Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=[CH2:22].C(N(C(C)C)C(C)C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1/[CH:21]=[CH:22]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1cnccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2cnccn2)c2ccc(C=O)cc21
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 43.3 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol), 2-vinylpyrazine (27 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(o-MeC6H4)3 (16 mg, 0.052 mmol) in anh MeCN (2.5 mL) was heated with stirring in a sealed tube under microwave irradiation at 120° C. for 40 min. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 2:1 hexanes/EtOAc) to provide the title compound as a colorless solid (28 mg, 43%): 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1H), 8.73 (s, 1H), 8.60 (br. s., 1H), 8.47 (d, J=2.26 Hz, 1H), 8.14-8.18 (m, 2H), 8.07 (d, J=16.06 Hz, 1H), 7.84 (d, J=8.53 Hz, 1H), 7.61 (d, J=16.31 Hz, 1H), 5.85 (s, 2H), 3.61 (t, J=8.28 Hz, 2H), 0.94 (t, J=8.53 Hz, 2H), −0.05 (s, 9H); MS ESI 381.2 [M+H]+, calcd for [C20H24N4O2Si+H]+ 381.5.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9](OCCCCl)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>ClCCl>[C:1]1([C:7]2[S:11][N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCOc1nsc(-c2ccccc2)n1
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2ncns2)cc1
Temperature: 65 °C
Reaction time: 10.5 h

Procedure:
0.85 g of the product obtained above were reacted with 0.7 g of 3-(5-phenyl-1,2,4-thiadiazole-3-yloxy)-propyl chloride [for preparation, see Example 54 B)] and the reaction mixture was stirred for 10.5 hours at 65° C. Then the reaction mixture was dissolved in dichloromethane and the solution shaken with water. The dichloromethane phase was separated, dried, and concentrated. The crude product obtained was purified by medium-pressure chromatography on fine-grained silica gel (Lichroprep Si 60®) using 9:1 ethyl acetate/methanol as the eluent. 0.5 g of 3-{3-[N-[2-(4-(2-trimethylsilyl)-ethoxymethoxy)-3-methoxyphenyl)-ethyl]-N-methylamino]-propyloxy)-5-phenyl-1,2,4-thiadiazole were obtained as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([OH:3])=[O:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:3][CH2:15][CH3:16])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCC1CCCC1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCC1CCCC1=O

Procedure:
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, diluted sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109° C. (0.23 mm).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1cccnc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccnc3)cc2F)cn1
Yield: 82.1 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(pyridin-3-yl)ethylamine (0.019 g, 0.154 mmol) gives the title compound (0.0463 g, 82.2%): TOF MS ES+ 367.2 (M+H)+, HRMS calcd for C20H20N4O2F 367.1570 (M+H)*, found 367.1553, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.9 min. 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH2:20][O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 2 -amino-5 -methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (2.20 g) in dimethylformamide (30 ml) were added potassium carbonate (4.00 g) and 2-chloroacetyl chloride (1.50 g) and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.00 g).
Reaction SMILES: [CH2:1]([C:4]([CH2:15][CH2:16][C:17]([OH:19])=O)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].C(Cl)(=O)C([Cl:23])=O>C1C=CC=CC=1>[C:5]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:1][CH:2]=[CH2:3])[CH2:15][CH2:16][C:17]([Cl:23])=[O:19])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCC(CCC(=O)O)(C(=O)OCC)C(=O)OCC
Solvent: c1ccccc1
Product: C=CCC(CCC(=O)Cl)(C(=O)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A benzene solution (14.5 ml) containing diethyl allyl(2-carboxyethyl)malonate (1.95 g, 7.2 mmol) and oxalyl chloride (2.3 g, 18.1 mmol) was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction liquid was freed of solvent by vacuum distillation. Thus there was obtained 1.92 g of 4,4-dicarboethoxy-6-heptenic acid chloride (yields: 91%). Characteristic Values of 4,4-dicarboethoxy-6-peptenic acid chloride
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[O:21]>CO.[BH4-].[Na+]>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH2:20][OH:21]
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1SC(c1ccccc1)C(CO)=C2Cl

Procedure:
As in example 14 but starting from 3.16 g 4-chloro-3-formyl-8-methoxy-thioflav-3-ene in 30 ml dry methanol and 0.35 g sodium borohydride. After work up, the crude oil is crystallized in a mixture of n-hexane and ethylacetate. Pure 4-chloro-3-hydroxymethyl-8-methoxy-thioflav-3-ene is obtained as yellow crystals; m.p. 143°-145° C.-TLC (SiO2, n-hexane CH2Cl2 1:1): Rf =0.05.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2>ClCCCl.O>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[C:22]2[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1
Reactant: O=S1(=O)NN=C(Cl)c2ccccc21
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 19085282 %

