Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]2.Br[C:34]1[S:38][C:37]([C@@:39]2([O:46][CH3:47])[CH2:44][CH2:43][O:42][C@@H:41]([CH3:45])[CH2:40]2)=[N:36][CH:35]=1>>[CH3:47][O:46][C@:39]1([C:37]2[S:38][C:34]([S:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]4)=[CH:35][N:36]=2)[CH2:44][CH2:43][O:42][C@@H:41]([CH3:45])[CH2:40]1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: CO[C@]1(c2ncc(Br)s2)CCO[C@@H](C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CO[C@]1(c2ncc(Sc3ccc4c(c3)CCC(=O)N4C)s2)CCO[C@@H](C)C1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1 except that triphenylphosphine (0.04 g) was added, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one (0.153 g) was reacted with (2S,4R)-4-(5-bromothiazol-2-yl)-4-methoxy-2-methyltetrahydropyran (0.23 g) to give (2S,4R)-4-methoxy-2-methyl-4-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-2-yl]-tetrahydropyran in 72% yield as a foam;
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])(=[O:26])[NH2:25]>>[NH2:25][C:24](=[O:26])[CH2:27][CH2:28][CH2:29][C:30]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:31]
Reactant: NC(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCC(N)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethyny-octahydro-indole-1-carboxylic acid methyl ester and 4-carbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-amino-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=427; RT=1.01 min; UPLC Method I
Reaction SMILES: C(SC=C)=C.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.O=O.C(S[C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)[O:33][O:32]1)C.[O:51]1[CH2:54][CH2:53][O:52]1>C(Cl)Cl>[OH:51][CH2:54][CH2:53][O:52][C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:40][CH:39]4[CH2:38][CH:37]([CH2:36][CH:35]2[CH2:43]4)[CH2:42]3)[O:33][O:32]1
Reactant: C1COO1
Reactant: CCSC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Agent: C=CSC=C
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: O=O
Solvent: ClCCl
Product: OCCOC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: -78 °C

Procedure:
The vinyl sulfide of Example 1(b) (0.099 g) was irradiated for 11.5 min in 15 mL of CH2Cl2 containing a few crystals (<1 mg) of methylene blue with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. TLC indicated that the vinyl sulfide was consumed. N-Chlorosuccinimide (0.044 g) was added and the mixture maintained at -78° C. for 15 minutes. Ethylene glycol (37 uL) was added and the solution warmed to room temperature. Progress of the reaction was monitored by the appearance of a new material by TLC (20% ethyl acetate in hexane) which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 1 was gradually replaced by the blue emission of dioxetane 10 over a period of an hour. The solution was concentrated to dryness and the residue extracted with ether. The ether was evaporated and the resulting residue chromatographed on a silica prep. TLC plate with 40% ethyl acetate in hexane. The major band contained 18 mg of dioxetane 10.
Reaction SMILES: Cl.[S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[S:2]([N:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 120 °C
Yield: 69.1 %

Procedure:
1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N,N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120° C. for 2 hours. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50 ml) to precipitate a tan solid. The solid was collected by filtration and dried at 80° C. for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05 g),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=3)[N:10]=2)=[CH:5][CH:4]=1>O1CCCC1>[O:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:1]
Reactant: COc1ccc(-c2nc3cccc(Nc4ccc([N+](=O)[O-])cc4)c3nc2-c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cccc(Nc4ccc(N)cc4)c3nc2-c2ccc(OC)cc2)cc1

