Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([NH:24][CH3:23])=[O:33])[CH:27]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CNC(=O)c1cccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-{3-[(methylamino)carbonyl]phenyl}-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-3-aminobenzamide using method I. LCMS; retention time 3.04 min, MH+ 427.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:6]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:5][CH:3]1[OH:4].C(N(C(C)C)CC)(C)C.[F:49][C:50]([F:55])([F:54])[C:51](O)=[O:52].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C@H:8]2[C@H:7]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C@@H:6]([CH2:29][O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[O:5][CH:3]([OH:4])[C@@H:2]2[NH:1][C:51](=[O:52])[C:50]([F:55])([F:54])[F:49])=[CH:12][CH:13]=1
Reactant: COc1ccc(COC[C@H]2OC(O)[C@H](N)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC[C@H]2OC(O)[C@H](NC(=O)C(F)(F)F)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of the amine 64 (75.6 mmol) in dry chloroform (400 ml) at 0° C. was added diisoproplyethylamine (113.4 mmol) and trifluoroacetic acid (16.0 mL, 113.4 mmol). The resulting reaction mixture was then stirred for 30 min after which time the reaction was allowed to return to room temperature and stir for a further 1 h. At this time the reaction was cooled to 0° C. and further diisoproplyethylamine (113.4 mmol) and trifluoroacetic acid (113.4 mmol) added, the reaction was allowed to return to room temperature and stirred for 3 h. The reaction mixture was then poured into dilute sodium hydrogen carbonate and the mixture stirred for 30 min. The solid was washed with water, transferred to a flask and dried by co-evaporation with acetonitrile to give the crude product. Ethyl acetate was then added to the residue and the resulting suspension refluxed for 2 h. Petrol ether (˜300 mL) was then added to this, the mixture cooled to room temperature, and the resulting solid filtered and dried under high vacuum to give the desired product 65 as a solid (77%), δH (400 MHz; CDCl3) 3.04-3.17 (1 H, m), 3.54-3.60 (2 H, m), 3.61-3.71 (2 H, m), 3.79 (3 H, s), 3.80 (3 H, s), 3.81 (3 H, s), 4.01 [dt, J 3.0 Hz and J 10.4 Hz] and 4.16 [dt, J 3.7 Hz and J 10.1 Hz] (1 H), 4.43 (2 H, t, J 10.4 Hz), 4.50-4.60 (2 H, m), 4.66-4.78 (2 H, m), 5.23 (1 H, d, J 4.0 Hz), 6.11 (1 H, br d, J 2.9 Hz), 6.80-6.90 (6 H, m), 7.06 (2 H, d, J 11.1 Hz), 7.18 (2 H, d, J 12.6 Hz) and 7.24 (2 H, d, J 11.1 Hz); LCMS [M+Na]+=658.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:24][CH:23]=1.[C:1]([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 2 h
Yield: 125.9 %

Procedure:
Using the method outlined in German Offenlegungschrift No. 2,103,014, 20.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid was dissolved in 60 ml of dry pyridine, with heating and then 6 ml of acetic anhydride was added to the cooled solution. The mixture solidified on standing for 2 hours. It was then diluted with 50 ml of pyridine and the solid filtered and washed with 150 ml of ethyl acetate. The product was recrystallized from 150 ml of ethyl acetate and 20 ml of alcohol to yield 15.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid pyridine salt, mp 150°-151° d.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[S:24]1[C:28]2[S:29][CH2:30][C:31]3[CH:48]=[CH:47][CH:46]=[CH:45][C:32]=3[C:33](=[C:34]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])[CH2:36][CH2:35]3)[C:27]=2[CH:26]=[CH:25]1>>[S:24]1[C:28]2[S:29][CH2:30][C:31]3[CH:48]=[CH:47][CH:46]=[CH:45][C:32]=3[C:33](=[C:34]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:36][CH2:35]3)[C:27]=2[CH:26]=[CH:25]1
Reactant: O=C(O)CCc1cccnc1
Reactant: NCCCCN1CCC(=C2c3ccccc3CSc3sccc32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(CCc1cccnc1)NCCCCN1CCC(=C2c3ccccc3CSc3sccc32)CC1

