Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:44]=2[CH:45]=[CH:46][NH:47]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.CC(O)C>[NH:47]1[C:48]2[C:44](=[C:43]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])=[C:4]([C:20]4[O:21][C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:28][CH2:27]5)=[CH:23][N:24]=4)[CH:3]=3)[CH:51]=[CH:50][CH:49]=2)[CH:45]=[CH:46]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (1.0 eq., 1 wt, 10.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.1 eq., 0.535 wt, 5.35 g) and K3PO4 (1.2 eq., 0.509 wt, 5.09 g) are charged sequentially to a stirred vessel containing IPA (5 vols, 50 ml) and water (5 vols, 50 ml). KHF2 (2.2 eq., 0.344 wt, 3.44 g) is then added and the mixture heated to 75-80° C. under a flow of N2 for at least 1 hr to degas. Meanwhile, IPA (5 vols, 50 ml) is charged to a separate vessel and heated to reflux for 1 hr under a stream of N2 to degas. The IPA is cooled to 20° C. and Pd(OAc)2 (0.02 eq., 0.0090 wt, 90.0 mg) and tricyclohexylphosphine (0.04 eq., 0.0224 wt, 224 mg) are added sequentially and aged for 1 hr until a yellow solution is observed. The yellow solution is then added over 10 mins to the first vessel maintaining the temperature at 75-80° C. and stirred for at least 4 hours. The mixture is cooled to 20° C. and aged for at least 1 hr. The slurry is then filtered and washed with 1:1 IPA:water (2 vols, 20 ml) followed by water (2×2 vols, 2×20 ml) and dried in vacuo at 60±3° C. to constant temperature to afford 2-(6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole as a yellow solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[F:28][CH:29]([F:55])[C:30]1[CH:34]=[C:33]([CH:35]([F:37])[F:36])[N:32]([CH2:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([C:47]3[S:48][CH:49]=[C:50]([C:52](O)=[O:53])[N:51]=3)[CH2:43][CH2:42]2)=[O:40])[N:31]=1>ClCCl.O>[F:55][CH:29]([F:28])[C:30]1[CH:34]=[C:33]([CH:35]([F:36])[F:37])[N:32]([CH2:38][C:39]([N:41]2[CH2:42][CH2:43][CH:44]([C:47]3[S:48][CH:49]=[C:50]([C:52]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:53])[N:51]=3)[CH2:45][CH2:46]2)=[O:40])[N:31]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (2.17 g), dimethylaminopyridine (0.20 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.35 g) are added to a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) in dichloromethane (80 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (2.83 g, 34%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:10][CH2:11][N:12]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:13][CH2:14]1
Reactant: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCN(S(C)(=O)=O)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution Trifluoro acetate salt of (Z)-5-(3-((5-methyl-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione (524 mg, 0.000974 mol) in dichloromethane (20 ml), was added triethyl amine (1.35 ml, 0.00974 mol) followed by methane sulfonyl chloride (0.150 ml, 0.001461 mol) at 0° C. and reaction mixture was stirred for 2 hrs at 30° C. Then reaction mixture was diluted with dichloromethane and washed with water, dried over calcium chloride and evaporated under reduced pressure to collect the crude product. Then the crude product was purified by column chromatography using 1% methanol in chloroform as eluent to yield 300 mg product as white solid.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)=[CH:6][CH:5]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:18][C:14]1[N:13]=[C:12]([CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:9][CH:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(OCc2cccc(C)n2)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: Cc1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)cc2)n1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(6-Methyl-pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 412.3
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH3:54][C:55]1[O:56][C:57]([C:61](Cl)=[O:62])=[C:58]([CH3:60])[N:59]=1>>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:61]([C:57]5[O:56][C:55]([CH3:54])=[N:59][C:58]=5[CH3:60])=[O:62])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C)c(C(=O)Cl)o1
Product: Cc1nc(C)c(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)o1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2,4-dimethyl-oxazole-5-carbonyl chloride (prepared above) according to General Procedure F and purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (9 mg). LCMS (m/z) 862.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([N:31](CC)CC)[CH3:30].ClCC#N>CC(C)=O>[C:23]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:30][C:29]#[N:31])=[O:15])=[N:12][CH:13]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC(C)=O
Product: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
To a stirred mixture of 5 g. 5-(triphenylmethyl)-picolinic acid and 6.1 g. triethylamine in 150 ml. acetone add 4.5 g. of chloroacetonitrile. Heat the resulting mixture at reflux 15 hr., cool, filter. Concentrate the filtrate to a residue and triturate residue with water, dry. Recrystallize twice from isopropyl ether-ethanol to obtain the product of this example, m.p. 173°-175°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)[CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cncc(I)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cncc(Br)c2)cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A slurry of 4.33 g (15.3 mmol) 3-bromo-5-iodo-pyridine, 3.49 g (16.8 mmol) 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol and 6.48 g (30.5 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80° C. under nitrogen. Then 321 mg (0.46 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 16 hours at 80° C. The reaction mixture was evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine als slightly yellow crystals; HPLC-MS: [M+H] 238/234.
