Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C([O-])(=O)C.[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CNc1ccc(Nc2ccc(OC(F)(F)F)cc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 132 °C

Procedure:
12.64 parts of 1-methylamino-4bromo-anthraquinone, 9.9 parts of para-trifluoromethoxyaniline, 6 parts of potassium acetate and 2 parts of copper acetate are introduced into 43 parts of 4-methyl-2-pertanol and the mixture is heated at 132° C. for 8 hours. The mixture is then cooled to 60° C., filtered, washed with water, then the precipitate is taken up in dilute caustic soda, filtered, washed and dried. 9.6 parts of 1-methylamino-4-(p-trifluoromethoxy-anilino)-anthraquinone are obtained.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-])=O.[ClH:11].[H][H]>[Pt].C(O)C>[ClH:11].[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: [H][H]
Reactant: O=C1CCCCC1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: NC1CCCCC1=O
Reaction time: 3 h
Yield: 40 %

Procedure:
Add 2-nitrocyclohexanone (7.0 g, 48.9 mmol), 5% platinum sulfided on carbon (500 mg), ethanol (120 mL) and concentrated hydrochloric acid (6 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen and stir the mixture for 3 h. Filter the mixture through Celite® and wash with ethanol followed by DCM under a nitrogen atmosphere. Concentrate the filtrate in vacuo. Slurry the residue in acetone (50 mL) and filter. Collect the solid to obtain the desired intermediate (2.2 g, 40%).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:19])[C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:9][CH:8]=1.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.CC(O)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CCCCCC.C1COCC1.O>[Cl:20][C:21]1[N:26]=[C:25]([C:17]2[S:18][C:14]([N:13]([C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=3)[CH3:19])=[CH:15][N:16]=2)[C:24]([F:27])=[CH:23][N:22]=1
Reactant: CN(c1ccc(F)cc1)c1cncs1
Reactant: Fc1cnc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccc(F)cc1)c1cnc(-c2nc(Cl)ncc2F)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2.1 mL (5.3 mmol) of a 2.5 M solution of nBuLi in hexane was added to a stirred solution of 1.0 g (4.8 mmol) of N-(4-fluorophenyl)-N-methylthiazol-5-amine in 30 mL of THF at −78° C. The solution was stirred for 30 min at −78° C. before 0.61 mL (5.3 mmol) of 2-chloro-5-fluoropyrimidine was added. The reaction solution was stirred for 1 h at −78° C., then quenched by addition of 0.83 mL (14 mmol) of AcOH. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.1 g, 4.8 mmol) in 5 mL of THF was added and the reaction solution was warmed to 0° C. and stirred for 10 min then poured into 600 mL of water and the solid product was collected by filtration, washed with water and dried in vacuo. MS (M+H)+ 339.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2c(C)ccc(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 4,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1ccn1nccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 6, 0.140 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) in pyridine (4 mL) and DCM (3 mL) was stirred at room temperature overnight. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60%. The resultant glass was triturated with ether to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.103 g) as an off-white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[CH:21]([CH3:23])[CH3:22])[C:14]([O:16]C)=O.O.Cl>CCOCC>[CH3:25][O:24][C:19]1[CH:18]=[C:13]([C:14]([OH:16])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:20]=1[CH:21]([CH3:23])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(O)(Cc2ccccc2)Cc2ccccc2)cc(OC)c1C(C)C
Temperature: 25 °C
Yield: 79 %