Procedure:
Batch size: 1.4 g (9.0 mmol) 3-(3-pyridyl)-propionic acid, 1.6 g (9.9 mmol) CDI and 4.0 g (10.8 mmol) 4-[4-(4,9-dihydro-thieno[2,3-b]-benzo[e]-thiepin-4-yliden)-piperidin-1-yl]butylamine.
Reaction SMILES: F.[Si]([O:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C@H:16]2[CH2:20][CH2:19][O:18][C:17]2=[O:21])=[CH:13][CH:12]=1)(C(C)(C)C)(C)C>CC#N>[OH:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C@H:16]2[CH2:20][CH2:19][O:18][C:17]2=[O:21])=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(O[C@H]2CCOC2=O)cc1
Agent: F
Solvent: CC#N
Product: O=C1OCC[C@@H]1Oc1ccc(CO)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 40% aqueous hydrofluoric acid in CH3CN (10 mL) was added to a 0° C. solution of (S)-3-(4-((tert-butyldimethylsilyloxy)methyl)phenoxy)-dihydrofuran-2(3H)-one in CH3CN (50 mL). The reaction was stirred for 30 minutes and then partitioned between a saturated NaHCO3 solution and diethyl ether. The organics were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed to provide the desired product (0.92 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.08 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The reaction mixture was poured into water and then filtered. The resulting filter cake was washed with water and methyl tert-butyl ether. The filter cake was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104, 1.17 g, 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was added chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.80 g (92%), was isolated by column chromatography (0-1.5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]Br.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(CBr)cc(OC)c1
Product: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1

Procedure:
In any or all of the above embodiments, converting the 3,5-methoxybenzoic acid to the (E)-5-(2-halo-3-iodoallyl)-1,3-phenylene bis(2,2-dimethylpropanoate) may include (1) reducing the 3,5-methoxybenzoic acid to produce 3,5-dimethoxybenzyl alcohol, (2) brominating the 3,5-dimethoxybenzyl alcohol to produce 3,5-dimethoxybenzyl bromide, (3) reacting the 3,5-dimethoxybenzyl bromide with ethynyl trimethylsilane to produce (3-(3,5-dimethoxyphenyl)prop-1-ynyl)trimethylsilane, (4) desilylating the (3-(3,5-dimethoxyphenyl)prop-1-ynyl)trimethylsilane to produce 1,3-dimethoxy-5-(prop-2-ynyl)benzene, (5) adding protecting groups to the 1,3-dimethoxy-5-(prop-2-ynyl)benzene to produce 5-(prop-2-ynyl)-1,3-phenylene bis(2,2-dimethylpropanoate), wherein the protecting groups are pivaloyl groups added by reacting the 1,3-dimethoxy-5-(prop-2-ynyl)benzene with boron tribromide and then with pivaloyl chloride, and (6) halogenating the 5-(prop-2-ynyl)-1,3-phenylene bis(2,2-dimethylpropanoate) to produce (E)-5-(2-halo-3-iodoallyl)-1,3-phenylene bis(2,2-dimethylpropanoate), wherein the 2-halo corresponds to R4.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[C:25]([CH2:29][C:30](O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Reactant: CC(C)(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNC(=O)CC(C)(C)C)ccc1-c1cnco1
Reaction time: 16 h

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 52 mg (0.45 mmol) of tert-butylacetic acid, 86 mg (0.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69 mg of HOAt were dissolved and stirred in 2 ml of dimethylformamide. After stirring for 16 hours the mixture was diluted with 10 ml of dichloromethane and washed with 10% citric acid solution in water, saturated sodium hydrogen carbonate solution and brine. The organic solution was then dried with solid magnesium sulphate, filtered and evaporated to give N-(3-methoxy-4-(5-oxazolyl)phenyl]-N′-[2-(3,3-dimethylbutyramido)-1,1-dimethylethyl]oxalamide as a pale yellow solid, MS: m/e 431.3 [M+H]+.
Reaction SMILES: CN.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C[CH2:28][N:29]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.O>[CH3:28][NH:29][C:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]2([CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)[CH:16]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.8 %

