Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1NC(=O)c2ccccc2S1
Yield: 61.3 %

Procedure:
Methyl thiosalicylate (6 g, 35.7 mM) and ethyl cyanoacetate (4 g, 35.4 mM) were dissolved in toluene (10 ml), and triethylamine (5 ml, 35.8 mM) was added to the solution, followed by heating for 7 hours under reflux. After the reaction solution was concentrated, ethanol was added to the residue. The mixture was allowed to stand, and the crystals precipitated were taken out by filtration to give crude crystals. The crude crystals were recrystallized from ethanol to give the title compound as needles (5.4 g, 60.7%).
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:20][S:21]([O:10][CH2:9][CH2:8][CH2:7][S:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCSC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCSC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-(cyclopentylthio)-1-propanol (for example, as prepared for Intermediate 23) (1.05 g, 6.56 mmol) in dry DCM (5 ml) was added diisopropylethylamine (1.37 ml, 7.87 mmol), and then methanesulfonyl chloride (commercially available, for example, from Aldrich) (0.609 ml, 7.87 mmol) at 20° C. The reaction mixture was stirred at room temperature, under nitrogen for 2.5 h and then diluted with DCM (10 ml) and saturated sodium bicarbonate solution (20 ml). The phases were separated using a hydrophobic frit. The organic phase was concentrated in vacuo to afford the title compound (1.74 g): LCMS RT=3.13 min, ES+ve m/z 239 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]=O)[CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=C[C:18]=1[N+:23]([O-:25])=[O:24].O>CN(C=O)C>[N+:23]([C:18]1[CH:17]=[CH:22][CH:21]=[CH:20][C:14]=1[NH:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:3]=[CH:4][CH:5]=[CH:6]2)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=CNc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
A dispersion of sodium hydride in mineral oil (0.261 mol) was added portionwise at room temperature under N2 flow to a mixture of N-8-quinolinylformamide (0.174 mol) in DMF (500 ml). The mixture was stirred at room temperature for 1 hour. A solution of 1-chloro-2-nitrobenzene (0.53 mol) in DMF (200 ml) was added dropwise. The mixture was stirred at 140° C. for 12 hours and then brought to room temperature. H2O was added and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (110 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 80/20; 20–45 elm). The pure fractions were collected and the solvent was evaporated, yielding 9.8 g (21%) of N-(2-nitrophenyl)-8-quinolinamine (interm. 23).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=[N:36][OH:37])CC(C3C=CC(F)=CC=3C3C=NC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:36][OH:37])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=NO
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=NO

Procedure:
The title compound was prepared from 2-amino-7-(2-pyridin-4-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one oxime (example 4/a stage 2).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:16])[NH:9][N:8]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1ccc(I)cn1
Solvent: ClCCl
Product: O=c1[nH]nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-iodo-2-hydrazinopyridine (470 mg, 2 mmol) in dichloromethane (30 mL) was added a solution of N,N-carbonyldiimidazole (389 mg, 2.4 mmol) in 20 mL of dichloromethane. After stirring at room temperature for 2 h, the mixture was washed sequentially with water, 0.5N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure to afford the product. The resultant yellow crystals that precipitated from the aqueous phase upon standing overnight were collected and dried in vacuo to afford additional product. LC/MS 261.8 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (10 g, 0.058 mol), in DMF (100 mL) was treated with phenol (6.6 g, 0.07 mol) and potassium carbonate (9.6 g, 0.07 mol) and the reaction mixture was stirred at 110° C. for 4 hr and then cooled. To the reaction mixture was then added water. The reaction mixture was extracted into EtOAc, dried and concentrated to a syrup, which was purified via column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc, v/v) to yield 4-methyl-5-nitro-2-phenoxy-pyridine as a light yellow solid.
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[F:37][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH3:40])[CH2:17][CH2:18]1)=[O:11]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCNCC2)c2ccccc21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a solution of 60 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(4-piperidyl)acetamide in 5 ml of dichloromethane were added 70 μl of a 40% aqueous solution of formaldehyde, 74 μl of acetic acid and 30 mg of sodium triacetoxy borohydride, followed by stirring at room temperature for six hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) and crystallized from diethyl ether to give 53 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(1methyl-4-piperidyl)acetamide as a colorless powder.
Reaction SMILES: [H-].[Na+].CC[O:5]CC.N1C=CC=N1.[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>O1CCCC1>[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]([OH:5])=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: CCOCC
Reactant: COc1cc(C=O)ccc1OCCCCl
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCCCCl
Reaction time: 0.25 h

