Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[C:4]([N+:12]([O-:14])=[O:13])[C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:16](=O)([O-])[O-].[K+].[K+].S([O:27][CH3:28])(OC)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([F:15])=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([O:27][CH3:28])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1O
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(F)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
5-Bromo-4-fluoro-2-hydroxy-3-nitrobenzoic acid (I-228) (35.89 g, 0.128 mol) was dissolved in acetonitrile (600 ml), then at room temperature, potassium carbonate (53.1 g, 0.358 mol) was added, and dimethyl sulfate (30.3 ml, 0.32 mol was dropwise added. After staring at 60° C. for 2.5 hour and then cooling to room temperature, the insoluble matter was removed by filtration (with washing with acetonitrile (400 ml)). The filtrate was concentrated under reduced pressure (about 800 ml of acetonitrile was evaporated away), and water (800 ml) was added to the residue, followed by stirring at room temperature. The precipitated crystal was washed with water and dried to obtain the entitled compound (36.5 g, 92%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCCC1
Reaction time: 2 h

Procedure:
To a stirred solution of cyclohexanol (Aldrich, 10.2 g, 100 mmol) in methylene chloride (250 mL) at 0° C., Methane sulfonyl chloride (8.52 mL, 110 mmol) and triethyl amine (17.5 mL, 125 mmol) were added slowly and the mixture was stirred for 2 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCl and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a yellow oil. 18.05 g.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][CH2:35][CH2:36]I>CN(C)C=O.O.C(Cl)Cl>[F:34][CH2:35][CH2:36][N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCF)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, from Example 519, (0.300 g, 0.000786 mol) and cesium carbonate (0.384 g, 0.00118 mol) in N,N-dimethylformamide (7.9 mL) was added 2-fluoro-1-iodoethane (0.137 g, 0.000786 mol) dropwise. The reaction was stirred at room temperature overnight. The mixture was diluted with water and methylene chloride and extracted 3 times with methylene chloride. The crude was purified by column chromatography then reverse-phase HPLC to obtain 521 as a white solid (84.0 mg). m+1 428.1 MS (ESI+) 428.1. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.20 (dd, J=8.2, 1.3 Hz, 1H), 7.04 (d, J=1.1 Hz, 1H), 5.84-5.66 (m, 1H), 4.48 (t, J=4.9 Hz, 1H), 4.40-4.32 (m, 3H), 3.70-3.56 (m, 3H), 3.42 (t, J=5.0 Hz, 2H), 3.20-3.14 (m, 2H), 2.73 (dt, J=28.8, 4.9 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[N:25]([CH3:34])[S:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=[O:28])=[O:27])=[N:8][CH2:7]1)C.O1CCCC1.CO.[BH4-].[Li+]>O>[OH:3][CH2:4][CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:15][C:14]=3[N:25]([CH3:34])[S:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=[O:28])=[O:27])=[N:8][CH2:7]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of ethyl{2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (350 mg), tetrahydrofuran (15 mL) and methanol (3 mL) was added lithium borohydride (30 mg), and the mixture was stirred at room temperature for 2 hr. Lithium borohydride (15 mg) was added to the mixture, and the mixture was further stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:4, volume ratio) to give the title compound (110 mg, yield 34%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 152-153° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][Br:19])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[Br-:19].[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][P+:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCCCOc2cccc(CCBr)c2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: Fc1ccc(OCCCOc2cccc(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Product: [Br-]
Yield: 50 %

Procedure:
A solution of 20 mmol of bromide (example 141) and 30 mmol of triphenyl phosphine in 60 ml of ethanol was refluxed 20 hours under nitrogen and then cooled and evaporated in vacuo. The residue was chromatographed on silica gel using first CHCl3 to elute starting material residues and then 5% CH3OH in CHCl3 to elute the product. Evaporation of pure fractions yielded the title compound as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([OH:10])=O)[C:6](=O)[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[S:3]1(=[O:17])=[O:16].C(N(CC)CC)C.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>O1CCCC1>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:35][C:8]([C:7]1[N:2]([CH3:1])[S:3](=[O:17])(=[O:16])[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6]=1[S:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:33])=[O:32])=[O:10]
Reactant: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(C(=O)Nc2ccccn2)=C(S(=O)(=O)c2ccccc2)c2ccccc2S1(=O)=O
Temperature: -5 °C
Yield: 68 %

