Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[N:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[Li+].[OH-].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:30])[NH:9][C:8]=1[C:6]([OH:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Yield: 95.8 %

Procedure:
5-(Benzyloxy)-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (61) (0.24 g, 520 μmol, Eq: 1.00) and LiOH (62.3 mg, 2.6 mmol, Eq: 5) were stirred in tetrahydrofuran (2 ml)/water (1.00 ml) at reflux overnight. The solvent was mostly removed. The residue was taken up in water and was extracted once with ethyl acetate. The aqueous layer was acidified with HCl conc. The precipitate was collected by filtration, washed with water and dried to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (62) (0.202 g, 498 μmol, 95.8% yield) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH2:16])[CH2:15][CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:4].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:16][C:5]2([C:3]([OH:2])=[O:4])[CH2:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)C1(N)CCCC2(CC1)OCCO2
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCC3(CC2)OCCO3)cc1OCCc1cccc(C)c1

Procedure:
The title compound was prepared from the compound of step 3 and 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to steps 3 and 4 of example 1.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.O[NH:14][C:15](=[NH:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:16][C:15]1[N:17]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:1])[O:11][N:14]=1
Reactant: CC(=N)NO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1noc(-c2ccccc2N)n1
Temperature: 180 °C
Yield: 69.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (3.5 g) in THF (35 mL) was treated with N-hydroxy-acetamidine (1.7 g), and DIEA (8 mL). The reaction mixture was microwave heated at 180° C. for 5 minutes, concentrated and purified by silica gel chromatography to afford 2.6 g of 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenylamine: 1H NMR (300 MHz, CDCl3) δ 8.0 (d, 1H), 7.4 (t, 1H), 6.9 (m, 2H), 6.0 (bs, 2H), 2.6 (s, 3H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A stirred mixture of methyl isocyanoacetate (7.0 g, 70 mmol, 1 eq) and DBU (10.06 g, 70 mmol, 1 eq) in THF was cooled to 0° C., and a solution of acetic anhydride (7.14 g, 70 mmol, 1 eq) in THF was added dropwise over 15 min. The reaction mixture was stirred for 12 h at room temperature. The solvent was removed by Rota-vapor and water was added. The mixture was extracted with EtOAc. The crude product was purified by silica gel (230-400) column chromatography using 30% EtOAc/hexane. Yield: 6.8 g (98%). 1H NMR (400 MHz, CDCl3): δ 2.54 (s, 3H), 3.80 (s, 3H), 7.69 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH3:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[O:22]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]2[CH2:12][CH:13]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[O:22][CH:21]2[C:20]([O:24][CH3:25])=[O:23])[CH3:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C=O
Reactant: Cc1nc(CCNC(C)Cc2ccc(O)cc2)cs1
Product: COC(=O)C1OC(c2csc(C)n2)CN1C(C)Cc1ccc(O)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using ether/petroleum ether =8:2 as eluant.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of cyclopentylamine (0.148 mL, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (622 mg, 4.50 mmol) followed by 1-(bromomethyl)-4-nitrobenzene (648 mg, 3.00 mmol). The resulting mixture was stirred at rt for 16 hours, more 1-(bromomethyl)-4-nitrobenzene was added (324 mg, 1.5 mmol), and stirring was continued for an additional 2 hours. The mixture was diluted with water, extracted with CH2Cl2, and the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by precipitation from methanol to afford the title compound (554 mg, quant.). MS (ESI) m/z 356.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[NH2:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1.Cl>CN(C=O)C.CCOCC>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:46][C:44]3[N:45]=[C:41]([NH2:40])[S:42][CH:43]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nc(CCl)cs1
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(N)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.569 g, 1.2 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-amino-4-chloromethylthiazole hydrochloride (0.222 g, 1.2 mmol) is added. The mixture is stirred for 48 hours and the filtered. The filtrate is concentrated in vacuo and dissolved in methylene chloride (30 mL). This solution is washed with water and drived over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo. This oil is dissolved in ether and treated with ethereal HCl to precipitate a gum which is collected by decantation. This gum is recrystallized from 2-propanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[F:19]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-chloro-3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:24][C:25](=[O:34])[C:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:24][C:25](=[O:34])[C:26]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: NCc1nc2c(c(=O)[nH]1)CCCCC2
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCCCC4)CC2)cc1
Yield: 43.7 %

