Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH2:15][CH2:16][N:17]([CH2:26][CH2:27][CH3:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[ClH:14].[ClH:14].[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:26][CH2:27][CH3:28])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCN(CCCl)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCSc1nnc(N)s1)CCc1ccccc1
Product: Cl
Temperature: 0 °C

Procedure:
4 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 2.5 g of potassium carbonate and 7.0 g of 2-chloroethyl-(n-propyl)phenethylamine in 10 ml of dimethylformamide were stirred at 100° C. for 30 min. The mixture was then cooled and poured into ice-water, and the precipitated brown solid was filtered off with suction and partitioned in methyl t-butyl ether/water. The organic phase was separated off, washed with water and concentrated. The residue was taken up in 2N HCl and extracted with methylene chloride. The aqueous phase was adjusted to pH 7 with 2N NaOH, the precipitated white solid was filtered off with suction and suspended in i-propanol, and ethereal HCl was added. The white solid which was precipated by addition of methyl t-butyl ether was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[Na+].[CH3:11][S:12]([O-:14])=[O:13]>O.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(Cl)nnc1Cl

Procedure:
3,4,6-Trichloropyridazine (2.5 g; 13.6 mmol) and methanesulfinic acid sodium salt (2.78 g, 27.26 mmol) were stirred in 20 ml of a solvent mixture of water/THF/DMF (5:10:5) at RT for 30 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic phase was removed and concentrated, and the crude product was purified by flash chromatography (dichloromethane:methanol). Yield: 1.4 g
Reaction SMILES: C[O:2][C:3](=[O:49])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Br:20])=[CH:18][C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][C:15]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=[CH:6][C:5]=1[OH:48].[OH-].[Na+]>CCO>[Br:20][C:19]1[C:14]([O:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:49])=[O:2])=[C:5]([OH:48])[CH:6]=2)=[C:15]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH:16]=[C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=1
Reactant: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (1.16 mmol, 1 eq) in EtOH (20 mL) was added 1M NaOH (10 mL) and the reaction was heated at reflux 90 min. It was then cooled to rt, concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:Hexane+1% Formic acid) to afford the title compound (0.607 g, 79%) as a white foam. 1H NMR (DMSO-d6) δ 13.55 (bs, 1H); 11.49 (bs, 1H); 8.58 (t, 1H); 8.14 (d, 1H); 7.90-7.84 (m, 3H); 7.73-7.61 (m, 3H); 7.26-7.12 (m, 5H); 6.27-6.23 (m, 2H); 4.00 (m, 2H); 3.92 (m, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2850, 1660, 1620, 1550, 1450, 1420, 1330, 1220, 1160, 1120 cm−1; mass spectrum [(−)ESI], m/z 726/728 (M−H)−; Anal. Calcd. for C37H37F3NO6: C, 60.99; H, 5.12; N, 1.92, Found: C, 60.32; H, 5.17; N, 1.83.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([O:11][CH3:15])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)c([N+](=O)[O-])cc1OC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OC)c([N+](=O)[O-])cc1OC
Temperature: 77.5 °C
Yield: 56.3 %

Procedure:
A mixture of 4,5-dimethoxy-2-nitro-phenol (2.00 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and iodomethane (0.75 mL, 12 mmol) in DMF was placed in a sealed tube and heated at 75-80° C. for 20 h. The reaction was cooled and was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (the first wash was back-extracted with ethyl acetate), sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided 1,2,4-trimethoxy-5-nitro-benzene (1.20 g, 57% yield) as a yellow solid. 1H-NMR (CDCl3, 500 MHz) 7.53 (s, 1H), 6.50 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.84 (s, 3H) ppm; MS (FIA) 214.1 (M+H); HPLC (Method A) 3.253 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:34])=O)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][C:37](=[O:39])[CH3:38].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC1CCCO1>>[CH2:36]([NH:35][C:32]([CH:30]1[O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH3:27])[CH:18]=3)[CH2:14][CH2:15]2)[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31]1)=[O:34])[C:37]([CH3:38])=[O:39]
Reactant: CC(=O)CN
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Product: CC(=O)CNC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 75 °C
Yield: 41 %

