Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([N:38](CC)CC)C.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:38])=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.320 g) in N,N-dimethylformamide (6 mL) were added 1-hydroxybenzotriazole ammonia complex (234 mg), triethylamine (0.271 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (186 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated, under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=50:50-100:0, volume ratio) and recrystallized from hexane-acetone to give the title compound (0.240 g, yield 75%) as colorless crystals. MS: 494 (MH+). melting point 151-153° C.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2C=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1.ClCCCl>[CH3:34][N:33]1[C:31](=[O:32])[CH:19]2[CH:18]([CH2:22][CH:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:25]=3)[CH2:20]2)[C:16](=[O:17])[NH:15][C:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH:11]([CH2:12]2)[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1COCCN1
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3ccnc(N4CCOCC4)n3)CC2C1=O
Temperature: 150 °C

Procedure:
Compound 10f (31 mg, 0.052 mmol) and morpholine (0.1 ml) in THF was left at ambient temperature for 20 hrs, volatiles were stripped of and the residue was dissolved in DCE (15 ml) to which Hoyeda-Grubbs II catalyst (7 mg) was added. The mixture was heated in a microwave oven at 150° C. for 10 min under an atmosphere of nitrogen, then concentrated to dryness and purified by column chromatography on silica gel eluted with DCM-MeOH 2% followed by prep. HPLC-MS-UV to give pure title compound, (4.7 mg), (M+H)+616.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:3]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (126 mg, 0.46 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred overnight under a nitrogen atmosphere at 130° C. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:4 to 100:2) to obtain the entitled compound (25 mg, yield: 25%) as a pale yellow solid.
Reaction SMILES: [Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:35])([CH3:34])[CH2:32][O:31][C:30]3=[O:36])[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]3[C@H:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][NH2+:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:37][C:38]([CH3:40])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:34])([CH3:35])[CH2:32][O:31][C:30]3=[O:36])[CH2:9][CH2:10][N:11]([C:14]([C@H:16]3[C@H:20]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:19][NH+:18]([CH:38]([CH3:40])[CH3:37])[CH2:17]3)=[O:15])[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@H]2C[NH2+]C[C@H]2c2ccc(F)cc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)[NH+]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Yield: 120.3 %

Procedure:
A solution of the product of step E (100 mg; 0.1916 mmol) in methylene chloride (100 mL) was converted to the free-base by washing with saturated sodium bicarbonate. The organic phase was washed with brine, dried (Na2SO4), filtered and the volatiles were removed in vacuo. The residue was dissolved in methylene chloride (2 mL) and cooled to 0° C. Acetone (111 mg; 0.14 mmol) was added, followed by acetic acid (57 mg; 0.9579 mmol) and sodium triacetoxyborohydride (0.575 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 36 h at which time the reaction was quenched with saturated sodium bicarbonate. After extracting three times with methylene chloride, the organic solution was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the crude residue which was purified on silica gel (93:7 methylene chloride/methanol (contaiing 10% v/v ammonium hydroxide). The product was dissolved in ethyl acetate (2 mL) and converted to the hydrochloride salt by addition of a saturated solution of hydrogen chloride in ethyl acetate (2 mL). The reaction mixture was maintained at ambient temperature for 30 min at which time the volatiles were removed in vacuo. The solid was triturated to high purity with diethyl ether which furnished 95 mg of the title compound as the hydrochloride salt [MS: m/z 528 (MH+)].
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)=[C:11]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)[CH:10]=1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)=[C:11]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[CH:10]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.08 mL, 0.25 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(4-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (45 mg, 0.08 mmol) and the homogeneous mixture was stirred at room temperature. After 3 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)=[CH:9][N:8]2[C:30]=1[CH3:31].[F:32][C:33]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34]1>>[F:32][C:33]1([F:38])[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[CH:17][CH:16]=4)=[CH:9][N:8]3[C:30]=2[CH3:31])[CH2:34]1
Reactant: FC1(F)CCNC1
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Product: Cc1c(CCCN2CCC(F)(F)C2)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Yield: 36.8 %

Procedure:
The compound (25.0 mg) obtained in Example 14 and 3,3-difluoropyrrolidine (3.4 mg) were processed in the same manner as in Example 19 to obtain the entitled compound (5.9 mg).
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:12].[CH2:13]([O:15]CC)[CH3:14]>C(O)C.O1CCCC1>[ClH:12].[S:10]1[C:11]2[C:3]([C:1](=[NH:2])[O:15][CH2:13][CH3:14])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=[N:9]1
Reactant: N#Cc1cccc2nnsc12
Reactant: CCOCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=N)c1cccc2nnsc12
Reaction time: 24 h

