]=4[F:39])[C:23]([Cl:40])=[CH:22][N:21]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as a pale yellow solid (99 mg, 53%). m.p.=242-244° C.; LCMS (m/e) 553 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.35 (m, 1H), 9.25-9.15 (m, 1H), 9.04-8.95 (m, 1H), 8.19 (s, 1H), 7.57-7.40 (m, 3H), 7.26 (s, 1H), 7.13-7.04 (m, 1H), 6.98-6.87 (m, 1H), 4.87-4.71 (m, 1H), 4.06-3.82 (m, 4H), 3.68-3.41 (m, 2H), 3.11 (s, 1H), 1.97-1.79 (m, 2H), 1.33-0.98 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2ccc3ccccc32)cc1

Procedure:
By the method of Preparation C43, p-bromoanisole (140 g, 0.75 mole), indole (60 g, 0.51 mole), K2CO3 (75 g, 0.54 mole) and Cu2Br2 (28 g, 0.1 mole) were converted to title product, purified by distillation, rather than chromatography, 67.7 g, b.p. 150-160/0.4-0.5 mm, which crystallized on storage in the refrigerator, m.p. 52°-54° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>O1CCCC1>[CH:17]([NH:20][C:21](=[O:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])([CH3:19])[CH3:18]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Isopropyl isocyanate (34 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by silica gel chromatography (1-3% gradient, 2M ammonia in methanol:methylene chloride). The solvent was evaporated to give 21.8 mg (63%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])/[CH:3]=[CH:4]/[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[Si](C)(C)[O:38][NH2:39]>C1COCC1>[OH:38][NH:39][CH:3]([CH:2]([CH3:35])[CH3:1])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: CC(C)/C=C/S(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Reactant: C[Si](C)(C)ON
Solvent: C1CCOC1
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of N-[(4′-{[(1E)-3-methylbut-1-en-1-yl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 106 (0.180 g, 0.369 mmol) in THF (4 mL) was added O-(trimethylsilyl)hydroxylamine (0.271 mL, 2.22 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound as a white powder (0.125 g, 65%).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH:12]3[CH:7]4[C:8]5([C:13](=O)[NH:14][C:15]6[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=6[NH2:21])[CH:11]3[CH:10]1[CH:9]5[CH:6]24)=[O:4].[OH-].[Na+]>CO>[O:25]=[C:18]1[N:19]([CH2:22][CH2:23][CH3:24])[C:20]2[N:21]=[C:13]([C:8]34[CH:11]5[CH:10]6[CH:9]3[CH:6]3[CH:7]4[CH:12]5[C:5]36[C:3]([OH:2])=[O:4])[NH:14][C:15]=2[C:16](=[O:29])[N:17]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(N)c(NC(=O)C23C4C5C2C2C3C4C52C(=O)OC)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34C5C6C3C3C4C5C63C(=O)O)nc2n(CCC)c1=O
Yield: 75.8 %

Procedure:
To a solution of 4-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-cubane-1-carboxylic acid methyl ester (400 mg, 0.966 mmol) in MeOH (20 ml) was added 4 ml of a 20% aq. NaOH solution and the resulting turbid mixture was heated at reflux overnight (12 h). The cool reaction mixture was concentrated in vacuo, diluted with several small ice chips and acidified by the dropwise addition of concentrated HCl. The resulting white precipitate was collected, dried, and washed with ether to give a white solid (280 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 1.05 (coincident t, 6H), 1.70 (m, 2H), 1.83 (m, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 4.27 (m, 3H), 4.38 (m, 3H). MS: 383 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(O)(=O)C>O1CCCC1.CCCCCC.O>[C:13]([O:17][C:18]([NH:20][CH:21]([C:35]1([OH:38])[CH2:36][CH2:37][O:32][CH2:33][CH2:34]1)[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCOCC1
Temperature: -72 °C
Reaction time: 0.33 h

