Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.CON(C)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)C(C)C
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(=O)Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: -40 °C

Procedure:
Following the procedure described by R. D. Clark et al. in Synthesis, 871 (1991), (4-chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (2.18 g, 9 mmole) was dissolved in anhydrous THF (30 ml) and cooled to −40° C. and s-BuLi (14.56 ml 1.3N in cyclohexane) was added slowly at such a rate to maintain the temperature below −25° C. The bright yellow solution was cooled to −50° C. and a solution of N-methoxy-N-methyl-isobutyramide (1.24 g, 9.5 mmole) in THF (5 ml) was added. The mixture was allowed to warm up to −10° C. over a 20 m period during which time the solution turned nearly colorless. Ether (50 ml) was added and the solution was poured into 1% aqueous HCl (50 ml). The aqueous layer was extracted a second time with ether (30 ml) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1) to afford pure [4-chloro-2-(3-methyl-2-oxo-butyl)-phenyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:31]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[N:30]=[CH:29][CH:28]=1)CCC>>[CH3:21][C:3]1[C:2]([C:27]2[N:31]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)=[CH:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: Cc1c(Br)cn2ccnc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2ccnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (Int. 9, 30 mg, 0.085 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 62 mg, 0.135 mmol) using a similar method to that used in Example 1 (Step 4) (28 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A solution of 1.41 g (5.0 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.10 (5.5 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 2.26 ml (15 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 30 ml of acetonitrile was heated under reflux for 4 hr. After cooling to room temperature, the precipitated solid was collected to give 0.97 g of the title compound, mp 255°-258° dec.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[S:10][C:9]=2[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C(O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1sc(C(O)C(C)C)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(1-hydroxy-2-methylpropyl)thiophen-3-yl]methyl}amino)benzoic acid (150 mg) synthesized above, ethyl β-alaninate hydrochloride (83.3 mg), 1-hydroxybenzotriazole monohydrate (83.0 mg) and triethylamine (76 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (135 mg, 77%) as a white solid. The obtained resultant product was a mixture of two diastereomers.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=S)[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1.[CH3:41][NH2:42]>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=[N:42][CH3:41])[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1
Reactant: CN
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl[Hg]Cl
Solvent: CCO
Product: CN=C1[C@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@@H](c2cccc(F)c2F)CN1CC(F)(F)F
Reaction time: 2 h

Procedure:
Mercury(II) chloride (23 mg, 0.084 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-thioxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (32 mg, 0.055 mmol) and methylamine (2.0 M in tetrahydrofuran; 274 μL, 0.547 mmol) in ethanol (1 mL). After 2 h, the mixture was filtered and concentrated. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound as a bis trifluoroacetate salt (33 mg). MS 580.2415 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)CCl.[NH2:28][C:29]1([CH2:35][OH:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[OH:36][CH2:35][C:29]1([NH:28][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:15])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: NC1(CO)CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2(CO)CCOCC2)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.59 mmol) in CH2Cl2 (5 mL) was added EDC (0.14 g, 0.72 mmol), 4-(dimethylamino)pyridine (0.088 g, 0.72 mmol), and (4-aminotetrahydropyran-4-yl)-methanol (0.094 g, 0.72 mmol). The reaction mixture was stirred at room temperature overnight then diluted with H2O and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (60% EtOAc/hexanes) to obtain 0.15 g (57%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1[N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[NH:2][CH3:1]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: CNc1ncnc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
6-Methylaminopurine (Sigma Chemical Company, 0.8 g, 5.4 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.39 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,400 I.U.) and purine nucleoside phosphorylase (3,900 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 6, the reaction was diluted to 100 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 17, the reaction was filtered. The filtrate was evaporated. The residue was suspended in methanol and then filtered. The filtrate was evaporated. The residue was dissolved in water and applied to a 2.5×7 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). The product was eluted with water. Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and filtered through a 0.2 μm-pore membrane filter. Lyophilization of the filtrate yielded title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14]=3[CH:27]=2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH:27]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
tert-Butyl 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285 mg, 0.70 mmol) was dissolved in 5 mL dichloromethane. 2 mL trifluoroacetic acid was added and the mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under vacuum and the residue was crystallized from ethyl acetate/hexane to give 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid (160 mg, 0.453 mmol).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[K+].[CH:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>CS(C)=O>[CH:13]1([O:19][C:2]2[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OC2CCCCC2)nc1
Reaction time: 21 h
Yield: 55.5 %

Procedure:
6-Chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and cyclohexanol (0.636 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube to 100 C for 18 h and then to 120 C for 21 h. The mixture was acidified to pH 1 by adding 2M hydrochloric acid. The mixture was then left to stand at room temperature overnight and the resultant precipitate filtered off, washed with water and dried under vacuum to afford the title compound as a cream solid (0.389 g, 55%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.76 (1H, d), 8.19 (1H, dd), 6.79 (1H, d), 5.11 (1H, m), 2.03 (2H, m), 1.83 (2H, m), 1.64 (1H, m), 1.56 (2H, m), 1.47 (2H, m) and 1.38 (1H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Li]c1ccccc1
Reactant: BrCCCCCCCBr
Solvent: C1CCOC1
Product: BrCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a stirred solution of 1,7-dibromoheptane (49 g, 0.18 mol) (Aldrich) in THF (300 ml), at -30° C. to -40° C., under N2, was added, dropwise, during 3 h, a solution of phenyllithium (15 g, 0.18 mol) in cyclohexane-ether (2.0M solution, Aldrich). The reaction was allowed to stir at -10° C. to -20° C. for 3 h and at room temperature overnight. After slow, careful dilution with H2O (50 ml), the aqueous layer was extracted with Et2O (2×150 ml). The extracts and the organic layer were combined, dried (Na2SO4) and concentrated to a yellow oil. Distillation through a Vigreaux column provided 22.5 g of 1-bromo-7-phenylheptane, bp 84°-88° C. (0.2 mm), nD24 1.5220.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:37]([C:33]2[CH:32]=[C:31]([CH3:30])[CH:36]=[CH:35][CH:34]=2)[N:38]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(C)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with 3-methylphenylhydrazine hydrochloride (CAS Reg. No. 637-04-7) to give the title compound as yellow solid. MS (ESI): m/z=508.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH2:22][OH:23].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][O:23][S:45]([CH3:44])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)OC)cc3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCOS(C)(=O)=O)Cc3ccc(CC(=O)OC)cc3)c2n1
Reaction time: 5 h