Procedure:
7.2 g of 7-cyanobenzo-1,2,3-thiadiazole are dissolved at 45° C. in 60 ml of absolute ethanol and 20 ml of tetrahydrofuran, and the solution is cooled to 0° C. and saturated with gaseous hydrochloric acid in the course of 1 hour at 0° C. to 15° C., with the exclusion of moisture. The reaction mixture is then stored for 24 hours in the refrigerator, treated with 70 ml of absolute diethyl ether and allowed to stand for another 4 days in the refrigerator. The solid is then filtered off, washed with diethyl ether and dried. This gives 9.4 g of compound 5.2 in the form of beige crystals of m.p. 270°-272° C.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)[CH3:25])[CH2:19][CH2:18]1.Cl.[OH-].[Na+]>C1COCC1>[CH2:24]([NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:18][CH2:19]1)[CH3:25]
Reactant: CC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a stirred solution of N1-{4-[(4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-ylamino)methyl]cyclohexyl}acetamide (0.380 g, 1.02 mmol) in anhydrous THF (4 ml) was added 1M BH3 in THF (5.0 ml, 5.0 mmol). The solution was stirred at room temperature overnight. 4N HCl (12 ml) was added slowly and stirring continued for 15 minutes. The resulting solution was made basic (pH˜9) with 2N NaOH. The cloudy solution was extracted with EtOAc and the organic layer washed with water. Removal of the solvent in vacuo, gave 69% (252 mg) of the product as a solid which was used without further purification: 1H-NMR (CDCl3) δ 0.96 (4H, m), 1.08 (3H, t, J=7.1 Hz), 1.47 (1H, m), 1.76 (2H, d, J=12.1 Hz), 1.90 (2H, m), 2.37 (2H, m), 2.63 (2H, q, J=7.0 Hz), 3.05 (2H, t, J=5.7 Hz), 3.11 (2H, t, J=5.1 Hz), 4.28 (2H, t, J=5.2 Hz), 5.73 (1H, broad t), 6.96 (1H, dd, J=0.9 Hz, 7.7 Hz), 7.10 (2H, m), 8.22 (1H, dd, J=1.3 Hz, 7.6 Hz); 358 (ESMS, MH+).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH2:18][CH2:17][CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH2:36][N:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2)=[O:38])[CH3:41]
Reactant: CCOC(=O)CI
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4cccc5ccccc45)ccc32)cc1
Product: CCOC(=O)CN(Cc1cccc2ccccc12)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 6-[(naphthalin-1-ylmethyl)-amino]-1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline (see Example 14(1)) and ethyl iodoacetate
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:24])=[C:18]([CH2:21][CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:24])=[C:18]([CH2:21][CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.5 g) in methanol (100 ml) and tetrahydrofuran (25 ml) was added conc. hydrochloric acid (1.5 ml). The solution was stirred for 90 minutes at 30° to 35° C. The resultant solution was adjusted to pH 5.0 with a saturated aqueous solution of sodium bicarbonate and then methanol was evaporated under reduced pressure. The residual oil was dissolved in ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.4 g), mp. 121° to 128° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24](C1C=CC(S(C2C=CC(CC(O)=S)=CC=2)(=O)=O)=CC=1)C>>[CH2:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)CC(=O)O)cc2)cc1
Reactant: CCc1ccc(S(=O)(=O)c2ccc(CC(O)=S)cc2)cc1
Product: CCc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)CC(=O)O)cc2)cc1