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:10])[CH:3]1[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1>[Zn].C(O)(=O)C>[Cl:1][CH:2]([Cl:10])[CH:3]1[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1
Reactant: OCC1COC(C(Cl)(Cl)Cl)O1
Agent: [Zn]
Solvent: CC(=O)O
Product: OCC1COC(C(Cl)Cl)O1
Reaction time: 0.25 h

Procedure:
To a mixture of 5.5 g of 2-(trichloro-methyl)-4-(hydroxy-methyl)-dioxolan and 30 ml of acetic acid under stirring 1.6 g of zinc dust are added within 30 minutes. After a further 15 minutes of stirring the reaction mixture is distilled.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42](N2CCSC2=S)=[O:43])[CH:28]=[C:29]([O:38][CH3:39])[C:30]=1[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]>CN(C)C=O>[CH3:39][O:38][C:29]1[CH:28]=[C:27]([CH:40]=[CH:41][C:42]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:22][CH2:21]2)=[O:43])[CH:26]=[C:25]([O:24][CH3:23])[C:30]=1[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)N2CCSC2=S)cc1OC
Reactant: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 86.5 %

Procedure:
To a solution of 424 mg (1.43 mmol) of N-(2-benzhydroxyethyl) piperazine in dry dimethylformamide (2 ml) was added 475 mg (1.15 mmol) of N-[3-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy) phenyl]-2-propenoyl]thiazolidine-2-thione, and the mixture was reacted at room temperature for 2 hours under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100 : 1), to give 588 mg (0.995 mmol) of N-[3[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]-N'-(2-benzhydroxyethyl) piperazine.
Reaction SMILES: C1OC(C2OCC(CC3C=CC=CC=3)N=2)=NC1CC1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:34][CH2:35][C@H:36]2[O:40][C@@H:39]([N:41]3[CH:48]=[CH:47][C:45](=[O:46])[NH:44][C:42]3=[O:43])[C@H:38]([OH:49])[C@@H:37]2[OH:50])=[CH:29][CH:28]=1.[C:65]1([N:71]=[C:72]=[O:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([C:57]2[CH:58]=[CH:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:34][CH2:35][C@H:36]2[O:40][C@@H:39]([N:41]3[CH:48]=[CH:47][C:45](=[O:46])[NH:44][C:42]3=[O:43])[C@H:38]([OH:49])[C@@H:37]2[O:50][C:72](=[O:73])[NH:71][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The THF solution (1 ml) containing 2,2′-bis[(4S)-4-benzyl-2-oxazoline] (0.02 mmol, 6.5 mg) and Cu(OTf)2 (II) (0.02 mmol, 7.2 mg) was stirred for 2 hours at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.2 mmol, 109 mg) and the THF solution (1 ml) of phenyl isocyanate (0.2 mmol, 23.8 mg) were added thereto. After the mixture was continuously stirred for 1 hour at 0° C. and overnight at room temperature, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 70:30, and the transformation ratio of the reaction was 83%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cccc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A mixture of benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.0 g), anisole (10 ml) and trifluoroacetic acid (60 ml) was stirred at ambient temperature for an hour. The reaction mixture was poured into diisopropyl ether (600 ml) with stirring, and the precipitated substance was collected by filtration, washed with diisopropyl ether and then dissolved in water (100 ml), followed by adjusting to pH 7.5 with 5% aqueous sodium bicarbonate and washing with ethyl acetate (50 ml). The resultant aqueous solution was adjusted to pH 2.5 with conc. hydrochloric acid, and extracted with ethyl acetate (200 ml) and tetrahydrofuran (200 ml). The remaining aqueous solution was further adjusted to pH 1.5 with conc. hydrochloric acid and extracted with tetrahydrofuran (100 ml). The combined extracts were washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was washed with acetone and diisopropyl ether to obtain 7-[2-(6-aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.4 g), mp 173°-178° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:18]=1[C:19](Cl)=[O:20]>O1CCCC1.Cl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:18]=1[C:19]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])=[O:20]
