Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[Cl:59][C:60]1[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=1[NH2:67]>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:61]2[CH:62]=[CH:63][CH:64]=[C:65]([Cl:66])[C:60]=2[Cl:59])[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Nc1cccc(Cl)c1Cl
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(Cl)c2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 2,3-dichloro-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.9, 146.4, 140.4, 139.1, 138.5, 135.1, 134.8, 134.0, 133.5, 132.7, 130.0, 127.6, 124.3, 123.2, 122.5, 121.0, 119.9, 118.6, 117.4, 115.2, 61.5, 28.7, 20.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 119 %

Procedure:
To a methylene chloride (100 mL) solution of 5-benzyloxy-2-methyl-pyridine (5.99 g, 30.1 mmol) described in Manufacturing Example 127-1-1 was added m-chloroperbenzoic acid (8.79 g, 33.1 mmol, purity: 65%) at 0° C., which was stirred for 2 hours at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture at 0° C., which was extracted with methylene chloride. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g). Acetic anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) thus obtained, which was stirred for 80 minutes at 120° C. This mixture was cooled to room temperature and then concentrated under a reduced pressure. To an ethanol (50 mL) solution of this residue was added a 5 N sodium hydroxide aqueous solution (7 mL), which was stirred for 50 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. The residue was partitioned into saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (4.17 g, 54%).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([C:45]1([C:48](O)=[O:49])[CH2:47][CH2:46]1)=[O:44].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[F:35])[CH2:46][CH2:47]4)=[O:49])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2F)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4F)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (410 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (223 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (90.6 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([C:19]([CH2:21][C:22](OCC)=[O:23])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)=[CH:21][C:22](=[O:23])[O:5]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1cccc2ccccc12
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: CCO
Product: O=c1cc(-c2cccc3ccccc23)c2ccc(O)cc2o1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of resorcinol (4.84g., 0.041 moles) and ethyl 1-naphthoylacetate (10g., 0.041 moles) in ethanol (50 ml.) was saturated with hydrogen chloride at room temperature (cooling with ice/water) and left to stand in a stoppered flask for 24 hours. The solution was filtered to give the required coumarin as an orange solid (7.8g., 66%, m.p. 292°-295° C.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]>O>[N+:10]([C:9]1[CH:8]=[CH:7][C:6]([NH2:1])=[CH:5][C:4]=1[C:3]([F:15])([F:14])[F:2])([O-:12])=[O:11]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A solution of ammonia in water (100 cm3, s.g. 0.88) was added to 3-trifluoromethyl-4-nitrofluorobenzene (5 g) and the mixture was heated in a bomb at 150° for 2 hours. Solvent was removed in vacuo to yield a yellow solid. Recrystallisation of this solid from hexane/ethyl acetate afforded yellow crystals of 4-nitro-3-trifluoromethylaniline, m.p. 134°, (3.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[N:4][C:3]=1[N+:15]([O-:17])=[O:16].CN1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[CH3:25][CH2:26]OC(C)=O>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[N:4][C:3]([N+:15]([O-:17])=[O:16])=[C:2]([N:22]3[CH2:23][CH2:24][CH:25]([CH3:26])[CH2:20][CH2:21]3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cnc([N+](=O)[O-])c(Cl)n2)CC1
Reactant: CCOC(C)=O
Reactant: CN1CCNCC1
Product: CC1CCN(c2nc(N3CCN(C)CC3)cnc2[N+](=O)[O-])CC1
Yield: 96 %

