Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=O.[O:32]1CCCC1>O.C(O)C.O>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:32])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(Cl)cc2c1C(=O)O
Temperature: 90 °C

Procedure:
A 3.63 g portion of 5-chloroisatin was added to 35 ml of water in a three-necked, 500 ml flask. A solution of 5.6 g of sodium hydroxide in 20 ml of water was added and the mixture was stirred at 90° C. A solution of 7.43 g of 2-amino-4'-phenylacetophenone hydrochloride in 93 ml of ethanol:water (1:1) was warmed, 25 ml of tetrahydrofuran added to maintain solution and this solution added dropwise to the 5-chloroisatin solution over 3 hours. The solvent was distilled off at 85° C. The remaining solution was cooled, 50 ml of water added and this mixture stirred for 10 minutes. The resulting red solid was collected, dried, stirred in 2.5 liters of water for 1.5 hours and filtered. The filtrate was acidified to pH 4, then the resulting solid was collected, washed with water and dried, giving 5.15 g of the desired product as a yellow solid, mp 244°-245° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[N:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]=[O:27]>C(N(CC)CC)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:25][C:26](=[O:27])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCN=C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 90 h
Yield: 37.8 %

Procedure:
The preparation is carried out as in Example 32 but from 4 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 86 ml of dimethylformamide, 7.3 ml of triethylamine and 4.42 g of ethyl 3-isocyanatopropionate and the reaction mixture is stirred at a temperature in the region of 20° C. for 90 hours. After evaporation of the dimethylformamide, 300 ml of water are added and the precipitate formed is filtered, washed with water (50 ml) and then with acetone (2×50 ml) and dried at 60° C. under vacuum (1 mm Hg, 0.13 kPa). There are obtained 2.1 g of 8-[3-(2-ethoxycarbonylethyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 59.84, H: 5.02, N: 18.36, O: 16.78, % found C: 59.5, H: 5.1, N: 18.5).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1(=[O:33])[N:23]([CH2:24][CH2:25][CH2:26]Cl)[C:22](=[O:28])[C:21]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]12>>[C:22]1(=[O:28])[N:23]([CH:24]([C:14]2[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9]3)[CH2:25][CH3:26])[C:19](=[O:33])[C:20]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCl
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Yield: 62.2 %