Reactant: CCc1nc(C)c[nH]1
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(C)cn1C(=O)c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
15.4 g of 2-ethyl-4-methyl-imidazole are dissolved in 100 ml of tetrahydrofuran; 14.6 g of triethylamine are added, and there can then added dropwise, within 30 minutes at reflux temperature, 30.8 g of 2-chloro-6-nitrobenzoyl chloride, dissolved in 50 ml of tetrahydrofuran, in the process of which triethylamine hydrochloride precipitates. After 3 hours of refluxing, the mixture is filtered with suction, and the solvent is removed in the rotary evaporator. Recrystallisation of the residue from 85 ml of toluene yields 27.7 g (67.3% of theory) of the desired product, m.p. 119°-120° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10]N)[CH:6]=[C:7]([Cl:9])[CH:8]=1.ClC1C=[C:20]2[C:16]([C:17](C)(C)CN2)=[CH:15]C=1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:4]=1[C:16]([CH3:20])([CH3:17])[CH2:15][NH:10]2
Reactant: CC1(C)CNc2cc(Cl)ccc21
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CC1(C)CNc2cc(Cl)cc(Cl)c21

Procedure:
Prepared from 3,5-dichlorophenylhydrazine hydrochloride in an analogous manner to that described for 6-chloro-3,3-dimethyl-2,3-dihydro-1H-indole (Preparation 25). MS: [M+H]+=216.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:19]2)=[CH:14][CH:13]=1)=[O:2]
Reactant: O=CO
Reactant: CCOC(=O)C1CCc2ccc(N)cc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCc2ccc(NC=O)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Mixed anhydride is prepared by stirring 1.25 equivalents of formic acid and 1 equivalent of acetic anhydride at 60° C. for 2 h. A solution of ethyl 7-amino-2-chromancarboxylate (1.25 g; 5.6 mmol) in THF is treated with triethylamine (0.78 mL; 5.6 mmol) and the previously prepared mixed anhydride (1.6 mL), stirred at ambient temperature for 1 h, poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl ether. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a straw colored oil (1.4 g; 100%), identified by NMR spectral analysis.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(O)CCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.8 Grams of 6-(1-hydroxy-4-chlorobutyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 7 hours. To the reaction mixture were added 2 g of triethylamine and 2.5 g of 4-phenylpiperazine and stirred at a room temperature for 24 hours. The reaction mixture was poured into 200 ml of 1%-sodium hydrogencarbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure. The obtained residue was recrystallized from isopropanol to obtain 2.5 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7](/[C:8](=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)/[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (12.4 g, 328 mmol) (Aldrich) was added in small portions to a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (25 g, 86 mmol) (from Example 30a supra) in methanol (400 mL) at such a rate that gas evolution was not too vigorous. When addition was complete, mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 1:2, V/V). The resulting yellow solid was recrystallized from ethyl acetate to give rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a pale yellow solid. (Yield 10 g, 40%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(Nc2ccc(N3CCCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C
Yield: 75.6 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.525 mmol), (4-piperidin-1-ylphenyl)amine (0.093 g, 0.525 mmol) and TEA (0.053 g, 0.525 mmol) in MeCN (2 ml) was heated in a microwave at 160° C. for 30 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography using 30% EtOAc in hexane as eluent, to give the title compound (0.169 g, 76%). 1H NMR (500 MHz CDCl3): δ 7.24-7.16 (m, 1H), 7.16-7.08 (m, 5H), 6.58 (d, 2H), 6.54 (d, 2H), 4.56-4.44 (m, 1H), 3.03 (t, 4H), 1.70-1.61 (m, 10H), 1.61-52(m, 3H); 13C NMR (125 MHz CDCl3): δ 159.2, 150.1, 131.1, 129.6, 128.8, 128.1, 127.6, 125.3, 123.6, 116.3, 109.3, 51.1, 47.9, 25.7, 24.4, 20.5; Mass Spectrum: M+H 426.