Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[CH:7]2.[F:15][C:16]([F:21])([F:20])[C:17](O)=O.[OH-].[Na+]>Cl>[CH3:14][N:13]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=[C:17]1[C:16]([F:21])([F:20])[F:15]
Reactant: CNc1ccc2cc(C)cnc2c1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(ccc3c2nc(C(F)(F)F)n3C)c1
Temperature: 95 °C

Procedure:
A mixture of 5.61 g (30 mmol) of 8-amino-3-methyl-7-methylaminoquinoline and 3.02 ml (40 mmol) of trifluoroacetic acid in 40 ml of 4N hydrochloric acid is heated at 95° C. for 2 h. It is then allowed to cool to room temperature and poured into 250 g of ice, the pH is adjusted to 9 with concentrated sodium hydroxide solution, and the precipitate is filtered off with suction. The crude product is dried and recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)cc1
Reaction time: 4 h
Yield: 44.7 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), p-anisidine (42 mg, 0.341 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-methoxyphenylamino)pyrazine-2-carbonitrile (43 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:10]([NH:17][C@H:18]([C:26]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1ccccc1
Yield: 87.3 %

Procedure:
In substantially the same manner as Working Example 2, 2-phenylethylamine (4.00 g) was condensed with Boc-L-phenylalanine (7.96 g) to give N-(Boc-L-phenylalanyl)-2-phenylethylamine (9.65 g) (yield 87%). The Boc group of the product was deprotected, in substantially the same manner as Working Example 91, to give N-(L-phenylalanyl)-2-phenylethylamine hydrochloride (4.93 g) (yield 81%). The compound thus obtained (1.00 g) was condensed, in substantially the same manner as Working Example 8, with monoethyl ester of (2S,3S)-N-methylaziridine-2,3-dicarboxylic acid (0.52 g) obtained in Working Example 42 to give the above-titled compound (Compound 93; 1.05 g) as white crystals (yield 83%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>C(O)(=O)C>[N+:11]([C:4]1[C:3]([CH2:1][CH3:2])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][C:5]=1[O:9][CH3:10])([O-:13])=[O:12]
Reactant: CCc1cccc(OC)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1c([N+](=O)[O-])ccc(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-ethyl-2-nitroanisole (89.73 mmol) in acetic acid (200 mL) is treated dropwise with a mixture of concentrated nitric acid (89.73 mmol, d=1.41 g/mL) and acetic acid (40 mL). After addition of the nitric acid solution, concentrated sulfuric acid (40 mL) is added dropwise. The reaction is poured over crushed ice (500 g) and stirred for 1 hour while a white precipitate forms. The precipitate is filtered and dried in a vacuum to afford a white solid. This material is purified by chromatography (silica gel, 20% ethyl acetate/hexanes) to afford 2,4-dinitro-3-ethylanisole.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:5][CH2:4]1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[O:17]=[C:9]1[C:6]2([CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2C12CCOCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (8.00 mg of a 60% dispersion in mineral oil, 0.207 mmol) was added to a solution of 2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one from Step A (35.0 mg, 0.172 mmol) in DMF (1 mL) at 0° C. After 1 hr, tert-butyl bromoacetate (0.280 mL, 0.189 mmol) was added and the reaction warmed to ambient temperature. After 18 h, the reaction was partitioned between CH2Cl2 (10 mL) and saturated NH4Cl (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=318 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[C@H:5]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]2[C:24]3[C:23](=[O:25])[NH:22][C:21]([NH2:26])=[N:20][C:19]=3[NH:18][CH2:17]2)=[CH:10][CH:9]=1)C.Cl>[OH-].[Na+]>[NH2:26][C:21]1[NH:22][C:23](=[O:25])[C:24]2[CH:16]([CH2:15][CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:35])=[O:3])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:9][CH:10]=3)[CH2:17][NH:18][C:19]=2[N:20]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(N)[nH]c(=O)c32)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Yield: 85.2 %

Procedure:
A solution of 1.50 grams (3.09 mmol) of N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester in 25 ml 1N NaOH was stirred at room temperature for 3 hours. The solution was carefully acidified to a of pH 2.8 by addition of 6M aqueous HCl and the resulting suspension was then filtered. The precipitate was consecutively washed with 20 ml water, 10 ml methanol, 10 ml ether, and dried overnight at 50° C. and 10 torr. 1.13 g (85% of theory) of N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid was obtained as an amorphous solid. Selected data: 1H NMR (DMSO-d6) δ12.20 (bs, 2H), 9.83 (bs, 1H), 8.48 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.32 (bs, 2H), 6.28 (bs, 1H), 4.33 (m, 1H), 3.43 (m, 1H), 3.01 (m, 2H), 2.61 (t, J=8.0 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.96 (m, 3H), 1.54 (m, 1H); 13C NMR (DMSO-d6) δ173.7, 173.1, 169.4, 166.5, 159.0, 156.7, 146.2, 131.4, 127.9, 127.2, 89.1, 52.1, 49.3, 36.9, 35.5, 32.3, 30.5, 26.2; IR (KBr) 3366, 2931, 1639, 1503, 1451, 1091 cm-1 ; MS(FAB) m/z 430 (MH+); UV (EtOH) 220 nm (ε27 660), 280 (11 300).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH:25](OC)=[O:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][CH:25]=[O:26])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: COC=O
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CNC=O