Procedure:
To 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P (641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL) and the reaction mixture was then heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 20-70% EtOAC in DCM as eluent to afford N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. Found 522.5 (M+1)+; Retention time: 1.48 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:21]=[CH:22]/[N+:23]([O-])=O)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:32](=[O:34])[CH3:33])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1ccccc1
Yield: 63.6 %

Procedure:
Nitrostyrene 7a (182 mg, 0.55 mmol) in THF (0.7 mL) was added dropwise to a solution of Lithiumaluminium hydride (42 mg, 1.12 mmol) in THF (2 mL) under organ atmosphere at RT. Upon completion (nearly immediately) the reaction was quenched by the addition of water (42 μL), 3M NaOH (42 μL), and water (84 μL). The resulted mixture was filtered through a plug of celite, washed with DCM, and dried over K2CO3. Upon filtration the mixture was concentrated to oil and used without further purification. Acetic anhydride (58 μL, 0.62 mmol) and triethylamine (93 μL, 0.67 mmol) were added to a solution of the crude amine in DCM (5.6 mL) under an organ atmosphere at RT. After 3 h the reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM (3×10 mL); combined organic fractions were washed with saturated aqueous sodiumchloride, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2; 3:1, Hex:EtOAc) to afford acetamide 8a (0.12 g, 0.35 mmol, 64%). 1H NMR (400 MHz, CDCl3) δ 7.50-7.38 (m, 8H), 7.38-7.30 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.01-6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 5.71 (br s, NH), 5.08 (s, 2H), 3.42-3.16 (q, J=7.0 Hz, 2H), 2.89-2.64 (t, J=7.2 Hz, 2H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 157.2, 143.4, 141.4, 137.0, 130.8, 129.1, 128.7, 128.6, 128.4, 128.0, 127.6, 127.2, 116.6, 114.2, 70.1, 40.7, 31.9, 23.2; HRMS m/z: [M+K+] for C23H23NO2K calcd, 384.1361. found, 384.1359.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH3:23])[C@@H:17]([CH:20]([CH3:22])[CH3:21])[CH:18]=O)=[O:15])=[CH:12][C:11]=1[CH3:26].[Na].[BH4-].[Na+]>CCO.C(Cl)Cl>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH2:18][C@@H:17]([N:16]([CH3:23])[C:14](=[O:15])[C:13]2[CH:24]=[CH:25][C:10]([F:9])=[C:11]([CH3:26])[CH:12]=2)[CH:20]([CH3:21])[CH3:22])[CH2:2][CH2:3]1)#[N:8]
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Reactant: N#CC1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(C#N)CC2)C(C)C)ccc1F
Reaction time: 1 h
Yield: 4 %

