Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(C(=O)c3ccc(C)cc3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4ccc(C)cc4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(4-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (1.45 g) was refluxed overnight in 20 ml of pyridine containing 3.0 g of hydroxylamine hydrochloride. The pyridine was then evaporated and the residue triturated with 5% hydrochloric acid and then washed with methanol. In this manner 1.26 g of product was obtained, mp 173°-175° C. An analytical sample was recrystallized from dichloromethane/hexane and the melting point was unchanged.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([CH2:23][NH:24][C:25]([CH:27]([C:33](OCC)=[O:34])[C:28](OCC)=[O:29])=[O:26])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([CH2:23][NH:24][C:25]([C:27]2[C:28](=[O:29])[N:17]=[C:14]3[CH:13]=[CH:12][C:11]([C:10]#[C:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:16][N:15]3[C:33]=2[OH:34])=[O:26])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Reactant: Nc1ccc(C#CCOC2CCCCO2)cn1
Solvent: Cc1ccccc1C
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCOC3CCCCO3)ccc2nc1=O

Procedure:
5-(3-(Tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-2-pyridinylamine (Preparation 6, 30 mg) and diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (Preparation 5, 50 mg) are dissolved in xylene and heated to reflux for 3 h. The solvent is evaporated and the residue is crystallized from ether/hexanes and dried to afford 20 mg of the a brown solid. Physical characteristics: MS (ESI+) m/z 470 (M+H)+. 1H NMR (CDCl3) δ9.80, 9.12, 7.80, 7.52, 7.32, 7.27, 4.86, 4.65, 4.51, 3.90, 3.5-3.6, 1.55-1.9.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C:17]([O:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=3)[C:28]([CH3:38])=[C:27]2[CH3:39])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:40]=[CH:41][C:21]([O:20][C:17]([CH3:19])([CH3:18])[C:16]([O:15][CH3:14])=[O:42])=[CH:22][CH:23]=2)[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:35][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C:9]1=[O:53])(C)(C)C.COC(=O)N.COC(=O)N[CH:64](C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(CN5CCCC(N)C5=O)=NC=4)=CC=3)=CC=2)=CN=1)=O)[CH:65](C)C>>[CH3:1][O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]2[N:10]([CH:14]([C:15]3[NH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:33][C:34]([CH:37]7[CH2:41][CH2:40][CH2:39][N:38]7[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:45])[CH3:46])=[N:35][CH:36]=6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)=[CH:18][N:19]=3)[CH2:64][CH2:65]2)[C:9]1=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: COC(N)=O
Product: COC(=O)NC1CCC2CCC(c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O

Procedure:
{3-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {1-[2-(5-{4′42-(6-Amino-5-oxo-octahydro-indolizin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for {1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester in method 805. C39H46N8O6 calculated 722.4 observed [M+1]+ 723.4; rt=1.62 min. 1H (DMSO-d6): δ=8.10 (m, 1H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 2H), 3.74 (m, 1H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd, J=8.8 Hz, J=17.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:19][NH:20][C:21](=[O:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(O)C=CC=CC=1>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:22]([C:21]([NH:20][CH3:19])=[O:28])[CH2:23][CH2:24]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: CNC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: O
Product: CNC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Temperature: 160 °C
Yield: 57.7 %

Procedure:
A mixture of 5.1 g (21 mmole) of 4-chloro-2-(4-chlorophenyl)quinoline, prepared as in Example 1(a), 6.2 g (42 mmole) of N-methylisonipecotamide, and 10 g of phenol was stirred and heated in an oil bath at 160° C. for 3.5 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching, warming and the addition of a small amount of ethanol. The solid was collected and washed with ether to give 7.0 g of crude product. Recrystallization from 150 ml of butanol gave 4.6 g of product, mp 251°-255° dec.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:30][C:26]([CH3:25])=[CH:27][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12i and 5-methylthiazole
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=23)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:24](O)(=O)[CH3:25]>>[Cl:1][C:2]1[C:14]2[CH2:15][CH2:16][N:17]([CH2:24][CH3:25])[CH2:18][CH2:19][N:12]3[C:13]=2[C:5]([CH:6]2[CH:11]3[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c3c(n4c2c1CCNCC4)CCCC3
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCc2c(Cl)ccc3c2N(CC1)C1CCCCC31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.20 g, 0.73 mmole) in acetic acid (50 mL) was added excess sodium cyanoborohydride (0.23 g, 3.65 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 0.10 g of the title compound. This compound was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 184-187° C. MS (ESI) m/z 305 ([M+H]+).
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:25])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:25])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCC1CN(C(C)(C)C)CC2(CCNCC2)O1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Tert-butyl 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (732 mg, 2.05 mmol) was dissolved in dichloromethane (10 mL) and treated dropwise with a solution of HCl in dioxane (12.8 mL of 4 M, 51.3 mmol). The reaction was stirred for 1.5 h and then diluted with dichloromethane. The organic phase was washed with 1:1 saturated NaHCO3/1 M NaOH, dried over Na2SO4 and concentrated to provide 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane (526 mg, 2.05 mmol, 99%) as a viscous amber colored oil. ESI-MS m/z calc. 256.2. Found 257.3 (M+1)+; Retention time: 0.2 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.88-3.71 (m, 1H), 3.43-3.38 (m, 1H), 3.37 (d, J=2.5 Hz, 3H), 3.35-3.30 (m, 1H), 3.24 (td, J=12.2, 3.4 Hz, 1H), 3.15-3.07 (m, 1H), 3.02 (td, J=12.2, 3.0 Hz, 1H), 2.93-2.84 (m, 1H), 2.78-2.68 (m, 1H), 2.58 (d, J=8.9 Hz, 2H), 2.48-2.19 (m, 1H), 1.97 (d, J=11.4 Hz, 1H), 1.92 (ddd, J=16.6, 12.2, 9.6 Hz, 2H), 1.84-1.74 (m, 1H), 1.70-1.55 (m, 2H), 1.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=O.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[N:10][OH:11]
Reactant: Cc1ncoc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncoc1C=NO
Reaction time: 2 h

