Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.22 (1H, br m), 8.61 (1H, s), 7.81 (2H, d, J=8 Hz), 7.29 (3H, m), 7.17 (2H, d, J=8 Hz), 7.06 (1H, s), 7.02 (2H, m), 5.41 (2H, br), 4.05 (2H, s), 3.67 (2H, m), 3.60 (2H, m), 3.40 (3H, s), 3.01 (3H, s); HRMS calcd for C27H27N3O6S+H+: 522.1699. Found: 522.1686.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=C[C:21]([CH2:24][N:25]4[CH2:30]COC[CH2:26]4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.CN(C)C1C=C(C=CC=1)C=O>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[C:24]([N:25]([CH3:30])[CH3:26])[CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: CN(C)c1cccc(C=O)c1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 86 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (86%). 1H NMR (d-chloroform): 16.5 (br s, 1H), 8.37 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.06 (dd, J=2.8 Hz, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 5.98 (m, 1H), 5.62 (m, 1H), 5.38 (t, J=8 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.06 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.33 (d, J=8 Hz, 1H), 1.68 (d, J=8 Hz, 1H). MS: 424.04 (M+H). HPLC retention time: 2.06 minutes (G Method).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10].CS>[Cl-].[Zn+2].[Cl-].CCOCC.C(O)(C)C>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCCS1
Agent: CS
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 1.25 h

Procedure:
To a mixture of 235 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1950)) and 2 g of zinc chloride at approximately 115° in a nitrogen atmosphere, 263 g of ethyl nitroacetate (S. Zen et al., Kogyo Kagaku Zosshi, 74, 70 (1971)) was added dropwise over a 1.5 hour period. The mixture was held at 110°-120°. When evolution of methyl mercaptan ceased after 45 minutes further stirring of the heated mixture, 1 g of zinc chloride was added and the mixture was stirred at about 115° for 1.25 hours. An additional 1 g of zinc chloride then was added and stirring of the mixture at about 115° was continued for 1.5 hours. The mixture then was poured into a cooled 2/1 ether/isopropyl alcohol mixture. The crystallized product was collected, washed with ether and dried under reduced pressure to leave a tan solid, m.p. 100°-102°, which on recrystallization from methanol gave ethyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate as a pale yellow solid, m.p. 105°-106°.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:28][CH2:29][O:30][C:31](C)=[O:32]>C1COCC1>[NH2:1][C:2]1[N:6]([C:31]([O:30][CH2:29][CH3:28])=[O:32])[N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12
Reactant: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Reactant: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Yield: 38 %

Procedure:
15 g of tert-Butyl 3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0° C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) and then with ClCO2 Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 l), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate in 30% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:50])=[O:51])[CH2:45][CH2:44]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(Cl)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc(Cl)nc2)n1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A brown solution of (R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (125.0 mg, 0.168 mmol) and trifluoromethanesulfonic acid (0.15 mL, 1.689 mmol) in TFA (1.5 mL) was stirred at 75° C. for 1.5 h. The mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in CH2Cl2 (50 mL), and the resulting solution was washed with saturated aqueous sodium bicarbonate (40 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). All organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 10% MeOH/CH2Cl2) furnished (R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (52.8 mg, 0.105 mmol, 62.4% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H), 8.88 (d, J=2.7 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.48 (dd, J=8.7, 2.8 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 3.59 (q, J=6.8 Hz, 1H), 3.09 (t, J=4.5 Hz, 4H), 2.86 (s, 3H), 2.56 (br. s., 2H), 2.46 (s, 3H), 2.41-2.45 (m, 2H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, +ve) 504.1 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)CCC.Cl>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([OH:15])=[CH:17][CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nccc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Product: Oc1ccc(Nc2nccc(Nc3ccccc3)n2)cc1
Temperature: 80 °C

Procedure:
4-Anilino-2-chloropyrimidine (Reference Example A-9, 0.921 g, 4.48 mmol) was dissolved in butanol (6 ml) and treated with 4-hydroxyaniline (0.489 g, 4.48 mmol) and conc. HCl (9 drops). The reaction was heated to 80° C. for 4 hours. The solvent was removed by evaporation at reduced pressure to give the title product as a solid which was used without further purification (1.4 g) NMR (300 MHz): 6.43 (d, 1H), 6.68 (d, 2H) 7.14 (t, 1H), 7.25 (m, 4H), 7.64 (m, 2H), 7.88 (s, 1H) 9.53 (brs, 1H), 10.27 (brs, 1H). 10.88 (brs, 1H); m/z: (ES−) 279 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([I:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(I)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-iodobenzoyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 574/576 (M-+H). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.62-3.71 (m, 2H), 4.25 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.22 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 2H), 7.04 (t, J=8.2 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.60 (d, J=8.2 Hz, 1H), 7:61 (d, J=8.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Cl)c(Cl)cc2[nH]c1=O

