Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1>>[NH:13]1[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)=[O:10])=[N:16][N:15]=[N:14]1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1nnn[nH]1
Product: O=C(Nc1nnn[nH]1)c1cc(Br)ccn1
Yield: 60.1 %

Procedure:
0.3 g of 4-bromo-2-pyridinecarboxylic acid, 0.25 g of N,N'-carbonyldiimidazole and 0.14 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.24 g of N-(5-tetrazolyl)-4-bromo-2-pyridinecarboxamide is obtained.
Reaction SMILES: N[C:2]1[C:3]([C:10]([N:12]2C=CN=C2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6](N)[N:7]=1>O1CCCC1>[Cl:9][C:5]1[N:4]=[C:3]([C:10]([NH2:12])=[O:11])[CH:2]=[N:7][CH:6]=1
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Solvent: C1CCOC1
Product: NC(=O)c1cncc(Cl)n1

Procedure:
U.S. Pat. No. 3,201,472 as an example of how to obtain this material) in 700 ml of tetrahydrofuran was added 88.6 g (0.372 mol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole (see U.S. Pat. No. 4,029,816 as an example of how to obtain this material) in 10 portions over 1.5 hours. After 1 hour at ambient temperature the reaction mixture was filtered and concentrated to 300 ml. The solution was added dropwise to 1.4 liters of ether with vigorous stirring. The solid was filtered, washed with ether and dried. There was obtained 74.3 g (0.258 mol, 70%) of 3,5-diamino-N-[2-(2-aminoethyl)methylamino]ethyl]-6-chloropyrazinecarboxamide. A sample was filtered through a pad of silica gel and eluted with 5:95 (v/v) methanol:methylene chloride saturated with ammonia gas; mp 138°-139.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.O>C(#N)C.C(Cl)Cl>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCN(C(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.6 %

Procedure:
To a solution of 1-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazine (10.0 g, 31 mmol) in acetonitrile (60 mL) was added tert-butyl bromoacetate (6.1 mL, 31 mmol) dropwise from a syringe. The reaction mixture was stirred at rt for 5 min. and triethylamine (11 mL, 78 mmol) was added. Water was added after 18 h followed by CH2Cl2. The layers were separated, the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-80% EtOAc in hexanes to give the title compound (9.1 g, 67% yield) as brown oil that solidified on standing. MS (ESI, pos. ion) m/z: 435.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:22])[CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C:12]#[CH:13].N12CCN(CC1)CC2.C(O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]([OH:22])[C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)c1cc(F)ccc1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: O=CO
Product: C#CC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)c1cc(F)ccc1F
Temperature: 45 °C

Procedure:
To a stirred vessel under nitrogen sweep was charged tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate (35.0 kg, 113 mol), 1,4-diazabicyclo[2.2.2]octane (38.0 kg, 339 mol), and THF (465 kg). After dissolution, chloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](pentafluorophenylsulfonyl)amido}-(p-cymene) ruthenium (II) (410 g, 576 mmol) was added. The vessel was vacuum sparged and back-filled with nitrogen three times. Then, formic acid (26.7 kg, 580 mol) was added and the reaction heated to 45° C. overnight.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(COC)OC>[Br:22][C:23]1[CH:24]=[C:25]([C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:18]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH:6]=[CH:7][C:8]=3[CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Brc1cccc(-c2cc3ccc4ccccc4c3c3ccccc23)c1
Yield: 63.5 %

