Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:47])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH2:20][CH:19]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:4].[OH-].[K+]>CO.O>[C:43]([O:42][C:40]([CH:19]1[CH2:20][CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:47])[NH:12][C:8]1[CH:7]=[C:6]([CH2:5][C:3]([OH:4])=[O:2])[CH:11]=[CH:10][CH:9]=1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(S(=O)(=O)c3ccc(Cl)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccc(Cl)cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Temperature: 20 °C
Yield: 38.8 %

Procedure:
A To a solution of 2.5 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-methoxycarbonylmethylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(4-chlorophenyl)sulphonyl-2-pyrrolidinecarboxylate in 60 cm3 of methanol and 30 cm3 of distilled water is added, at a temperature in the region of 20° C., 0.2 g of potassium hydroxide. The reaction mixture is stirred for twenty hours at a temperature in the region of 20° C., and then concentrated under reduced pressure. The residue is taken up in 100 cm3 of distilled water, washed with three times 75 cm3 of diethyl ether, acidified to a pH in the region of 1 by aqueous normal hydrochloric acid and extracted with three times 75 cm3 of ethyl acetate. The extracts are combined, washed with three times 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on 80 g of silica contained in a column 3.2 cm in diameter [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 0.95 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-(4-chlorophenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)phenylacetic acid is thus obtained [Rf=0.5; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (250 MHz, (CH3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.54 (s, 9H: C(CH3)3); from 2.40 to 2.60 and 2.85 (2 mts, 1H each: CH2 at 3); 3.50 (s, 2H: ArCH2COO); 3.70 and 3.97 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.09 (mt, 1H: H4); 4.68 (t, J=8 Hz, 1H: H2); 5.73 (d, J=3 Hz, 1H: H5); 6.86 (broad d, J=7.5 Hz, 1H: aromatic H (H4: ortho to the CH2)); from 7.00 to 7.40 (mt, 6H: aromatic H); 7.68 (broad d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the Cl)); 7.82 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 7.96 (broad d, J=8.5 Hz, 2H: aromatic H at 4 (H meta to the Cl))].
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3cccc(C(F)(F)F)c3)c(=O)c2=O)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 3-trifluoromethylphenethyl-amine (0.23 g, 1.22 mmol) in ethanol (3 mL) were converted to the title compound (0.155 g, 68%) m.p.: 220.2-222.3° C.; 1H NMR (DMSO-d6) δ 9.05(br t,1H), 7.95(ABq,2H), 7.60-7.45(m,4H), 7.08(ABq,2H), 3.94(br t,2H), 3.83(s,3H), 3.04(t,3H); IR (KBr) 3210, 3170, 1775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840, 800, 695 cm−1; MS (m/z) 375 [M+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10][C:11]=1[NH2:12])=[O:5])[CH3:2].N1C=CC=CC=1.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:10][C:11]=1[NH:12][C:26]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Ethyl-4-amino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (23.6 g) was dissolved in methylene chloride (460 ml), and pyridine (13 ml) and phenyl chlorocarbonate (15 ml) were added under ice cooling and the resultant mixture was stirred for one hour at the same temperature. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed sequentially with 1 N hydrochloric acid and saturated saline solution in this order, the organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure. To the resultant residue, diethyl ether was added to obtain a precipitate by filtration. The titled compound (10.57 g) was obtained as a colorless solid substance. Furthermore, the filtrate was concentrated under reduced pressure. Thereafter, the resultant residue was purified by medium-pressure silica gel column (solvent; ethyl acetate:hexane=10:90 to 50:50). The resultant crude crystal was washed with a solvent mixture of diethyl ether-hexane to obtain the titled compound (11.10 g) as a slightly yellow solid substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCc1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccc(Cl)cc1
Product: Nc1ccccc1
Yield: 71 %

Procedure:
The crude reaction mixture of 4-bromo-5-[2-(4-chloro-benzyloxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (as described below) was treated with SnCl2.2H2O (0.378 g, 1.64 mmol, 4.0 equiv.) in EtOH (5 mL), in a similar manner as described in Example 1.1, providing-aniline 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.114 g, 0.29 mmol, 71% for two steps). LCMS m/z (%)=392 (M+H79Br35Cl, 70), 394 (M+H81Br35Cl, 100), 396 (M+H81Br37Cl, 23), 1H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.11 (d, J=8.2 Hz, 2H), 6.90 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.7, 8.7 Hz, 1H), 6.63 (d, J=2.7 Hz, 1H), 4.86 (AB quartet, J=12.1, 20.9 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.[CH3:34][O:35][C:36]1[CH:61]=[CH:60][C:39]([CH2:40][N:41]2[C:45]3=[N:46][CH:47]=[CH:48][C:49]([O:50][C:51]4[CH:56]=[CH:55][C:54](N)=[CH:53][C:52]=4[CH3:58])=[C:44]3[C:43]([CH3:59])=[N:42]2)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:54]2[CH:55]=[CH:56][C:51]([O:50][C:49]3[CH:48]=[CH:47][N:46]=[C:45]4[N:41]([CH2:40][C:39]5[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:61][CH:60]=5)[N:42]=[C:43]([CH3:59])[C:44]=34)=[C:52]([CH3:58])[CH:53]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4C)ccnc32)cc1
Reactant: Nc1ccc(F)cc1
Agent: O=C(O)C1(C(=O)O)CC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4C)ccnc32)cc1
Yield: 11 %