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in methyl formate (10 ml) was heated at reflux for twenty seven hours. The solvent was evaporated under reduced pressure and the residue washed with diethyl ether, to give 0.42 g of 6-nitro-2,2-dimethyl-3-(formamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 170° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(OC([O-])=O)(OC(C)(C)C)=O>CN(C=O)C>[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc2nccn12
Reactant: NCCCCO
Agent: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCOc1cccc2nccn12
Yield: 41 %

Procedure:
To a suspension of 60% sodium hydride (oily; 1.32 g, 33 mmoles) in DMF (60 ml) was added a solution of 5-chloroimidazo[1,2-a]pyridine (4.59 g, 30.1 mmoles) and 4-aminobutanol (2.68 g, 30.1 mmoles) in DMF (60 ml) at room temperature with stirring and the mixture was stirred at the same temperature for 5 hours. Tert-butyl dicarbonate (9.83 g, 45 mmoles) was added to the reaction solution, which was stirred at room temperature for 13 hours. After the solvent was distilled off, water was added to the residue, which was extracted with ether twice, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was dissolved in methanol (20 ml), followed by the addition of conc. hydrochloric acid (20 ml) and stirring at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with 3N NaOH. After drying over anhydrous potassium carbonate, the solvent was distilled off. The residue was purified by column chromatography (eluent:methanol/chloroform=1:5) to obtain 2.53 g of the desired product (40.9%, light brown oily product).
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[NH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:2]([CH3:1])=[C:6]([B:7]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH3:15])([CH3:14])[O:8]2)[C:5]([CH3:16])=[N:4]1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 94.2 %

Procedure:
Using similar reaction conditions as described in (step i of Intermediate-2), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.5 mmol) was reacted with 3-fluoro benzyl bromide (1.02 g, 5.4 mmol) in DMF (10 ml) and potassium carbonate (1.86 g, 13.5 mmol) to afford 1.4 g (94.59% yield) of the pure product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](OCC)=[O:28].[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:27]/[OH:28])/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccc(C(=O)c3cccc(NCc4ccccc4)c3)cc2N1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(C(=O)c3cccc(NCc4ccccc4)c3)ccc2/C1=C/O
Temperature: 78 °C
Yield: 33.5 %

Procedure:
6-[3-(benzylamino)benzoyl]-1,3-dihydro-2H-indol-2-one (0.057 g, 0.167 mmol) and ethyl formate (0.040 mL, 0.500 mmol) were dissolved in anhydrous ethanol (1.67 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.310 mL, 0.833 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-(3-Benzylamino-benzoyl)-3-[1-hydroxy-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one as an orange solid (0.021 g, 0.056 mmol, 34%) which was carried on without further purification.
Reaction SMILES: C(NC(/[N:6]=[C:7]1/[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH3:22])[C:9](=[O:14])[N:10]([CH2:12][CH3:13])[S:11]/1)=O)C.[OH-].[Na+]>CO>[CH2:12]([N:10]1[C:9](=[O:14])[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH3:22])[C:7](=[NH:6])[S:11]1)[CH3:13]
Reactant: CCNC(=O)/N=c1\sn(CC)c(=O)n1-c1ccccc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccccc1-n1c(=N)sn(CC)c1=O
Temperature: 25 °C
Yield: 66.1 %