Procedure:
A solution of methylamine in THF (2 mL) was added to a stirred solution of 1′-(tert-butyoxycarbonyl)spiro[indene-1,4′-piperidine]-3-carboxylic acid (C4) (0.51 g, 1.55 mmol), EDAC HCl (0.6 g, 3.00 mmol), HOBt (0.31 g ) in DMF (10 mL), and the solution was stirred at room temperature for 12 h. The solution was poured into water (50 mL), the aqueous layer was extracted with EtOAc (3×50 mL), dried, and concentrated under reduced pressure. The crude product was purified by Biotage SP1 on silica gel eluting with 12-100% EtOAc in hexanes to provide tert-butyl 3-(methylcarbamoyl)spiro[indene-1,4′-piperidine]-1′-carboxylate (C5) as a white solid (0.45 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 343 (M+1), Rt 3.0 minutes. 1HNMR (500 mHz, CDCl3) δ 7.73 (d, 1H), 7.23 (m, 3H), 7.14 (s, 1H), 6.05 (brm, 1H), 4.11 (m, 2H), 3.03 (m, 2H), 2.93 (d, 3H), 1.95 (m, 2H), 1.44 (s, 9H), 1.30 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[CH3:35])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[Cl:34][C:30]1[C:29]([CH3:35])=[C:28]([N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH2:16][C:15]([NH:14][CH2:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][CH:11]=2)=[O:36])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OCc3ccccc3)cc2)c2cccc(Cl)c2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.8 %

Procedure:
668 mg of N-[4-(benzyloxy)benzyl]-N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 5.00 mL of methanol and 2.00 mL of THF, and 70 mg of 10% Pd—C (Kawaken, AD type, water content 54%) was added thereto, followed by stirring at room temperature for 6.5 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50 to 30:70) to obtain a product, which was recrystallized from ethanol/water to obtain 373 mg of N2-(3-chloro-2-methylphenyl)-N-(4-hydroxybenzyl)-N2-[(4-methylphenyl)sulfonyl] glycinamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[C:10]([C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)c1c[nH]c(C(=O)O)c1
Yield: 92.8 %

Procedure:
A mixture of 1.2 g (4 mmol) 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid methyl ester and 1.3 g (31 mmol) LiOH.H2O in 40 mL THF, 5 mL methanol and 10 mL water was heated to reflux for 3 h. The mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to yield 1.1 g (96%) of the title compound as light yellow solid. (m/e): 295.1 (M−; 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CC1C=CC=CC=1)=O.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:20])=[CH:31][CH:30]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Product: CN1C(C(=O)Nc2ccc(Cl)cc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 52 %

