Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](=[O:25])[NH:23][CH3:24])[N:20]=2)=[O:14])=[C:8]([C:26]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:7]=1)C.[CH3:34][NH2:35]>>[CH:28]1([C:26]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:11]=[CH:10][C:9]=2[NH:12][C:13]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](=[O:25])[NH:23][CH3:24])[N:20]=2)=[O:14])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH:28]1([C:26]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([NH:35][CH3:34])=[O:3])[CH:11]=[CH:10][C:9]=2[NH:12][C:13]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](=[O:25])[NH:23][CH3:24])[N:20]=2)=[O:14])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2nc(CC(=O)NC)cs2)c(C(=O)C2CCCC2)c1
Product: CNC(=O)Cc1ccc(NC(=O)Nc2nc(CC(=O)NC)cs2)c(C(=O)C2CCCC2)c1
Product: CNC(=O)Cc1csc(NC(=O)Nc2ccc(CC(=O)O)cc2C(=O)C2CCCC2)n1
Yield: 60 %
Yield: 70 %

Procedure:
{3-Cyclopentanecarbonyl-4-[3-(4-methylcarbamoylmethyl-thiazol-2-yl)-ureido]-phenyl}-acetic acid (155 mg, 70%) was prepared from {3-cyclopentanecarbonyl-4-[3-(4-methylcarbamoylmethyl-thiazol-2-yl)-ureido]-phenyl}-acetic acid ethyl ester (236 mg, 0.5 mmol) following the general procedure J. The acid (222 mg, 0.5 mmol) was coupled with 1 N methyl amine following the general procedure K furnished 2-{3-cyclopentanecarbonyl-4-[3-(4-methylcarbamoylmethyl-thiazol-2-yl)-ureido]-phenyl}-N-methyl-acetamide (137 mg, 60%).
Reaction SMILES: [Li][CH:2](CC)C.C1CCCCC1.C[N:13]([CH2:15][CH2:16]N(C)C)C.Br[C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]=1[C:23]([OH:25])=O.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:15]([NH:13][C:23](=[O:25])[C:22]1[C:26]([Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=1[CH3:2])[CH3:16]
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)O
Reactant: CN(C)CCN(C)C
Reactant: [Li]C(C)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CI
Product: CCNC(=O)c1c(C)cccc1[Si](C)(C)C
Yield: 20 %

Procedure:
1.3M s-BuLi in cyclohexane (25.4 mL, 0.033 mol) was added dropwise to THF (50 mL), TMEDA (3.83 g, 0.033 mol), and the compound of Example c (4.10 g, 0.015 mol), cooled to -78° under nitrogen with stirring. After stirring for 20 min, MeI (2.45 g, 0.01725 mol) was added all at once. The mixture was stirred for 1 h, and 25% citric acid (50 mL) was added. The mixture was extracted three times with CH2Cl2. The combined extracts were washed twice with water, dried (MgSO4), and concentrated. To the resulting mixture were added 30 mL thionyl chloride and 5 drops of DMF. After stirring at RT overnight, the mixture was concentrated to dryness; 50 mL toluene were added; and again the mixture was concentrated. This process was repeated 3 times. The crude product, a brown oil, was dissolved in 30 mL toluene and added to a 100 mL solution of 70% ethyl amine in water which had been cooled to 5° in an ice bath. After stirring overnight, the mixture was washed with 10% HCl and three times with water, dried (MgSO4), concentrated, and purified by HPLC eluting with 1:3 ethyl acetate/hexanes. Two fractions were obtained. When each was concentrated, Compound 48 crystallized as a white solid in a 20% yield. m.p. 115-117° C. Compound 49 crystallized as a white solid in a 42% yield. m.p. 64-66° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](C=O)=[N:12][N:13]3[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C1(N)[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=1.[S].[CH3:35][N:36]([CH:38]=[O:39])[CH3:37]>[Cl-].[Na+].O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([C:37]4[N:36]([CH2:38][O:39][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:35]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]=4)=[N:12][N:13]3[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: Nc1ccccc1N
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccc(-c3ccncc3)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [S]
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(-c3ccncc3)cc21
Yield: 65 %

