Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:12]1([NH:18][C:19]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCCCC1=N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to free base by adding 5 mls. of 50% NaOH to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K2CO3 the benzene solution is stirred at room temperature and 5.96 g. (0.05 mole) of phenylisocyanate, dissolved in anhydrous benzene, is added dropwise. Cloudiness occurs and eventually solid precipitates from the solution. The reaction mixture is stirred at room temperature overnight (about 17 hours). The solid is collected, m.p. = 145°-158° C. The filtrate is taken to dryness in vacuo to give further solid material. Repeated recrystallizations of the combined solids from methanol yields the pure product, 1-phenyl-3-(1-methyl-2-piperidylidene)urea, m.p. = 160°-161° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=3[C:12]=2[CH2:11][CH:10]([CH3:22])[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:9]2[CH:10]([CH3:22])[CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][C:17]([F:21])=[CH:16][C:15]=4[NH:14][C:13]=3[C:7]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1cc(F)ccc21
Product: CCCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1cc(F)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 2-methyl-8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester and 4-fluorobenzoyl chloride; 1H NMR (CDCl3) δ 10.47 (1H, s), 7.96 (1H, s), 7.61-7.65 (2H, m), 7.41 (1H, m), 7.17 (2H, t), 7.05 (1H, dd), 6.90 (1H, t), 5.63 (1H, m), 4.17 (2H, m), 4.05 (2H, m), 3.38 (1H, dd), 3.07 (1H, dd), 1.55 (2H, m), 1.07 (3H, d), 0.77 (3H, t); MS (ES): 425 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[Br-:12].[C:13]1([PH+:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:12].[CH3:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COc1sc(C)c(CO)c1C
Agent: [Br-]
Solvent: CC#N
Product: COc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
6.1 G. (35.5 mmol) of 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene were added at 35° C. with vigorous stirring to a suspension of 13.4 g. (39.0 mmol) of triphenylphosphonium bromide in 250 ml. of acetonitrile. The deep purple color which was formed immediately, disappeared after some minutes. The reaction mixture was stirred for 3 hrs. The solvent was evaporated to a volume of about 25 ml. and an excess of cold ether was added. The solvent then was decanted from the resulting oily precipitate which was dissolved in warm acetone and again precipitated by adding cold ether. The solvent was decanted and the resulting oily residue was dried in high vacuum to yield (2,4-dimethyl-5-methoxy-3-thenyl)triphenylphosphonium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C(O)(=[O:19])C.C([O-])(=O)C.[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:19])[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: CC(=O)O
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccccc1Oc1nnc(O)cc1Cl
Yield: 85.9 %

Procedure:
A mixture comprising 578 mg (2.27 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), acetic acid (10 mL) and 0.45 g (4.6 mmol) of potassium acetate was refluxed for 5 hours. The reaction mixture was allowed to stand for cooling, and after adding 50 mL of water, the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed to obtain 461 mg (1.95 mmol, Yield: 85.9%) of 5-chloro-6-(2-methylphenoxy)-3-pyridazinol.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]3[NH:17][C:16](=O)[CH2:15][N:14]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:12]=3[CH:26]=2)=[O:7])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]3[NH:17][C:16](=[S:30])[CH2:15][N:14]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:12]=3[CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCC(=S)N2
Temperature: 60 °C
Reaction time: 6 h
Yield: 25.9 %

Procedure:
A mixture of intermediate (6) (0.01 mol) and tetraphosphorus decasulfide (0.012 mol) in THF (100 ml) was stirred at 60° C. for 6 hours, poured out into ice water and stirred for 1 hour. DCM was added. The mixture was stirred for 30 min, filtered over celite and washed several times with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.85 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 100%; 35–70 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.3 g, 30.5%) was crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 1.1 g (26%) of (4-chlorophenyl)[5-(3-chlorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-7-yl]-methanone (intermediate 13), mp. 125° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>[Ti](Cl)(Cl)(Cl)Cl.CCCCC>[C:8]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]=1
Reactant: O=C1CCc2ccccc21
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Product: C1=C(N2CCCC2)c2ccccc2C1
Reaction time: 2 h