Procedure:
1.29 g (0.005 mole) 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide and 4.18 ml triethylamine were dissolved in 15 ml tetrahydrofuran and the mixture cooled to -5° C. and 1.91 ml benzenesulfonyl chloride was added slowly to the stirred mixture and stirred, and after one hour 0.52 g 2-aminopyridine was added to the mixture. The temperature of the mixture was raised slowly to ambient temperature and stirred for 4 hours, and twice the volume of ice water was added to the mixture to form precipitates. The obtained precipitates were filtered and recrystallized in ethanol and ethylether to obtain 1.6 g of the title compound. Yield: 68%. m.p 192°-195° C.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].B(OCC)(OCC)OCC.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OC(=O)C)C.C1CCCCC1>[CH2:20]([O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc(O)c1O
Reactant: BrCc1ccccc1
Agent: CCOB(OCC)OCC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Oc1cccc(OCc2ccccc2)c1O

Procedure:
Using the procedure of Example 13, 25.22 g of pyrogallol, 35.1 ml of triethyl borate and 23.76 ml of benzyl bromide were reacted to obtain 33.8 g of the expected product in the form of a thick red oil after chromatography on silica eluting with a cyclohexane - ethyl acetate (6-4) mixture (Yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.ClC1C=C(Cl)N=C(N)N=1.[Br:27]C1C=CC(OC)=C(B(O)O)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:27])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: COc1ccc(Br)cc1B(O)O
Agent: Nc1nc(Cl)cc(Cl)n1
Product: COc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 53 %

Procedure:
Following the method described in Example 4 for the synthesis of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine, 4,6-dichloro-pyrimidin-2-yl-amine and 5-bromo-2-methoxy-phenyl boronic acid provided 4-chloro-6-(5-bromo-2-methoxy-phenyl)-pyrimidin-2-yl-amine (53% yield).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C(Cl)(Cl)[Cl:14].[Cl-].[C:18]([NH:21][C@H:22]([C:28](O)=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:20])[CH3:19]>FC(F)(F)C(O)=O.C(OCC)C.CC(C)=O>[ClH:14].[C:18]([NH:21][C@H:22]([C:28]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:29])[CH2:23][CH2:24][C:25](=[O:26])[OH:27])(=[O:20])[CH3:19]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)N[C@@H](CCC(=O)O)C(=O)O
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](CCC(=O)O)C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Reaction time: 14 h

Procedure:
4.2 g (0.021 moles) of carnitine hydrochloride are dissolved in 12 mls of trifluoroacetic acid, then at 35° C. and under vigorous stirring 20 cc of a solution of anhydrous chloroform wherein about 4.36 g (0.021 moles) of the acide chloride of the N-acetyl glutamic acid have been dissolved are added dropwise. The reaction is allowed to proceed for about 14 hours at 35° C., and subsequently at 50° C. for two further hours. The reaction mixture is cooled. Upon acetone addition (40 mls) no precipitate forms even though the mixture is cooled below 0° C. 140 mls of ethyl ether are added and after keeping the mixture at 8° C. overnight there are obtained 6.2 g of a solid white product which is crystallized with ethyl ether. After 2 crystallizations 5.4 g (68%) of the desired product having the following characteristics are obtained:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[C:13]([C@@H:15]1[CH2:19][C@@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:17][N:16]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=C)C.CCCCCC.[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43]>>[CH2:46]([O:45][C:42](=[O:44])[CH2:43][CH:13]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:15]1[CH2:19][C@@H:18]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22])[CH2:17][N:16]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH3:47]
Reactant: CCOC(C)=O
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OCC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: CCCCCC
Product: CCOC(=O)CC(NCc1ccccc1)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.5 %