Procedure:
0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde [prepared from the corresponding alcohol (Chem. Ber. 1961, 1248) by Swern oxidation (Tetrahedron 34, 1651 (1978))] is initially charged in 3 ml of water and treated with 0.66 g (9.45 mmol) of hydroxylamine hydrochloride in 2 ml of water. 0.68 g (4.95 mmol) of potassium carbonate is then added. After 2 h, the mixture is filtered off with suction and the product is washed with water and dried at room temperature. The yield is 0.41 g (72.2% of theory).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9](#[N:11])[CH3:10].[CH:12]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.C1COCC1>[CH:12]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:24]([OH:25])[CH2:10][C:9]#[N:11])[CH:26]=[CH:27][CH:28]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1cccc(OCC2CCCCCC2)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: N#CCC(O)c1cccc(OCC2CCCCCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of LDA (10 mL of a 2M solution in heptane/THF/ethylbenzene, 20.09 mmol) in THF (30 mL) was added acetonitrile (0.97 mL, 18.41 mmol) dropwise over ca. 2 min. After stirring for 15 min, a solution of 3-(cycloheptylmethoxy)benzaldehyde (3.89 g, 16.74 mmol) in THF (20 mL) was added. The reaction was allowed to warm to 0° C. over 2 h then quenched with the addition of saturated aqueous NH4Cl (30 mL). The mixture was extracted with EtOAc twice. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20% EtOAc-hexanes) gave 3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (2.102 g, 46%): 1H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J=8.0 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.81 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.83 (dt, J=6.4, 4.8 Hz, 1H), 3.71 (d, J=6.8 Hz, 2H), 2.86 (dd, J=16.8, 5.0 Hz, 1H), 2.78 (dd, J=16.4, 6.6 Hz, 1H), 1.86-1.92 (m, 1H), 1.76-1.82 (m, 2H), 1.61-1.67 (m, 2H), 1.37-1.59 (m, 6H), 1.20-1.30 (m, 2H).*
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:17]1([CH2:23][CH2:24][C:25]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a solution of 2-phenylbenzo[d]oxazol-5-amine (50 mg, 0.24 mmol) in dichloromethane (2 mL) at room temperature was added 3-phenylpropanoyl chloride (44.1 mg, 0.26 mmol) followed immediately by diisopropylethylamine (82 μL, 0.48 mmol). The resulting mixture was stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous Na2CO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was dissolved in methanol, passed through an acidic scavenger column (silica-based quaternary amine SPE-AX from Biotage®) and then evaporated to afford 61.1 mg (75%) of the title compound (LCMS RT=6.45 min, MH+ 343.2)
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][C:27](=[O:43])[C@@H:28]1[CH2:32][C@@H:31](O)[CH2:30][N:29]1[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35].C(N(CC)CC)C>CCOC(C)=O.C1(C)C=CC=CC=1>[C:37]1([S:34]([N:29]2[CH2:30][C@@H:31]([O:3][S:2]([CH3:1])(=[O:5])=[O:4])[CH2:32][C@H:28]2[C:27]([O:26][CH3:25])=[O:43])(=[O:36])=[O:35])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 59 %