Procedure:
AlCl3 (1.2 g, 10.5 mmol) was added to a solution of 4-chloro-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (1.5 g, 7.0 nmol) and 5-fluoro-2-methyl indole (1.0 g, 7.0 nmol) in DCE (35 mL), and stirred overnight at 70° C. The reaction solution was diluted with H2O, and the product was extracted with a solution of CH2Cl2/EtOH (9/1, v/v). The extracted product was concentrated and purified via silica gel chromatography eluting with a gradient of 0 to 70% EtOAc in hexanes to afford 0.44 g (19%) of the sub-title compound. MS calculated for C16H12FN3O2S—H: 328, observed: 328.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: COc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC
Yield: 74.5 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), 2-methoxycinnamic acid (2.0 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (2.8 g, 76%) as an amorphous solid product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:14][C:13]1[N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)ccc1C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Glycine ethyl ester HCl (22 g, 158 mmol) was added to a stirring mixture of hexane-2,5-dione (18 g, 158 mmol) in dichloromethane (100 mL) in an Erlenmeyer flask. To the stirring heterogeneous mixture was slowly added triethylamine (66 mL, 473 mmol). After 30 minutes, dichloromethane (50 mL) and NaHCO3 (sat. aq. 100 mL) were added and the mixture continued to stir for 20 minutes. The dichloromethane layer was injected directly onto a 330 g silica gel column and the product was eluted with 0-100% ethyl acetate in hexanes. Pertinent fractions were combined and concentrated to afford ethyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)acetate as a white solid (16 g, 56%). 1H NMR (CDCl3/400 MHz) δ (ppm) 5.8 (s, 2H), 4.85 (s, 2H), 4.22 (q, 2H), 2.17 (s, 6H), 1.28 (t, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].O(CC)[C:13]([S-])=[S:14].[K+]>C(O)C>[SH:14][C:13]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(S)nc2c1
Yield: 76.1 %

Procedure:
A mixture of 2-amino-4-nitrophenol (12.5 g, 71 mmol) and potassium ethyl xanthate (13 g, 81 mmol) were dissolved in ethanol (200 mL). The reaction was heated at reflux overnight. After cooling, solvent in the reaction mixture was evaporated under reduced pressure. The resultant residue was dissolved in water and adjusted to pH 2-3 with 2N HCl, resulting in the formation of a red solid. The red solid was filtered giving 2-mercapto-5-nitrobenzoxazole (10.6 g, 76%).
Reaction SMILES: O[CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:44](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[NH2:44][CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N)o1
Temperature: 25 °C

Procedure:
3.66 g of ethyl 5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate in 40 ml of tetrahydrofuran was mixed with 4.32 g of triphenylphosphine, 2.60 ml of diethyl azodicarboxylate and 4.53 g of diphenylphosphoryl azide under cooling with ice under stirring and stirred at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=50/1→30/1]. The resulting azide was refluxed together with 2.37 g of triphenylphosphine in 55 ml of 10% hydrous tetrahydrofuran under heating for 6 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [ethylene chloride/methanol=100/1→20/1] to give 2.89 g of the title compound as a yellow oily substance.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH:22]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-allyloxy-4-acetylxanthen -9one (2.2 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2 g of product m.p. 150-152° C., 1H-NMR (CDCl3)δ:4.73-4.74 (m, 2H); 5.25-5.42 (m, 2H); 5.92-6.05 (m, 1H); 7.07 (d, 1H, J=8.9 Hz); 7.13 (d, 1H, J=16 Hz); 7.36-7.44 (m, 6H); 7.52-7.60(m, 2H); 8;31-8.36 (m, 1H); 8.43 (d, 1 H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH:9]2[CH2:12][N:11]([C:13]([N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH:9]2[CH2:12][N:11]([C:13]([N:15]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:30])=[O:7])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)cc1)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 949.8 %

Procedure:
To a solution of 4-chloro-N-{1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}benzamide (15 mg, 38 μmol) in THF (2 ml) was added NaH (3 mg of a 60% dispersion in mineral oil, 76 μmol). The reaction was stirred at room temperature for 30 minutes and then MeI (2.6 μmol, 46 μmol) was added. The reaction was heated in a sealed tube at 50° C. for 3 hours and then concentrated at reduced pressure, diluted with dichloromethane (30 ml), washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 95:5:1 to 90:10:1) to provide the title compound as colourless oil (10 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc2c(cc1[N+](=O)[O-])C(C)CNCC2
Yield: 98.3 %

