Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O:24][C:25]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CCCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-butyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:92]([O:99][CH2:100][CH:101]=O)([C:95]([CH3:98])([CH3:97])[CH3:96])([CH3:94])[CH3:93]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:101]\[CH2:100][O:99][Si:92]([C:95]([CH3:96])([CH3:97])[CH3:98])([CH3:93])[CH3:94])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\CO[Si](C)(C)C(C)(C)C)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 60 %

Procedure:
A solution of 4-methoxyphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (9.07 g; 7.27 mmol) and t-butyldimethylsilyloxyacetaldehyde (1.8 g; 10.34 mmol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=2.5:1) whereby the title compound (4.99 g; 4.36 mmol; 60.0%) was obtained.
Reaction SMILES: OC1C=CC(C(NN(C(=O)/C=C/C2C3C(=CC=CC=3)N(C(OC(C)(C)C)=O)C=2)C(C)C)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].BrCCBr.Br[CH2:46][CH2:47][O:48][C:49]1[CH:81]=[CH:80][C:52]([C:53]([NH:55][N:56]([C:60](=[O:79])/[CH:61]=[CH:62]/[C:63]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[N:65]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH:64]=2)[CH:57]([CH3:59])[CH3:58])=[O:54])=[CH:51][CH:50]=1.[NH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>C(#N)C>[CH:57]([N:56]([C:60](=[O:79])/[CH:61]=[CH:62]/[C:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[N:65]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH:64]=1)[NH:55][C:53](=[O:54])[C:52]1[CH:80]=[CH:81][C:49]([O:48][CH2:47][CH2:46][N:82]2[CH2:87][CH2:86][O:85][CH2:84][CH2:83]2)=[CH:50][CH:51]=1)([CH3:59])[CH3:58]
Reactant: C1COCCN1
Reactant: CC(C)N(NC(=O)c1ccc(OCCBr)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCBr
Solvent: CC#N
Product: CC(C)N(NC(=O)c1ccc(OCCN2CCOCC2)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 85 °C

Procedure:
(E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (50.0 mg, 0.11 mmol) and K2CO3 (59.63 mg, 0.43 mmol) dissolved in anhydrous acetonitrile (10.0 ml), 1,2-dibromoethane (0.0465 ml, 0.54 mmol) was added drop-by-drop. The reaction mixture was refluxed at 85° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (n-hexane:EtOAc:methanol=14:3:1) so that ivory solid form of (E)-tert-butyl 3-(3-(2-(4-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained.(34 mg, 55.3%). The resultant (E)-tert-butyl 3-(3-(2-(4-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (34.0 mg, 0.06 mmol) and K2CO3 (16.5 mg, 0.12 mmol) were dissolved in anhydrous acetonitrile (10.0 ml), and the solution was drop-wise added with morpholine (0.01031 ml, 0.053 mmol). The reaction mixture was refluxed at 85° C. for 12 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (MC:methanol=30:1) so that ivory solid form of (E)-tert-butyl3-(3-(1-isopropyl-2-(4-(2-morpholinoethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (8.2 mg, 23.9%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:11][NH:12]2>O.CO>[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:18][C:19]([OH:21])=[O:20])=[CH:11][NH:12]2
Reactant: COC(=O)Cc1c[nH]c2ccc(Cl)c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1c[nH]c2ccc(Cl)c(Cl)c12
Yield: 72.1 %