Procedure:
8.3 g (17.3 mmol) of 2,3-di(4-methoxyphenyl)-5-(4-nitrophenyl)aminoquinoxaline was dissolved in 100 ml of tetrahydrofuran, and a reaction container was purged with nitrogen. Thereafter, 5.0 g of 5% Pd/C (hydrous) was added, followed by sufficient purging with nitrogen again. This system was purged with hydrogen, followed by reaction at room temperature for 10 hours. After completion of the reaction, the system was filtered, and the resulting filtration residue was washed with tetrahydrofuran and filtered again. The solvent was removed from the resulting filtrate, and a reaction product was recrystallized in hexane to obtain the intended product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Hydroxy-benzoic acid methyl ester (3.19 g, 21 mmol) was dissolved together with pyridine (1.97 g, 25 mmol) in dry THF (20 mL) and after cooling down to 0° C., methanesulfonyl chloride (2.29 g, 20 mmol) was added dropwise. The ice bath was removed and mixture was stirred at r.t. for 5 h. After diluting with DCM and extraction with water and aq. HCl (2N), the organic layer was dried (MgSO4) and evaporated to afford the crude but highly pure product as a solid which was used in the next step without further purification (4.38 g, 95.1%). 1H NMR (400 MHz, CDCl3): δ 8.07-8.09 (d, 2H), 7.32-7.34 (d, 2H), 3.90 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][NH2:5].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=O)[CH3:18])[N:12]=1)(=O)[CH3:9].C(O)(=O)C>CCO>[CH3:1][N:2]([CH3:7])[C:3](=[S:6])[NH:4][N:5]=[C:8]([C:11]1[N:12]=[C:13]([C:17](=[N:5][NH:4][C:3]([N:2]([CH3:7])[CH3:1])=[S:6])[CH3:18])[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CN(C)C(=S)NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=S)N(C)C)c1cccc(C(C)=NNC(=S)N(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and 2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min and allowed to cool to ambient temperature. The yellow precipitate was collected by filtration, washed with 95% EtOH, and subsequently recrystallized from toluene: yield 2.72 g (73%); mp 215° (dec).
Reaction SMILES: O=P(Cl)(Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1)([O-:8])=[O:7].CN([CH:27]=[O:28])C>[OH-].[Na+]>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:23]=1[CH:27]=[O:28])([O-:8])=[O:7]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2[N+](=O)[O-])nc2ccccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a dry flask charged with DMF (2.7 g, 37 mmol) and cooled to 0° C. was added slowly POCl3 over 5 minutes. The solution was stirred for 10 min at 0° C. was warmed to room temperature over 1 hour. To the deep red color solution recooled to 0° C. was added 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (1.0 g, 4.18 mmol) in DMF (8 ml). The reaction was stirred for 5.5 hours; LC-MS indicated some product formation. A second addition of the Vilsmeier complex (from 2.7 g of DMF and 1.47 g POCl3) was charged and the reaction stirred overnight, then heated to 50° C. for 3 hours until reaction completion. The reaction was cooled to room temperature, poured onto ice, adjusted to pH=7 with IN NaOH. The product was extracted into CH2Cl2 (3×50 ml), washed with brine, dried over Na2SO4 and concentrated to obtain the product as a white solid (1.03 g, 92% yield). (MS, M++H=268.0)
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCCCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and Cul (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=1)=[O:3].[O:30]1[CH2:33][CH2:32][CH:31]1[CH2:34][NH2:35].O.ON1C2C=CC=CC=2N=N1.N=C=N>CN(C=O)C>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([C:27]([NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][O:30]2)=[O:29])[CH:24]=[CH:23][CH:22]=1)=[O:3]
Reactant: NCC1CCO1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)O)n3)s2)c(F)c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)NCC4CCO4)n3)s2)c(F)c1

Procedure:
A mixture of 6-({3-(aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridine-2-carboxylic acid (Table 3, Example 40) (50 mg, 0.12 mmol), 1-oxetan-2-ylmethanamine (11 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and PS-Carbodiimide (240 mg, 0.30 mmol, 1.25 mmol/g) in DMF (4 mL) was irradiated in a microwave at 100° C. for 10 minutes. Upon completion, the crude reaction was filtered, concentrated, and purified by silica gel chromatography (0-7% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: C1C=CC=CC=1.Cl.[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=O)[CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1>CCOCC.C(O)C.C(O)(C)C>[ClH:8].[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:23]3[CH2:24][CH2:25]3)[CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1
Reactant: O=C(C1CC1)N1CCN(c2cncc(Cl)n2)CC1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Solvent: CCOCC
Product: Clc1cncc(N2CCN(CC3CC3)CC2)n1