Procedure:
To 6′-chloro-4-methyl-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (32 mg, 0.12 mmol) was added N-methylpiperazine (370 mg, 3.7 mmol) and the resultant solution was stirred for 15 min. The reaction was diluted with EtOAc (50 mL), washed with H2O (2×20 mL), dried (K2CO3) and concentrated in vacuo to afford 37 mg (96%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C15H24N6O2, 321.2 (M+H), found 321.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:10])=[CH:8][N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16]Br>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[Cl:10][C:7]1[S:6][C:5](=[N:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH:8]=1
Reactant: COCCBr
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCn1cc(Cl)sc1=NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A flask was charged with 2-acetamido-5-chlorothiazole (Lancaster, 19.3 g, 110 mmol) in 200 mL of 2:1 THF/DMF. To the solution was added sodium hydride (60% dispersion in mineral oil, 5.44 g, 142 mmol). The mixture was stirred at room temperature for 15 min and then 2-bromoethyl methyl ether (18.3 g, 131 mmol) was added. The reaction mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate: hexane to provide 10.3 g (42%) of the title compound as the more polar regioisomer: 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3H) 3.35 (s, 3H) 3.65-3.71 (m, 2H) 4.28-4.36 (m, 2H) 7.00 (s, 1H); MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and p-toluenesulfonylchloride (46 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 487.2; Calcd: 487.14; 1H-NMR δ 7.73–7.45 (m, 7H), 7.26 (d, 2H), 6.74 (s, 1H), 6.62–6.60 (m, 2H), 3.69 (app t, 2H), 3.39 (app t, 2H), 3.29–3.74 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH:11]=O.[C:17]([N:20]1[CH2:25][C:24](=[O:26])[N:23](C(=O)C)C[C:21]1=[O:30])(=[O:19])[CH3:18].[CH3:31]C(C)([O-])C.[K+].Cl>CN(C)C=O.C(O)(C)(C)C.O>[C:17]([N:20]1[C:25](=[CH2:31])[C:24](=[O:26])[NH:23][CH:11]([C:10]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=2)[C:21]1=[O:30])(=[O:19])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COCCOCOc1cc(C=O)ccc1C
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: O
Product: C=C1C(=O)NC(c2ccc(C)c(OCOCCOC)c2)C(=O)N1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
To a stirred mixture of 3-[(2-methoxyethoxy)methoxy]-4-methylbenzaldehyde (1.70 g) and 1,4-diacetyl-2,5-piperazinedione (1.6 g) in a mixture of N,N-dimethylformamide (17 ml) and tert-butanol (17 ml) was added potassium tert-butoxide (900 mg) at 5° C. The mixture was stirred for 24 hours at room temperature and then poured into water (300 ml). The aqueous mixture was adjusted to pH 4–5 with aqueous diluted hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using mixed solvents of toluene and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-acetyl-3-[3-[(2-methoxyethoxy)methoxy]-4-methylphenyl]-methylene-2,5-piperazinedione (2.05 g) as a powder.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:20]1N=CN(C(N2C=NC=C2)=O)C=1.C(Cl)Cl.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>N1C=CC=CC=1>[CH2:2]([C:1]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:20]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCC(=O)N[C@H](CO)C(C)C
Reaction time: 48 h

Procedure:
To oleyl alcohol (22) (0.5 g, 1.58 mmol) in 5 ml pyridine, and while stirred at r.t., CDI (0.26 g, 1.58 mmol) was added. The reaction mixture was stirring at r.t for 48 hrs. Reaction was followed using TLC (100% DCM). When the starting material disappeared Valinol (0.162 g, 1.58 mmol) was added to the mixture was stirred for 1 week at room temperature. Reaction progress was followed by TLC (Eth. Ac100%). After the reaction was completed was the volatiles were removed under reduced pressure. The desired product Oleylcarbonyl-L-Valinol (25) was obtained using column chromatography (DCM/ethyl acetate.=1:1; v/v; I2).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Li+].C(O)C>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Yield: 96.5 %

Procedure:
To a solution (20 mL) of methyl 4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoate (1.86 g) synthesized above in tetrahydrofuran was added 2N lithium hydroxide aqueous solution (10.2 mL), and the mixture was stirred with heating under reflux for 2 hr. A 4N aqueous lithium hydroxide solution (5.10 mL) was additionally added, and the mixture was stirred with heating under reflux for 4 hr. A 4N aqueous lithium hydroxide solution (5.10 mL) and ethanol (20 mL) were further added, and the mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (61.2 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.74 g, 96%) as a pale-brown solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[C:1]1([C:11]([Cl:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2ccccc12
Reaction time: 24 h
Yield: 100.2 %

