Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>O.CC(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCCCC(=O)O
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCCCC(=O)O)c2)C1
Temperature: 25 °C

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (1.75 g.) is added to a solution of 4-aminobutyric acid (0.54 g.) in water (30 ml.), acetone (30 ml.) and 1N sodium hydroxide (10 ml.). After stirring at room temperature for a half hour, the acetone is removed by evaporation, and the aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is dissolved in 50 ml. of hot acetone-methanol (1:1) and concentrated to half volume. Hexane is added to crystallize the product, m.p. 193°-195° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:54])[C@H:21]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:48][CH2:47][C:46]5[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=5[NH:44][C:43]4=[O:53])[CH2:38][CH2:37]3)=[O:35])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:54]=[C:20]([N:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1)[C@H:21]([NH:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH2:48][CH2:47][C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[NH:44][C:43]2=[O:53])[CH2:40][CH2:41]1)=[O:35])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1
Reactant: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 100 mg (0.14 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid [(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide (Example 50) in 10 mL MeOH was hydrogenated in the presence of 20 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Cc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(O)(c2cccc(C)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 3-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1484 g, 0.810 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.1806 g, 69.4%). E-MS m/z 322 (M+H+) Rt (1.54 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccc(Cl)nc3)n2)CCN1

Procedure:
75 mg (0.14 mmol, 84% purity) of the compound of Example 40A is reacted analogously to the synthesis of the compound of Example 4 with 15 mg (0.15 mmol) of 2-oxopiperazine. 56 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22](CN)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)=[O:5].CC(O)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:46][N:47]([CH:49]=O)[CH3:48]>>[Cl:1][C:2]1[CH:23]=[C:22]([CH2:49][N:47]([CH3:46])[CH3:48])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reaction time: 16 h

Procedure:
2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminomethyl)benzamide (80 mg, 0.20 mmol) was dissolved in DMF (5 mL) and treated with AcOH (10 uL), paraformaldehyde (43 mg, 0.47 mmol), and sodium triacetoxyborohydride (125 mg, 0.59 mmol). After stirring for 16 h, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 N Sodium hydroxide, dried (MgSO4) and concentrated. The crude product was purified by reverse phase HPLC to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl) benzamide. MS (Q1) 400.0 (M)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH2:17]2)#[N:13].[H-].[Na+].[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([C:65](=O)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:61][CH:60]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:60]=[CH:61][C:62]([C:65](=[CH:24][CH:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[N:13])[CH:15]=4)[CH2:20]3)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:63][CH:64]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: N#Cc1ccc2c(c1)CCC(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCc2cc(C#N)ccc2C1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
9.0 g of (6-cyano-1,2,3,4-tetrahydro-2-naphthyl)methyltriphenylphosphonium p-toluenesulfonate was suspended in 150 ml of tetrahydrofuran, followed by gradual addition of 600 mg of 60% sodium hydride. The thus prepared mixture was refluxed under heating for 20 minutes. After cooling down to room temperature, to the resulting reaction solution was added 10 ml of a tetrahydrofuran solution containing 4.16 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. The resulting reaction mixture was stirred for 10 minutes, and then refluxed under heating for 2 hours. After cooling down to room temperature, the reaction product thus obtained was dissolved in ethyl acetate, and washed with water and saturated sodium chloride aqueous solution in that order. After drying the resulting organic layer to distill off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 3.90 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-1,2,3,4-tetrahydro-2-naphthyl)acrylate in a yellow oily form as a mixture of E and Z forms. 2.58 g of the thus obtained E/Z mixture was dissolved in 40 ml of ethanol, and the resulting solution was mixed with 650 mg of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure for 5 hours. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent. In this way, 1.69 g of the title compound was obtained in a yellow oily form.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10]CC)=[O:9])=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:19][C:18]=1[CH3:26]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ethyl 2-(3-formylphenoxy)acetate (20.8 g, 0.1 mol) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (21.0 g, 0.375 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 20 g (64%) of yellowish solid was obtained. 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 8.40 (br, 1H), 7.80 (s, 1H), 7.65 (m, 2H), 7.22-7.55 (m, 5H), 6.85 (d, 1H), 4.75 (s, 2H), 2.22 (s, 3H). MS (EI): 313 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[F-:12].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([F:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=S(=O)(F)c1ccccc1F
Temperature: -5 °C

Procedure:
A 100-L round bottomed flask fitted with overhead stirrer, nitrogen inlet, temperature probe and ice bath was charged with 2-fluorobenzenesulfonyl chloride (50 g) and tetrahydrofuran (220 g). The solution was cooled down to −5° C. with an ice bath. Tetrabutylammonium fluoride (270 mL of 1M in tetrahydrofuran solution) was added slowly to the reactor. The internal temperature was kept less than 8° C. After the addition was completed, HPLC showed the reaction was completed. The reaction was quenched by slowly adding 250 g of water. Then 430 g of toluene was added to the reaction mixture. The layers were separated. The organic layer was washed with 250 g of water twice. The organic layer was distilled down under vacuum with the bath temperature at 48° C. 1H NMR (400 MHz, CDCl3) δ 8.01-7.96 (m, 1H), 7.76-7.83 (m, 1H), 7.32-7.44 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg of biphenyl-4-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H), 7.77-7.84 (m, 3H), 8.73 (d, 2H, J=4.4 Hz), 10.01 (s,1H). MS: m/z 449.0 (M++1).
Reaction SMILES: [CH:1](=[N:8][NH:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]([CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN=Cc1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CN(C)N=Cc1ccccc1
Yield: 90.5 %