Procedure:
To a 100 ml reaction tube equipped with a stirrer bar, Suba.Seal™ stopper, and a nitrogen balloon, was added pyrrolidine (1.3 ml) and pentane (8 ml). Titanium tetrachloride (0.2 ml) was added slowly to each tube. 1-Indanone (0.2 g, 1.33 mmol) was added as a solid and the reaction stirred vigorously for 2 h. The reaction mixture was filtered through Celite and the solvent removed in vacuo to give the title compound as a dark solid. m/z (ES+) 186 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12].Br[CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O>[CH3:3][C:4]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=1)=[O:12]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2ccc(O)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(NC(=O)C(C)(C)CCCOc2cc(C)ccc2C)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
Sodium hydride, 50% dispersion in mineral oil, 2.2 g, is added to 15.3 g of 5-(2,5-dimethylphenoxy)-N-(4-hydroxyphenyl)-2,2-dimethylpentanamide in 200 ml of N,N-dimethylformamide (DMF). Then 10 g of methyl 5-bromo-2,2-dimethylpentanoate (Journal of Medicinal Chemistry, Vol. 26, pp 1020-1027 (1983)) is added to the previous mixture. The mixture is stirred overnight and then stirred three hours on a steam bath, the DMF is removed on a rotary evaporator and water is added to the residue. The product is taken up in diethyl ether, extracted with base, washed with water and concentrated on a steam bath. Isopropyl ether is added to afford 10.4 g of 5-[4-[[5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-oxopentyl]amino]-phenoxy]-2,2-dimethylpentanoic acid, methyl ester after recrystallization from isopropyl ether (2X); mp 62°-63° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09 mmol, Example 1, Step H), 3-methoxybenzoyl chloride (389 mg, 2.28 mmol), and triethylamine (757 μL, 5.43 mmol) were placed in DCM (5 mL) and stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was added. The reaction was stirred for 10 minutes and then poured onto water. The mixture was then filtered and washed with DCM and water to provide solid N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide (219 mg, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(N-Boc-2-aminoethyl)aniline (2.5 g, 7.0 mmole) in CH2Cl2 (15 mL) was cooled in an ice bath under stream of nitrogen and TFA (15 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. and then concentrated in vacuo. The crude product was dissolved in 20% MeCN/H2O and purified by preparative reversed phase HPLC (5 to 2% MeCN/H2O over 50 min; 254 nm; 20 mL/min.), to give N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate salt 31 as a colorless oil. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm); 7.45-7.25 (m, 9H) 4.9 (dd, 1H), 3.55-3.45 (m, 2H), 3.21-3.15 (t, 2H), 3.05-2.95 (t, 2H) ESMS (C16H20N2O1): calcd. 256.4, obsd. 257.1 [M+H]−, 280.2 [M+Na]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[O:32]=[S:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: O=S1(=O)CCCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 67.3 %

