Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[N:9]12[CH2:16]C[CH:12]([CH2:13][CH2:14]1)[C@@H:11](O)[CH2:10]2>ClCCl>[ClH:1].[Cl:1][C:2]([O:4][C@@H:5]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:16]1)=[O:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8.7 mL (74.8 mmol) of trichloromethyl chloroformate in 240 mL of dichloromethane, a solution of 4.75 g (37.4 mmol) of (R)-3-quinuclidol in 240 mL of dichloromethane was added dropwise at 0° C. under inert atmosphere and with continuous stirring. Then, the mixture was stirred at room temperature for 24 h, and the solvent was distilled off under reduced pressure to give 8.46 g (37.4 mmol) of a white solid corresponding to the title compound. IR (KBr, cm−1): 3380, 2650-2500, 1776.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]([F:15])([F:16])[F:2])[CH:7]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: CC(N)c1cccc(OCC(F)(F)F)c1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1cccc(OCC(F)(F)F)c1
Yield: 42 %

Procedure:
The title compound is prepared in 42% yield (102 mg, a white solid) from 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (139 mg, 0.72 mmol, Amine-16, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:59])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([C:32]3[CH:36]=[C:35]([C:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[NH:38])[S:34][C:33]=3[S:47][CH3:48])(=[O:31])=[O:30])[CH:24]=2)=[C:18]([NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])[CH:17]=1)=[O:14])C>CO.O>[C:43]([O:42][C:40]([NH:39][C:37](=[NH:38])[C:35]1[S:34][C:33]([S:47][CH3:48])=[C:32]([S:29]([C:25]2[CH:24]=[C:23]([C:19]3[C:20]([CH3:22])=[CH:21][C:16]([NH:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:59])=[O:5])=[CH:17][C:18]=3[NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])[CH:28]=[CH:27][CH:26]=2)(=[O:30])=[O:31])[CH:36]=1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCC(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)NCCCCCC(=O)O)cc2NC(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
Lithium hydroxide (53.8 μL, 0.215 mmol, 4N aqueous) was added to a solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (45.5 mg, 53.8 μmol, Example 278: step d) in MeOH/H2O (10 mL, 2:1) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The solvents were removed in vacuo to afford the title compound as a yellow solid (50 mg, quantitative). ESI-MS (m/z): Calcd. for C36H45N5O10S3: 804.2 (M+1); found: 803.9.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH3:13].[CH3:15][C:16]1([CH3:29])[C@@H:18]2[CH2:19][C:20]3[C:24]([C@H:17]12)=[C:23]([CH3:25])[S:22][C:21]=3[C:26](O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]1[N:14]=[C:26]([C:21]2[S:22][C:23]([CH3:25])=[C:24]3[C:20]=2[CH2:19][C@H:18]2[C:16]([CH3:29])([CH3:15])[C@H:17]23)[O:1][N:2]=1
Reactant: COc1ccc(C(=N)NO)c(OC)c1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.9 %