Procedure:
TEA (0.552 mL, 3.98 mmol) was added to a mixture of piperidine-4-carbonitrile (0.132 g, 1.19 mmol) in EtOH (2 mL) and DCM (3 mL). To the mixture was added (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.2 g, 0.80 mmol). The resultant mixture was stirred at rt for 15 min before sodium triacetoxyhydroborate (0.337 g, 1.59 mmol) was added. The stirring was continued at rt over night. Sodium tetrahydroborate (0.015 g, 0.40 mmol) was added and the mixture was stirred for 1 h. The solvents were removed on a vacuum centrifuge. The residue was diluted with DCM and washed with NaOH (aq., 1M). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak IC 5 μm 20×250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title compound (11 mg, 4%). Enantiomeric excess: 98.2%. Mixture of rotamers: (400 MHz, CD3OD) δ 0.85-1.08, 1.69-2.02, 2.12-2.96, 3.37-3.50, 4.41-4.59, 7.07-7.16, 7.19-7.36.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29](O)[N:28]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[N:28]=[C:29]([O:5][CH2:6][C@@H:7]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:8])[CH:30]=[CH:31][CH:32]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](COc1cccc(Nc2cc(Br)cn(C)c2=O)n1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A mixture of 107a (964 mg, 5.5 mmol), 5-Bromo-3-(6-hydroxypyridin-2-ylamino)-1-methylpyridin-2(1H)-one 101a (4 g crude, 16.5 mmol), Cs2CO3 (5.38 g, 11 mmol) in DMF (20 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with DCM, washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give 107b (550 mg, 22%) as a brown solid. MS-ESI: [M+H]+ 453.1
Reaction SMILES: [Na].N.[CH3:3][C:4]1[CH:5]=[C:6]([P:11]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)C2C=C(C)C=C(C)C=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[C:28]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35](Cl)[N:34]=1)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[C:28]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([P:11]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[C:6]2[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=2)[N:34]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Oc1nc(Cl)cc2ccccc12
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc3ccccc3c(OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
At −78° C., sodium (0.28 g, 12.3 mmol) is added slowly to liquid ammonia (40 mL) followed by tris(3,5-dimethylphenyl)phosphine (2.1 g, 6.0 mmol), and the resulting mixture is stirred for 2 hours. A solution of 1-tert-butoxy-3-chloroisoquinoline (1.4 g, 6.0 mmol) in tetrahydrofuran (6 mL) is then added drop-wise and the resulting mixture slowly warmed to ambient temperature over 16 hours. The residue is quenched with water (30 mL), extracted with diethyl ether (3×25 mL), and the combined extracts are percolated through a column of magnesium sulfate-ZSM-5. The filtrate is concentrated under reduced pressure and the opaque residue is purified by a re-crystallization from methanol, yielding 1-tert-butoxy-3-(bis(3,5-dimethylphenyl)phosphino)isoquinoline (0.94 g, 73%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1>CC(C)=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[C:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=1)([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)C1Cc2c(-c3cccc(C(F)(F)F)c3)ccc(OC)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CC2(C(=O)OC)Cc3c(-c4cccc(C(F)(F)F)c4)ccc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
Potassium carbonate (15 mg, 0.11 mmol) was added to a solution of methyl 7-methoxy-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate (26 mg, 0.07 mmol) in acetone (1.0 mL). Methyl 4-(bromomethyl)benzoate (32 mg, 0.14 mmol) was added and the mixture was stirred at room temperature. After 4 d, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→EtOAc, gradient) to afford 36 mg (98%) of methyl 7-methoxy-2-(4-(methoxycarbonyl)benzyl)-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.O>CN(C)C=O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[CH:20]=[CH:19][CH:18]=[C:17]3[C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: Cc1ccc(-n2cccc2)c(C(=O)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)c1cccn1-2
Temperature: 25 °C
Yield: 35 %