Procedure:
A solution of 17.7 g. of 4,5-dichloro-o-phenylenediamine and 200 ml. of anhydrous ethanol was prepared. A 17.4 g. batch of diethyl 2-keto-malonate was added to this solution and the mixture was heated to refluxing temperature for about 17 hours. The volatile constituents were removed by evaporation in vacuo. Recrystallization of the residue from ethanol yielded 20 g. of ethyl 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction; melting in the range of 226°-227° C.
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=O)(C)(C)C.[CH2:16]([O:20][C:21]1[C:25](S(C)(=O)=O)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([O:20][C:21]1[C:25]([O:15][CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CC(C)(C)NC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CCNC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (0.066 g, 0.0028 mol) in THF (25 mL) was treated with 1-t-butylcarbamoyl-3-hydroxypyrrolidine (Ref. Syn. Commun. 15, 587.) (0.5 g, 0.0027 mol) and the reaction warmed to 50° C. for 30 min. After cooling to ambient temperature, 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (0.55 g, 0.0027 mol) in THF (5 mL) was added and the reaction heated to reflux for 2.5 h. The solvent was evaporated, the residue treated with ice-water, and the mixture extracted with ether. The extracts were washed with brine, dried, and the solvent evaporated. The residue was dissolved in ether (50 mL) and treated with a slow stream of HCl for 5 min. After stirring overnight, the reaction was extracted with cold water. The aqueous was washed with ether, made basic, and extracted with EtOAc. The extracts were washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.42 g) crystallized from EtOAc, m.p. 127°-128° C. (Compound 27).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=3)=[CH:3][N:4]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1nccc2c1c(I)cn2C1CCOCC1
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)cn2C1CCOCC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine (20.0 mg) obtained in Step A of Example 16 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (13.5 mg), tetrakis(triphenylphosphine)palladium(0) (6.45 mg) and potassium carbonate (15.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 2/1) to give the title compound (12.0 mg) as a white solid.
Reaction SMILES: C1C=CC=CC=1.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([SH:27])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([OH:32])=[O:31]>C(N(CC)CC)C>[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]([S:27][CH2:29][C:30]([OH:32])=[O:31])[S:25][CH:26]=2)[CH:14]=[C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:16]=1[OH:17])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2csc(SCC(=O)O)n2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To 20 ml of benzene were added 0.64 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole and 0.32 g of bromoacetic acid and then 0.5 g of triethylamine was added dropwise to the mixture with stirring. After one hour, triethylamine hydrobromide thus precipitated was filtered off and the benzene solution was extracted with 10 ml of a 2% sodium hydroxide solution. The aqueous extract was acidified by the addition of hydrochloric acid and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated. The crystals thus obtained were recrystallized from benzene to provide 0.52 g of [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thiazolylthio]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([N:31]4[CH2:32][CH2:33][C:28]([F:34])([F:27])[CH2:29][CH2:30]4)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC1(F)CCNCC1
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Agent: Cl
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)N1CCC(F)(F)CC1
Yield: 67 %

Procedure:
As described for example 107, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol) was converted, using 4,4-difluoropiperidine hydrochloride instead of 2-amino-2-methyl-1-propanol, to the title compound (87 mg, 67%) which was obtained as a colorless gum. MS: m/e=467.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of (−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step G (13.7 g, 35.9 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylene diamine (2.40 mL, 35.9 mmol) and 10 N NaOH (7.20 mL, 72.0 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (2×1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[F:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:32])[F:31])=[CH:28][C:23]=1[O:22][CH:20]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(C(F)(F)F)cc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 163.3 %