Procedure:
A mixture of N-hydroxy-2,4-dimethoxy-benzamidine (98 mg, 0.50 mmol), (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (178 mg, 0.55 mmol) and DIPEA (646 mg, 5 mmol) in DMF (4 mL) is stirred at rt for 45 min, then at 110° C. for 1 h. The reaction mixture is directly subjected to prep. HPLC purification (Phenomenex Aqua 75×30 mm, gradient with acetonitrile/water containing 0.5% formic acid) to give 3-(2,4-dimethoxy-phenyl)-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (19 mg) as a colourless lyophilisate; LC-MS: tR=1.17 min, [M+1]+=383.13; 1H NMR (CDCl3): δ 7.89 (d, J=8.8 Hz, 1H), 6.46 (dd, J=2.3, 8.8 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.96 (dd, J=5.9, 18.8 Hz, 1H), 2.80 (d, J=18.8 Hz, 1H), 2.29 (s, 3H), 1.88-1.78 (m, 2H), 1.02 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11](=[O:29])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][C:15]=1[NH2:28])([CH3:9])([CH3:8])[CH3:7]>C(O)(=O)C.CCO>[C:6]([O:10][C:11](=[O:29])[CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][C:15]=2[N:28]=[C:1]1[CH2:2][CH2:3][CH3:4])([CH3:8])([CH3:7])[CH3:9]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (0.65 mL, 9.0 mmol) and acetic acid (7 drops) were added to a solution of (2-amino-4-tert-butoxycarbonylamino-phenylamino)-acetic acid tert-butyl ester (2.2 g, 6.5 mmol) in EtOH (100 mL), and stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-title compound that was used without further purification. MS calculated for C21H31N3O4+H: 390, observed: 390.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16].Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:19]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])[C:27](=[O:28])[O:29][CH3:30]
Reactant: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-fluorobenzyl)amine from Step A (0.14 g) in methylene chloride at room temperature, excess methyl chloroformate (0.1 ml) and triethyl amine (0.1 ml) were added. The solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (1:9) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.48 (m, 1H), 6.88 (m, 2H), 4.60 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2cccc(Cl)c2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(Cl)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])=[O:19]
Reactant: [H][H]
Reactant: O=C(NNC(=O)C(F)(F)F)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)C(F)(F)F)[C@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 87.3 %

Procedure:
To a solution of (2R,5R)-6-(benzyloxy)-7-oxo-N′-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 185 (0.224 g, 0.58 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite and the filtrate was evaporated to give (2R,5R)-6-hydroxy-7-oxo-N′-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 186 (0.15 g, 88%) as a colorless foam.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:10][CH3:11]
Reactant: O=C1CCCCCN1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2CCCCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one was prepared as for Example 10 from caprolactam and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[O:14]=[C:15]1[N:20]2[CH2:21][CH:22]3[CH2:27][CH:26]([C:19]2=[CH:18][CH:17]=[CH:16]1)[CH2:25][NH:24][CH2:23]3>>[O:14]=[C:15]1[N:20]2[CH2:21][CH:22]3[CH2:27][CH:26]([C:19]2=[CH:18][CH:17]=[CH:16]1)[CH2:25][N:24]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:23]3
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: O=c1cccc2n1CC1CNCC2C1
Product: N#Cc1ccc(N2CC3CC(C2)c2cccc(=O)n2C3)c2ccccc12
Yield: 7.5 %

Procedure:
The title compound (3 mg, 8% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocine (89 mg, 0.468 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Nc2ccc(N)cc2)cc1
Yield: 85 %

Procedure:
Reduction of the nitro function of N-(4-methylphenyl)-4-nitroaniline (Indian J. Chem. (1981) 20B, 611–613) is carried out in the presence of Pd/C in ethanol, under the conditions described for intermediate 2.2. A grey solid is obtained with a yield of 85%.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[N:3]=1.[N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:17]=[O:18]>C1COCC1>[C:19]([NH:16][C:17]([N:7]1[CH2:8][CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6]1)=[O:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1c(I)nn2c1CNCC2
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CN(C(=O)NC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a stirred solution of Intermediate 104F (2.4 g, 7.47 mmol) in THF (20 mL) was added 2-isocyanato-2-methylpropane (0.741 g, 7.47 mmol) and the reaction mixture was stirred for 1.5 h. The volatiles were evaporated under reduced pressure. The crude was purified by silica gel chromatography (120 g REDISEP® column, eluting with 28% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104G (2.2 g, 70%). MS(ES): m/z=421 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (s, 1H), 4.72 (s, 2H), 4.25 (q, J=6.8 Hz, 2H), 4.10 (t, J=5.24 Hz, 2H), 3.75 (m, 2H), 1.30 (t, J=7.2 Hz, 3H) 1.28 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]1[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:7]1=[C:6]([C:27]([O:29]CC)=[O:28])[C:5]2=[O:32].[OH-].[K+].C(O)(C)(C)C.O.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]1[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:7]1=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:32]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)C(c1ccccc1)S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3C(c3ccccc3)S2)CC1
Temperature: 50 °C