Procedure:
An aqueous solution prepared by dissolving 120 mg of potassium carbonate in 2.5 ml of water was added to a solution of 44 mg of methyl 4,5-dichloroindole-3-acetate in 5 ml of methanol. The mixture was refluxed for 1.5 hours, after which the methanol was removed by distillation under reduced pressure, and the aqueous solution thus obtained was extracted with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by a silica gel thin-layer chromatography to obtain 30 mg of 4,5-dichloroindole-3-acetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH2:39][CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CCO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3ccnc(C)c3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-ethoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 522.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Oc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
With the exclusion of moisture, 1.795 g (8.5 mmol) of 6-phenyl-7H-pyrrolo[2,3-d]-pyrimidin-4-ol and 27 ml of phosphorus oxychloride are heated at boiling for 3 hours. Pouring the reaction mixture into ice-water, filtering and washing with hot isopropanol and hexane yield the title compound; FAB-MS: (M+H)+ =230.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].BrN1[C:30](=[O:31])CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:31][CH3:30])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: COCCOc1nc(N)c2ncn(Cc3cccc(C#N)c3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(C#N)c3)c2n1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (7) (1.0 g) was suspended in acetonitrile. N-Bromosuccinimide (1.0 g) was added in small portions over 10 minutes. After stirring for 1 hour, the mixture was diluted with ethyl acetate, washed with 10% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4 and evaporated to dryness under vacuum. The crude 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (8) was dissolved in methanol (50 mL) and 50% aqueous KOH solution (1 mL) was added. The mixture was heated under reflux for 3 hours and then concentrated under vacuum. The product was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: 0-10% MeOH in ethyl acetate) gave 3-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (9) (0.45 g) as a pinkish solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CNc1ccccc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C#N)cc1
Reaction time: 6 h
Yield: 96.5 %

Procedure:
The above general procedure was followed using 4-bromobenzonitrile (187 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 10% ethyl acetate/hexanes to give 201 mg (97%) of N-(4-cyanophenyl)-N-methylaniline. 1H NMR (500 MHz, CDCl3) δ 7.45-7.42 (m, 4H), 7.27 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.73 (d, J=9.0 Hz, 2H), 3.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 152.0, 146.8, 133.1, 130.1, 126.4, 126.2, 120.2, 114.0, 99.4, 40.1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([N:17](C)[C:18](=O)OC(C)(C)C)[C:11]1=[O:26]>O1CCOCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:17][CH3:18])[C:11]1=[O:26]
Reactant: COc1ccccc1N1CCCC[C@H](N(C)C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H]1CCCCN(c2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 4 N HCl in dioxane (0.15 mL, 0.60 mmol) was added dropwise to a 0° C. solution of (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-yl(methyl)carbamate (52 mg, 0.15 mmol) in dioxane (0.6 mL). The reaction mixture was then stirred at rt for 2 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-1-(2-methoxyphenyl)-3-(methylamino)azepan-2-one hydrochloride (41.5 mg, 0.146 mmol, 98% yield) as a white solid. Anal. Calcd. for C14H20N2O2 m/z 248.3. found: 249.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:7][CH2:8][CH3:9]
Reactant: ClCC1CO1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A stirred solution of epichlorohydrin (20.0 g, 0.22 mole) is treated dropwise with di-n-butylamine (29.73 g, 0.23 mole) over a 1 hour period followed by continued stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour and then extracted with 3×100 ml portions of ether. The etheral extracts are pooled and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to leave the crude product (I) weighing 39.42 g. The crude product is distilled at 52°/0.15 mmHg to give 8.24 g (20.2%) pure product to be used as an intermediate in Part B.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7](O)[CH2:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:15])C.[Cl-].[Na+]>O.C(O)(=O)C>[OH:15][CH:3]1[CH2:4][C:5](=[O:6])[C:7]([CH2:8][CH3:9])=[C:2]1[CH3:1]
Reactant: CC(=O)O
Reactant: CCC(O)c1ccc(C)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1=C(C)C(O)CC1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixed solution of 28.97 g of the 1-(5-methyl-2-furyl)propanol thus obtained, 0.394 g of 50% aqueous acetic acid, 0.394 g of a 23% (w/v) sodium hydroxide solution in 579.4 g of water was heated and refluxed at the constant pH of 5.70 to 5.85 for 38 hours. After the mixed solution was cooled to the room temperature, a 23% (w/v) sodium hydroxide solution was added to the mixed solution to adjust the pH of the solution to 8.0 to 8.2, and then refluxed for three hours. A 50% acetic acid solution was added to the refluxing solution to adjust the pH to 6.0 to 6.5. The reaction solution was then cooled to the room temperature, mixed with 300 g of sodium chloride, and extracted three times with 500 ml of diethyl ether. The combined ether layer was washed twice with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was distilled, and a distillate fraction of 157° to 162° C. at 19 mmHg was collected to yield 15 g of (RS)-4-hydroxy-3-methyl-2-ethylcyclopent-2-en-1-one. Yield 52% b.p.: 157°-162° C. (19 mmHg)
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccc(CO)cc1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(CO)cc1
Reaction time: 6 h
Yield: 53.5 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2 g, 8 mmol), 4-aminobenzyl alcohol (2.3 g, I2 mmol) and 1,4-dioxan (50 ml) were heated at 70° for 1.5 hours, then more amine (0.9 g, 8 mmol) was added and heating continued for a further 6 hours. The solvent was evaporated and the product converted to free base. Recrystallisation from chloroform/ether gave 3-butyryl-4-(4-hydroxymethylphenylamino)-8-methoxyquinoline (1.5 g), m.p. 187°-189°.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([N:13]=[N+:14]=[N-:15])(C)(C)C.CCCCCC>CCOCC>[C:1]1([C:7]2[N:13]=[N:14][NH:15][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc(-c2c[nH]nn2)cc1
Temperature: 150 °C
Yield: 76.3 %