Procedure:
A solution of 6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyde (0.70 g, 2.0 mmol), benzene-1,2-diamine (0.26 g, 2.4 mmol) and sulfur (77 mg, 2.4 mmol) in DMF (10 ml) was heated in an oil bath at 90° C. overnight. The resulting mixture was poured into brine (200 ml), then extracted with EtOAc (3×60 ml). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to yield 6-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole as a light brown oil (0.75 g, 65%). 1H NMR (CDCl3) δ 8.82 (d, 1H, J=8.5 Hz), 8.73 (d, 1H, J=5.8 Hz), 7.94–7.89 (m, 2H), 7.87 (s, 1H), 7.69–7.62 (m, 4H), 7.40–7.34 (m, 2H), 3.70–3.49 (m, 4H), 0.94 (t, 2H, J=8.3 Hz), 0.67 (t, 2H, J=8.2 Hz), −0.03 (s, 9H), −0.13 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH2:11](Cl)[C:12]#[CH:13]>CN(C)C=O>[CH2:13]([O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]#[CH:11]
Reactant: C#CCCl
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOCc1cccnc1
Yield: 45.3 %

Procedure:
While maintaining the reaction mixture at 5°-10° C., 3-pyridylcarbinol (50.0 g, 0.45 mol) was slowly added to a mixture of sodium hydride (24.0 g of a 50% suspension in mineral oil, 0.5 mol) in 250 ml dry N,N-dimethylformamide. Propargyl chloride (37.0 g, 0.5 mole) was then slowly added to this mixture at 15° C. Following the addition, the reaction mixture was warmed to 35° and maintained for 15 mins at this temperature. The reaction was then cooled to 15°-20°, carefully quenched by dropwise addition of water and extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 45 g crude product. Distillation gave 30.0 g of 3-(2-propynyloxymethyl) pyridine. Yield 44% theory; b.p. 95° C. (0.9 mm).
Reaction SMILES: O[C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2C(=O)C)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O:52][CH2:53][CH3:54])=O)=NC(OCC)=O.C1(P([N:69]=[N+:70]=[N-:71])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:69]([C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:53](=[O:52])[CH3:54])[CH2:3]1)=[N+:70]=[N-:71]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3β-hydroxy-5α-pregnan-20-one (60 mg, 0.19 mmol) in THF (2 mL) was treated with triphenylphosphine (100 mg, 0.38 mmol) and diethyl azo-dicarboxylate (0.03 mL, 0.19 mmol). To the resulting solution was added dropwise diphenylphosphoryl azide (0.04 mL, 0.19 mmol) and the mixture was stirred at RT for 24 h. Evaporation of the solvent in vacuo and purification of the residue using flash column chromatography using petroleum ether/ethyl acetate 90/10 as elution solvent afforded the compound named above.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH3:50])[CH2:48][OH:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:42])[NH:46][C@@H:47]([CH3:50])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@H](N)CO
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)N[C@@H](C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-oxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:11]=O)[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:9]([CH2:8][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:11]=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:10]
Reactant: N#CCC(C=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=CC(CC#N)(c1ccccc1)c1ccccc1
Yield: 63.5 %

Procedure:
3,3-Diphenyl-3-formylpropionitrile (0.85 g) and (carbethoxymethylene)triphenylphosphorane (1.46 g) were heated in chloroform (20 ml) on reflux for 7 hours. The reaction mixture was then concentrated to dryness and the group was purified by silica gel column chromatography to provide the title compound (0.7 g) as colorless oil.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][C@@H:7]([OH:21])[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[CH3:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH:28]([OH:44])[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>>[C:18]([OH:20])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:21].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([OH:44])[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]
Reactant: CC/C=C\CCC(O)C/C=C\CCCCCCCCCC(=O)O
Reactant: CC/C=C\CC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Product: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Product: CCCCCC[C@@H](O)C/C=C\CCCCCCCCCC(=O)O

Procedure:
The process is particularly advantageous for feedstocks comprising densipolic acid and auricolic acid, as or not as a mixture with ricinoleic acid and lesquerolic acid, as, after hydrogenation, saturated acids having the same C18 or C20 chain length are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:24])[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1.CCOC(C)=O>[ClH:32].[F:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:15]([O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[N:16][N:17]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3cccc(F)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1nc(OC2CCNCC2)c2c(F)cccc21

Procedure:
The title product was prepared as described above for Example 41 using (Intermediate 46) (265 mg, 0.617 mmol) and 4 M HCl in dioxane (2.00 ml) in EtOAc (2 ml) to afford 202 mg (89%) as a white solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH2:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[F:1][CH2:2][CH2:3][NH:4][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Reactant: NCCF
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCF)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 5 %