Procedure:
In argon atmosphere, a mixture of 6.32 g (22.3 mmol) of 5-benzo[c]phenanthreneboronic acid, 5.07 g (18.6 mmol) of 3-bromoiodobenzene, 1.29 g (1.12 mmol) of tetrakis(triphenylphosphine)palladium (0), 80 ml of toluene, 80 ml of dimethoxyethane, and 33.8 g of a 2 M sodium carbonate aqueous solution was refluxed for 8 h under stirring. After the reaction, the reaction mixture was added with water and extracted with toluene. The organic phase was washed with water and dried over sodium sulfate, and then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 4.53 g (yield: 56.8%) of 5-(3-bromophenyl)benzo[c]phenanthrene.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[CH2:39]([N:46]([CH2:77][CH2:78][O:79][Si](C(C)(C)C)(C)C)[C:47]([C:49]1[C:54]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:53]([OH:63])[N:52]=[C:51]([CH2:64][C:65]2([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=3)[CH2:69][CH2:68][CH2:67][CH2:66]2)[N:50]=1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([N:46]([CH2:77][CH2:78][OH:79])[C:47]([C:49]1[C:54]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:53]([OH:63])[N:52]=[C:51]([CH2:64][C:65]2([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=3)[CH2:66][CH2:67][CH2:68][CH2:69]2)[N:50]=1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccccc1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from N-benzyl-5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxamide (506).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:7]1[NH:8][S:9](=[O:11])(=[O:10])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: O=C1Nc2ccc(Cl)cc2S(=O)(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: O=S1(=O)NC(Cl)=Nc2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 8.0 g of 7-chloro-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide in 80 g of phosphorus oxychloride is added dropwise 7.4 g of 2,6-lutidine, while the mixture is cooled in an ice bath. After the addition, the mixture is heated under reflux for 12 hours and concentrated under reduced pressure. To the residue is added 400 ml of ice water and the resulting mixture is stirred for 30 minutes. The crystalline precipitate is collected by suction filtration, washed with water and then with 2-propanol, and recrystallized from 2-propanol to afford the desired product, m.p. 242°-244° C.
Reaction SMILES: [C:1]([CH:3]([C:13]([C:15]1[C:16]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH2:33][OH:34])[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:14])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[C:38]([CH2:37][CH2:36][C:35]([O:34][CH2:33][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][C:16]1[C:15]([C:13](=[O:14])[CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:5])=[N:19][N:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:17]=12)=[O:41])([OH:40])=[O:39]
Reactant: O=C1CCC(=O)O1
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(CO)cccc1-2
Solvent: c1ccncc1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(COC(=O)CCC(=O)O)cccc1-2
Temperature: 45 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
2-cyano-3-(1,4-dihydro-5-hydroxymethyl-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.1 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45° C. for 20 hours. After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH2Cl2 /isopropanol yields 0.85 g of 3-[5-(3-carboxy-propanoyloxymethyl) -1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:28][CH3:29])[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:28][CH3:29])[C:20]2[C:25]([CH:26]=[CH:1][CH3:2])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CCN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=Cc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 14 and making non-critical variations but starting with n-butyl lithium (1.6M, 1.16 ml, 1.86 mmol), ethyltriphenylphosphonium bromide (0.69 g, 1.86 mmol), and 1-benzyl-4-[N-ethyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 12, 0.40 g, 1.24 mmol), the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH:30]([CH3:39])[CH3:31])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:15]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)Nc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 65 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (60 mg, 0.14 mmol), acetone (97.6 mg, 1.68 mmol) and NaBH(OAc)3 (385.7 mg, 1.82 mmol) yielded 43 mg (65%) of intermediate 4a. MS (ESI) 469.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].Cl>O1CCCC1.[OH-].[Li+]>[CH3:23][N:14]1[C:13](=[O:24])[C:12]2([CH2:25][CH2:26][N:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:8])[CH2:10][CH2:11]2)[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15]1
Reactant: COC(=O)CCNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CN(c2ccccc2)C2(CCN(C(=O)NCCC(=O)O)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 171 mg (0.31 mmol) of 2-(3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of tetrahydrofuran, 4 ml of 0.1M aqueous lithium hydroxide solution was added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 0.1M hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was reprecipitated from ether/chloroform to obtain 135 mg of 2-(3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid (yield: 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])[CH3:2].[CH3:19][NH:20][CH3:21].Cl>C(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7]([N:20]([CH3:21])[CH3:19])(=[O:9])=[O:8])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N(C)C
Reaction time: 0.25 h

Procedure:
A solution of 359 mg of 2-benzyl-3-chlorosulphonylpropionic acid ethyl ester in 2 ml of methylene chloride is cooled to -10° and 0.464 ml of a 5.6M solution of dimethylamine in ethanol is added thereto. The solution is stirred for 15 minutes at -15°, mixed with 2N HCl and extracted with methylene chloride. The extracts are washed with water, dried with magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with eluant C. Rf (A)=0.43.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12]O)=[N:10][CH:11]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:10][CH:11]=1
Reactant: C1COCCN1
Reactant: OCc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Brc1ccc(CN2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Thionyl chloride (0.57 g, 5 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (5-bromo-pyridin-2-yl)-methanol (0.3 g, 1.59 mmol) in DCM (5 mL) while cooling to 0° C. The mixture was allowed to warm to room temperature and, after 1 h, evaporated to low volume in vacuo. The residue was dissolved in CHCl3, and a solution of morpholine (0.41 g, 5 mmol) in CHCl3 was added at 0° C. After 3 h, the reaction was completed. The solvent was evaporated and addition of ether afforded the target compound (85%) as a white solid. Calculated mass=257. Observed mass=258
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:39]1([CH:45]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:46][C:47]([C:49]2[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=2)=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([CH:45]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:46][C:47]([C:49]2[CH:50]=[CH:51][C:52]([O:1][CH2:2][C:3]3[CH2:4][S:5][C@@H:6]4[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:25](=[O:38])[N:7]4[C:8]=3[C:9]([O:11][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:10])=[CH:53][CH:54]=2)=[O:48])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-(diphenylmethoxycarbonyl)phenol, to afford 864 mg of the title compound as a powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(Cl)Cl>[C:32]([NH:36][CH2:20][C:18]1[CH:19]=[C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to tert-butylamine (0.81 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (Et2O/MeOH/NH4OH//90/10/1 then 80/20/1) to yield expected compound as a yellow solid (103 mg, 92% yield). LC-MS: m/z (ESI) 425.2 [M+H]+.
Reaction SMILES: N[C@H](C(O)=O)C(C)C.N[C@H](C(O)=O)[C@H](CC)C.[NH2:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].[NH2:27][C@H:28]([C:34]([OH:36])=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32]N>>[NH2:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].[NH2:27][C@H:28]([C:34]([OH:36])=[O:35])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Product: CCCC[C@H](N)C(=O)O