Procedure:
At 0° C., add 1.36 ml (14.9 mmol) of phosphorus oxychloride to 1.14 ml (14.9 mmol) of dimethylformamide, then add a solution of 3 g (14.9 mmol) of 5-methyl-2-pyrrol-1-ylbenzoic acid (Preparation 25) in 30 ml of dimethylformamide. After one night's stirring at room temperature, hydrolyse the reaction mixture by pouring into 50 ml of water, extract with 200 ml of diethyl ether, and wash the ethereal phase in succession with water, a saturated aqueous hydrogen carbonate solution and then water. After drying over magnesium sulfate and rendering colourless with animal charcoal, the ethereal phase is concentrated to dryness to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH:32][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: NCCc1ccccc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H26ClNO5 [M−H]−: 420.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH3:7])[CH2:5][CH2:4][S:3]1.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>C1C=CC=CC=1>[CH3:7][N:6]1[CH2:5][CH2:4][S:3][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:16]
Reactant: CN1CCSC1=N
Reactant: S=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CCSC1=NC(=S)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 0.043 mole of 2-imino-3-methylthiazolidine and an equimolar amount of phenylisothiocyanate in 70 ml of dry benzene is refluxed under nitrogen for 2.5 hours. Some ether is added to the cooled reaction mixture and solids are filtered off, 9.8 g (90%). Recrystallization from acetonitrile-ether (1:1) gives 8.0 g (75%) of pure N-(3-methyl-2-thiazolidinylidene)-N'-phenylthiourea; m.p. 168.5°-170.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:3]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[N:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methyl 3-amino-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (120 mg, 0.33 mmol) was dissolved in trifluoroacetic acid (1.6 mL) and the solution was cooled in an ice bath. Sodium nitrite (45 mg, 0.66 mmol) was added with stirring to give a dark red suspension. After 30 min, sodium azide (214 mg, 3.3 mmol) was added followed immediately by diethyl ether (1.6 mL). This was stirred in the ice bath for 30 min. and then partially concentrated on the rotary evaporator. The residue was partitioned between ethyl acetate and sufficient saturated aqueous sodium bicarbonate solution (gas evolution) to neutralize the mixture. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 3-azido-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (122 mg, 95% yield) as a yellow solid. MS (ESI) m/z 392.1 (M+H). 1H NMR (CDCl3) δ ppm 8.74 (1H, d, J=2.52 Hz), 8.13 (1H, dd, J=8.69, 2.39 Hz), 8.01 (2H, d, J=9.07 Hz), 7.98 (1H, s), 6.97 (2H, d, J=8.81 Hz), 6.85 (1H, d, J=8.81 Hz), 4.03 (3H, s), 4.01 (4H, s), 3.85 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]12)=[O:7])(O)=O.C(N(CC)CC)C.ClC(OCC)=O.NN.C1(CC(Cl)=O)C=CC=CC=1>O1CCCC1>[C:32]1([CH2:5][C:6]([NH:8][CH:9]2[C:30](=[O:31])[N:11]3[C:12]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]23)=[O:7])[CH:33]=[CH:34][CH:35]=[CH:4][CH:1]=1
Reactant: CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1
Agent: CCOC(=O)Cl
Agent: NN
Agent: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
To a suspension of p-nitrobenzyl 7-(2-carboxybenzamido)-3-methyl-3-cephem-4-carboxylate (462 mg., 1 mmol.) in tetrahydrofuran at 0° C. is added triethylamine (0.14 ml., 1 mmol.). After 15 minutes, ethyl chloroformate (0.1 ml., 2 mmol.) is added, and then after 0.5 hour at 0° C., anhydrous hydrazine (0.03 ml., 1 mmol.) is added to the reaction mixture. After 15 minutes, the mixture is filtered, and the filtrate is evaporated to dryness in vacuo. The residue is taken up in acetone (15 ml.) and tetrahydrofuran (15 ml.), and phenylacetyl chloride (0.13 ml., 1 mmol.) is added. After refluxing for 30 min., the mixture is cooled and evaporated in vacuo to dryness. The product is taken up in chloroform (50 ml.) and washed successively with 1N HCl (30 ml.), 10% sodium bicarbonate (40 ml.), and brine (40 ml.), dried over MgSO4, and evaporated in vacuo to dryness. The colorless product is slurried with ethyl acetate (12 ml.). Filtration gives p-nitrobenzyl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate. Recrystallization from ethyl acetate gives an analytical sample: m.p. 227°-230°.
Reaction SMILES: C1N([CH2:7][CH2:8][OH:9])CCN(CCS(O)(=O)=O)C1.[OH-].[Na+].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP([O:40][C@H:41]3[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([OH:49])[C@H:43]([OH:50])[C@H:42]3[OH:51])(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.CC1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(OC3[O:83][C@H:82]([CH2:84][OH:85])[C@@H:81]([OH:86])[C@H:80]([OH:87])[C@H]3O)(O)=O)(O)=O)[C@@H](O)C2)C=1>>[CH2:47]([OH:48])[C@H:45]1[O:46][C@H:41]([O:40][C@:7]2([CH2:8][OH:9])[O:83][C@H:82]([CH2:84][OH:85])[C@@H:81]([OH:86])[C@@H:80]2[OH:87])[C@H:42]([OH:51])[C@@H:43]([OH:50])[C@@H:44]1[OH:49]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OC3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
It was found that the hitherto used hepes-NaOH-buffer was most suitable for the synthesis of UDP-glucose and TDP-glucose. For both enzymes, the Mops-buffer and the TES-buffer gave 60 to 80% residual activity. The commercial enzyme indicated, by contrast to the rice enzyme, in TEA-buffer, an about 30 to 40% higher residual activity. In the remaining buffers, both enzymes had a residual activity of less than 50%.