Procedure:
A solution of diisopropylamine (17.5 ml, 0.127 moles) in 300 ml of dry tetrahydrofuran at -45° C. under argon was treated with 70 ml (0.117 moles) of 1.71M n-butyllithium (in hexane). After 20 minutes at -45° C., the mixture was cooled to -72° C. and treated with 13.3 g (0.05 moles) of dried N-(t-butoxycarbonyl)glycine, benzyl ester in 60 ml of dry tetrahydrofuran. After 50 minutes, the dark yellow homogeneous solution was treated with 5 ml (5.43 g, 0.0543 moles) of tetrahydro-4-pyranone in 50 ml of tetrahydrofuran and the temperature allowed to rise to 0° C. over 1.5 hours. A solution of 7.2 g (0.12 moles) of glacial acetic acid in 20 ml of tetrahydrofuran was added to the purple solution, and the resulting light yellow turbid mixture was poured into 1L of water and extracted with ethyl acetate. The organic layer was washed with 2% potassium bisulfate, 5% sodium bicarbonate and brine, dried (sodium sulfate) and evaporated to an oil. Chromatography on 800 ml of LPS-1 in hexane:ethyl acetate (1:1) and combination of the product fractions (Rf=0.32 in the same solvent) gave an oil which solidified on trituration with hexane yielding a total of 10.34 g of product as a white solid, melting point 90°-93° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26]N.[O-]CC.[Na+]>C(O)C>[NH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C:1]2[NH:2][CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:9][CH2:8]1
Reactant: N#CCC1CCN(C=O)CC1
Reactant: NCCCN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: C1CN=C(CC2CCNCC2)NC1
Temperature: 200 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyanomethyl piperidine-1-carboxaldehyde (4. g, 0.026 M) and 1,3-diaminopropane mono p-toluenesulfonate (7.3 g, 0.052 M) was heated at 100° C. for 1/2 hrs and 200° C. for 2 hrs. The reaction mixture was dissolved in ethanol (50 ml) and sodium ethoxide (0.052 M) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled from about 170° to about 190° C./0.2 mmHg to yield 1,4,5,6-tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine (2.7 g, 56.7% yield). This compound was characterized as dihydrochloride salt, [mp 279°-28]° C. (EtOH).
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:42][C:31]3([CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>>[CH2:32]1[C:31]2([CH2:42][C:28]([C:27]#[C:26][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)=[N:29][O:30]2)[CH2:34][NH:33]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#Cc3cccc(O)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Product: Oc1cccc(C#CC2=NOC3(CNC3)C2)c1
Yield: 90.4 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 80b. The crude residue was used without further purification in the next reaction. Yield: 90.4%.
Reaction SMILES: C(O[C:6]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.C[NH2:22]>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:8][CH3:6])=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:22])([OH:17])=[O:16]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1C(C(=O)O)C1C(N)C(=O)O
Reaction time: 8 h
Yield: 139.8 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (312 mg, 0.9 mmol) in dry THF (6 mL) under argon was added methylamine (2.74 mL, 5.4 mmol) and potassium cyanide (3 mg, 0.05 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 272 mg of the desired compound (80% yield).
Reaction SMILES: S(C)(C)=O.[H-].[Na+].[CH3:7][O:8][C:9]([O:26][CH3:27])([CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][C:21](=[O:24])[O:20]1)[CH2:10][CH:11]=O.CO[CH2:30][CH2:31][O:32]C>O>[O:24]=[C:21]1[O:20][CH:19]([CH2:18][CH2:17][CH2:16][C:15](=[O:25])[CH2:14][CH2:13][C:9]([O:26][CH3:27])([O:8][CH3:7])[CH2:10]/[CH:11]=[CH:30]/[C:31](=[O:32])[CH2:11][CH2:10][CH2:9][CH2:13][CH3:14])[CH2:23][CH2:22]1
Reactant: COCCOC
Reactant: COC(CC=O)(CCC(=O)CCCC1CCC(=O)O1)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(=O)/C=C/CC(CCC(=O)CCCC1CCC(=O)O1)(OC)OC
Reaction time: 0.08 h