Procedure:
(Z)-1-Ethyl-3-(2-ethyl-4-(2-ethylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea (CB42) (0.484 g, 1.51 mmol) was dissolved in methanol (150 mL). Sodium hydroxide (3.36 g, 84.0 mmol) was slowly added and the reaction was stirred at room temperature. After 4 hours the solution was concentrated to 1/2 volume, poured onto water, and extracted with ethyl acetate. The organics were dried and concentrated to give the title compound as an orange solid (0.249 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.35-7.32 (m, 2H), 7.30 (dd, J=5.4, 1.5 Hz, 1H), 7.25-7.20 (m, 1H), 3.65 (q, J=7.2 Hz, 2H), 3.39-3.19 (m, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.26-1.13 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.32, 165.49, 141.20, 135.74, 130.42, 129.31, 127.67, 126.01, 39.50, 24.79, 15.22, 14.93; ESIMS m/z 250 ([M]+).
Reaction SMILES: [OH:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]3[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[C:31]([CH3:44])([CH3:43])[CH2:30]3)[N:21]=[C:20](Cl)[N:19]=2)[CH2:7][C:6]1([CH3:47])[CH3:46].[CH2:50]([CH2:52][NH2:53])[OH:51].[OH-].[Na+]>>[OH:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]3[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([O:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[C:31]([CH3:44])([CH3:43])[CH2:30]3)[N:21]=[C:20]([NH:53][CH2:52][CH2:50][OH:51])[N:19]=2)[CH2:7][C:6]1([CH3:47])[CH3:46]
Reactant: NCCO
Reactant: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of the intermediate prepared in Example 11 with ethanolamine and sodium hydroxide. The aqueous layer is removed, and the remaining layer is extracted with cyclohexane. Solvent is evaporated at reduced pressure, and the crude product is purified by flash chromatography on silica gel with 1:2 (v/v) hexane/ethyl acetate to afford 4.1 g of the title compound as a white solid, melting at 110-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[S:20][C:19]([C:21]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:39][CH2:38]3)=[O:23])=[N:18][N:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: C1CCN(CCCN2CCNCC2)C1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (200 mg, 0.50 mmol), 1-(3-pyrrolidin-1-ylpropyl)piperazine (118 mg, 0.60 mmol), THF (10 mL) and trimethylaluminium (2.0 M in toluene, 0.55 mL). The crude product was purified by FCC, eluting with 0-2% MeOH in DCM to afford the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>ClCCl>[Br:21][C:20]([Br:24])=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.2 %

Procedure:
To a stirred solution of triphenylphosphine (155.6 g, 0.59 mol) in dry dichloromethane (870 mL) at 0° C. was added carbon tetrabromide (100.86 g, 0.304 mol) portionwise. The mixture was stirred at RT for 30 min and then cooled to −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (30 g, 0.15 mol) in CH2Cl2 (90 mL) was added dropwise and the reaction was stirred at −78° C. for 30 min and then at RT overnight. The mixture was filtered and the filtrate was evaporated to dryness. Diethyl ether was added and the mixture was filtered again. The filtrate was evaporated to dryness to give the title compound (64 g). 1H NMR (500 MHz, CDCl3): δ 3.44 (m, 4H), 2.46 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cnc(-c2ccc(Br)cc2)cn1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
(4-Bromophenyl)boronic acid (100 mg, 0.498 mmol) and 5-bromopyrazin-2-amine (173 mg, 0.996 mmol) were added to a 5 mL sealable vial equipped with a stir bar. To this vial was added toluene (1.5 mL), ethanol (1.5 mL) and K2CO3(0.7 mL, 2 M). The solvent was sparged with argon for 10 min before adding Pd(PPh3)4 (17 mg, 0.004 mmol), the vial sealed and the mixture stirred at 50° Celsius for 15 hours. The reaction was cooled to rt and then diluted with ethyl acetate (50 mL) and water (50 mL) and the layers separated. The aqueous layer was further extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with Na2SO4 and concentrated to dryness. The crude material was purified FCC to give 5-(4-bromophenyl)pyrazin-2-amine. 1H NMR (500 MHz, CDCl3) δ 8.52-8.31 (d, J=1.5, 1H), 8.08-7.95 (d, J=1.6, 1H), 7.86-7.71 (d, J=8.4, 2H), 7.63-7.49 (d, J=8.6, 2H), 4.70 (s, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl>[OH-].[Na+].O.O1CCOCC1>[C:29]([CH2:28][CH2:27][C:26]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:20][CH2:19]1)=[O:32])([OH:31])=[O:30]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)N1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Reaction time: 12 h
Yield: 55.7 %

Procedure:
3.5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are dissolved in a mixture of 0.4 g of sodium hydroxide in 20 ml of water, and a solution of 1 g of succinic anhydride in 10 ml of dioxane, and a solution of 0.4 g of sodium hydroxide in 10 ml of water, are simultaneously added dropwise at 20° C. After standing for 12 hours, the mixture is adjusted to pH 5 with 2N hydrochloric acid, and the precipitate is filtered off under suction, washed with water, heated with methanol, filtered off under suction and dried. 2.5 g of 7-[4-(3-carboxypropionyl)-piperazin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 217°-219° C. are obtained. The following compounds are obtained analogously to Example 21:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)[CH:17]=[CH:16][C:15]=2[CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[CH2:40][C:39]([CH3:46])([CH3:45])[CH2:38]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:17]=[CH:16][C:15]=2[CH:37]2[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]([CH3:44])([CH3:43])[CH2:42]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC1(C)CC(c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of 4-[5-(nonafluorobutane-1-sulfonyloxy)-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.286 mmol) produced in Example (81c), morpholine (37.8 mg, 0.429 mmol), sodium t-butoxide (56.7 mg, 0.572 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.1 mg, 0.0143 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11.5 mg, 0.0286 mmol) and xylene (3 mL) was stirred for 13 hours and 30 minutes at an external temperature of 100° C. under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 103 mg of the title compound as a light yellow oil.