Procedure:
The title compound (89 mg, 44% yield) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (124 mg, 0.45 mmol) and 2-(aminomethyl)-6,7,8,9-tetrahydro-3H-cyclohepta[d]pyrimidin-4(5H)-one (87 mg, 0.45 mmol). 1H NMR (400 MHz, CDC3) δ 11.36 (br. s., 1H), 8.01 (br. s., 1H), 7.83-7.89 (m, J=9.1 Hz, 2H), 6.85-6.91 (m, 2H), 4.30 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.12-3.29 (m, 1H), 2.97-3.12 (m, 2H), 2.92 (br. s., 2H), 2.55-2.83 (m, 4H), 2.30 (br. s., 2H), 1.67-1.94 (m, 6H), 1.40-1.67 (m, 4H). HRMS calculated for C23H32N4O4 453.2502. found (ESI, [M+H]+), 453.2509. Retention time=3.09.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1c(C2CCN(S(C)(=O)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (4 μL, 0.05 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (17.0 mg, 0.05 mmol) and triethylamine (0.02 mL, 0.14 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-0% hexanes in ethyl acetate) to afford (S)-1-(2-methyl-6-(1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (14 mg, 72%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 6H), 1.19-1.26 (m, 1H), 1.58-1.81 (m, 6H), 2.02 (s, 3H), 2.17-2.30 (m, 2H), 2.68-2.85 (m, 3H), 2.89 (s, 3H), 2.89-2.99 (m, 1H), 3.60-3.76 (m, 4H), 4.57 (br d, J=6.45 Hz, 1H), 7.09 (br s, 2H). MS (ESI, pos. ion) m/z 409 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:20]2[CH:25]=[CH:24][C:23](S(C)(=O)=O)=[CH:22][CH:21]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CNC2C=CC=C([Br:43])C=2)CCCC1.C([O:46][C:47](=[O:56])[CH2:48][S:49]C1SC(N)=NC=1)C>>[Br:43][C:22]1[CH:21]=[C:20]([N:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:49][CH2:48][C:47]([OH:46])=[O:56])=[CH:13][N:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: Brc1cccc(NCC2CCCC2)c1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Br)c2)s1

