Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:30]([O:37][C@@H:38]([C:53]1[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=1)[C@H:39]1[CH2:43]OS(=O)(=O)[N:40]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].S1C=CN=N1>C1COCC1>[C:49]([O:48][C:46]([NH:40][C@@H:39]([C@@H:38]([O:37][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:31])[CH3:32])[C:53]1[CH:54]=[CH:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=1)[CH2:43][N:16]([C:14]1[S:15][C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)=[N:12][N:13]=1)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1csnn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of tert-butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate (0.64 g, 1.89 mmol) in THF (6 mL) was added cesium carbonate (1.07 g, 3.28 mmol). The mixture was heated to 55° C. for 10 minutes and then tert-butyl (4R)-4-((S)-((tert-butyl(dimethyl)silyl)oxy)(4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.84 g, 1.64 mmol) in THF (4 mL) was added. The mixture was heated for 1 hour after the addition. HPLC-MS showed the product and thiadiazole starting material. The reaction was concentrated in vacuo and EtOAc (75 mL) was added. The mixture was cooled to 0° C. and 5% HCl (50 mL) was slowly added. The mixture was stirred for 1 hour. The organic phase was separated, and the aqueous phase was extracted twice with EtOAc. To the combined EtOAc solution was added saturated NaHCO3 and Na2CO3 until it was basic (pH=9). The organic layer was washed with brine, dried over Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (50%-100% DCM-hexane) to provide the product as a yellow solid (1.18 g, 93%). LCMS (API-ES) m/z: 772 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:28][CH2:29]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCN(C(=O)c2ccccc2)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and phenyl-piperazin-1-ylmethanone in DME. ES-MS m/e (%): 397 (M+Na+, 25),375 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].[CH3:26][S-:27].[Na+].O1CCOCC1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:26][S:27][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25]
Reactant: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Reactant: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CSc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(CC(=O)O)c1=O
Yield: 90.2 %

Procedure:
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (220 mg, 0.533 mmol) and sodium thiomethoxide (112 mg, 1.60 mmol) in toluene (22 mL) were stirred at 80° C. for 3 hours. After cooling, the reaction solution was stirred with 1,4-dioxane (6 mL) and 1 M aqueous sodium hydroxide (1.59 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was mixed with toluene and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (169 mg, 90% yield).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14](N2CCOC2=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.NO.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=C1)=[O:26]>C(Cl)(Cl)Cl.ClCCl>[O:26]1[CH2:30][CH2:31][N:27]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:25]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCOC2=O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C1CCN(N2CCOC2)CC1

Procedure:
1-Benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine. A solution of the amino alcohol (1.7 g) and 1,1'-carbonyldiimidazole (2.4 g) in chloroform (30 mL) was heated at reflux for 6 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N sodium hydroxide and water. The separated organic phase was dried and evaporated to give the oxazolidin-3-yl piperidine as a viscous oil (1.9 g); NMR: 7.35 (m,5), 5.13 (s,2), 4.34 (m,4), 3.89 (m,1), 3.49 (m,2), 2.86 (m,2), 1.78 (m,2), 1.58 (m,2); MS: m/z=305(M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.N>S1(CCCC1)(=O)=O>[CH3:11][C:9]1[CH:8]=[C:7]([CH3:12])[C:3]2[C:4](=[O:6])[NH:22][C:16]3[CH:15]=[C:14]([CH3:13])[C:19]([CH3:20])=[CH:18][C:17]=3[NH:21][C:2]=2[N:10]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Cc1cc(C)c(C(=O)O)c(Cl)n1
Agent: N
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1NC2=O
Temperature: 220 °C
Reaction time: 0.75 h

Procedure:
A mixture consisting of 52.0 gm of 2-chloro-4,6-dimethyl-nicotinic acid, 38.0 gm of 4,5-dimethyl-o-phenylenediamine and 150 ml of sulfolane was heated on an oil bath at 220° C. After 45 minutes the mixture was allowed to cool to 100° C. and was then poured over ice. After neutralization with ammonia and standing for several hours the precipitate which had formed was suction-filtered off and admixed with dilute acetic acid. The mixture was suction-filtered after one hour, and the filter cake was recrystallized from aqueous 80% acetic acid, yielding 34% of theory of the compound named in the heading, which had a melting point of 264°-268° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:19]\[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])=[CH:6][CH:7]=1
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])CCc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCC/C=C(\Cc1ccc(Br)cc1)[N+](=O)[O-]
Yield: 43 %