Procedure:
To a mixture of 70 parts of sulfinylbismethane with approximately 2 parts of a 50% dispersion of sodium hydride in mineral oil is added 11 parts of dimethyl (2-oxoheptyl) phosphonate. The resultant mixture is added, with stirring during 1 hour, to a solution of 10 parts of tetrahydro-β,β-dimethoxy-ε,5-dioxo-2-furannonanal in 52 parts of 1,2-dimethoxyethane at 0°-5° under nitrogen. Stirring is continued for 5 minutes longer, whereupon the reaction mixture is poured into 5 volumes of water, and the mixture thus obtained is extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a 50:50 (by volume) mixture of ethyl acetate and hexane. The resultant solution is chromatographed on silica gel. Elution with a 75:25 (by volume) mixture of ethyl acetate and hexane affords, upon removal of solvent by vacuum distillation, (E)-1-(tetrahydro-5-oxofuran-2-yl)-7,7-dimethoxyhexadec-9-ene-4,11-dione as the residue, an oil. It has the formula ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23].[BH4-].[Na+]>CO.[Co](Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a suspension of 6-cyano-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (13.1 g, 38.2 mmol) in methanol (285 mL) was added cobalt (II) chloride (18.2 g, 76.4 mmol). The reaction mixture was cooled to 0° C. and sodium borohydride (14.5 g, 382 mmol) was added in small portions over 20 minutes (CAUTION: EFFERVESCENCE). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of concentrated hydrochloric acid (50 mL) and the mixture stirred at 0° C. for 10 minutes and at room temperature for 45 minutes. Diethylenetriamine (9 mL) was then added and the mixture stirred for a further 15 minutes. The reaction mixture was filtered to remove a white solid, which was washed with dichloromethane. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate, followed by water then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a brown solid (13.2 g, 100%). LCMS (method B): RT=2.82 min, M+H+=348.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([S:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])C.[OH-].[K+]>C(O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([S:13][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:6])[C:4]([OH:26])=[O:3])[S:15][C:16]=2[CH:22]=1)[CH3:25]
Reactant: CCOC(=O)C(C)(Sc1nc2ccc(OCC)cc2s1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc2nc(SC(C)(C(=O)O)c3ccccc3)sc2c1

Procedure:
6 g of 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester and 6 g of KOH in 100 ml of ethanol are stirred at 20°; the mixture is evaporated; the residue is dissolved in water; and the solution is washed with ether, acidified with hydrochloric acid and extracted with CH2Cl2. The phases are separated and the organic phase is dried and evaporated to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid. M.p. 152°-153° (from CCl4).
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:44])[C@H:25]([CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([OH:42])=[CH:37][C:36]=1[CH3:43])[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4].[OH-].[Li+].O>C1COCC1>[C:30]([O:29][C:27]([NH:26][C@H:25]([C:24]([NH:23][C@@H:10]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[O:44])[CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([OH:42])=[CH:37][C:36]=1[CH3:43])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCCCC(C)C(=O)O)C(=O)NCCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCCCCC(=O)O)C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (7R)-7-{[N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl]amino}-8-oxo-8-[(3-phenylpropyl)amino]octanoic acid (400 mg, 0.65 mmol) from preparation 14 in 3 ml dry THF was added a 0.5M solution of lithium hydroxide in water (3 ml, 1.5 mmol) and the reaction mixture stirred at rt overnight. Volatiles were evaporated and the residue acidified with 0.5M KHSO4. Product was extracted with ethyl acetate and the organic extract washed with brine, dried over MgSO4 and concentrated to a fine white solid which was taken directly into boc deprotection (preparation 28) on basis of LRMS m/z 598 [M+H].
Reaction SMILES: [C:1]1([C@H:7]([NH2:16])[C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([CH:19]([C:31](=[O:33])[CH3:32])[C:20]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])=[O:21])=O>C(O)C.ClCCl.CCOCC.CCCCCC>[O:33]=[C:31]([CH3:32])[CH:19]([C:20](=[O:21])[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[CH:17]=[N:16][C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:9]=[CH:17][CH:19]([C:20](=[O:21])[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:31](=[O:33])[CH3:32]
Reactant: N[C@@H](c1ccccc1)[C@@H](N)c1ccccc1
Reactant: CC(=O)C(C=O)C(=O)c1c(C)cc(C)cc1C
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)C(C=N[C@@H](c1ccccc1)[C@@H](N=CC(C(C)=O)C(=O)c1c(C)cc(C)cc1C)c1ccccc1)C(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
In 70 ml of ethanol was dissolved 1.06 g (5 mmol) of (S,S)-1,2-diphenylethylenediamine. In a nitrogen atmosphere and at room temperature, 30 ml of an ethanol solution containing 2.32 g (10.5 mmol) of 2-formyl-(2,4,6-trimethylphenyl)-1,3-dioxobutane was added to the solution, which was stirred for 2 hours at room temperature. The reaction mixture was then heated to 50° C. and reaction took place in 2 hours. After the completion of reaction, the solvent was distilled off in vacuum, obtaining a crude product. The crude product was dissolved in dichloromethane/ether/hexane for recrystallization, obtaining 2.28 g (isolation yield 71%) of an optically active ligand (N,N'-bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-(1S,2S)-1,2-diphenylethylenediamine) as white crystals. The thus obtained optically active ligand was analyzed by 1H-NMR, IR, and elemental analysis and measured for melting point and specific rotatory power. The results are shown below.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].O=O.C(C1C=CC=CN=1)#N.N1C=CC=CC=1C(N)=[O:27]>>[OH:27][C:6]1[N:1]=[C:2]([C:7]([OH:9])=[O:8])[CH:3]=[CH:4][CH:5]=1
Reactant: NC(=O)c1ccccn1
Reactant: O=C(O)c1ccccn1
Agent: O=O
Solvent: N#Cc1ccccn1
Product: O=C(O)c1cccc(O)n1
Reaction time: 0.5 h