Procedure:
a mixture of 17.2 g (0.1 mole) 1-naphthoic acid, 14 g (0.11 moles) oxalyl chloride, 150 ml methylene chloride and three drops DMF (dimethylformamide) were stirred for about 24 hours. The clear reaction mixture was stripped to give about 19.1 g of the 1-naphthoyl chloride as a brown liquid which was used in step (b) without further isolation.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl[C:26]1[C:27](=[O:43])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C1(C)C=CC=CC=1.O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:35]=[C:26]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]2=[O:43])=[CH:41][CH:40]=1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c(Oc2ccccc2)nc2ccccc2n1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of sodium hydride (0.65 g), "15-crown-5" (1,4,7,10,13-pentaoxacyclopentadecane) (0.5 ml), phenol (2.2 g), and dry toluene was stirred for 30 minutes. To this was added a suspension of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (6.0 g) in dry toluene (30 ml) and stirring was continued for 2 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent and crystallisation from ethanol gave the title compound (4.5 g) mp 239°-241° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=4)[C:13]([C:27]([O:29]CC)=[O:28])=[CH:12][N:11]=3)[CH2:6][C:5]=12.[OH-].[Na+].O1CCCC1>CS(C)=O.O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=4)[C:13]([C:27]([OH:29])=[O:28])=[CH:12][N:11]=3)[CH2:6][C:5]=12
Reactant: CCOC(=O)c1cnc(N2CCn3ccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc(N3CCn4ccnc4C3)ncc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 97) 290 mg and 2N aqueous sodium hydroxide solution 1.64 ml are suspended in dimethyl sulfoxide-water (5 ml:1 ml) and stirred at room temperature for 1 hour. Tetrahydrofuran 5 ml is added thereto and the mixture is stirred at room temperature for 13 hours. After removal of tetrahydrofuran in vacuo, the residue is diluted with water and neutralized with a 10% aqueous citric acid solution. The precipitate is collected, washed with water, methanol and isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a colorless crystalline powder, 187 mg. mp 223-226° C. (decomposition), MS(m/z): 413(M−H)−
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([CH2:17]O)=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=S(Cl)Cl.[CH3:23]O>C1(C)C=CC=CC=1>[Cl:1][CH2:17][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH3:23])=[O:15])[N:9]([C:4]2[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][N:5]=2)[N:10]=1
Reactant: CO
Reactant: O=C(O)c1cc(CO)nn1-c1ncccc1Cl
Reactant: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 70 °C

Procedure:
1-(3-Chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acid hydrochloride 29 g (0.1 mol) was initially charged in 100 ml of toluene. 24 g SOCl2, was added in portions at 60° C. The mixture was heated at 70° C. for 3 h, in the course of which the precipitate went completely into the solution. Methanol (30 ml) was slowly added dropwise to the mixture and the solution was stirred at 30° C. for another hour. Subsequently, the solution was concentrated under reduced pressure. This afforded 95% of the product with a purity of 96%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][CH:4]=1.[C:32]([O:36][C:37]([NH:39][S:40](N1C=CC(=[N+](C)C)C=C1)(=[O:42])=[O:41])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[O:11]=[C:10]([NH:12][CH2:13][C:14]1[C:15]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:41])=[O:42])=[CH:8][CH:7]=1)[CH3:31]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)cc2)c1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc2)c1
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) in dichloromethane the intermediate (A) (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) was added was stirred for overnight. The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with dichloromethane and washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography. Tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (118 mg) was obtained as 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12]C(=O)OCC3C=CC=CC=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Nc1cc(F)cc2c1OCCC2)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cc2c1OCCC2

Procedure:
8.1 g of the compound of Step 3 are dissolved in 80 ml of ethanol. The solution is hydrogenated at normal pressure and room temperature in the presence of 0.39 g of palladium-on-carbon. Filtration and evaporation yield 4.6 g of a liquid which corresponds to the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[Cl:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>>[Cl:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:28]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)(CCl)C(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)CCl)nc3cc21

Procedure:
3-Chloro-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-chloropivaloyl chloride (115 μl, 0.89 mmol). The title compound was obtained as yellow powder (239 mg, 69%).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:28]([NH:30][C:31]1[S:32][C:33]([Br:43])=[C:34]([C:36](=[N:40][O:41][CH3:42])[C:37](O)=[O:38])[N:35]=1)=[O:29]>C(OCC)(=O)C.CN(C)C=O>[CH:28]([NH:30][C:31]1[S:32][C:33]([Br:43])=[C:34]([C:36](=[N:40][O:41][CH3:42])[C:37]([NH:1][CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]23)=[O:38])[N:35]=1)=[O:29]
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1nc(NC=O)sc1Br
Yield: 78.6 %

Procedure:
A solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.0 g.) and trimethylsilylacetamide (3.7 g.) in dry ethyl acetate (30 ml.) and a solution of dimethylformamide (0.47 ml.), phosphoryl chloride (0.56 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.6 g.) in dry ethyl acetate (11.6 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.85 g.).