Procedure:
The title compound was prepared via {2-[3-(3-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-bromo-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.Cl[Si:10]([CH2:13][Cl:14])([CH3:12])[CH3:11].C([Li])CCC>O1CCCC1.CCCCCC.CCOCC.[Cl-].[Li+]>[Cl:14][CH2:13][Si:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: C[Si](C)(Cl)CCl
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(CCl)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A solution of 9.6 g (0.050 mol) of 4-bromochlorobenzene and 6.6 ml (7.2 g, 0.050 mol) of chloro(chloromethyl)dimethylsilane in 75 ml of tetrahydrofuran was stirred at -78° under nitrogen while 31 ml (0.050 mol) of 1.6 molar n-butyllithium in hexane was added dropwise. The resulting clear solution was allowed to warm to room temperature, diluted with ether until no more lithium chloride precipitated, and filtered. Evaporation of the filtrate left 10.6 g of a light yellow liquid, which was distilled to give 6.0 g (55%) of the title compound as a colorless liquid: bp 54°-58° C. (0.05 mm); ir (neat) 2910, 1560, 1470, 1370, 1250, 1080, 1010, 840, 805, 790, 740 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 2.9 (2H, s), 7.1-7.6 (4H, q).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:17]2[CH2:19][CH2:18]2)[C:3]1=[O:20].[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:29])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.CS(C)=O>O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@@H:28]([C@H:30]1[CH2:34][CH2:33][N:32]([C:7]2[C:6]([O:15][CH3:16])=[C:5]3[C:10]([C:11](=[O:12])[N:2]([NH2:1])[C:3](=[O:20])[N:4]3[CH:17]3[CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:13])[CH2:31]1)[CH3:29])([CH3:22])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1c(N2CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 0.57 g (2.0 mmol) of 3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (Example 24d), 0.64 g (3.0 mmol) of ((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at 110° C. for 4 hours. The reaction mixture is cooled to room temperature, poured into 150 mL of ice and water, and extracted with ethyl acetate (2×125 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 1.1 g of crude product. Chromatography on flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (9:1) provided 0.92 g of the title compound, mp 96–98° C.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27](N(CC)CC)C.CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[C:9]([CH3:27])([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(C)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 1 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide (300 mg), prepared as described in PCT EP 90/02189 in dimethyl sulphoxide (3 ml), was treated at room temperature with triethylamine (0.110 ml) and methyl iodide (0.135 ml). After 1 hr, the reaction mixture was diluted with ethyl acetate, sequentially washed with a dilute solution of hydrochloric acid and brine and eventually dried over Na2SO4. Removal of the solvent and flash chromatography of the residue afforded the title compound as a white solid (160 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]3[CH:19]=[N:20][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](O)[N:25]=4)[C:22]=3[CH3:23])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:26]1[N:25]=[C:24]([N:21]2[C:22]([CH3:23])=[C:18](/[CH:17]=[CH:16]/[CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)[CH2:10][CH2:11]3)[CH:19]=[N:20]2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: Cc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(Cl)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To 250 mg of the compound obtained in Example 34 was added 5 ml of phosphorus oxychloride. The mixture was stirred at 60° C. for 2.5 hours, followed by concentration. A mixture of the concentrate and water was neutralized with sodium hydrogencarbonate and extracted with chloroform three times. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform was a developing solution. Concentration of the fraction containing the desired compound gave 180 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCCCCCC(=O)O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)CCCCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 85 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 6-aminohexanoic acid (0.68 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from EtOH yielded 1.35 g (85%) of 104 as a white solid: mp=202–204° C.; Rf 0.80 (A): Rf 0.84 (B): Rf 0.47 (D): IR (cm−1): 2800–3250 (OH), 3103 (C═CH), 2675 (C—H), 1769 (C═O), 1709 (bs, C═O), 1625 (C═C), 1485 (C═C), 1403(C—O), 1303 (C—O), 730 (C═CH); MS m/z (rel intensity) 305 (16), 304 (100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][CH2:25][OH:26])[CH2:22][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:20](=[O:34])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][CH:25]=[O:26])[CH2:22][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:20](=[O:34])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.608 mL, 6.97 mmol) in dichloromethane (40 mL) at -78° C. was added DMSO (0.990 mL, 13.9 mmol) over 2-3 minutes. The solution was stirred for 10 minutes, then a solution of the alcohol from Step E of Example 43 (2.06 g, 5.81 mmol) in 10 mL of dichloromethane was added over 5 minutes, keeping the reaction temperature below -70° C. The reaction was stirred for 10 minutes, then triethylamine (2.43 mL) was added, and the reaction was stirred at -78° C. for 5 minutes, then allowed to warm to room temperature. After 45 minutes, the solution was poured into dichloromethane, and washed with sat. NH4Cl soln., 10% citric acid soln., water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:45][CH2:44]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:44][CH2:45]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCC(NC2CC2)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)C(CNCCOc2ccc(C(=O)O)cc2OC)NC2CC2)ccc1NC(=O)Nc1ccccc1C
Reaction time: 15 h
Yield: 32.2 %

Procedure:
A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-N-[2-cyclopropylamino]ethylamino]ethoxy]benzoate (195 mg, 0.30 mmol)) in THF:MeOH(4:1, v/v) (5 mL) and 1N NaOH (0.756 mL) was stirred at 50 C. for 15 hr. The pH of the mixture was adjusted to 7.4 by the addition of 1N HCl, and extracted with CHCl3:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was crystallized with Et2O to give 57 mg (38%) 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-[2-cyclopropylamino]ethylamino]ethoxy]benzoic acid 264 as a white crystalline material. mp 135-140° C.; IR (KBr), 3324, 2937, 1535, 1032, 754 cm−1; 1H-NMR (CD3OD, 400 MHz) δ0.50-0.73 (m, 4H), 2.29 (s, 3H), 2.53 (m, 1H), 2.98 (m, 1H), 3.21 (m, 1H), 3.58-3.88 (m, 11H), 3.91 (s, 1H), 4.09 (m, 1H), 4.25 (m, 1H), 6.76-6.92 (m, 3H), 7.01 (m, 1H), 7.18 (m, 2H), 7.60 (m, 3H), 8.00 (d, J=8.3 Hz, 1H); MS (FAB) m/z 591(M+H)+; Anal Calcd. for C32H38N4O7.3.0H2O, C, 59.62; H, 6.88; N, 8.69. Found, C, 59.25; H, 6.29; N, 8.29.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[C:16](=[O:18])[CH2:15][CH2:14]3)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:17]=3[C:16](=[O:18])[CH2:15][CH2:14]4)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C1CCc2cccc(Oc3cncc(Cl)n3)c21
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc4c3C(=O)CC4)n2)cc(OC)c1OC
Yield: 4 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-7-oxy)-pyrazine (200 mg, 0.77 mmol) and 169 mg (0.92 mmol) 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (11 mg). Yield: 4%.