Procedure:
In a two-neck 50 mL flask was combined 0.55 mL (8.42 mmol, 1.2 equiv.) of methanesulfonic acid and 20 mL of anhydrous toluene under N2 and a Dean-Stark trap. The solution was heated to reflux for 90 minutes, then cooled, and the trap removed. Triphenylphosphine (2.21 g, 8.42 mmol, 1.2 equiv.) was added with stirring, the solution was cooled to 0° C. (ice water bath), and 1.93 mL (9.83 mmol, 1.4 equiv.) of diisopropyl azidodicarboxylate was added slowly via syringe over 15 minutes. The bright yellow slurry was warmed to RT, compound 15 added (2.0 g, 7.02 mmol), then triethylamine (0.39 mL, 2.81 mmol, 0.4 equiv.), and the resulting yellow slurry was heated to ˜70° C. for two hours. The mixture was then cooled to room temperature, diluted with ˜25 mL EtOAc, and a white precipitate filtered off. The filtrate was concentrated, redissolved in EtOAc, loaded onto silica, and eluted with 2:1 EtOAc/hexanes to give 0.63 g (1.73 mmol, 59% yield based on 1.16 g of recovered starting material) of 16 as a colorless glass which crystallized on standing. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.89 (dt, J=2 Hz, 7 Hz, 2H), 7.60 (tt, J=1 Hz, 8 Hz, 1H), 7.53 (td, J=2 Hz, 7 Hz, 2H), 5.14 (m, 1H), 4.57 (dd, J=3 Hz, 10 Hz, 1H), 3.71 (m, 1H), 3.69 (s, 3H), 3.62 (dq, J=1 Hz, 12 Hz, 1H), 2.94 (s, 3H), 2.52 (dq, J=1 Hz, 15 Hz, 1H), 2.32 (m, 1H); 13C-NMR (400 MHz, CDCl3, δ ppm) 171.47, 138.42, 133.67, 129.61, 127.94, 78.23, 59.33, 53.88, 53.07, 39.30, 37.41; m/z: 364 (M+1)+. See, for example, Anderson, N. G., et al.; J. Org. Chem.; 61(22), pp. 7955–7958 (1996), which is incorporated by reference in its entirety.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH2:40]Br)(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OCOC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (300 mg, 0.69 m mole) and K2CO3 (95 mg, 0.69 m mole) in dry DMF (3 ml) was added dropwise at 0° C. a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml) and the mixture was stirred at 0° C. for 15 minutes. To the mixture was added again a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml). The reaction mixture was stirred for another 30 minutes and diluted with ethyl acetate (20 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was dissolved in methanol and passed through a column of the packing (40 ml) of a PrepPAK cartridge (Waters), which was washed with water and then eluted with 50% methanol. The eluate was monitored by HPLC. The desired fractions were collected and evaporated to give 96 mg (27%) of the title compound. Estimated purity 90% (by HPLC). M.p. 149°-152° C.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[OH-].[Na+]>CN(C)C=O.[Cl-].[Na+].O.O>[CH3:12][C:4]1[C:5]([C:9]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)=[O:11])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.67 g, 10 mmol) in dimethylformamide (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)- phosphonium hexafluorophosphate (BOP reagent, 6 g, 13.5 mmol) followed by 3 mL of diisopropylethylamine. After stirring for 5 minutes, 2 mL of 1-methylpiperazine was added and the mixture was stirred at room temperature for 24 hours. To the reaction was then added 25 mL of 1N sodium hydroxide and 25 mL of brine. After stirring for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted (3×200 mL) with 10% of methanol in dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The residue which remained was purified by chromatography(silica gel column, 5%-10% of methanol in dichloromethane) to give 1 g (40%) of 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carboxaldehyde.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]([C:15]([CH2:17][Cl:4])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NOC)C(=O)CCl

Procedure:
Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 l.). After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:21][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][OH:24])[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:25]1([CH:22]([NH:21][C:13]2[C:12]3[C:11]4[CH2:10][CH2:9][NH:8][CH2:20][C:19]=4[S:18][C:17]=3[N:16]=[CH:15][N:14]=2)[CH2:23][OH:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(NC(CO)c4ccccc4)c23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCC(Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a mixture of 4-(2-hydroxy-1-phenyl-ethylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (0.6 g) in dichloromethane (2 mL) at room temperature was added TFA (1 mL). The reaction mixture was stirred for 4 h, then neutralized by slow addition of sodium bicarbonate solution. The precipitate formed was collected by filtration and washed with water then dichloromethane to give the title compound (0.350 g, 76%). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.26-7.38 (m, 5H), 6.04 (d, 1H, J=6.4 Hz), 5.38 (d, 1H, J=4.8 Hz), 4.01 (d, 2H, J=7.6 Hz), 3.99 (d, 2H, J=3.2 Hz), 3.20 (t, 2H, J=4.4 Hz), 2.84-3.04 (m, 2H). LC-MS (ESI) m/z 327.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([O:22][CH3:23])[C:19](Cl)=[O:20].N1C=CC=CC=1.Cl.N1C=CC=CC=1>C1C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:19]([N:18]([CH3:17])[O:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)Cl
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-fluorobenzyloxy)aniline (21.7 g) in benzene (150 ml), N-methyl-N-methoxycarbamyl chloride (14.7 g) and pyridine (11.8 g) are added thereto, and the reaction mixture is heated under reflux for 17 hours. The reaction mixture is cooled to room temperature, and water is added thereto to dissolve the by-produced pyridine hydrochloride. After separation of the aqueous layer, the benzene layer is washed with dilute hydrochloric acid and water in that order, dried and concentrated in vacuo to give N-[4-(4-fluorobenzyloxy)phenyl]-N'-methyl-N'-methoxyurea (Compound No. 3) (11 g) as white plates. M.P., 123° to 124.5° C.