Procedure:
Nitric Acid (200 μl) was added dropwise to a stirred solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (174 mg, 604 μmol) in H2SO4 (1.5 ml). The reaction mixture was added into cold water after 3 d of stirring at room temperature. K2CO3 was added to neutralize the mixture to pH=8. After extraction with EtOAc, the organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 155 mg (77%) of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 334. After treatment of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (30.0 mg, 90.0 μmol) with K2CO3 (30 mg), methanol (1 ml) and H2O (0.2 ml) at 60° C. for 10 minutes, the reaction was quenched with sat. aq. NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 21 mg (99%) of 2-methoxy-5-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 4.09 (s, 3H), 3.25 (m, 2H), 3.10 (m, 3H), 2.93 (dd, 1H), 2.72 (dd, 1H), 1.39 (d, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:41]/[O:42]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S:20][CH2:21][C:22](/[CH:30]=[C:31]2/[C:32](=[O:40])[N:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]/2)=[C:23]3[C:27]([OH:29])=[O:28])=[O:16])[N:13]=1.C([SiH](CC)CC)C>C(OCC)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:41]/[OH:42])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S:20][CH2:21][C:22](/[CH:30]=[C:31]2/[C:32](=[O:40])[N:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]/2)=[C:23]3[C:27]([OH:29])=[O:28])=[O:16])[N:13]=1
Reactant: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(N)n4)[C@H]3SC2)C1=O
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
16.8 ml (219.4 mmol) Trifluoroacetic acid was cooled to 0° C., and 2.0 g (2.62 mmol) (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-3-[(E)-1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were added portionwise, keeping the temperature below 5° C. After 5 min. at that temperature, 0.96 ml (6.06 mmol) of triethylsilane were added dropwise and the reaction mixture was stirred for 1 h at 0° C. During this time a beige suspension was formed which was poured with stirring into 100 ml of diethyl ether. After 1 h the crystals were collected by filtration and retreated with 50 ml diethyl ether. After 1.5 hours the product was filtered and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][C@@H:15]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2.[OH-].[Li+].Cl>O1CCCC1.O>[ClH:1].[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:24][C:25]([C:27]2[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=2)=[O:26])[CH2:16]1)([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
(1R*,2S*,4S*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (180 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (2 ml), and lithium hydroxide (17 mg) was added to stir the mixture at room temperature for 45 minutes. After adding 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and solids deposited were collected by filtration to obtain the title compound (140 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:29]1([C:33]2[O:37][N:36]=[C:35]([CH2:38]O)[C:34]=2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:32][CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH:29]1([C:33]2[O:37][N:36]=[C:35]([CH2:38][O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:34]=2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:30][CH2:31][CH2:32]1
Reactant: Cc1cccc(C)c1O
Reactant: CCOC(=O)c1c(CO)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(COc2c(C)cccc2C)noc1C1CCC1
Temperature: 90 °C
Yield: 81.8 %

Procedure:
To a solution of 2,6-dimethylphenol (503 mg, 4.12 mmol), triphenylphosphine (1.08 g, 4.12 mmol) and ethyl 5-cyclobutyl-3-(hydroxymethyl)-4-isoxazolecarboxylate (929 mg, 4.12 mmol, from multiple batches) in toluene (10 mL) was added diisopropyl azodicarboxylate (0.741 mL, 4.12 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes. The solution was then concentrated and the residue was purified by chromatography (silica gel, 2.5% acetone in hexanes) to afford ethyl 5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolecarboxylate (1.11 g, 81%). 1H-NMR (400 MHz, DMSO-d6) δ 7.01-6.90 (m, 3H), 5.02 (s, 2H), 4.20 (q, J=7 Hz, 2H), 4.20-4.10 (m, 1H), 2.37-2.30 (m, 4H), 2.14 (s, 6H), 2.11-2.01 (m, 1H), 1.95-1.85 (m, 1H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:15]2)=[O:11])[S:6][CH:7]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][N:16]1[CH2:17][CH2:18][O:19][C@@H:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][S:8][C:5]2[S:6][CH:7]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[N:4]=2)[CH2:15]1
Reactant: N#Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CSc1nc(-c2nnn[nH]2)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
The resultant product (457 mg) of (22-1), sodium azide (78 mg) and ammonium chloride (525 mg) were suspended in dimethylformamide (3 mL), and the mixture was heated under reflux for 4 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (193 mg) as an orange powder.