Procedure:
Prepared according to the general procedure B from 1-bromo-4-(2-nitroethyl)benzene 112h (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (2.15 g, 43% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23](OCC)=[O:24].[SH:28][C:29]1[NH:30][CH:31]=[CH:32][N:33]=1.O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]1[C:23](=[O:24])[N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[S:28][C:2]2=1)=[O:22]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: Sc1ncc[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1cccc2c1ncc1c(=O)n3ccnc3sc12)c1c(Cl)cccc1Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (251 mg) in N-methylpyrrolidone (2 ml) was added 2-mercaptoimidazole (89 mg), and the mixture was stirred for 1 hour at 65° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 4-(2,6-dichlorobenzoylamino)-7H-imidazo[2',1':2,3][1,3]thiazino-[5,6-c]quinolin-7-one (248.2 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Br>C(O)CC>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[C:13]([NH:12][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)[CH:14]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: Br
Solvent: CCCO
Product: CCOC(=O)c1cccc(Nc2ncc(Br)n3ncnc23)c1
Temperature: 85 °C
Yield: 98 %

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (1.39 g, 5.00 mmol) and ethyl 3-aminobenzoate (0.93 g, 5.60 mmol) are stirred in PrOH (10 mL) and HBr (48% aq., 1.14 mL, 10 mmol) is added. The mixture is heated at 85° C. for 4 h and then cooled to rt and quenched with NaHCO3 (sat. aq., 25 mL). The resulting suspension is cooled to 0° C. and the white solid is collected by suction filtration and washed with water (10 mL). The crude product is taken up in EtOH and the solvent evaporated to afford the title compound as an off-white solid (1.79 g, 4.9 mmol) which is used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[CH3:23][NH2:24]>O>[CH2:21]([C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:24][CH3:23])=[CH:5][CH:6]=2)[C:14]2=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)[CH3:22]
Reactant: CN
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7 of Example 1, 627 mg, 9.0 mmol), a solution of methylamine (40% in methanol, 6 mL) and water (6 mL) was placed in a sealed tube and heated overnight at 130° C. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (5:1) to afford 523 mg (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H, br.s), 2.93 (4H, s), 2.82 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:37](=[O:38])[N:28]2[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:37](=[O:38])[N:28]3[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 67.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.6 g.) were treated in a similar manner to that of Example 21-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[C:25]([C:27]2[CH2:28][CH2:29][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:31][CH:32]=2)[CH:24]=[CH:23][C:22]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:22]2[CH:23]=[CH:24][C:25]([C:27]3[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH:28]=3)=[CH:26][C:21]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)N1CC=C(c2ccc(O)c(F)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1

Procedure:
Prepared essentially as Preparation 2 (step 2) using 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenol as starting materials. MS (m/z) 414 (M−55).
Reaction SMILES: C(C1OC(N)=NC=1)C1C=CC=CC=1.Br[CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17].NC(N)=O>C(O)C>[C:19]1([CH2:18][CH2:15][CH:16]=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CC(Br)Cc1ccccc1
Agent: NC(N)=O
Agent: Nc1ncc(Cc2ccccc2)o1
Solvent: CCO
Product: O=CCCc1ccccc1

Procedure:
5-Benzyl-oxazol-2-ylamine A mixture of 2-bromo-3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated at reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was washed three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were brought to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid (1.6 g, 9.2 mmol, 9.2% from 3-phenyl-propionaldehyde). ESI-MS m/z calc. 174.1, found 175.1 (M+1)+; 1H NMR (CDCl3) δ 7.32-7.22 (m, 5H), 6.39 (s, 1H), 4.72 (bs, 2H), 3.84 (s, 2H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH2:15]>C1COCC1.O>[CH3:14][NH:15][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc2ccc([N+](=O)[O-])cc2s1
Yield: 88 %

Procedure:
Place 2-chloro-6-nitro-benzothiazole (5.82 g, 27.1 mmol) in THF (130 mL). Add 40% methylamine in water (7 mL) and stir until the product precipitates out. Concentrate in vacuo and then triturate with methanol. Filter off the product and wash with methanol, Dry thoroughly to yield 4.99 g (88%) of the title compound: mass spectrum (ion-spray): (m/z)=210.0 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CC1C=CC=CC=1)[C@H](O)CN(OC1CCCC1)S(C1C=CC(OC)=CC=1)(=O)=O.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][C@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC2CCOC2)cc1
Agent: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@@H](N)Cc2ccccc2)OC2CCCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Reaction time: 18 h
Yield: 87 %