Procedure:
Benzylamine (1.2 ml, 11 mmol) was added to [(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylic acid ethyl ester (2.18 g, 5.46 mmol, compound of Reference Example 1-4). The mixture was stirred at room temperature for five days. Then, this mixture was subjected to silica gel column chromatography (Wakogel™ C-300, hexane-ethyl acetate 3:1) to obtain 3-benzylamino-3-[(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]propionic acid ethyl ester (1.95 g, yield: 70.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]([OH:29])[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[O:29]=[C:20]1[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=3)[CH2:14][CH2:15]2)=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: OC1Nc2ccccc2C=C1C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCC(c3cc4ccccc4[nH]c3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
730 mg (3.91 mmol) ethyl 6-chloropyrimidine-4-carboxylate were placed in 10 mL DMF. 900 mg (3.94 mmol) 3-piperidin-4-yl-1,2-dihydro-quinolin-2-ol and 2.30 mL (13.4 mmol) DIPEA were added and the reaction mixture was stirred overnight at RT. The reaction mixture was mixed with 60 mL water and stirred for 30 min. The precipitated solid was suction filtered and dried.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[N:8][C:9](=[S:11])[N:10]=1.[Na].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1>>[N+:19]([C:16]1[S:15][C:14]([S:11][C:9]2[N:10]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[NH:7][N:8]=2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: S=C1N=NC(c2cccs2)=N1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2n[nH]c(-c3cccs3)n2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting the acid chloride of thiophene-2-carboxylic acid (prepared from the acid and oxalyl chloride) for the benzoyl chloride in Example 1 gave the thiosemicarbazide of thiophene-2-carboxylic acid and then 3-(thien-2-yl)-1,2,4-triazole-5-thione. Reaction of 1.73 g of the sodium salt of the thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole, an orange solid, MP 179-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21]C(CC(N)(C)C(O)=O)=O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([NH:38][C@H:39]([C:48]([N:50]([C:56](=[O:60])[CH:57]([CH3:59])[CH3:58])[CH:51]([NH2:55])[C:52]([OH:54])=[O:53])=[O:49])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[CH2:61]([O:68][C:69](=[O:115])[C@H:70]([CH2:111][CH:112]([CH3:114])[CH3:113])[NH:71][C:72](=[O:110])[C@H:73]([CH2:103][C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)[NH:74]C(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC1C=CC(O)=CC=1)NC(OC(C)(C)C)=O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>>[CH2:61]([O:68][C:69](=[O:115])[C@H:70]([CH2:111][CH:112]([CH3:113])[CH3:114])[NH:71][C:52](=[O:53])[C@:51]([NH2:55])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:50]([C:48](=[O:49])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:56](=[O:60])[CH:57]([CH3:58])[CH3:59])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1.[CH2:61]([O:68][C:69](=[O:115])[C@H:70]([CH2:111][CH:112]([CH3:113])[CH3:114])[NH:71][C:72](=[O:110])[C@H:73]([CH2:103][C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)[NH:74][C:52](=[O:54])[CH:51]([NH2:55])[N:50]([C:48](=[O:49])[C@H:39]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1)[NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:37])[C:56](=[O:60])[CH:57]([CH3:58])[CH3:59])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)CC(C)(N)C(=O)O
Reactant: CC(C)C(=O)N(C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)C(N)N(C(=O)C(C)C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@](N)(Cc1ccccc1)N(C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)C(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-L-tyrosylglycyl-α-aminoisobutyric acid or N-t-butoxycarbonyl-L-tyrosyl-α-aminoisobutyrylglycine is substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine of Example 12, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycyl-α-aminoisobutyryl-L-phenylalanyl-L-leucine benzyl ester or N-t-butoxycarbonyl-L-tyrosyl--α-aminoisobutyrylglycyl-L-phenylalanyl-L-leucine benzyl ester, respectively.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)C>[N:2]1[NH:3][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[C:11]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: NN
Reactant: O=C(O)CCC(=O)C1CCCCC1=O
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1[nH]nc2c1CCCC2
Yield: 97.1 %