Procedure:
Val, 1.1(1); Ile, 0.9(1); Leu, 8.0(8); Lys, 4.0(4).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:36][C:37]12[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][C:39]([C:47]([O:49][CH3:50])=[O:48])([CH2:40]3)[CH2:38]1)[CH2:44]2.NC12CC3CC(CC(C(OC)=O)(C3)C1)C2>CN(C)C=O.O>[C:1]([NH:8][C@H:9]([C:17]([CH:38]1[C:37]2([NH2:36])[CH2:44][CH:43]3[CH2:42][CH:41]([CH2:40][C:39]1([C:47]([O:49][CH3:50])=[O:48])[CH2:45]3)[CH2:46]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
5.09 Grams of Boc-L-phenylalanine is dissolved in 25 ml of dry dimethylformamide and 2.13 ml of N-methylmorpholine is added. The reaction mixture is cooled to -50° C. and 2.51 ml of isobutylchloroformate is added. The reaction mixture is stirred for 15 minutes, then 1.77 ml of N-methylmorpholine and 3.93 g of methyl 3-amino-1-adamantanecarboxylate hydrochloride are added and the reaction mixture is stirred until all the methyl 3-amino-1-adamantanecarboxylate dissolves then stored for 3 days at 5° C. The reaction mixture is poured into 100 ml of water and extracted twice with 50 ml of ethyl acetate. The ethyl acetate fractions are washed twice with 50 ml of water, 50 ml of a 0.5 solution of potassium bisulfate, 50 ml of water, 50 ml of a 0.5 M solution of potassium bicarbonate, and 50 ml of water then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is dissolved in 150 ml of 10% chloroform in hexane and purified by low pressure chromatography on silica gel using a gradient of 10% to 50% solution of chloroform in hexane as eluent. Removal of the solvent under vacuum gives the product methyl Boc-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR23##
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Fc1ccc(OC2CCN(Cc3ccccc3)C2)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2ccc(F)c(Cl)c2)C1
Reaction time: 48 h
Yield: 7.2 %

Procedure:
To a stirred solution of 19.6 g (0.2 mole) of phosgene in benzene (100 ml of 2 molar solution) under nitrogen gas was added dropwise 61.1 g (0.2 mole) of 1-benzyl-3-(3-chloro-4-fluorophenoxy)pyrrolidine in 100 ml of dry benzene. The mixture was stirred for about 21/2 days. The mixture was filtered to remove 8 g of starting compound as the hydrochloride salt and the filtrate was concentrated under reduced pressure. The resulting oil was triturated in succession with three 100 ml portions of 30/60 petroleum ether. The oil residue was again subjected to reduced pressure to remove petroleum ether. The oil residue, 46 g contained 5-10% benzyl chloride. The combined ether washes yielded 4 g of crystalline product on standing. Yield of product was 50 g (93%)., m.p. 63°-65° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17](=[N:20][N+:21]([O-:23])=[O:22])[NH:18][CH3:19]>CO>[CH3:19][NH:18][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[N:20][N+:21]([O-:23])=[O:22]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CO
Product: CNC(=N[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1

Procedure:
A reaction mixture was prepared containing 1.2 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.77 g. of S-methyl-N-methyl-N'-nitroisothiourea and 10 ml. of methanol. The reaction mixture was heated under reflux for 4.25 hours, after which time the solvent was removed by evaporation. The partially solid residue was chromatographed over silica using a gradient elution technique employing ethyl acetate containing increasing quantities of methanol as the eluant. Fractions shown by tlc to contain N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-nitroguanidine formed in the above reaction were pooled and the solvent removed from the pooled fractions. Trituration of the resulting residue with ether yielded a crystalline solid which, upon recrystallization from a methanol-ethyl acetate solvent mixture, yielded 0.83 g. of crystals melting at about 86.5°-88° C.