Procedure:
##STR9## Phenylethyne (12.0 g) and Me3SiN3 (7.8 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 150° C. for 10 hrs., cooled, and dissolved in Et2O. The Et2O was treated exactly as in Example 2, reduced to 100 ml total volume, a little hexane added and chilled in a refrigerator overnight. Filtration gave 7.5 g (76%) white crystals mp 146.9-149.0.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH:7]([CH3:19])[C:6]=2[NH:5][C:4](=[O:20])[CH:3]=1>[Pd].CCO>[CH3:19][CH:7]1[C:6]2[NH:5][C:4](=[O:20])[CH:3]=[CH:2][C:12]=2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8]1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2c(Br)cc(=O)[nH]c21
Agent: [Pd]
Solvent: CCO
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(=O)[nH]c21
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.[NH2:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25].O>CN1C(=O)CCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25])[N:11]=[CH:10]2
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Reactant: CCC(N)(CO)CO
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CO)(CO)Nc1ncc2cc(Oc3ccc(F)cc3F)ccc2n1
Temperature: 25 °C
Yield: 47 %

Procedure:
Compound (1G) (250 mg, 0.85 mmol) and 2-amino-2-ethyl-1,3-propanediol (298 mg, 2.5 mmol) in NMP (0.25 mL) were stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, CH2Cl2:MeOH, 95:5) to afford 150 mg of the above-titled compound (Example 1). Mp=110-112.9° C. MW (M+H)+=376.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-:46].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[OH:46][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(O)c2)s1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a solution of tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (630 mg, 982 μmol) (prepared as described in Example 1) in 15 mL DMF were added cesium carbonate (3199 mg, 9819 μmol) and acetic acid (590 mg, 9819 μmol). The mixture was heated at 70° C. for 45 minutes. The reaction mixture was concentrated, and the resulting residue was diluted with 100 mL EtOAc. The organic phase was washed with water and saturated aqueous ammonium chloride twice and then dried over sodium sulfate. Removal of the solvent gave the compound as a tan solid (500 mg, 79%). LCMS (API-ES) m/z (%): 640.0 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 9H) 1.54 (s, 9H) 2.84-2.94 (m, 2H) 4.23-4.31 (m, 3H) 7.47 (t, J=8.78 Hz, 3H) 7.62-7.69 (m, 3H) 8.01 (d, J=8.53 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:32])[CH:21]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:34].C(OCC)(=O)C>>[ClH:34].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:32])[CH:21]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3=O)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3=O)c2)cc1

Procedure:
A mixed solution of tert-butyl{trans-2-[4-({[3-(2-oxopiperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (53.4 mg) in 4N hydrochloric acid/ethyl acetate solution (2 mL) was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (38.5 mg).