Procedure:
To a stirred suspension under nitrogen of sodium hydride (6.4 g, 130 mmol, of about 50% oil dispersion-ether washed) in tetrahydrofuran (220 ml) was added pyrazole (4.4 g, 60 mmol) in tetrahydrofuran (60 ml), dropwise. After complete addition, the reaction was stirred for about 15 minutes, and then 4-(3-chloropropoxy)-3-methoxybenzaldehyde (24.5 g, 107 mmol) was added. The nitrogen was stopped and air was sparged into the reactor for about 3 hours. The reaction was then allowed to stir at ambient temperature open to the atmosphere for 6 hours. Water was added, the reaction was cooled in an ice bath, and concentrated hydrochloric acid (25 ml) was added dropwise. More water was added and the yellow solid that separated was collected to afford 16.2 g of product. The filtrate was then extracted with ethyl acetate to afford an additional 9.3 g. The samples were combined and recrystallized from acetonitrile to yield 12.6 g of a light, yellow solid, m.p.=154°-156° C. A 4.0 g sample was recrystallized from acetonitrile to yield 2.6 g of a yellow solid. This was combined with 0.4 g from another sample and recrystallized again from acetonitrile with charcoal treatment to afford 2.0 g of 4-(3-chloropropoxy)-4-methoxybenzoic acid as a yellow solid, m.p.=157°-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19]O)=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C([Mg]Br)C=C>ClCCl.O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH2:31][CH:26]=[CH2:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccc2ncccc2c1OCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCCc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of [5-(benzyloxy)quinolin-6-yl]methanol with carbontetrabromide and triphenylphosphine in dichloromethane and subsequent treatment with allyl magnesiumbromide in tetrahydrofu ran following the procedure described for Example 1, step 1 provides 5-(benzyloxy)-6-but-3-enylquinoline.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[NH:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:25])=[O:26])[CH:28]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: CS(=O)(=O)c1cccc(NC(=N)N)c1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)sc1-c1ccnc(Nc2cccc(S(C)(=O)=O)c2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(3-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.1 min (0-60% MeCN, purity>97%). 1H-NMR (DMSO-d6) δ: 2.55 (s, 3H, CH3), 3.19 (s, 3H, CH3), 6.97 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.47 (m, 1H, Ph-H), 7.54 (t, 1H, J=7.5 Hz, Ph-H), 8.08 (m, 1H, Ph-H), 8.34 (brs, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.86 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[CH:6]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:34]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH3:24])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C)S(=O)(=O)c2ccc(OC)cc2)c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methoxybenzenesulfonyl chloride.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[CH:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:30]([OH:32])[CH3:31])[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (1.3 mL, 9.092 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (10 mL) was treated with a solution of n-butyllithium in hexanes (3.4 mL, 8.524 mmol, 2.5 M). After stirring at −78° C. for 30 minutes, the mixture was treated with a solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.394 g, 5.683 mmol) in anhydrous tetrahydrofuran (10 mL). After stirring at −78° C. for 20 minutes, the mixture was treated with acetaldehyde (0.96 mL, 17.05 mmol). After stirring at room temperature for 1 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (1.476 g, 90%) as a yellow oil and as a 2:1 mixture of diastereoisomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[C:12](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Preparation H11, Step 1: 10 g (0.068 mol) of 3-cyano benzoic acid was taken in 150 ml of dry dichloromethane and cooled to 0° C. Added 50 ml of oxalyl chloride drop wise followed by 5 drops of dry DMF. The reaction mixture was stirred at RT overnight. Dichloromethane was removed and dry methanol (50 ml) was added and stirred at rt for 2 h. Excess methanol was removed and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with 10% of sodium bicarbonate, brine and concentrated to give methyl 3-cyanobenzoate (7 g) as a white solid.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:14].[C:15](=O)([O-])[O-].[K+].[K+].N>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[CH:9]=[CH:8][C:7]2=[O:14]
Reactant: Oc1ccnc2ccc(F)cc12
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ccc(=O)c2cc(F)ccc21
Reaction time: 18 h

