Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.CC1C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.[C:24]([O:35][CH3:36])(=[O:34])/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:36][O:35][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:21][NH:22][CH:23]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/CCCC(=O)OC
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCc1c[nH]cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
To a 1 M solution of LiN(TMS)2 in THF (5.9 mL, 5.9 mmol) cooled at −78° C. under argon was added a solution of TOSMIC (1.15 g, 5.9 mmol) in THF (15 mL) dropwise. After 40 min at −78° C. a solution of dimethyl (2E)-hept-2-enedioate (1.1 g, 5.9 mmol) in THF (15 mL) at −78° C. was added slowly. The solution was stirred for 10 min, then the cold bath was removed and the reaction was allowed to warm at room temperature. THF was evaporated and the residue partioned between H2O (200 mL) and DCM (200 mL). Aqueous layer was extracted with DCM and the combined organic layers anidrified on Na2SO4, filtered and concentrated to give a residue which was chromatographed on silica gel (eluant: AcOEt/hexane 3/7) to afford 633 mg (yield: 40%) of the title compound as white solid.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1.[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C1=COCCC1
Reactant: C#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC2CCCCO2)cc1
Reaction time: 15 h

Procedure:
Poly(p-hydroxystyrene) (weight average molecular weight: 9,600) in an amount of 9 g was dissolved in 100 ml of dimethoxyethane, and thereto 12.6 g of 3,4-dihydro-2H-pyran and 0.5 ml of sulfuric acid were added. This solution was stirred for 15 hours at 30°-40° C. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue obtained was neutralized with sodium carbonate, and then poured into water to precipitate crystals. The crystals were filtered off, washed with water and dried under reduced pressure. Thus, 11.0 g of poly(p-tetrahydropyranyloxystyrene-p-hydroxystyrene) was obtained as white powder. The ratio of the p-tetrahydropyranyloxystyrene units to the p-hydroxystyrene units in the polymer obtained was determined to be 3:7 by 1H-NMR analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]3[CH:43]=[CH:44][CH:45]=[N:46][C:39]=3[N:38]=[C:37]2[C@H:47]([NH:49][CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[CH3:48])=[CH:32][CH:31]=1)[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]3[CH:43]=[CH:44][CH:45]=[N:46][C:39]=3[N:38]=[C:37]2[C@H:47]([N:49]([CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)[CH3:48])=[CH:32][CH:31]=1)[CH3:28]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOc1ccc(-n2c([C@@H](C)NCCC(C)=O)nc3ncccc3c2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)=O)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
4-fluoro-3-trifluoromethylphenylacetic acid (707 mg, 3.18 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (278 μL, 3.18 mmol) was added, then after 5 min, dimethylformamide (24.7 μL, 0.32 mmol) was added. The reaction stirred at 0° C. for 30 min and room temperature for 1 h. The solution was added slowly to a mixture of E2 (713 mg, 1.87 mmol) and triethylamine (784 μL, 5.62 mmol) in dichloromethane at −78° C. The reaction stirred for 30 min, then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, concentrated in vacuo. Purified by column (2% to 10% methanol in dichloromethane), to yield 859 mg of E3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:27]([O:31][CH2:32]Cl)([CH2:29][CH3:30])[CH3:28]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:32][O:31][CH:27]([CH2:29][CH3:30])[CH3:28])[C:19](=[O:24])[N:18]([CH2:25][CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(C)OCCl
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)OCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC)c1=O
Reaction time: 1 h

Procedure:
2.45 g (18.0 mmol) of potassium carbonate were added at 60° C. to a suspension of 3.0 g (11.0 mmol) of 7-benzyl-3-ethylxanthine (prepared according to Example 5a) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.77 g (14.0 mmol) of sec-butoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 5 hours. 0.7 g (5.5 mmol) of sec-butoxymethyl chloride was then added again and the mixture was stirred for a further 3 hours. 12 ml of water and 5 ml of methanol were then added and the mixture was stirred at 50° C. for 2 hours. A further 60 ml of water were then added, the mixture was extracted three times using 200 ml of methyl tert-butyl ether each time, and the combined organic phases were washed with 200 ml of water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12.O>C(Cl)Cl>[N+:12]1([O-:9])[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)N1Cc2cccnc2C1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
mCPBA (7.3 g, 30 mmol) was added into a solution of ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (5 g, 26 mmol) in CH2Cl2 (200 mL) and stirred for 2 hours. The reaction was poured into water and extracted with CH2Cl2. The organic layer was washed with aqueous sodium bisulfate, NaHCO3 and brine, dried with Na2SO4, filtered and concentrated to afford the title compound (4 g, 74% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH2:30])[CH3:29].C(N(CC)CC)C>C(O)C>[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH:30][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14])[CH3:29]
Reactant: C[C@@H](N)Cc1sccc1Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H](C)Cc3sccc3Cl)ncnc21

