Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]12.C(=O)(O)[O-].[Na+].[CH:37]([NH:39][C:40]1[S:41][CH:42]=[C:43]([C:45](=[N:49][O:50][CH3:51])[C:46](O)=[O:47])[N:44]=1)=[O:38].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O1CCCC1.O.CN(C)C=O>[CH:37]([NH:39][C:40]1[S:41][CH:42]=[C:43]([C:45](=[N:49][O:50][CH3:51])[C:46]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:47])[N:44]=1)=[O:38]
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Yield: 52.7 %

Procedure:
tert-Butyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate tosylate (2.0 g) was dissolved in a mixture of acetone (40 ml) and a saturated aqueous solution of sodium bicarbonate (15 ml), and thereto was added dropwise a solution of the activated acid, which was prepared from 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.06 g), phosphorus oxychloride (0.85 g) and N,N-dimethylformamide (0.41 g) in tetrahydrofuran (10 ml), at 0° to 5° C. over a period of 10 minutes. During the addition, the pH value of the reaction mixture was maintained at pH 7.0 to 7.5 with a saturated aqueous solution of sodium carbonate. After stirring for an hour, the reaction mixture was diluted with water (50 ml), followed by extracting twice with ethyl acetate. The combined extract was washed with 5% aqueous solution of sodium bicarbonate and water, dried and then evaporated to dryness under reduced pressure to give a residue, which was triturated with diethyl ether to obtain tert-butyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (1.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH2:12][CH2:13]O)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][Cl:19])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2cc(Cl)ccc2n1CCCO
Solvent: ClC(Cl)Cl
Product: CCc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 4 parts of 5-chloro-2-ethyl-1H-benzimidazole-1-propanol and 150 parts of trichloromethane are added dropwise 9.6 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is taken up in water and stirred with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 5-chloro-1-(3-chloropropyl)-2-ethyl-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31]OC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC[NH:72][S:73]([CH3:76])(=[O:75])=[O:74])=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][NH:72][S:73]([CH3:76])(=[O:75])=[O:74])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CS(=O)(=O)NCCN=[N+]=[N-]
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCNS(C)(=O)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.87 mmol) and compound 413 (1.3 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 65:35 to 85:15 as the eluent to afford the title compound as almost white solid. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.4, 145.3, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.4 (dd), 124.9, 124.1 (dd), 121.9, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 49.8, 42.2, 39.5, 19.4
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:5]([OH:7])=[O:6]>CN(C=O)C.[Ni]>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)O)ccc1N
Reaction time: 6 h

Procedure:
To a solution of 3-methyl-4-nitro-benzoic acid (100 g, 0.55 mol) in DMF (500 mL), suspension of activated Raney Ni (50 g) in DMF (50 mL) was added and was subjected to hydrogenation (200 psi pressure and 25° C.) for 6 h. The reaction mixture was filtered through celite bed and was concentrated to one third of the total volume. The reaction mixture was poured into water (1300 mL) with stirring. The solid was filtered, washed with water and dried to obtain the title compound. Yield: 70 g (84%); 1H NMR (DMSO-d6, 300 MHz): δ 2.03 (s, 3H, CH3), 5.60 (s, 2H, NH2), 6.56 (d, 1H, Ar), 7.46 (d, 1H, Ar), 7.49 (s, 1H, Ar); MS: m/e (ES−) 150 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cccc(Br)c2[nH]1
Temperature: 195 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a 100 mL round bottom flask, 2-amino-3-bromo-benzoic acid (5 g, 0.0234 mol) and urea (7.33 g, 0.122 mol) were added. The reaction mixture was stirred at 195° C. for 3 h. The reaction mixture was allowed to reach 80° C. and water was added. The aqueous reaction mixture was stirred for 5-10 min and filtered to afford the title compound [5.4 g, 97%]. This material was taken to the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27]O)[CH2:17][CH3:18]>>[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH2:17][CH3:18]
Reactant: CCC(C)Oc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCC(C)Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-butan-2-yloxy-4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H19ClN4O2, 383. Found, 383.
Reaction SMILES: [Si:1]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14])([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:3].[Si:15](CCCCl)([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17]>CO>[CH3:3][O:2][Si:1]([CH:8]([Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CO[Si](CCCNCCN)(OC)OC
Solvent: CO
Product: CO[Si](OC)(OC)C(CCNCCN)[Si](OC)(OC)OC
Temperature: 200 °C