Procedure:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.2187 g, 0.6076 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) and 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-methylbenzenamine (0.091 g, 0.2430 mmol) according to the procedure of Example 13, Step C. The crude product was purified by preparative TLC (0.5 mm) eluting with EtOAc. The product (18 mg, 11%) was obtained as an orange solid. LRMS (esi pos) m/e 579 (M+1).
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].FC(F)(F)C(O)=O.[N-:15]=[N+:16]=[N-:17].[Na+].Cl>N1C=CC=CC=1>[NH:15]1[C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:2][N:17]=[N:16]1
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1nnn[nH]1
Temperature: 60 °C

Procedure:
To a stirred, room temperature solution of ethyl cyanoformate (19.57 g, 0.1975 mol) in pyridine (78 mL) was added a chilled (+5° C.) mixture of trifluoroacetic acid (33 mL) and pyridine (118 mL) followed by sodium azide (14.06 g, 0.2163 mol), and the mixture was heated at 60° C. for 46 hours. The mixture was allowed to cool, poured into a mixture of concentrated hydrochloric acid (180 mL) and ice (400 g), and extracted with ethyl acetate several times. The extracts were washed with saturated sodium chloride, dried (MgSO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel (500 g, 70-230 mesh) using ethyl acetatemethanol (15:1, 10×1 L) as eluent. Fractions containing product were rotoevaporated to an oil. The oil was dissolved in chloroform, filtered to remove a precipitate, and the filtrate extracted with aqueous sodium hydroxide. The extracts were acidified to pH 1 and extracted with ethyl acetate. The extracts were dried (MgSO4) and rotoevaporated to a white solid, yield 1.91 g (7%) of the title compound, mp=87.5°-91.5° C.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1[S:37][C:36]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:48]=O)[CH:46]=3)[C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=2)=[CH:35][CH:34]=1>C1COCC1.CCOCC>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:48]\[C:45]1[CH:46]=[C:47]2[C:42]([C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=[C:38]2[C:36]2[S:37][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6M solution in hexane, 2.5 mL, 4 mmol). The mixture was stirred for 20 minutes at -78° C. and 10 min. at -10° C. The reaction mixture was recooled to -78° C. and 1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The mixture was stirred for 2 hours at -10° C. and diluted with ether (100 mL), washed with brine (10 mL) dried with MgSO4 and the solvent was removed by distillation to to afford a cis and trans (E and Z) isomeric mixture. Purification by chromatography on silica gel of the crude material afforded the title compound as an off (~ 90% purity).
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].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>>[O:38]1[C:42]2([CH2:47][CH2:46][N:45]([C:21]3[N:20]=[C:19]([O:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:29]=[C:30]([N:32]6[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]6)[CH:31]=[C:2]([F:1])[CH:3]=5)=[CH:9][CH:10]=4)[CH:24]=[CH:23][N:22]=3)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C1CC2(CCN1)OCCO2
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC4(CC3)OCCO4)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 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure C. Mp: 195-196° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.46-1.59 (s, 10 H), 3.27-3.31 (m, 4 H), 3.56 (s, 4 H), 3.84 (s, 4 H), 6.20-6.22 (m, 1 H), 6.95 (d, J=12.8, 1 H), 7.15 (d, J=9.1 Hz, 1 H), 7.40-7.42 (m, 1 H), 7.45 (s, 1 H), 7.55-7.60 (m, 3 H), 7.83 (d, J=7.7 Hz, 1 H), 7.97 (d, J=8.0 Hz, 1H), 8.25-8.27 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([O-:26])=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+].[CH2:34](O)[CH3:35]>>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([O:26][CH2:34][CH3:35])=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C([O-])c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Temperature: 25 °C
Reaction time: 3.8 h