Procedure:
To a stirred slurry of 3.0 g (11 mmol) of the product from the previous step in 30 ml dry ether is added 5.5 ml of a 70% benzene solution of sodium bis-2-methoxyethoxyaluminum hydride at -20° C. under N2. The temperature of the mixture is raised to +10° C. for 20 minutes and the mixture is recooled to -20° C. and treated dropwise with 33 ml 4 N aqueous hydrochloric acid. The aqueous acid layer is extracted with chloroform, adjusted to pH8 with sodium bicarbonate and the crude title base extracted with chloroform and chromatographed on silica gel. Elution with ethylacetatechloroform gives fractions containing 0.8 g (29%) of pure title base which is converted to the hydrochloride, mp 254° C. dec in ethanol-isopropanol containing hydrochloric acid.
Reaction SMILES: [OH-].[Na+].BrBr.[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16](=[O:18])C)[CH3:6].S(=O)(O)[O-:20].[Na+]>O1CCOCC1.O>[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([OH:18])=[O:20])[CH3:6]
Reactant: CCc1sc2ccccc2c1C(C)=O
Reactant: O=S([O-])O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1sc2ccccc2c1C(=O)O
Temperature: 0 °C
Yield: 92 %

Procedure:
Into a one-litre flask equipped with a mechanical stirrer and a dropping-funnel were introduced 39 g (0.97 mol) of sodium hydroxide with 270 ml of water. The solution was cooled to 0° C by means of an ice-bath and 20 ml (0.333 mol) of bromine were then added through the dropping-funnel followed by 190 ml of dioxan, care being taken to maintain the temperature at 0° C. Finally, still at the same temperature, a solution of 22.6 g (0.111 mol) of 2-ethyl-3-acetyl-benzo[b]thiophene in 25 ml of dioxan were introduced drop-by-drop. The mixture was then allowed to return to room temperature and stirring was maintained for 2 hours. A solution of sodium bisulphite was then added and the reaction medium was acidified and extracted with ether. The organic phase was washed with water, dried and evaporated to dryness to give 20.2 g of 2-ethyl-3-carboxy-benzo[b]thiophene. Yield 92%; M.P. 136° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([S:16]Cl)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:18][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(SCl)cc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was dissolved in 50 ml. of methylene chloride. To the stirred solution there was added dropwise p-toluenesulfenyl chloride (2.92 g., 20 mmoles), with the temperature maintained below 30° C. by occasional cooling with an ice-water bath. The reaction was stirred for 60 minutes at room temperature. The reaction mixture was concentrated in vacuo to an oil. The residue was taken up in a mixture of isopropyl alcohol and hexane, a small amount of gum removed by filtration and the filtrate evaporated in vacuo to an oil (5.0 g.). The latter was chromatographed on 150 g. of silica gel, with 100 ml. fractions of the benzene eluant collected. Fractions 10 to 19 were combined to yield the desired product (1.41 g.) contaminated with an impurity showing a mass spectral peak at 281. The latter was removed by recrystallization from methylene chloride/hexane to yield purified methyl 5-(4-methylphenylthio)pyrrole-3-carboxylate (1.14 g., m.p. 118°-121° C., m/e 247).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:19]CC2C=CC=CC=2)=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:19])=[C:8]([CH:18]=1)[O:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(OCC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1ccc(O)c(OCC(=O)OC(C)(C)C)c1
Reaction time: 1.25 h