Procedure:
Iodomethane (6.9 ml) was added to a stirred suspension of 6-fluoro-4-hydroxyquinoline (16.3 g) and anhydrous potassium carbonate (15.2 g) in dry tetrahydrofuran (100 ml) at ambient temperature and stirring was continued for 18 hours. More iodomethane (1.8 ml) and anhydrous potassium carbonate (3.8 g) were added and stirring was continued for 4 hours at ambient temperature. Concentrated aqueous ammonia (specific gravity 0.88; 100 ml) was added and the mixture was evaporated to dryness. The residue was treated with water (200 ml) and extracted with dichloromethane (2×400 ml). The extract was dried and evaporated to dryness. The residue was crystallised from ethyl acetate to give the novel compound 6-fluoro-1-methyl-4-quinolone, m.p. 88°-89°.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH2:14])=[S:13])=[CH:6][CH:5]=1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:27][CH:26]=1)=O>>[CH:15]1([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:20])=[CH:5][CH:6]=2)[C:12]2[S:13][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C@H:32]4[CH2:37][CH2:36][C@@H:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[N:14]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(CN(C(N)=S)C2CCCC2)cc1
Reactant: CC1CCC(Oc2ccc(C(=O)CBr)cc2)CC1
Product: C[C@H]1CC[C@@H](Oc2ccc(-c3csc(N(Cc4ccc(C(=O)O)cc4)C4CCCC4)n3)cc2)CC1
Yield: 36.7 %

Procedure:
4-[(Cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-methyl]-benzoic acid (90 mg) was prepared following procedure B using 4-[(1-cyclopentyl-thioureido)-methyl]-benzoic acid methyl ester (150 mg, 0.5 mmol) and 2-bromo-1-[4-(4-methyl-cyclohexyloxy)-phenyl]-ethanone (0.5 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following procedure T. Sodium 4-[(cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-methyl]-benzoate was made following procedure J. LCMS m/z: 492 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCOCC1.O.Cl>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])(=[O:26])=[O:27]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
4.13 g of 3-amino-3-phenylpropionic acid are dissolved in 100 ml of dioxane and 25 ml of 1N sodium hydroxide and 5.6 g of 2-naphthalenesulphonyl chloride are added portionwise, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 400 ml of water and 2N HCl is added in order to obtain pH=2. This mixture is extracted with EtOAc and the extracts are washed with a KHSO4/K2SO4 buffer, dried over Na2SO4 and evaporated to dryness. The residue is triturated from heptane and the product is isolated by decanting and is then dried under vacuum. 7.33 g of the expected product are obtained, m.p.=126-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:20])([F:19])[CH:16]([OH:18])[CH3:17].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH:16]([CH3:17])[C:15]([F:20])([F:19])[F:14]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: CC(O)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1nc(C(=O)O)ccc1Br)C(F)(F)F
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stirred for 15 min. Then 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto icewater/1N HCl (200 mL) and extracted with EtOAc (2×400 mL). The organic layers were washed with icewater/brine (200 mL), combined and dried over Na2SO4 and concentrated in vacuo to give the title compound (6.9 g, quant.) as orange solid. MS (EI): m/e=312.3 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1.O>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1csc(C)n1
Reaction time: 0.25 h

Procedure:
To a solution of Example 74B (0.79 g, 2.43 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (Aldrich, 98 mg, 2.43 mmol) and the reaction mixture was stirred for 15 min and 4-(chloromethyl)-2-methylthiazole (0.36 g, 2.43 mmol) was added. The reaction mixture was stirred at room temperature for 18 hr, poured into water (75 mL) and then extracted with EtOAc (75 mL). The organic layer was washed with water (2×75 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS, DCI, m/z 436 (M+H)+.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1/[CH:48]=[CH:49]/[C:50]([NH2:52])=[O:51])=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1/[CH:48]=[CH:49]/[C:50]([NH2:52])=[O:51])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C/C(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 5 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a solution of allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (27.0 g, 54.06 mmol) and (E)-3-[(2S,4S)-N-allyloxycarbonyl-4-mercaptopyrrolidin-2-yl]acrylamide (16.63 g, 64.88 mmol) in acetonitrile (405 ml) was dropwise added N,N-diisopropylethylamine (9.42 ml, 54.06 mmol) at -30° C. over 15 minutes. The reaction mixture was stirred at -30° C. for 4 hours and at 5° C. for another 16 hours, partitioned between ethyl acetate (400 ml) and water (400 ml), and the each layer separated. The aqueous layer was treated with ethyl acetate (200 ml) for back extraction, the combined organic layer washed successively with saturated aqueous sodium bicarbonate (300 ml) and saturated aqueous sodium chloride (300 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Wakogel® C-300, 400 ml; elution with ethyl acetate-acetone 7:3) to afford allyl (1R,5S,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-[(E)-2-(aminocarbonyl)vinyl]pyrrolidin-4-ylthio]-6-[(R)-1hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (22.64 g, 82.8% yield) as a foam powder.