Procedure:
A mixture of ethyl (4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate (0.800 g) and 2.14 g of stannous chloride dihydrate in 36 ml of ethanol is refluxed for 1 hour, cooled to room temperature and diluted with ice water. The mixture is made basic with 10% sodium bicarbonate and stirred 3.8 hours. The mixture is extracted with chloroform and the extracts combined, treated with activated carbon and filtered through anhydrous magnesium sulfate. The filtrate is concentrated under vacuum to give 0.690 g of ethyl 4,5-dihydro-6-(4-aminobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate as a tan foam: mass spectrum (CI) 393 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:13]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[NH2:13][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[CH2:3][CH2:2][OH:1]
Reactant: COc1ccccc1C(CCO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccccc1C(N)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 172A, 100 mg (0.36 mmol) were dissolved in 2 ml of dichloromethane, and 1.63 ml (6.52 mmol) of a 4M solution of hydrogen chloride in dioxane were added. The yellow solution was subsequently stirred at RT for 1 h. The reaction mixture was evaporated to dryness on a rotary evaporator and dried in an HV. This gave 88 mg (100% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:21](#[N:24])[CH:22]=[CH2:23].[ClH:25]>CCOCC>[ClH:25].[C:21]([CH2:22][CH2:23][N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)#[N:24]
Reactant: C=CC#N
Reactant: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Product: N#CCCN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.82 g of trans-4-(4-fluorophenoxy)-3-phenylpiperidine and 5 ml of acrylonitrile is stirred for two hours at room temperature under nitrogen. The mixture is diluted with ether (50 ml) and treated dropwise with 20 ml of saturated ethereal hydrogen chloride solution. After stirring for a few minutes the solid is filtered, washed with ether and dried to afford a colorless solid. Recrystallization from isopropanol (80 ml) gives of product as colorless crystals, mp 212°-214°0 C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH:2]2[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([Cl:24])=[O:23])#[N:18]>>[ClH:24].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH:2]2[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:17]#[N:18])[CH:20]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(C2CNC3CCN2CC3)cc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: Cl
Product: N#Cc1cccc(C(=O)Nc2ccc(C3CNC4CCN3CC4)cc2)c1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non yl)-phenylamine and 3-cyanobenzoyl chloride. Mp. 250° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[CH2:12][C:13](=[O:19])[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH:20](OCC)=[O:21].[O-]CC.[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:11]3[CH2:18][CH2:17][CH2:16][CH:15]2[C:14](=[CH:20][OH:21])[C:13](=[O:19])[CH2:12]3)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Temperature: 60 °C

Procedure:
To a stirring mixture of 9-(5-chloro-thiophene-2-sulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (160 mg, 0.50 mmol) in THF/ethanol (3 mL, 1/1, v/v) was added ethyl formate (500 mg, 6.76 mmol) followed by sodium ethoxide (0.56 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=1.985 min, Method [1], MS (ESI) 348.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=1)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18]>>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=3)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18])[CH:3]=[CH:4][C:5]=12
Reactant: O=C(NCCF)c1cncc(Br)c1
Reactant: Brc1ccc2nonc2c1
Product: O=C(NCCF)c1cncc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-bromo-benzo[1,2,5]oxadiazole and 5-bromo-N-(2-fluoro-ethyl)-nicotinamide. Beige powder. MS(ES−): 285 (M−1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:12][CH:13]=O.Cl[CH2:16][CH2:17]Cl.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:41]=[CH:40][C:27]2[N:28]([CH2:38][CH3:39])[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=2[CH:25]=1.[Na]>C(OCC)(=O)C.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH2:17][N:19]([CH2:13][CH2:12][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:41]=[CH:40][C:27]2[N:28]([CH2:38][CH3:39])[C:29](=[O:37])[C:30]([CH3:35])([CH3:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=2[CH:25]=1
Reactant: O=CCn1ccc2ccccc2c1=O
Reactant: ClCCCl
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCn3ccc4ccccc4c3=O)CCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Oxo-1H-isoquinolin-2-yl)acetaldehyde (207 mg, 1.1 mmol) was added to a 1,2-dichloroethane solution (4 ml) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (329 mg, 1.0 mmol) and sodium triacetoxyhydroborate (381 mg, 1.8 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The purified product was concentrated under reduced pressure to thereby obtain 7-(3-{bis-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:19](=[N:25]/O)/[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:19]\[C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: O/N=C\c1ccco1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 15 h
Yield: 40.5 %

Procedure:
In 450 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 131 g (0.5 mol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 66.5 g (0.6 mol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 15 hours. The solvent was evaporated under reduced pressure, and the residual oily material was poured into 3 l of ice-cooled water, and crystals precipitated were collected by filtration. The crystals were washed with water (500 ml×2), dried under reduced pressure and recrystallized from ethanol and then from ethyl acetate-hexane (7:3) to yield 63.5 g of ethyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5carboxylate. m.p. 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:48][CH2:47][CH2:46][N:45]([CH2:49][CH3:50])[CH2:43][CH3:44])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (52 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 41%).