Procedure:
A mixture of 10.8 g (0.11 mole) of phosgene and 14.2 g (0.11 mole) of potassium carbonate in 200 mL of methylene chloride was cooled to 5° C. in an ice bath while stirring undr nitrogen. After 30 min, the reaction mixture was treated with 40 g (0.1 mole) of 1-(diphenylmethyl)-3-[2-fluoro-5-(trifluoromethyl)phenoxy]azetidine in 100 mL of methylene chloride added dropwise. After stirring for 16 h, the reaction mixture was treated with small pieces of ice to destroy any excess phosgene. Then the reaction mixture was decanted from the inorganic paste and concentrated in vacuo to give 48.6 g of pale yellow oil. The residual oil was distilled at 0.15 mmHg to yield 3 fractions: #1, 12.7 g at 120°-128°; #2, 1.5 g at 128°, and #3 at 128°-132°; with total yield of 19.7 g (66.2%). A sample of fraction #2 was submitted for analysis.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H](C)[CH2:5][C:4](=[C:9]2SCCCS2)[CH2:3]1.[C:15]([OH:21])([C:17](F)(F)F)=[O:16].OO.[OH-].[Na+].Cl>C(#N)C.O>[CH3:1][C@H:2]1[CH2:3][C@@H:4]([CH3:9])[CH2:5][CH:17]([C:15]([OH:21])=[O:16])[CH2:7]1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1CC(=C2SCCCS2)C[C@H](C)C1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CC(C(=O)O)C[C@H](C)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-((3S,5R)-3,5-Dimethyl-cyclohexylidene)-[1,3]dithiane (8.36 g, 0.036 mmol) and TFA (9.5 mL, 0.12 mol) were placed in acetonitrile (480 mL) and water (120 mL) and the mixture was heated at 65° C. for 1 h. 30% Aqueous hydrogen peroxide (48 mL, 0.49 mol) was added carefully and the mixture was warmed to 80° C. slowly. After 1 h, the reaction mixture was cooled to 40° C. and was added slowly to an aqueous solution of NaOH (6N, 475 mL). The resulting mixture was cooled to 0° C. and acidified with aqueous 6N HCl. The acetonitrile was removed by rotary evaporation. The residue was extracted with dichloromethane (100 mL×5) was dried (MgSO4) and was evaporated in vacuo to yield the title compound as a white wax (4.1 g, 72%). MH+157.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([F:25])[CH:12]=1)[C:2]1C=CC=C[CH:3]=1.C([Li])CCC.CCCCCC.[O:38]1CCCC1>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH:2]([CH3:3])[C@H:1]([OH:38])[O:8][C:9]2=[O:26])=[CH:12][C:13]=1[F:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1[C@H](O)OC(=O)N1c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 17.5 g (4-benzyloxy-3-fluoro-phenyl)-carbamic acid benzyl ester (MW: 351.38, 50 mmol) in 30 ml of dry tetrahydrofuran was cooled to −78° C. with a dry ice/acetone bath. 22.8 ml of a 2.3M n-butyl-lithium solution in n-hexane (52.5 mmol) was added drop wise and the reaction mixture stirred at −78° C. for 15 min. 7.92 g R(−)-glycidyl butyrate (MW: 144.17, 60 mmol) were added and the reaction was allowed to warm up to room temperature. The reaction was monitored by HPLC, quenched with a saturated ammonium chloride solution and diluted with 100 ml of ethyl acetate. The organic layer was washed with 200 ml water and 200 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue was crystallized from 200 ml of a 1/1-ethyl acetate/hexane mixture. The solid was collected and recrystallized from 150 ml of a 9/1 ethyl acetate/dichloromethane mixture. The colorless crystals were collected and dried. Yield: 10.4-g, 65.5%. MS: 318.1 (M+H)+. Method ESI+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH:8]=[CH:7]1)C.O.[NH2:15][NH2:16]>C(O)C>[O:12]=[C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH:7]=[CH:8]1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1ccc(=O)cc1

Procedure:
As described for example 112a, (4-oxo-4H-pyridin-1-yl)-acetic acid ethyl ester (Bambury, Ronald E.; Edwards, Michael Louis; Miller, Laird Foulis. 4-Oxo-1-pyridinylpeniclliin and -cephalosporin derivatives. Ger. Offen. (1975)) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the title compound was obtained as a yellow solid (yield: 98%). MS: m/e=168.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:21].O>O1CCOCC1.[Cu-]=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[N:10]=[CH:11][O:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: Fc1ccc(-c2ncoc2-c2ccnc(Br)c2)cc1
Agent: O=[Cu-]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Temperature: 150 °C

Procedure:
2-Bromo-4-[4-(4-fluoro-phenyl)-oxazol-5-yl]-pyridine (700 mg, 2.19 mmol), 28% aqueous ammonium hydroxide solution (14 mL) and Copper (I) oxide (314 mg, 2.19 mmol) are mixed in 1,4-dioxane (14 mL) in a microwave reaction tube. The tube is sealed and heated at 150° C. for 25 min in a microwave reactor. Then water (80 mL) is added and the mixture is extracted with EtOAc (3×50 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 320 mg of desired product.