Procedure:
To Mg (0.252 g, 10.4 mmol) in dry ether (5 mL) was added benzylbromide (1 mL, 8.41 mL) in dry ether (3 mL) dropwise under reflux. After the addition was complete, the reaction mixture was further refluxed for 1 h. Methyl 3,5-dimethoxy-4-i-propylbenzoate (1.00 g, 4.20 mmol) in ether (15 mL) was added. After the ester completely disappeared, the reaction mixture was cooled to room temperature. Water (10 mL) was added followed by addition of 2N HCl (10 mL) to dissolve precipitate. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was dried over anhydrous Na2SO4. Evaporation of solvent followed by flash chromatography using ethyl acetate:hexane (1:9) afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1,3-diphenylpropan-2-ol (1.29 g, 79%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.28 (d, J=7.2 Hz, 6H), 3.08 (d, J=13.3 Hz, 2H), 3.35 (d, J=13.3 Hz, 2H), 3.6 (m, 1H), 3.95 (s, 6H), 6.44 (s, 2H), 6.9-7.5 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][CH2:12]O)[C:7]=2[CH:14]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:12][CH2:11][N:8]1[C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1
Reactant: COc1ccc2ncn(CCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2ncn(CCBr)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(6-methoxy-1H-benzo[d]imidazol-1-yl)ethanol (200 mg, 1.04 mmol) in DCM (6.0 mL), CBr4 (397 mg, 1.20 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (314 mg, 1.20 mmol) was added. After stirring at rt for 2 h the solvent was removed under reduced pressure to yield the title compound as a brown oil, which was used us such in the next step. LC-MS conditions B: tR=0.42 min, [M(79Br)+H]+=255.08.
Reaction SMILES: C([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH3:8])C.[OH-].[Li+].C(OCC)(=O)C>O1CCOCC1.O>[C:14]([O:13][C:11]([NH:10][C:7]([CH3:9])([CH3:8])/[CH:6]=[CH:5]/[C:4]([OH:18])=[O:3])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
(2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid ethyl ester (5.0 g, 19.4 mmol) was dissolved in dioxane (50 ml). A solution of lithium hydroxide (0.61 g, 25.3 mmol) in water (25 ml) was added. The solution was stirred for 16 h at 20° C. Ethyl acetate (75 ml) and water (20 ml) were added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were extracted with 1N sodium hydroxide solution (30 ml). The combined aqueous phases were acidified with 1N sodium hydrogensulfate solution until pH=2. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (magnesium sulfate) and the solvent removed in vacuo. The crude (2E)-4-tert-butoxycarbonylamino-4-methylpent-2-enoic acid was used for further syntheses.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH2:8][CH2:7]2)([O-])=O.C([O-])=O.[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH2:8][CH2:7]2
Reactant: CCOC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)CCc2cc(N)ccc21
Yield: 31 %

Procedure:
To a suspension of 1 ethyl 2-(6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate in EtOH (10 mL) and H2O (5 mL) was added ammonium formate (1.5 g, 23.8 mmol) and Fe (0.3 g, 5.4 mmol). After stirring at reflux for 2 h, the black mixture was filtered, the filtrate was diluted with EtOAc and water, EtOAc layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated in vacuo to provide ethyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (0.2 g, 31%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=2)[CH2:3][CH2:2]1.CO[Na].CO.[CH2:29](I)[CH3:30]>CS(C)=O.O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH3:30])=[CH:19][N:18]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c(c1)nc(Cc1ccc(O)cn1)n2CC1CC1
Reactant: CCI
Agent: CO[Na]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-[(5-hydroxy-2-pyridinyl)methyl]-1H-benzimidazole-5-carbonitrile (120 mg, 0.394 mmol) in DMSO (1 mL) was added MeONa (25% in MeOH, 0.47 mmol). After being stirred at room temperature for 30 min, MeOH was removed in vacuo and EtI (0.47 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The solution was diluted with H2O (10 mL), extracted with EtOAc (2×20 mL), washed with H2O (2×10 mL), and lastly dried over MgSO4. The residue obtained after evaporation was purified by silica gel column chromatography to give the pure product as an oil (84 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J=3.0 Hz, 1H), 8.04 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.13 (dd, J=10.0 Hz, J=2.8 Hz, 1H), 4.47 (s, 2H), 4.15 (d, J=6.8 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14–1.08 (m, 1H), 0.60–0.54 (m, 2H), 0.36–0.30 (m, 2H). MS (ES) (M+H)+=333.
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:16][CH:15]3[N:17](CC4C=CC=CC=4)[CH2:18][CH:11]2[CH2:12][CH2:13][CH2:14]3)C=CC=CC=1>[Pd].CO.O>[ClH:1].[ClH:1].[CH:15]12[NH:17][CH2:18][CH:11]([NH:10][CH2:16]1)[CH2:12][CH2:13][CH2:14]2
Reactant: c1ccc(CN2CC3CCCC2CN3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: C1CC2CNC(C1)CN2
Yield: 184.7 %