Procedure:
To a solution of 2-fluoroethanamine (107 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of sodium cyanoborohydride (7.58 mg, 0.121 mmol). The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (2.9 mg, 0.006 mmol, 5%).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C:19]2=[C:20]([NH:35][S:36]([CH:39]3[CH2:42][CH:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:40]3)(=[O:38])=[O:37])[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[C:22]([CH3:25])[C:23](=[O:24])[N:18]2[CH2:17][CH2:16]1)=O)(C)(C)C.CO>C(Cl)(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:21]1[C:20]([NH:35][S:36]([CH:39]2[CH2:42][CH:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:40]2)(=[O:38])=[O:37])=[C:19]2[NH:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]=1[CH3:25]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
Dioxane hydrochloride (3 mL) was added to 8-(3-benzyloxy-cyclobutanesulfonylamino)-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (250 mg) and the resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was concentrated; the concentrate was neutralized with NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 120 mg of the product (55.8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNCC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 101) (220 mg, 0.49 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with piperidine in DMF according to the method described in Example 45. Obtained as a light brown solid (250 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].O.O.Cl[Sn]Cl.O.C(=O)(O)[O-]>C(O)C.C(OCC)(=O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
A mixture of compound 50 (4.40 g, 14.30 mmol) and SnCl2.2H2O (16.13 g, 71.5 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 h. Water and saturated bicarbonate solution (˜250 ml) was added (very effervescent). The reaction mixture was diluted with ethyl acetate and then Celite® was added and the mixture was stirred for 15 min then filtered. The filtrate was extracted with ethyl acetate twice, and the organic extract was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography, dry loaded with THF onto 80 g SiO2 and eluted with 0% to 50% ethyl acetate in hexanes to afford title compound 51 (2.10 g, 51%) as a beige solid. LRMS (ESI): (calc) 277.05 (found) 278.2 (MH)+. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (ddd, J=7.9, 7.4, 1.8 Hz, 1H), 7.17 (td, J=7.6, 1.2 Hz, 1H), 6.97 (dd, J=8.3, 0.9 Hz, 1H), 6.94 (dd, J=8.4, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.05 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+:29].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:29].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Product: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
Sodium 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.36 g), which was prepared from 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.33 g) and sodium bicarbonate (0.304 g), was dissolved in N,N-dimethylformamide (14 ml). To this solution was added iodomethyl pivalate (0.932 g) in N,N-dimethylformamide (3 ml) under ice-cooling, followed by stirring at the same temperature for 10 minutes. After addition of ethyl acetate (80 ml), the reaction mixture was washed twice with water, three times with 5% aqueous solution of sodium bicarbonate and twice with an aqueous solution of sodium chloride in turn, dried over anhydrous magnesium sulfate, and then evaporated to dryness under reduced pressure to give a residue, which was pulverized with diisopropyl ether to obtain pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.0 g), mp 128°-132° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8]COC.CC(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1ccc(N2CCN(CCc3ccccc3)CC2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)cc1Cl
Reaction time: 4.5 h
Yield: 49.5 %

Procedure:
To 1-(3-chloro-4-methoxymethoxyphenyl)-4-phenethyl-piperazine (214 mg), 2-propanol (1 mL) and tetrahydrofuran (1 mL) were added, followed by cooling with ice and addition of conc. hydrochloric acid (0.5 mL). Raising the temperature back to the ambient level, the mixture was stirred for 4.5 hours. The reaction mixture was poured in saturated saline solution, rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting crude product was purified on TLC (developer, chloroform: acetone=5:1) to provide 2-chloro-4-(4-phenethylpiperazin-1-yl)phenol (93 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][CH2:21]OS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCOCC1>[N:27]1([CH2:21][CH2:20][CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[O:12]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2C1=C1OC(CCN2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and pyrrolidine (113 μl, 1.35 mmol) in dioxane (0.8 ml) was heated at 85° C. for 2 minutes and then stirred at room temperature for 4 hours. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give brown oil. The brown oil was chromatographed (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from EtOAc/hexane to produce 3-[3-(2-pyrrolidin-1-yl-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (25 mg, 54%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)c1ccc(CCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Yield: 77 %

Procedure:
Prepared analogously to Example 10 from 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 77% of theory, C26H24N4O3S (472.57) Rf value: 0.18 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU5##