Procedure:
A solution of 6-chloro-9-(2′-O-methyl-b-D-ribofuranosyl)-9H-purine (prepared as in EP Publication No. 0378518) (0.28 g), 2-(3-chloro-2-thienyl)-(1R)-1-methylethylamine (0.163 g), and triethylamine (0.5 mL) in ethanol (30 mL) is refluxed for about 18 hours, cooled and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% methanol in methylene chloride, followed by crystallization from hexanelethyl acetate, to give the desired product, m.p. 75-76° C.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Cl:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:21]=[CH:20][N:19]=[CH:18]1>C(O)C>[ClH:16].[Cl:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: NCCCCn1ccnc1
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Solvent: CCO
Product: Cl
Product: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1CCCCn1ccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3.49 g of 4-chloro-1,8-naphthalic anhydride, 50 ml of ethanol and 2.1 g of 1H-imidazol-1butanamine as stirred at room temperature for 5 hours and concentrated. The residue was washed on to a funnel with a little ethanol, washed with ether and dried in vacuo. The solid material, 3.72 g, was mixed with 15 ml of acetic anhydride and 5 ml of acetic acid and heated at 110°-120° C. in an oil bath for 6 hours. The reaction mixture was concentrated and shaken with 20 ml of 1N sodium hydroxide and 150 ml of methylene chloride and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain the desired product, mp 138°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 88-89° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.39 (m, 6 H), 1.58-1.61 (m, 6 H), 1.99-2.27 (m, 6H), 2.90-3.24 (m, 2 H), 3.23-3.29 (m, 4 H), 6.20-6.31 (bd, 1 H), 6.90-6.98 (m, 2 H), 7.15 (d, J =8.8 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.50-7.62 (m, 3 H), 7.78-7.80 (m, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 8.20 (s 1 H), 10.40 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12
Reactant: CON(C)S(=O)(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CON(C)S(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg, 2.05 mmol) and K2CO3 (756 mg, 5.48 mmol) were heated to 190° C. in diphenyl ether (55 ml) for 3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated and purified by column chromatography (eluent EtOAc:hexane, 1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0 (M+H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), ethyl bromoacetate (75 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 49%).
Reaction SMILES: [NH2:1][C:2]1([C:15]#[N:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=N)SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1>CC(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([NH:1]/[C:36](=[N:35]\[C:33]([C:26]3[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=3)=[O:34])/[NH:16][CH2:15]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: N#CC1(N)CCN(Cc2ccccc2)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2/NCC3(CCN(Cc4ccccc4)CC3)N2)nc1Cl
Temperature: 70 °C

Procedure:
4-Amino-1-benzyl-piperidine-4-carbonitrile (Intermediate G) (200 mg, 0.91 mmol) in dry propan-2-ol (10 ml) is treated with triethylamine (0.25 ml) followed by 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (355 mg, 0.91 mmol). The mixture is heated at 70° C. for 5 hours and then allowed to cool to room temperature. The precipitate is collected and washed with methanol to afford the title compound as a light yellow solid, 190 mg; [M+H]+ 415
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:32]2[CH2:33][CH2:34][CH:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[N:21]=4)[CH2:23][CH2:24]3)[CH2:30][CH2:31]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1nccc(N2CCN(CC3CCNCC3)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCN(CC3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
A solution of 4-chlorophenylsulphonyl chloride (1.78 g) in methylene chloride (10 ml) was added dropwise over 15 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)piperazine-4-ylmethyl]piperidine trihydrochloride (2.78 g) and triethylamine (6.72 ml) in dichloromethane (40 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4ylmethyl]piperidine (2.50 g), mp 191-193° C. (decomp.).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][CH3:33].C(OCC)(=O)C.CCCCCC>CC(C)=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4O)c3c2CC1
Reactant: CCCI
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)c1ccccc1)CC3