Procedure:
The intended 4-(4-ethylphenylsulfonyl)phenylsulfonyl acetic acid was prepared in the same manner as in the synthesis of 4-(4-methylphenylsulfonyl)phenylsulfonyl acetic acid of Example 6 except that 104 g of 4-(4-ethylphenylsulfonyl)phenylthio acetic acid was used in place of 100 g of 4-(4-methylphenylsulfonyl)phenylthio acetic acid. The yield was 97.1 g. NMR (heavy methanol): δ8.3-8.1 (m, 4H), 7.9 (d, 2H), 7.4 (d, 2H), 4.4 (s, 2H), 2.7 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[O:8][N:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[F:20][C:17]([F:18])([F:19])[C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:10]=1
Reactant: CCOC(=O)c1noc(-c2cnccc2C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
15.8 g of 3-ethoxycarbonyl-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole are initially charged in 13 ml of methanol, and, with ice-cooling at 0° C., a solution of 2.8 g of lithium hydroxide in 50 ml of water is added dropwise. The mixture is stirred at room temperature for 2 h, 20 ml of ice-water are added and the mixture is extracted with 200 ml of diethyl ether. The aqueous phase is adjused to pH═2 using dil. HCl, and the precipitated product is filtered off with suction. After drying, 13.8 g of 5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole-3-carboxylic acid are obtained as a white solid of mp. 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
To a solution of methyl 5-chloro-2-[(5-fluoropyridin-2-yl)oxy]benzoate (204 mg, 0.72 mmol) in tetrahydrofuran (3 mL) was added 2 M sodium hydroxide aqueous solution (1.5 mL) and the reaction mixture was stirred at room temperature for 24 h. Then the reaction mixture was acidified with 2 M hydrochloric acid (2 mL). The precipitates were collected by filtration and dried under reduced pressure to afford 184 mg (95%) of the title compound: 1H-NMR (DMSO-d6) δ 8.02 (1H, d, J=3.1 Hz), 7.85–7.66 (2H, m), 7.66 (1H, dd, J=8.8, 2.8 Hz), 7.26 (1H, d, J=8.8 Hz), 7.11 (1H, dd, J=9.0, 3.5 Hz).
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[F:34][C:22]1[CH:23]=[C:24]([N:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]2=[O:33])[CH:25]=[CH:26][C:21]=1[NH:20][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccncc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide. Yellow solid. MS: 477.0 ([M+H]+)
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C)C=O.O>[CH3:1][S:2][CH:3]1[N:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:5](=[O:7])[CH2:4]1
Reactant: COC(=O)CBr
Reactant: CSC1CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CC1SC
Yield: 63.4 %

Procedure:
4-Methylthioazetidin-2-one (2.34 g, 20 mmole) was dissolved in dry dimethylformamide (40 ml) and treated at 0°-5° C. with sodium hydride (20 mmole). After 3 minutes methyl bromoacetate (3.37 g, 22 mmole) dissolved in dry dimethylformamide (20 ml) was added and the reaction mixture stirred for 3/4 hour at 0°-5° C. After diluting with water (300 ml), the mixture was extracted with ethyl acetate (3×100 ml) and the extracts combined, washed with water, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel eluting with 30% ethyl acetate in petrolether provided methyl (4-methylthio-2-oxoazetidin-1-yl)acetate (2.4 g, 62%) as a mobile liquid. νmax (CHCl3): 1760 (b), 1410, 1240, 1185 cm-1 ; δ(CDCl3): 2.13 (s, 3H, SCH3); 2.95-3.75 (2H, AB of ABX, CH2); 3.88 (s, 3H, OCH3); 3.93 and 4.23 (2H, main peaks of ABq, J=18 Hz, NCH2) and 5.02 (1H, X of ABX, CH).
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].P(Cl)(Cl)([Cl:14])=O>O>[Cl:14][C:9]1[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6](=[O:7])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: O
Product: Cn1c(Cl)cc(=O)n(C)c1=O
Temperature: 0 °C

Procedure:
To a stirred solution of 1,3-dimethylbarbituric acid (20.0 g, 128.09 mmol) in water (10 ml), phosphorous oxychloride (80 ml) was added slowly by externally cooling and reaction was then refluxed for 3 h. The reaction mixture was allowed to cool to 0° C. and quenched with ice cold water (350 ml). The reaction mixture was extracted with chloroform (2×200 ml) and the combined organic extracts were washed with water, dried over Na2SO4 and concentrated to obtain 21.0 g of the product as a pale brown solid; 1H NMR (300 MHz, CDCl3) δ 3.33 (s, 3H), 3.57 (s, 3H), 5.94 (s, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>O.CO>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of hydroxylamine hydrochloride (15.3 mg, 0.22 mmol) and Na2CO3 (28 mg, 0.26 mmol) in water (0.7 mL) was added a solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (50 mg, 0.147 mmol) in MeOH (0.5 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The mixture was poured into water and extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC and then by SFC to give EX. 8-92 (10 mg, 19%) as a white solid.