Procedure:
A solution of 20.28 g (53.5 mmol) of 6,8-bis(phenylmethyl)-6,8-diazabicyclo[3.2.2]nonane dihydrochloride in 400 of 2:1 methanol-water was hydrogenated using 2.5 g of 20% Pd/C catalyst. The reaction mixture was filtered and evaporated to dryness. The residue was triturated with 2-propanol and filtered to give 9.84 g of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, mp 300°-310° dec (92%).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:56]2[N:57]=[C:58]([NH:61]C(OC(C)(C)C)=O)[S:59][CH:60]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43](=[O:55])[O:44][CH2:45][CH2:46][NH:47]C(=O)OC(C)(C)C)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][O:44][C:43]([NH:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:56]3[N:57]=[C:58]([NH2:61])[S:59][CH:60]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)=[O:55]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 44.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(10,10-dimethyl-3,8-dioxo-4,9-dioxa-2,7-diazaundecyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (68 mg, 69 μmol), DCM (0.7 mL) and TFA (0.32 mL, 4.15 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (19 mg, 44%). LCMS: R=0.54 min, m/z=617.3 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.67 (s, 1H), 7.10 (s, 1H), 5.60-5.52 (m, 1H), 5.01-4.84 (m, 3H), 4.43-4.37 (s, 2H), 4.35-4.27 (m, 2H), 3.33-3.25 (m, 2H), 1.36-1.13 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:24]([NH:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:3]2[C:2]([CH3:1])=[N:6][S:5][N:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCI
Reactant: Cc1nsnc1C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCNc1cccc(CON=C(c2ccccc2)c2nsnc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a stirred solution of tert-butyl {6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate (104 mg, 0.24 mmol) in dry DMF (5 mL) was added sodium hydride (60 wt.-% in mineral oil, 11 mg, 0.27 mmol). After stirring at room temperature for 15 min, 1-iodohexane (62 mg, 0.29 mmol) was added, and the mixture stirred at room temperature for 16 h. After dropwise addition of trifluoroacetic anhydride (1 mL, 13 mmol), the mixture was stirred at 50° C. for 8 h. The cooled reaction mixture was poured into sat. aq. NaHCO3 (40 mL), extracted with ethyl acetate (2×30 mL), the organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-hexyl-6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-amine as an orange oil [79 mg, yield 75%; HPLC/MS: m/z=410 (M+H); log P(HCOOH)=3.11].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(F)cc1F
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(F)c1

Procedure:
Using 2,4-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 163. 1H NMR (CDCl3) δ: 7.30-7.20 (m, 1H), 6.80-6.70 (m, 2H), 6.27 (d, 1H, J=2.2 Hz), 6.15 (d, 1H, J=2.2 Hz), 4.20 (broad s, 2H), 3.59 (ABq, 2H, JAB=15.2 Hz), 3.53-3.40 (m, 2H), 3.29-3.21 (m, 1H), 3.20-3.10 (m, 1H), 3.02-2.77 (m, 5H), 2.52 (dd, 1H, J=12.8, 9.2 Hz), 1.82-1.70 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH3:18][C:19]1[NH:17][C:15](=[O:16])[C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of 3-amino-6-(4-fluorophenyl)-pyridine-2-carboxylic acid amide (0.46 g, 2.0 mmol) in triethyl orthoacetate (10 ml) was heated under reflux for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with diethyl ether, yielded the title compound as a white solid (360 mg, yield 70%) which was characterised as follows: MS (m/z): 256 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+]>C(O)(=O)C.O>[N:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]2[C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:19][CH:20]=1)=[N+:29]=[N-:30]
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncnc(N3CCc4ccc(N=[N+]=[N-])cc43)c2cc1OC
Temperature: 22 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (104 mg, 0.323 mmol; from Example 30) in 80% acetic acid/H2O (8 mL) was added NaNO2 (35 mg, 0.35 mmol) in H2O(200 μL) at 5° C. After stirring 10 min. at 5° C. a solution of NaN3 (22mg, 0.34 mmol) in H2O(200 μL) was added and the mixture was allowed to warm to 22° C. and stirred for 1 hour. Following the removal of solvents by lyophilization the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 (2×), and brine, and the organic phase was dried over MgSO4(s), filtered and concentrated in vacuo. The residue was chromatographed on silica (2% MeOH/CHCl3) to afford 72 mg of the azide. (M.P. 184°-186° C. (dec); LC-MS: 349 (MH+); anal. RP18-HPLC RT: 4.70 min.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:35])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Yield: 80.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 4-acetoxycinnamic acid (2.0 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (2.6 g, 79%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13]Br>C(=S)=S>[Br:13][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2ccc(Cl)cc21
Solvent: S=C=S
Product: O=C1c2cc(Cl)ccc2CCC1Br

Procedure:
To a solution of 7-chloro-1-tetralone, 204.3 g, (1.1 moles), in carbon disulfide (1.08 liters) there is dropwise, with stirring, 176 g (1.1 moles) of bromine in 540 ml carbon disulfide at 0°-5° C. After stirring for an additional 30 minutes, the solvent is removed, giving a dark brown syrup, weighing 315 g. The crude product is used as is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Cl)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc2ccoc2c1
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2,3-dihydro-1-benzofuran-3-one (2.5 g, 14.83 mmol) in methanol (50 mL) was treated with NaBH4 (1.2 g, 31.58 mmol) in four equivalent portions at room temperature, until the reaction was complete, as monitored by TLC (1 h). The reaction mixture was quenched by the addition of acetone (10 mL). This mixture was then treated with HCl (3N, 20 mL). After stirring for another 1 h, the resulting solution was extracted with ethyl acetate (3×50 mL) dried over anhydrous magnesium sulfate and concentrated under vacuum to give 6-chloro-1-benzofuran as oil (2 g, crude).