Procedure:
The biomass was cultured as described in Example 1. The formation of picolinic acid took place under strictly anaerobic conditions. A 500 ml glass bottle with rubber septum charged with 400 ml of biomass of OD650 =20 was used for the biotransformation. Incubation took place at 30° C. Before the biotransformation was started, the mixture was made anaerobic with pure nitrogen. For this purpose, nitrogen (50 mbar gauge pressure) was passed through a needle into the stirred mixture for about 30 minutes in order to drive out the oxygen quantitatively. In order to prevent oxygen from entering during the biotransformation or on addition of the 2-cyanopyridine, the gas introduction was maintained during the biotransformation (about 10 mbar gauge pressure). 2-cyanopyridine was added in 12 steps each of 10 g/l, in each case after one hour had elapsed. The addition can, however, also take place continuously. HPLC was used to check whether 2-cyanopyridine had been completely converted into picolinic acid before adding another portion. During the biotransformation there was no detectable formation of picolinamide. It was possible with this process to prepare about 150 g/l picolinic acid within 26 hours. 6-Hydroxypicolinic acid was not formed during this.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[N:33][C:22]=4[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:19]=3[CH:18]=[N:17][C:16]=2[C:37]#[N:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]1([S:24]([N:23]2[C:19]3[CH:18]=[N:17][C:16]([C:37]#[N:38])=[C:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20]=3[C:21]3[CH:36]=[CH:35][CH:34]=[N:33][C:22]2=3)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc2c(c1CC1CCNCC1)c1cccnc1n2S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-(9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.38 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (2 mL) and the resultant mixture stirred for 1 h then concentrated in vacuo. The residue was purified by flash chromatography (silica, 5 g column, SPE-NH2, 0-8% methanol in DCM) to give title compound as an off white solid (150 mg, 80%). LCMS (Method G): RT=3.07 min, M+H+=432.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4](C)[CH:3]=1.BrC1C=CC(S(Cl)(=O)=O)=C([O:32][C:33]([F:36])([F:35])[F:34])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:10])=[O:9])=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Br)cc1OC(F)(F)F

Procedure:
The title compound was prepared in the same manner as described for 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide, replacing 4-bromo-2-methyl-benzene sulfonyl chloride with 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride. 1H-NMR (DMSO-d6) δ 7.88 to 7.77 (m, 4H), 3.43 (t, J=4.2 Hz, 4H), 2.99 to 2.97 (broad s, 2H), 2.29 to 2.20 (m, 6H); MS LC-MS [M+H]+=433 & 435, RT=2.03 min.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH2:3]OC(Cl)=O.[OH:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[CH:13][S:12]1>N1C=CC=CC=1>[OH:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[C:13]([C:3]2[CH:2]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:12]1
Reactant: CC1=CSC(O)C(=O)N1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(c2ccncc2)SC(O)C(=O)N1

Procedure:
A mixture of pyridine, 2,2,2-trichloroethylchloroformate and 2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one was treated in the same manner as described in Example 6. The residue was recrystallized from ethanol to give the titled compound as pale yellow crystals.