Procedure:
A slurry of 2-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenol (357 mg, 0.93 mmol), CS2CO3 (1.24 g, 3.82 mmol) and 1-iodopropane (195 mg, 1.15 mmol) in acetone (10 mL) was stirred at room temperature under nitrogen for 15 hours. The reaction was filtered and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow oil which was passed through a column of silica gel with 50% ethyl acetate/hexane to give 276 mg (70%) of a white foam as the title compound: MS m/z 425.3 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32]>>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:33][C:31](=[O:32])[N:14]([C@@H:13]1[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OCC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2,2-dimethyl-propyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using neopentyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a yellow foam. MS m/e: 552.3 [M]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[N:7][CH:8]=1.[Cl:20][C:21]1[C:26]([C:27]([N:29]=[C:30]=[O:31])=O)=[C:25]([F:32])[C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([F:32])[C:26]=1[C:27]1[NH:29][C:30](=[O:31])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cn3)c(=O)[nH]2)c1F
Yield: 14.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate (Intermediate-60, 0.050 g, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.120 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.012 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 4.30 (d, J=5.6 Hz, 2H), 7.11 (br s, 1H), 7.46 (1, J=8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.14 (m, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.35 (dd, J=7.2 Hz, 1H), 8.87 (s, 1H); MS (m/z): 472.24 (M+H+).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH2:25][C:24]=23)=[CH:16][CH:15]=1.[CH:33]([N:36]([CH:39]([CH3:41])C)CC)([CH3:35])C.N1CCCC1>C(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([C:5]([N:36]4[CH2:33][CH2:35][CH2:41][CH2:39]4)=[O:11])[CH2:25][C:24]=23)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2ncn3c2CNc2ccccc2-3)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(N1CCCC1)N1Cc2c(-c3ccc(F)cc3)ncn2-c2ccccc21
Reaction time: 16 h

Procedure:
Triphosgene (427 mg) is added to a mixture of 3-(4-fluorophenyl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXVI, EXAMPLE 247, 702 mg), methylene chloride (27.0 ml) and diisopropylethylamine (0.53 ml) at 0°. The resultant solution is stirred for 1 hr at 0° and for 2 hr at 20°-25°. The mixture is cooled to 0° and pyrrolidine (0.85 ml) is added. The mixture is maintained at 0° for 1 hr and is allowed to warm to 20°-25°. After stirring for 16 hr, basic workup using sodium bicarbonate, methylene chloride and magnesium sulfate and purification by flash chromatography eluting with ethyl acetate/hexane (1/1), pooling the appropriate fractions and concentration gives the product. Recrystallization from hot ethyl acetate-hexane give the title compound, mp 217°-218°; IR (mineral oil) 2925, 1641, 1506, 1414 and 753 cm-1 ; NMR (CDCl3) 8.07, 7.64, 7.53, 7.05-7.3, 4.89, 3.25 and 1.7-1.85 δ; MS (m/z) 362, 264, 98 and 55.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6](=[N:33][OH:34])[C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 12 (0.01 mmol, 1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyridine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H22FNO5 [M+H]+: 448.2, [M−H]−: 446.2.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(N(CC)CC)C>ClCCl>[C:21]([CH2:23][C:24]([NH:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:10])=[O:6])[CH3:4])=[O:25])#[N:22]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reactant: N#CCC(=O)O
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC#N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
1.7 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 50 ml of dichloromethane at 0° C. 0.42 g (0.005 mol) of cyanoacetic acid, 0.7 ml (0.005 mol) of triethylamine and 1.1 g of N,N-dicyclohexylcarbodiimide were added and the mixture was stirred at 0° C. overnight. The solvent was removed by evaporation, the residue suspended in 50 ml of ethyl acetate, the suspension filtered and the filtrate washed with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated to give a white solid. Recrystallisation of this solid from ethyl acetate yielded 0.6 g (37%) of N-cyanoacetyl-L-alanyl-L-proline anilide of melting point 183°-184° C.; [α]D20 =-204.6° (c=0.78% in methanol).