Procedure:
Prepared analogous to Example 1 from benzyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-chloro-aniline with a yield of 52% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[S-:24][C:25]#[N:26].[K+].BrBr>C(O)(=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:16]=[C:17]3[S:24][C:25]([NH2:26])=[N:21][C:18]3=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]=1[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)ccc1F
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl{5-[(5-aminopyridin-2-yl)oxy]-2-fluorophenyl}carbamate (3.00 g, 9.4 mmol) and potassium thiocyanate (3.93 g, 40 mmol) in acetic acid (40 mL) was added dropwise bromine (2.40 g, 15 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To residue was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (3.20 g, 90%) as a pale-yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4](F)F.[Li]CCCC.[C:14]1([Sn:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[F:1][C:2]([F:8])([F:7])[C:3]#[C:4][Sn:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)CC(F)(F)F
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: FC(F)(F)C#C[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
The triphenylstannane derivative was prepared using a modified procedure of Brisdon (Chem. Commun. 2002, 2420-2421). Accordingly, 1,1,1,3,3-pentafluoropropane (2.0 g, 14.9 mmol) was condensed into a 500 mL three neck round bottom flask containing ether (20 mL) cooled to −15° C. The mixture was maintained below −10° C. while n-BuLi (2.5 M in hexanes, 16.08 mL, 40.2 mmol) was added. After the reaction was stirred for 10 minutes at −10° C., triphenyl tin chloride (5 g, 13.4 mmol) was added as a solution in ether, maintaining −10° C. The mixture was slowly warmed to room temperature and allowed to stir for an additional 4 hours. An excess of hexanes (300 mL) was added and then the settled mixture was filtered through Celite®. Concentration of the filtered solution in vacuo afforded a pale yellow solid which was purified by column chromatography (SiO2: ether/hexanes, 1:10) affording 5.2 g (78%) of the triphenylstannane derivative as an off white solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20](=[O:23])[CH2:21][SH:22])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Br[C:28]1[C:29]([C:34](OC)=[O:35])=[N:30][CH:31]=[CH:32][N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]([CH:21]2[S:22][C:28]3=[N:33][CH:32]=[CH:31][N:30]=[C:29]3[C:34]2=[O:35])=[O:23])[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Reactant: COC(=O)c1nccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)C1Sc2nccnc2C1=O
Yield: 43.2 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (0.054 mmol, 20 mg), methyl 3-bromopyrazine-2-carboxylate 101 (0.054 mmol, 11.8 mg) and Na2CO3 (1.2 eq, 7 mg) in ethanol (1 mL) was stirred overnight at 70° C. The reaction mixture was quenched in cold 1N HCl solution and extracted with CH2Cl2. Organic layer was dried and evaporated. Purification by chromatography (0-10% methanol in CH2Cl2) gave N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-oxo-6,7-dihydrothieno[2,3-b]pyrazine-6-carboxamide 102 (11 mg, 42.9%). NMR (400 MHz, DMSO-d6) 1.77 (s, 6H), 2.35 (s, 3H), 7.15 (d, J=8.6 Hz, 1H), 7.48 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 8.54 (br s, 1H), 8.62 (br s, 1H), 8.66 (d, J=1.6 Hz, 1H), 10.29 (s, 1H). (m/z)=473 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[N:1]([CH3:23])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[C:14]2[N:15]=[N:16]1
Reactant: CI
Reactant: Cn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc2c(-c3nc4ccccc4n3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a 0° C. solution of 8-(1H-benzo[d]imidazol-2-yl)-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.54 mmol, 0.144 grams, 1 eq.) in anhydrous DMF (2.5 mL) was added sodium hydride 60% in mineral oil (0.59 mmol, 24 mg, 1.1 eq.) portion-wise. The formed suspension was stirred at low temperature for 10 minutes and methyl iodide (1.07 mmol, 67 μL, 2 eq.) was added into it in one portion. The suspension was stirred over night at room temperature. The reaction mixture was filtered and the obtained solid was washed with water, acetonitrile and ethyl acetate, and dried under vacuum to give the title compound. Yield: 55%. δH (DMSO-d6) 9.02 (1H, s), 7.77 (1H, d, J: 8.09), 7.68 (1H, d, J: 8.12), 7.36 (1H, m), 7.32 (1H, m), 4.14 (3H, s), 3.90 (3H, s).
Reaction SMILES: CCCCCCCCC.[F:10][C:11]([F:31])([F:30])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=O)[CH:25]3[NH:28][CH:21]([CH2:22][CH2:23][CH2:24]3)[C:20]2=O)=[CH:15][CH:14]=1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1.[OH-].[Na+]>C1COCC1>[F:31][C:11]([F:10])([F:30])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:26][CH:25]3[NH:28][CH:21]([CH2:22][CH2:23][CH2:24]3)[CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCCCCC
Product: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reaction time: 0.67 h

Procedure:
3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane: A solution of 3-(4-trifluoromethoxyphenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (80 mg, 0.25 mmol) and THF (4 mL) was heated at 70° C. under N2. A solution of BH3—SMe2 (2M in THF, 0.4 mL, 0.8 mmol) was added dropwise. After 40 min, 6N HCl (1.0 mL) was added dropwise (Caution: H2 evolution). After an additional 30 min, the reaction was poured into 1N NaOH (8 mL) and extracted with dichloromethane (30 mL×2). The combined organic extracts were dried, filtered and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: MS (ESI): 287.5 (M+H).