Procedure:
The product from step (iii) (0.39 g) was dissolved in DCM (20 mL) and triethylamine (0.15 g) added, followed by addition of methanesulfonyl chloride (0.3 mL) and the mixture stirred for 5 hrs. The mixture was concentrated in vacuo to afford the subtitle compound as a crude product (0.45 g); MS multimode (+) 579.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].[C:12](OCC)(OCC)(OCC)[CH3:13]>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[C:12]1[CH3:13]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cc(=O)n(N)c(NN)n1
Solvent: CCCCO
Product: Cc1cc(=O)n2nc(C)n(N)c2n1

Procedure:
A 3.0 g portion of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone, 20 ml of triethyl orthoacetate and 100 ml of n-butanol was reacted as described in Example 1, giving 2.36 g of the desired intermediate, mp 287°-289° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+].[Cl-].[NH4+]>CO.O1CCCC1>[CH:25]1([C:23]2[C:22]3[CH:21]([N:28]([CH:30]4[CH2:31][CH2:32]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:34])[C:17]=3[CH:16]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:35])=[O:2])=[CH:12][CH:11]=3)[CH:24]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc(C3CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 2-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 166, 0.125 g, 0.266 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) was treated with 3M potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product as an amorphous pale yellow solid (0.12 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)([O-])=O.CO.O.NN>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(N)c1

Procedure:
15 g (0.043 mol) of the compound from Example XXVIII are dissolved in 100 ml of tetrahydrofuran and 100 ml of methanol and 4 g (0.08 mol) of hydrazine monohydrate are added. Raney nickel is added in portions under argon with stirring, the temperature rising to 50° C. After the evolution of gas has ended, the mixture is heated to boiling for a further hour and then filtered while hot. The filtrate is concentrated in vacuo and the residual oil is taken up using 250 ml of dichloromethane. After washing twice using water and drying with sodium sulphate, the solvent is evaporated in vacuo and a colourless oil is obtained which crystallises overnight.
Reaction SMILES: [CH:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.P(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: OC1Cc2cccc3cccc1c23
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrC1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acenaphthen-1-ol (88 mol) was dissolved in diethyl ether (150 mL) and cooled down to 0° C. Phosphorous tribromide (3.2 mL, 35 mmol) was then added slowly under nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at room temperature and cooled to 0° C. The reaction mixture was partitioned with water and diethyl ether. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O: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].[NH:38]1[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][O: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]([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: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidine according to conditions described in general procedure C. Mp: 190-191° C.; 1H NMR (400 MHz, CDCl3) δ 1.52-1.63 (m, 6 H), 3.27-3.63 (m, 4 H), 3.72 (m, 4 H), 3.87 (m, 4 H), 5.81-5.83 (m, 1 H), 5.92-5.94 (m, 1 H), 6.78 (d, J=10.0 Hz, 1 H), 7.08 (d, J=6.4 Hz, 1 H), 7.33-7.35 (m, 2 H), 7.50-7.61 (m, 2 H), 7.89-7.91 (m, 1 H), 7.96-8.14 (m, 1 H), 8.12-8.17 (m, 2 H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:43](=[O:44])[C:35]3([CH2:37][CH:36]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:34](=O)[NH:33][C:32]3[CH:46]=[CH:47][CH:48]=[CH:49][C:31]2=3)=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:43](=[O:44])[C:35]3([CH2:37][CH:36]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:34](=[S:10])[NH:33][C:32]3[CH:46]=[CH:47][CH:48]=[CH:49][C:31]2=3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CC12C(=O)Nc1ccccc1N(c1ccc(Cl)cc1)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1NC2=S
Temperature: 80 °C
Yield: 44.8 %

Procedure:
Lawesson's Reagent (237 mg, 0.58 mmol) was added to a solution of ethyl 1-(4-chlorophenyl)-2,4-dioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (150 mg, 0.39 mmol) in THF (20 mL). The resulting mixture was heated at 80° C. overnight. The solution was evaporated and purified by CombiFlash (PE:EA=1:1) to get ethyl 1-(4-chlorophenyl)-2-oxo-4-thioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (70 mg, 45%) as brown solid. LRMS (M+H)+: 400 m/z. 1H NMR (300 MHz, CDCl3): δ 0.96-1.04 (t, J=7.2 Hz, 3H), 1.19-1.25 (m, 1H), 1.70-1.76 (m, 1H), 2.17-2.19 (m, 1H), 3.73-3.96 (m, 2H), 6.68-6.71 (d, 1H, J=8.1 Hz), 7.11-7.12 (m, 1H), 7.14-7.24 (m, 4H), 7.24-7.26 (m, 2H).