Procedure:
Hydrazine hydrate (1.1 g) was added to a solution (40 ml) of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.1 g) in ethanol and the mixture was refluxed for 1 hour. After the completion of the reaction, the reaction mixture was cooled and the precitated crystals were collected by filtration to give 3.9 g of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid, m.p. 135-136° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:41])=O.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:41])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reaction time: 4 h

Procedure:
To a solution of 4.39 mg. (0.93 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml. of DMF cooled in an ice bath was added dropwise 118 mg. (0.07 ml., 0.93 mmole) of oxalyl chloride. The reaction mixture was allowed to stand for 4 hours at room temperature and was then poured into a mixture of aqueous 5% hydrochloric acid and ethyl acetate. The organic layer was separated and was washed sequentially with 5% hydrochloric acid, water and a saturated solution of sodium chloride. The washed layer was dried and evaporated to dryness to yield the reaction product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate as an amorphous solid. The product was obtained crystalline by triturating the amorphous residue with ether. Yield 360 mg. The infrared spectrum and NMR spectrum of the crystalline product were consistent with the spectra of authentic material.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=[O:16])=[CH:14][C:9]=2[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH2:6][C:5]1=[O:24].O1CCCC1.O.O.O.C([O-])(=O)C.[Na+]>CO>[OH:16][NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([CH2:3][O:2][CH3:1])[C:5](=[O:24])[CH2:6][N:7]=[C:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]=2[CH:14]=1
Reactant: COCN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCN1C(=O)CN=C(c2ccccc2)c2cc(NO)ccc21

Procedure:
A mixture of 33 g. (0.1 mol) of 1,3-dihydro-1-methoxymethyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 1 l. of tetrahydrofuran, 1 l. of methanol. 113 g. (0.5 mol) of stannous chloride dihydrate and 136 g. (1 mol) of sodium acetate trihydrate was stirred at room temperature for 6 hrs. under an atmosphere of nitrogen. The inorganic salts were separated by filtration over celite. The filtrate was evaporated and the residue was partitioned between methylene chloride and 1N sodium hydroxide solution. The methylene chloride layer was washed with water, dried and evaporated. Crystallization of the residue from methylene chloride/ether yielded light yellow product with m.p. 168°-170°. For analysis it was recrystallized from the same solvents, m.p. 168°-171°.
Reaction SMILES: [I-].[K+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.C[NH:28]C1CC1.O1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:28][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: CNC1CC1
Reactant: C1CCOC1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Product: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 2, potassium iodide and 8-fluoro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 8-fluoro-1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:13]2[N:18]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:16]=[C:15]([N:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)[C:14]=2[CH3:27])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[N:6]1([C:13]2[N:18]=[C:17]([CH:19]3[CH2:20][CH2:21]3)[N:16]=[C:15]([N:22]3[CH2:23][CH:24]([O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:25]3)[C:14]=2[CH3:27])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
A solution of methanesulfonyl chloride (0.63 ml, 7.6 mmol) in dichloromethane (10 ml) is added dropwise to a solution of 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl)-azetidin-3-ol 189 (1.90 g, 6.3 mmol) and triethylamine (1.74 ml, 13 mmol) in dichloromethane (90 ml) at 0° C. The mixture is stirred 1 hour at 0° C. and 1 hour at room temperature. Water (40 ml) is added and the mixture is extracted three times with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford pure methanesulfonic acid 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl)-azetidin-3-yl ester 190 (2.66 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[O:16]1[CH2:18][C@H:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:16]1[CH2:18][C@H:17]1[CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (282 mg, 1.28 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (331.5 mg, 1.28 mmol) and Cs2CO3 (487.5 mg, 1.28 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (150 mg).