Procedure:
In a manner similar to that shown in examples 1 and 2 above, 44 gms. of (CH3O)3Si(CH2)3NH(CH2)2NH2 and 40 gms. of (CH3O)3Si(CH2)3Cl were mixed together and warmed to 140° C. whereupon the reaction exothermed to 200° C. The reaction mass was heated at 140° C. for about 2 hours and then cooled and diluted using 168 gms. of CH3OH. After removal of HCl as an ethylenediamine salt, the crude product was distilled to recover a center cut boiling at 160° C. at 0.5 mm Hg, d425 =1.048, ND25 =1.4462.
Reaction SMILES: N[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]1[F:19].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>O>[F:19][C@@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:22])[NH:10][CH:9]=[N:8][C:7]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reaction time: 24 h

Procedure:
6-Amino-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-9H-purine (0.29 g, 1.0 mmole), prepared as in Example 8, was dissolved in 100 ml of water. Calf intestinal adenosine deaminase (4 I.U., Boehringer Mannheim) was added and the solution incubated at 37° C. for 24 hrs. The solvent was removed under vacuum. The residue was dissolved in water/n-propanol (7/3) and chromatographed on a 5×90 cm column of Sephadex G-10 (Pharmacia LKB) with water/n-propanol (7/3) as the solvent. Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as a hydrate.
Reaction SMILES: ClCCN=C=O.Cl[CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].[NH2:14][C:15]1[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=1>>[CH3:20][C:18]1[N:19]=[C:15]([N:14]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[O:13])[S:16][C:17]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C=NCCCCl
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: O=C=NCCCl
Product: CCOC(=O)c1sc(N2CCCNC2=O)nc1C
Yield: 32 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace 2-chloroethyl isocyanate with 3-chloropropyl isocyanate to react with ethyl 2-amino-4-methylthiazole-5-carboxylate, the title compound was obtained as a brown solid in 32% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 4.75 (q, J=7.1 Hz, 2H), 4.57 (t, J=5.9 Hz, 2H), 3.80-3.75 (m, 2H), 3.05 (s, 3H), 2.54-2.46 (m, 2H), 1.81 (t, J=7.1 Hz, 3H); MS (ES+) m/z 270.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-bromo-3H-benzoxazol-2-one (15 g; ca. 0.07 mol, containing 8-9% 3H-benzooxazol-2-one) and triethylamine (11.1 mL, 0.08 mol) in DCM (250 mL) was added trityl chloride (21.5 g, 0.08 mol). The solution was stirred at room temperature for 18 h and was then washed with distilled water (3×250 mL), brine (250 mL) and dried (MgSO4), filtered and evaporated to give an off-white colored solid. The product was dissolved in refluxing EtOAc then allowed to cool to room temperature with constant stirring for several hours. The solids were collected (21.16 g) and the filtrate was concentrated until precipitation occurred, re-heated (reflux) for several hours and allowed to cool with stirring to encourage a second crystallization (7.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:34])([CH3:33])[CH2:14][O:15][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C:10](=[O:35])[C@@H:9]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:8][C@H:7]([C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:6]=2[CH:52]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:33])([CH3:34])[CH2:14][OH:15])[C:10](=[O:35])[C@@H:9]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:8][C@H:7]([C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:6]=2[CH:52]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CO)C1=O
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Ethyl trans-7-chloro-5-(1-naphthyl)-1-(3-tert-butyldiphenylsilyloxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (8.52 g, 11.62 mmol) was dissolved in acetonitrile (200 ml). A solution of HF in water (50%, 50 ml) was added at room temperature. Stirring for 18 hours was followed by hydrolysis with saturated sodium bicarbonate and repeated extraction of the aqueous layer with dichloromethane. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (dichloromethane/methanol 99:1) to give the title compound (4.64 g, 81%) as a colorless solid.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N+:7]([O-:9])=[O:8])[CH:5]=O.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=O)[CH3:12].CC(C)([O-])C.[K+].C([O-])(=O)C.[NH4+]>O1CCCC1.C(O)(=O)C>[N+:7]([C:4]1[CH:5]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:2][CH:3]=1)([O-:9])=[O:8]
Reactant: CN(C)C=C(C=O)[N+](=O)[O-]
Reactant: CC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccncc2)nc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