Procedure:
Using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (307 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:29][C@@H:27]([C:24]3[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=3)[CH3:28])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(C(F)(F)F)nc1
Yield: 90.8 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.00 g, 19.2 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (4.76 g, 25.0 mmol), N,N-diisopropylethylamine (6.71 mL, 38.5 mmol), and acetonitrile (15 mL) were divided evenly between two 20 mL microwave vials. The reactions were subjected to microwave irradiation at 200° C. for 3.5 h. The two reactions were mixed together and evaporated the acetonitrile off. The residue was redissolved in CH2Cl2 (150 mL) and washed with 1M NaH2PO4 (2×50 mL). The product was extracted with 1M HCl (2×50 mL). The aqueous extracts were basified to pH 14 and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated to produce a yellow to orange solid (7.21 g). The crude product was washed with ether (25 mL) by stirring the solids for about 30 minutes. The solids were filtered from the ether and washed with ether (2×5 mL) to obtain a pale yellow powder (3.55 g, 45% yield). The ether filtrate was absorbed onto silica and purified by column with MeOH/CH2Cl2 (0-10%) to yield more product (2.38 g, 30% yield; 75% combined yield).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29]([C@H:31]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (175 mg, 0.91 mmol) and Et3N (127 μL, 0.91 mmol) in anhydrous DCM (8.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (219 mg, 0.91 mmol) and DMAP (22 mg, 0.18 mmol) and stir the resulting solution for 10 min. Add cis-4-Amino-cyclohexanecarboxylic acid methyl ester (74) (136 mg, 0.87 mmol) and stir the reaction solution 2d at rt Remove solvent and purify the crude product by flash chromatography (silica gel, EtOAc/CyH 3+1, later EtOAc) to obtain cis-{4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid methyl ester (75) (254 mg, 76%) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): 1.40-1.51 (m, 2 H); 1.59-1.70 (m, 4H); 1.70-1.82 (m, 2H); 2.40-2.48 (m, 3H); 2.88 (t, 2H, J=7.6 Hz); 3.65 (s, 3H); 3.79 (s, 3H); 3.82 (s, 6H); 3.86-3.95 (m, 1H); 5.33 (br.d, 1H, J=7.3 Hz); 6.40 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[CH:16]=O)[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[N+](=[C:23](P(=O)(OCC)OCC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[C:16]#[CH:23])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Reactant: CO[C@H]([C@@H](C)[C@H](C=O)OC)[C@@H](C)COC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2,2-Dimethyl-propionic acid (2S,3S,4R,5R)-3,5-dimethoxy-2,4-dimethyl-6-oxo-hexyl ester (2.0 g, 6.94 mmol) in anhydrous methanol (100 ml) at 0° C. and under an atmosphere of nitrogen was added diethyl 1-diazo-2-oxopropylphosphonate (1.6 ml, 10.4 mmol) and potassium carbonate (1.44 g, 10.4 mmol). The reaction was stirred at 0° C. for 1 hour and then room temperature for 2 hours, after which it was quenched with saturated ammonium chloride and extracted with diethyl ether (3×). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 15:1) to afford 1.67 g (85%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 4.22 (dd, J=10.7 Hz, 3.6 Hz, 1H), 4.07 (dd, J=10.7 Hz, 5.8 Hz, 1H), 3.87 (dd, J=9.6 Hz, 2.0 Hz, 1H), 3.46 (s, 3H), 3.44 (m, 1H), 3.40 (s, 3H), 2.48 (d, J=2.0 Hz, 1H), 1.97 (m, 2H), 1.23 (s, 9H), 1.00 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:17]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:18])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)C1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) in CH2Cl2 (101 mL) was added cyclopropanecarboxylic acid (276 μL, 3.48 mmol), followed by the addition of HATU (1.3 g, 3.48 mmol) and triethylamine (725 μL, 5.2 mmol). The reaction was complete after stirring for 1 h. After quenching with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified via silica gel chromatography 0-20% EtOAc/CH2Cl2 to afford (R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 73%). LC/MS: m/z 255.3 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:8]([NH:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH:26]=[CH2:27])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:8]([NH:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH:26]=[CH2:27])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76.7 %

Procedure:
Conc. hydrochloric acid (0.33 g) was added to a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.30 g) in methanol (13 ml) and the mixture was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (25 ml). The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give colorless powder of 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(C)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1F
Yield: 100.7 %

Procedure:
To a stirred solution of 5-bromo-2-fluoro-1,3-dimethylbenzene (5.0 g, 25 mmol) in carbon tetrachloride (100.0 mL) was added N-bromosuccinimide (4.11 g, 23.1 mmol) and benzoyl peroxide (100.0 mg, 0.017 mmol). The reaction was heated at reflux for 7 hours. The reaction was filtered and the filtrate washed with 2N HCl, saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was flash chromatographed (5% EtoAc/Haptanes) to obtain 6.56 g of 5-bromo-1-(bromomethyl)-2-fluoro-3-methylbenzene as an oil product. 1H NMR (400 MHz, CDCl3) δ ppm 2.22-2.36 (s, 3 H) 4.42 (d, J=0.98 Hz, 2 H) 7.21-7.37 (m, 2 H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25]O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C(=O)OC
Yield: 102.5 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyphthalate (3.00 g, 14.27 mmol), N-Boc-prolinol (2.87 g, 14.26 mmol), Ph3P (4.49 g, 17.12 mmol) in THF (50 mL) was added DIAD (3.40 mL, 17.27 mmol) at 0° C. Then the resulting mixture was heated under reflux overnight. The resulting mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 5.75 g (q.y.) dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]phthalate as an oil. 1H-NMR (CDCl3) δ 1.47 (s, 9 H), 1.86–2.05 (m, 4 H), 3.36–3.40 (m, 2 H), 3.87 (m, 3 H), 3.91 (s, 3 H), 3.96–4.19 (m, 3 H), 7.03–7.24 (m, 2 H), 7.80 (m, 1H).