Procedure:
To a solution of t-butyl (5-acetyl-2-benzyloxyphenoxy)-acetate (2.0 g, 5.6 mmol) in EtOH (25 mL) is added 10% Pd/C (0.10 g), and the mixture is hydrogenated at 1 atm for 1.25 hours. Filtration through celite, followed by solvent removal in vacuo yields t-butyl (5-acetyl-2-hydroxyphenoxy)-acetate.
Reaction SMILES: [C:1]([O:7][CH2:8][Cl:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br-].[Na+].C(OC([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)=O)(C)(C)C.C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C.CCOCC>[ClH:9].[NH2:19][CH2:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:29][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)C(=O)OCOC(=O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloromethyl pivalate (33.2 g; 0.22 mol) was added to a suspension of sodium bromide (22.4 g; 0,22 mol) in dimethylformamide. After 2 h a solution of trans-4-(tert.-butyloxycarbonylaminomethyl)cyclohexanecarboxylic acid in triethylamine (24 g; 0.24 mol) and dimethylformamide was added. The mixture was stirred overnight at room temperature. The solvent was distilled off and water (1 L) and dichloromethane was added. The organic layer was separated, washed, dried and evaporated to yield 55 g. This product was dissolved in ethyl acetate and cooled. A solution of hydrochloric acid in ethyl acetate was added. After 1 h ether was added. The precipitate was filtered, washed and dried to yield 30.2 g, m.p. 165° C. after crystallisation from acetone.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH:7](S(C2C=CC=CC=2)(=O)=O)[C:6]2[CH:18]=[C:19]([C:22](=[O:24])[CH3:23])[CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].CO.O1CCCC1>[Na].[Hg].O>[CH2:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:18]=[C:19]([CH:22]([OH:24])[CH3:23])[CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1
Reactant: C=C1COc2ccc(C(C)=O)cc2C(S(=O)(=O)c2ccccc2)C1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C1CCc2cc(C(C)O)ccc2OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
3.14 mg (6.82 mmol) of 5% sodium amalgam are added portionwise at 0° C. to 389 mg (1.14 mmol) of 1-[3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-yl]ethanone, prepared according to example 13, and 648 mg (4.55 mmol) of sodium hydrogenphosphate in suspension in 50 ml of a 1/1 methanol/tetrahydrofuran binary mixture. The reaction medium is subsequently stirred at ambient temperature for 4 hours. After addition of water and of dichloromethane and filtering off the mercury, the phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a slightly acidic aqueous solution and then with brine. Purification on silica gel (ethyl acetate/heptane 30/70) makes it possible to obtain 188 mg of 1-(3-methylene-2,3,4,5-tetrahydro-1-benzoxepin-7-yl)ethanol as a mixture with its pinacol dimer.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH:79]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]1)([CH3:81])[CH3:80]>C(Cl)Cl>[CH:79]([N:82]1[CH2:87][CH2:86][N:85]([C:38]([C:10]2[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)[NH:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:42])[F:1])=[CH:4][CH:5]=2)=[O:39])[CH2:84][CH2:83]1)([CH3:81])[CH3:80]
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid from step (e) above (200. mg, 0.325 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (216 mg, 0.488 mmol, Aldrich), DIEA (0.17 mL, 0.98 mmol, Aldrich), and 1-isopropylpiperazine (62 mg, 0.49 mmol, Aldrich) in DCM (2 mL) was stirred at RT for 70 h. The solvents were removed and the residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound, which was used in the next step. MS (ESI, positive ion) m/z: 726 (M+1).
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41](O)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N.O>[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41]([O:9][C@H:8]4[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]4)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (0.484 g, 1.16 mmol) and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.300 g, 1.07 mmol) were slurried in CH3CN (5.0 mL). To this mixture was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.259 mL, 1.28 mmol) dropwise. The dark solution was warmed to 40° C. and stirred overnight. The mixture was cooled to ambient temperature and diluted with water (10 mL) and stirred for 15 minutes, then filtered. The solid was washed with water and hexanes and dried in vacuo. The product was purified via column chromatography (10 to 50% Acetone/CH2Cl2) to provide the product as off-white solid. MS ESI (+) m/z 496.0 (M+1) detected.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.BrC1C(=O)NC2C=CC=CC=2CC1.C1(=O)C2C(=CC=CC=2)CCC1.[N-:38]=[N+:39]=[N-].[Na+]>>[N:1]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: NC1CCc2ccccc2NC1=O
Agent: O=C1CCCc2ccccc21
Agent: O=C1Nc2ccccc2CCC1Br
Agent: [Na+]
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O

Procedure:
In U.S. Pat. No. 4,873,235, W. H. Parsons et al. describes the synthesis of 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one by reacting 3-bromo-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, which is synthesized by bromination of 1-tetralone, followed by reaction with sodium azide to form 3-azido-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. Subsequent hydrogenation of the azido group e.g. by reaction with sodium cyanoborohydride or in the presence of hydrogen on a suitable catalyst leads to 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one.