Procedure:
By the procedure similar to that described in Example 24, 3-phenyl-5-chloroindazole (9.2 g), sodium hydride 50% pure (2.3 g) and phthalimidopropyl chloride (9.0 g) were treated to obtain 10.4 g of 1-phthalimidopropyl-3-phenyl-5-chloroindazole. Recrystallization from methanol gave a product having a melting point between 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(4-Bromo-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (12 g) was dissolved into concentrated sulfuric acid (50 ml) to which then nitric acid (60%, d=1.38; 5.0 g) was added under ice-cooled condition, and stirred for 2 hours at room temperature. The reaction solution was poured into ice water and the thus obtained solid was filtered off. The solid was washed with water and dried to give the compound of interest (12.5 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](OC(=O)C(C)(C)C)[C@@H](c1ccccc1)N3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
140 g of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one (WO 00/17200, example B1) are suspended in 1100 ml of dichloromethane under argon and with exclusion of moisture. After addition of 70 ml of triethylamine and 2.5 g of 4-dimethyl-aminopyridine, a solution of 62 ml of pivaloyl chloride in 70 ml of dichloromethane is added dropwise such that the temperature of the reaction mixture does not rise above 30° C. (cooling with a water bath). After stirring overnight, the mixture is added to 1 l of ice water and stirred in the cold for a further 10 min. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×200 ml). The combined organic phases are washed with water (3×300 ml) until neutral, dried over sodium sulfate and evaporated. 220 g of yellowish oil are obtained, which is crystallized using 600 ml of tert-butyl methyl ether. After stirring in the cold for 2 h, the solid is filtered off, washed with 200 ml of tert-butyl methyl ether and the filter residue is dried to constant weight in a vacuum drying oven. 175 g (97%) of the title compound are obtained as a slightly yellowish solid of m.p. 185-187° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].I[CH3:35].O>CN(C=O)C>[CH3:35][N:19]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[N:18]=1
Reactant: COc1ccccc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1nc(-c2ccccc2O)nc2ccccc12)[C@H]1CCNC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
(S)-tert-Butyl 3-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.259 g, 0.616 mmol) (prepared by methods analogous to those described in Synthesis 2) was dissolved in DMF (6.16 mL) and cooled to −30° C. NaH (60% dispersion in mineral oil, 0.041 mg, 0.678 mmol) was added and the mixture was stirred at −30° C. for 15 minutes. The mixture was cooled to −78° C. and iodomethane (0.046 mL, 0.727 mmol) was added dropwise. The solution was warmed to room temperature over 2 hours. Water (5 mL) was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (1.3 mL) and 1 M boron tribromide in dichloromethane (1.3 mL). The solution was stirred at room temperature for 18 hours. Methanol (5 mL) was added and the mixture was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient from 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.028 g, 66%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCC(CN2CCOCC2)NC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)CN2CCCCC2CN2CCOCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[(4-morpholinyl)methyl]piperidine to give colorless crystals, mp. 203°-205° C. (acetonitrile using activated charcoal).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccc(CNC3CC3)cc2n2cccc12
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1ccc2[nH]c(=O)c3cccn3c2c1)C1CC1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 12 (26 mg) and triethylamine (25 μL) in 1 mL dioxane was added methanesulfonyl chloride (5.53 μL). The mixture was stirred for 24 hours and concentrated. The title compound was purified by RP-HPLC using a gradient elution of 10/90 to 70/30 acetonitrile/0.1% TFA in water at 254 nm over 30 minutes. The free base was isolated after eluting from an ion exchange column (10 g). 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.14 (m, 1H), 7.95 (s, 1H), 7.29 (s, 2H), 7.03 (m, 1H), 6.70 (m, 1H), 4.41 (s, 2H), 2.96 (s, 3H), 2.46 (m, 1H), 0.68 (d, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=1)CCC>>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:30]3[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=3)=[CH:3][CH:4]=2)[CH:19]=[CH:18][C:17]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Reactant: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(Br)cc2)o1
Product: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)o1

Procedure:
The title compound was prepared according to the procedure of Example 153 (step 4) using 4-[5-(4-Bromophenyl)-2-methyl-1,3-oxazol-4-yl]-2-fluorobenzenesulfonamide instead of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole and using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of 4-(tributylstannyl)thiazole.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][CH:4]=[C:5]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:7].[CH3:32]N(C)C=O.[H-].[Na+].CI>O>[F:1][CH:2]([F:31])[O:3][CH:4]=[C:5]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=1)[C:6]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:32])=[O:7]
Reactant: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(CCN(C)C(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Five hundred milligrams (500 mg) of 3-difluoromethoxy-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.16 mmol) and 5 ml of anhydrous N,N-dimethylformamide were mixed and cooled, and then 49 mg (1.22 mmol) of 60% sodium hydride was added thereto and stirred at 0° C. for 30 minutes. To the mixture, 164 mg (1.16 mmol) of methyl iodide was added and stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. Water was added to the reaction mixture, which which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=3:1) to give 460 mg of 3-difluoromethoxy-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1125).
Reaction SMILES: I.CS[C:4]([C:6]1[S:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)=[NH:5].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](OCC)(OCC)[CH:32]([NH2:42])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].B(F)(F)F.CCOCC>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:5]=[C:4]([C:6]3[S:7][C:8]4[C:14]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=4[N:10]=3)[NH:42][C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=N)SC)nc12
Agent: FB(F)F
Agent: I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CN(C(=O)OC(C)(C)C)CC4)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.5 %