Procedure:
258 g (1.92 mol) of N-benzylidene-N′-methylhydrazine and 325 g (1.92 mol) of ethyl ethoxy-methylenecyanoacetate were initially charged in 1000 ml of toluene and heated at the boil for 1 hour. After cooling, the mixture was filtered off with suction, which gave 447 g (89.5% of theory) of ethyl 3-(N′-benzylidene-N-methylhydrazino)-2-cyanoacrylate [logP (pH 2.3)=2.31]. The filtrate was allowed to stand for 16 hours and then again filtered off with suction, which gave another 7.7 g (1.5% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[F:11][C:12]([F:22])([F:21])[C:13](=O)[CH2:14][C:15](OCC)=[O:16].C[O-].[Na+].CO>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:15](=[O:16])[CH:14]=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=c1cc(C(F)(F)F)nc(-c2cccc(Cl)c2)[nH]1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide (4.81 g, 25.3 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (5.00 g, 27.1 mmol), and ethanol (90 mL) and cooled to 0° C. A 25% sodium methoxide solution in methanol (13.0 mL, 55.3 mmol) was added to the mixture. The resulting mixture was stirred at reflux for 20 h. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL) forming a solid. The solid was collected by filtration and washed with water followed by ether to afford the title compound (3.60 g, 48%) as a white solid, which was carried forward into the next step without further purification. MW=274.63. 1H NMR (DMSO-d6, 500 MHz) δ 13.39 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.94 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:31]([O-:33])=[O:32])=[C:13]([CH:30]=1)[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15]>>[CH:26]1([NH:25][C:23]([C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([NH:16][C:14](=[O:15])[C:13]3[CH:30]=[C:9]([N:6]4[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]4)[CH:10]=[CH:11][C:12]=3[N+:31]([O-:33])=[O:32])[CH:22]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNCCN1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN[C@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material (R)-2-methylpiperazine was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3R)-3-methylpiperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.04 (d, 3H), 2.30 (s, 3H), 2.52 (m, 2H), 2.71 (m, 2H), 2.84 (m, 2H), 2.98 (d, 1H), 3.92 (t, 2H), 7.04 (m, 2H), 7.27 (d, 1H), 7.56 (d, 1H), 7.97 (s, 1H), 8.03 (d, 2H), 8.35 (d, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 438.
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].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]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:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylpiperazine according to conditions described in general procedure C. Mp: 195-197° C.; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3 H), 2.39 (t, J=4.4 Hz, 4 H), 3.25 (t, J=4.8 Hz, 4 H), 3.69 (s, 4 H), 3.87 (t, J=4.4 Hz, 4 H), 6.01 (d, J=5.6 Hz, 1 H), 6.78 (d, J=11.6 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1 H), 7.30-7.32 (m, 2 H), 7.49-7.59 (m, 2 H), 7.89-8.00 (m, 3 H), 8.15-8.18 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[CH:21]=[C:22]([S:27]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1
Yield: 47.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150 mg, 0.611 mmol) prepared in Example 14a, 3-chloro-4-fluorobenzenesulfonyl chloride (280 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (127 mg, 47%) as a colorless amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)=[CH:3][C:2]=1[O:1][CH2:23][C:22]#[CH:21]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(O)c2)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOc1cc(-c2cccc(CC(=O)OC)c2)ccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
207 mg methyl (3′-hydroxy-4′-methoxybiphenyl-3-yl)acetate was dissolved in 3 ml N,N-dimethylformamide, 0.17 ml propargyl bromide and 150 mg potassium carbonate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 221 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]1([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([NH:42]/[C:4](=[C:11]4\[C:12](=[O:23])[NH:13][C:14]5[C:19]\4=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=5)/[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:43][CH:44]=3)[CH2:35][CH2:36]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-phenylmethyl-piperidino)methyl-aniline in DMF.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Temperature: 25 °C

Procedure:
The product from Example 351A (1 equiv) and 4-mercaptophenol (1 equiv) were dissolved in dimethylformamide and cesium carbonate (5 equiv) added. The resultant mixture was stirred at 80° C. for 2.5 hours, cooled to room temperature and water added. The solution was extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:15](Br)[CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:16]
Reactant: O=[N+]([O-])c1cc(O)cc2cccnc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c2ncccc2c1
Yield: 85.4 %

Procedure:
A solution of 6-hydroxy-8-nitro-quinoline (2.5 g, 13.2 mmol), ethylbromide (1.08 mL, 14.5 mmol), and K2CO3 (4 g, 26.4 mmol) in DMF (50 mL) under a nitrogen atmosphere was heated at 40° C. for 5 hours. The cooled reaction mixture was poured into H2O (200 mL) and extracted into EtOAc (2×200 mL). The organic fractions were combined, dried over NaSO4 and concentrated. The resulting beige solid was triturated with 40% EtOAc/hexane to give 2.46 g (85%) of the title compound as beige crystals.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:12])(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH2:14][C:15]#[N:16]>C1COCC1.CCOCC>[C:4]([S:11][CH2:14][C:15]#[N:16])(=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(=S)c1ccccc1
Reactant: N#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Sodium methoxide (5.13 g; 0.095 mol) is added with stirring to an ice cold solution of thiobenzoic acid (13.8 g; 0.095 mol) in THF (100 ml). A yellow slurry forms. Next, chloroacetonitrile (6.45 ml; 0.10 mol) is added, and the reaction mixture stirred overnight at room temperature. It is then filtered, and the filtrate concentrated in vacuo to yield a yellow oil. This oil is dissolved in ether, the solution washed with saturated sodium bicarbonate solution, saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The residual oil is distilled (boiling point 105°-106° C. at 10.5 mm) to afford 12.8 g (76%) of title product, a yellow oil.