Procedure:
tetrahydro-3-furanyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate. A mixture of 2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furanyl]carbonate (13.8 mg, 0.0602 mmol, WO94/05639), N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide×trifluoracetic acid (Step 1, Example 48), (30 mg, 0.0547 mmol), and N,N-diisopropylethylamine (23.8 μL, 0.137 mmol) were combined at ambient temperature under an Argon atmosphere. After stirring for 18 hours, the reaction mixture was evaporated in vacuo to a residue and purified on a preparative silica gel TLC plate (20×20 cm, 500 μM) eluting with 96:4 chloroform:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, evaporated in vacuo and dried under high vacuum to provide (3S)tetrahydro-3-furanyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (26 mg, 87%) as a foam. H1-NMR (chloroform-D3): 1.73 (m, 9H), 2.14 (m, 1H), 2.92 (m, 5H), 3.77 (m, 6H), 3.87 (s, 3H), 4.79 (bm, 2H), 5.10 (bs, 1H), 6.97 (d, 2H), 7.23 (m, 5H), 7.70 (d, 2H). MS(ESI): 571 (M+Na).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].C[O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[CH:12][C:11]=1Br.[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>CN(C=O)C>[Cl:16][C:14]1[C:13]([CH3:17])=[CH:12][C:11]([N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[C:10]([CH:15]=1)[C:9]([OH:8])=[O:19]
Reactant: COC(=O)c1cc(Cl)c(C)cc1Br
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2nccn2)c(C(=O)O)cc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Cs2CO3 (742 mg, 2.28 mmol) was added portionwise to a rt solution of 2-bromo-5-chloro-4-methyl-benzoic acid methyl ester (300 mg, 1.14 mmol) in DMF (3 mL) followed by 1H-1,2,3-triazole (0.1 mL, 1.71 mmol), Cu(I)I (13 mg, 0.068 mmol) and DMCDA (40 uL, 0.23 mmol). The resulting suspension was stirred at 120° C. for 4 h. The rxn mixture was quenched with 2M aq. HCl and extracted with EtOAc (3×). The combined org. layers were dried (Na2SO4), filtered and evaporated in vacuo to obtain the crude product that was purified by prep. HPLC (method C) to give the title compound A-1-15 as a pale yellow solid. LC-MS A: tR=0.72 min; [M(35Cl)+H]+=238.01.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.Cl>O1CCCC1.O>[CH2:7]([O:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:26][CH:27]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a suspension of lithium aluminum hydride (0.47 g) in tetrahydrofuran (5 mL) was added dropwise a solution of methyl 4-(2-benzyloxybenzyl)benzoate (2.1 g) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (10 mL) was added to the reaction mixture, and the resulting mixture was stirred for 30 minutes. To the reaction mixture were added water and dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzyl alcohol (1.9 g).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO>[Cl:31][C:19]1[NH:20][C:21]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2nccs2)c1F
Agent: Cl
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NCc2nccs2)c1F

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.5826, 1.015 mmol) was dissolved in MeOH (10 mL) and HCl (4M in 1,4-dioxane) (10 mL) at room temperature and stirred overnight. Removal of the solvents in vacuo provided 2-chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone, presumed dihydrochloride, as a beige solid (0.3507, 100%). LCMS: (M+H)+=274.8.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[O:53]1[CH2:56][CH:55]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:54]1.Br[C:64]1[C:65]([Cl:90])=[C:66]([N:73]([CH2:81][C:82]2[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=2)[C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:67]=[C:68]([CH:70]([F:72])[F:71])[CH:69]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:90][C:65]1[C:64]([N:60]2[CH2:61][CH2:62][N:57]([CH:55]3[CH2:56][O:53][CH2:54]3)[CH2:58][CH2:59]2)=[CH:69][C:68]([CH:70]([F:72])[F:71])=[CH:67][C:66]=1[N:73]([CH2:81][C:82]1[CH:83]=[CH:84][C:85]([O:88][CH3:89])=[CH:86][CH:87]=1)[C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77]
Reactant: C1CN(C2COC2)CCN1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(F)F)cc(Br)c2Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(F)F)cc(N3CCN(C4COC4)CC3)c2Cl)cc1
Temperature: 106 °C

Procedure:
Cesium carbonate (672 mg, 2.063 mmol), BINAP (64.2 mg, 0.103 mmol), 1-(oxetan-3-yl)piperazine (176 mg, 1.238 mmol) and Pd2(dba)3 (94 mg, 0.103 mmol) were weighed into a 25 mL round bottom flask at room temperature. A solution of tert-butyl (3-bromo-2-chloro-5-(difluoromethyl)phenyl)(4-methoxybenzyl)carbamate in toluene (4294 μl, 1.031 mmol) was added and the reaction was degassed 3 times by evacuating the flask under vacuum and then purging with N2. The reaction mixture was heated to 106° C. for 16 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc, sonicated, filtered through celite and concentrated. The product was purified by column chromatography (40 g SiO2, 30 to 100% EtOAc-hexane gradient elution) to afford 312 mg of tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[C:23](O)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CC(C)(C)C(=O)O
Product: CC(C)(C)C(=O)NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with pivalic acid similarly to as described in Example 2 with non-critical modifications to afford crude 10-bromo-9-fluoro-3-(pivalamidomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 15 mg (37%) of 3-[(2,2-dimethylpropanoylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=453.3.