3-(Dimethylamino)-2-nitro-2-propenal (60.5 g) was dissolved in tetrahydrofuran (500 ml). To the resulting solution were added 4-acetylpyridine (48.5 g) and potassium t-butoxide (121.14 g), for agitation at 30° C. for 30 minutes. After ammonium acetate (185 g) and acetic acid (140 ml) were added, reaction was progressed at an inner temperature of 95° C. for 4 hours while tetrahydrofuran was distilled off. To the reaction solution was added aqueous 25% NaOH solution (400 ml), for crystallization. The resulting crystal was dried to obtain the object compound in pale dark brown crystal (58 g; yield of 72%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCC1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=S)NC1CCCCC1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 3, Table I). 1H NMR (CDCl3, 300 MHz): δ 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H). Analysis calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:25]\[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:20][CH:19]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:40][C:30]1[CH:29]=[C:28]([O:27][CH2:26]/[CH:25]=[C:24](\[C:21]2[CH:20]=[CH:19][C:18]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:23][CH:22]=2)/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH:39]=[CH:38][C:31]=1[O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-Propargylmorpholine (193 mg, 1.55 mmol) and diisopropylamine (0.51 mL, 3.64 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (12 mg, 0.063 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) were added. The reaction mixture was stirred at ambient temperature for 19 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[OH:28][B:16]1[C@@H:15]([NH:14][C:12](=[O:13])[CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([NH:4][CH2:3][CH2:2][NH:1][CH:34]([CH3:36])[CH3:33])[CH2:6][CH2:7]2)[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=2[O:17]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), acetone (0.1 mL) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 432 (MH)+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:72])[CH2:68][C:69]([NH2:71])=O)[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:73])[CH2:28][CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22](O)[C@H:21]([OH:75])[CH2:20]1)=[O:17])[CH3:7])[CH3:4].[CH2:76]([NH2:79])[CH2:77][NH2:78].B([O-])([O-])OC1C=CC=CC=1>>[CH3:1][CH2:2][CH:3]([CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:72])[CH2:68][CH2:69][NH2:71])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:73])[CH2:28][CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22]([NH:78][CH2:77][CH2:76][NH2:79])[C@H:21]([OH:75])[CH2:20]1)=[O:17])[CH3:7])[CH3:4]
Reactant: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Reactant: NCCN
Agent: [O-]B([O-])Oc1ccccc1
Product: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
In CN101792486A and CN 101648994A, a method has been disclosed, comprising the following steps: Pneumocandin B0 as the starting material reacts with ethylenediamine under the protection of phenyl borate, and then the amide group in the resulting intermediate is reduced to amine group to obtain caspofungin.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.Cl.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH2:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C.C[O-].[Na+].CO>>[CH3:27][O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH:39][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Temperature: 140 °C
Yield: 56.1 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in a CEM microwave tube (10 mL) with (S)-3-amino-3-pyridin-3-yl-propionic acid ethyl ester dihydrochloride (134 mg, 0.5 mmol) (commercially available from AstaTech 46247) and a solution of sodium methoxide in methanol (2 mL, 0.5M, 1 mmol) was added with stirring. The reaction was heated to 140° C. in the CEM microwave apparatus for approximately 90 minutes. The reaction was cooled, concentrated under vacuum and filtered through silica to provide 41 mg of the desired product which was used without additional purification.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]([O:12]C)=O)[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3].[NH2:18][C@@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)[C:20]([N:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]([NH:18][C@@H:19]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[C:20]([N:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH3:23])=[O:21])=[O:12])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Reactant: CN(C(=O)[C@@H](N)Cc1cccc(Br)c1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)N(C)c1ccc(Cl)cc1
Yield: 24.3 %

Procedure:
To a solution of methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (110 mg, 0.48 mmol) and (S)-2-amino-3-(3-bromophenyl)-N-(4-chlorophenyl)-N-methylpropanamide (194 mg, 0.48 mmol) in DMF (2 mL) was added HATU (228 mg, 0.6 mmol) and DIEA (193 mg, 1.5 mmol). Upon completion of the reaction, the product was purified by reverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford (S)-2-(2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-3-(3-bromophenyl)-N-(4-chlorophenyl)-N-methylpropanamide (68 mg, 24%) as a solid. MS (m/z): 582.9 [M+H]+; HPLC retention time 4.52 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).