Procedure:
Three grams of ethyl 6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1-phenyl-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate was suspended in 30 ml of mixed solution of 5% potassium hydroxide/tert-butanol-water (75:25) and the suspension was heated at 50° C. for 4 hours with stirring. To this was added 30 to 40 ml of water to prepare homogeneous solution. The solution was neutralized with acetic acid and extracted with chloroform to which small amount of methanol was added. The extract was dried, concentrated, and the resulting residue was recrystallized from ethanol to give desired product. Yield: 2.23 g. M.p. 216°-217° C. (decomp.).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[I:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CNCC2
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A solution of N-trifluoroacetyl-8-iodo7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.600 g, 1.45 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.425 g of a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.52 (s, 1 H), 6.57 (s, 1 H), 3.86 (s, 3 H), 3.12−3.06 (m, 4 H), 2.95 (m, 2 H), 2.75 (m, 1 H), 2.43 (bs, 1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C12H16INO+H: 318, observed: 318.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCc1ccccc1
Reaction time: 10 h
Yield: 63.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.02 ml (0.016 mol) of 2-phenylethylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. The product was crystallized in hexane/ethyl acetate. There were obtained 3.13 g (64%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-2H-benzo[e]indol-2-one as white crystals with m.p. 89°-90°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH:32][CH3:33]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:32]([CH3:33])[CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CNC
Product: CN(C)CC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and dimethylamine (0.14 g, 3.0 mmol). mp 199-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:5]([CH2:11][C:12]#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:24].[K+].[OH2:26]>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:5]([CH2:11][C:12]([OH:26])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(CCc2c(CC#N)ccc(OC)c2OC)c1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: COc1cccc(CCc2c(CC(=O)O)ccc(OC)c2OC)c1

Procedure:
A solution of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneacetonitrile (4.9 g) and potassium hydroxide (4.41 g) in ethanol (150 ml) and water (50 ml) was heated under reflux for 18 hours. The mixture was evaporated to dryness and the residue dissolved in water and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to leave the sub-title compound as an oil which solidified on trituration with petrol ether (1.72 g), mp 77°-79°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[NH2:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 16.1 %

Procedure:
2-Fluoro-4-nitrophenol (1.736 g) was dissolved in dimethyl sulfoxide (10 ml), and sodium hydride (400 mg) was added thereto, followed by stirring for 20 min. Then, 4-Amino-6-chloropyrimidine (648 mg) was added thereto and stirred at 100° C. for 45 min. The reaction mixture was heated up to 120° C. and stirred for 1 hr 25 min. The reaction mixture was then heated up to 140° C. and stirred overnight. The reaction mixture was allowed to cool down to room temperature, a 1N aqueous solution of sodium hydroxide (10 ml) was added thereto and stirred, then extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). The solvent was concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (7 ml)-hexane (3.5 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as pale brown powder (201 mg, 16.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)[C:23]=3[CH2:22][C:9]2=1
Reactant: CO/N=C/c1ccc2c(c1CN1CCCC1)OCO2
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1CN1CCCC1)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
The amine 8 (1.90 g, 7.45 mmol) and oxime ether 13b (0.90 g, 3.44 mmol) were mixed with concentrated hydrochloric acid (15 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3), and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was dissolved in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=3:97:2) to yield the final pure product 14b as a light yellow solid (84.9 mg, 6.1%): mp 210° C. (dec). IR (KBr) 2958, 1449, 1406, 1326, 1246 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.01 (s, 1H), 6.04 (s, 2H), 4.07 (s, 3H), 4.02 (s, 3H), 3.85 (s, 2H), 3.79 (s, 2H), 2.67 (broad s, 4H), 1.82 (broad s, 4H); low resolution ESIMS m/z (rel intensity) 405 (MH+, 15), 334 (100). Anal. (C24H24N2O4.1.75H2O) C, H, N.