Procedure:
To a suspension of 0.50 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboximidothioic acid methyl ester hydroiodide in 33 ml tetrahydrofurane was added 1.34 g 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for two days. Then 0.2 ml boron trifluoride etherate was added and the solvent was distilled off under vacuum. Again 0.2 ml boron trifluoride etherate was added and the mixture was dissolved in 30 ml dimethylformamide and heated for 10 minutes at 125° C. The solvent was distilled off and the residue was dissolved in dichloromethane and extracted with water. The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. Chromatography on silicagel with ethylacatate/hexane 1:1 followed by chromatography on aluminiumoxide with ethylacatate/hexane 1:1 yielded 0.18 g (35%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester as an amorphous solid; m/e=472 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2].ClCl.[Cl:14]C(Cl)(Cl)Cl.O>C(O)(=O)C>[CH2:1]([C:3]1[C:7]([Cl:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(NC(C)=O)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Solvent: O
Solvent: CC(=O)O
Product: CCc1noc(NC(C)=O)c1Cl
Temperature: 25 °C
Yield: 203.3 %

Procedure:
3-Ethyl-5-acetylaminoisoxazole (1) (1.98 g) was dissolved in acetic acid (15 ml), chlorine-tetrachloromethane (18 ml, containing 1.09 g of chlorine) was added thereto under stirring at room temperature and after addition of water the mixture was extracted with chloroform after 5 minutes. The extract was washed with water, dried over sodium sulfate and evaporated. The resulting crystalline residue was recrystallized from ether/hexane to give 3-ethyl-4-chloro-5-acetylaminoisoxazole (2) (1.86 g), mp. 113°-114° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH3:17])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1.C(O)(=O)C>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH2:17][N:1]=[O:3])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1
Reactant: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NCNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.3 g. (0.0625 mol) of sodium nitrite was added in small portions to a stirred solution of 16.4 g. (0.05 mol) of 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine in 200 ml. of glacial acetic acid. After addition (15 minutes), the mixture was stirred for 30 minutes at room temperature, diluted with water and extracted with ether. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, giving crude 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine as an oil. 2 g. of the remaining oil was chromatographed over 60 g. of silica gel using 10 percent ethanol in methylene chloride. The clean fractions were combined and evaporated. The residue was stirred in isopropanol overnight, whereupon crystalline 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine separated, m.p. 102°-106°.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O.O>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[NH:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1)#[N:17]
Reactant: Nn1cnnc1
Reactant: N#Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
6.67 Grams of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, and 5.00 g of 4-amino-4H-1,2,4-triazole was added thereto and the mixture was stirred for 15 minutes at room temperature. Subsequently, 9 ml of an anhydrous dimethylsulfoxide solution containing 3.23 g of 2-fluorobenzonitrile was added dropwise to the solution over a period of 10 minutes, and the mixture was stirred for further 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and the solution was then adjusted to have pH of 5.7 with 1N hydrochloric acid. The crystals precipitated out were collected by filtration and dried to give 2.64 g of 4-[(2-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[N:3]=1.C(C1N=C(C2C=C(O[CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:1][CH:38]1[CH2:56][CH:55]3[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]4[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]3=[O:57])[CH2:51]4)[CH2:39]1)=[N:3][C:4]([N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)=[CH:5]2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)nc(-n3cccn3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title compound was prepared from 1-hydroxy-6-methoxy-3-(pyrazol-1-yl)-isoquinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=574 (M+H)+.
Reaction SMILES: ClC1C=CC2N([CH:11]3[CH2:14][O:13][CH2:12]3)C(CCl)=NC=2C=1.[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([C@@H:39]3CCS(=O)(=O)[CH2:40]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1.CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([CH2:39][CH2:40][CH:11]3[CH2:14][O:13][CH2:12]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCC2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole (Example 2-1) instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][C:12]2=[O:20])[CH:7]=[CH:8][CH:9]=1>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:12](=[O:20])[CH2:13][CH2:14][CH:15]2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCC(=O)N1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 16.00 g of sodium hydroxide pellets in 165 ml of water was treated with 99.01 g of (±)-1-[(3-chlorophenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and was heated for two hours with a steam bath. The solution was cooled to room temperature and extracted with diethyl ether (2×300 ml). The aqueous phase was acidified with 45 ml of concentrated hydrochloric acid and extracted with dichloromethane (3×200 ml). Crystals precipitated out of the dichloromethane. The crystals (80.21 g, damp with solvent) were dried overnight at 65° C. under vacuum.