Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12]Cl)=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([CH2:12][O:2][CH3:1])=[CH:7][N:6]=1
Reactant: ClCc1cnc(Cl)c(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cnc(Cl)c(Cl)c1
Temperature: 60 °C

Procedure:
Under argon and at room temperature, 4.14 g (23 mmol) of sodium methoxide (30 percent strength solution in methanol) was added dropwise within 5 minutes to a solution of 4.11 g (20.9 mmol) of 2,3-dichloro-5-(chloromethyl)-pyridine [prepared from 2,3-dichloro-5-(hydroxymethyl)-pyridine by reaction with thionyl chloride] in 40 ml of methanol. The reaction mixture was subsequently heated to 60° C. for 3 hours. After the reaction had ended, the solvent was distilled off and the residue was admixed with 100 ml of water and extracted with dichloromethane (3×75 ml). The organic phase was dried over magnesium sulfate and evaporated. The yield of the product was 4.06 g (90.4 percent) of a yellow oil, purity (GC) 90.8 percent.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)(CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCC(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 73.2 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and sec-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 10.7 g of p-cyanobenzamide (yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCCNc1ccc(OC)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b) the reaction is carried out with 2 g. (6.8 mmol) of 9-(4-methoxyphenylamino)-pelargonic acid methyl ester, 0.75 g (7.5 mmol) of triethylamine, 1.2 g (6.8 mmol) of 4-chlorobenzoic acid chloride and 80 cc. of ether. The crude product is used in the next reaction step without further purification.
Reaction SMILES: C(OC(=O)[NH:6][CH2:7][C:8]1[CH:13]=[C:12]([I:14])[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][C:9]=1[Cl:20])(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:6][CH2:7][C:8]1[C:9]([Cl:20])=[CH:10][C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([I:14])[CH:13]=1
Reactant: CC(C)OC(=O)NCc1cc(I)c(NS(C)(=O)=O)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(Cl)c(CN)cc1I
Reaction time: 12 h
Yield: 128.7 %

Procedure:
(2-chloro-5-iodo-4-methanesulfonylamino-benzyl)-carbamic acid isopropyl ester (100 mg, 0.22 mmol) was put into a dried 25 ml of round-bottom flask and dissolved in methylenechloride. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield a brown syrup (102.1 mg, 130.48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]2[C:8]=1[CH:11]=[CH:12][CH:14]=[N:7]2
Reactant: OCC(O)CO
Reactant: Cc1ccc(Br)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(Br)c2cccnc12
Temperature: 0 °C
Yield: 67.6 %

Procedure:
A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150° C. for 3 hrs. The solution was cooled to 0° C. then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (dichloromethane) to afford the title compound as a solid (6 g). 1H-NMR (CDCl3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(NCc2ccccc2)cc1)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)cc1)N1CCCCC1
Temperature: 40 °C
Yield: 62.5 %

Procedure:
To a stirred solution of (4-benzylamino-phenyl)-piperidin-1-yl-methanone (39 mg, 0.14 mmol) in dichloromethane (1 ml) was added benzene sulfonylchloride (57 μl, 0.46 mmol) followed by pyridine (42 μl, 0.5 mmol) and the reaction was heated to 40° C. for 20 hours. The reaction was allowed to cool to room temperature and partitioned between water (5 ml) and dichloromethane (5 ml). The organics were collected, concentrated in vacuo and purified by preparative TLC to afford the title compound as a white solid (38 mg, 62% yield). HPLC retention time 5.8 min. Mass spectrum (ES+) m/z 435 (M+H).
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCC=Cc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCC=Cc2ccccc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-(cinnamylamino)benzoate (prepared as described in Example 24), 10 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) is refluxed for 3 hours. The solution is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give off-white crystals. Recrystallization from ethanol gives pale yellow crystals, m.p. 200°-202° C.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][O:4][CH:3]1[N:7]1[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH:9]=[N:8]1.CC(C)([O-])C.[K+].CS(C)=O>C(O)(=O)C>[O:4]1[CH2:5][CH:6]=[CH:2][CH:3]1[N:7]1[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH:9]=[N:8]1
Reactant: O=c1cnn(C2OCCC2Cl)c(=O)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=c1cnn(C2C=CCO2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Chloro-tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (0.8 g) and potassium t-butoxide (0.7 g) are added to dimethyl sulfoxide (3 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water. The mixture is acidified with acetic acid and extracted with chloroform. The chloroform extract is washed with water, dried and evaporated to remove the solvent. The crude residue is recrystallized from ethanol to give 2-(2,5-dihydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 81). Yield, 0.5 g (76%). M.P., 147°-148° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.O>CS(C)=O.C(O)(=O)C>[Br:8][C:6]1[N:7]=[C:2]2[N:20]([CH2:19][CH2:18][O:17][CH3:16])[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: COCCN
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COCCN1C(=O)CNc2ncc(Br)nc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 1.C) (1 equiv), 2-methoxyethanamine (1 equiv), diisopropylethylamine (3 equiv), were suspended in dimethylsulfoxide and heated in an Emrys Biotage microwave reactor at 150° C. for 1 h. Standard ethyl acetate/water work up gave crude material, which was suspended in 99.7% acetic acid. The reaction was sealed, heated to 120° C. and allowed to stir for 2 h. The reaction was extracted in ethyl acetate. The organic layers were pooled and washed with saturated sodium bicarbonate, followed by brine and dried over magnesium sulfate. Concentration and flash column chromatography (0-100% ethyl acetate in hexanes) gave the desired product in 27% yield over two steps. MS (ESI) m/z 287.4 [M]+, 289.4 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(C(F)(F)F)c4)noc3C)CC2)c1
Yield: 74.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a gel-like required compound (602 mg, 1.37 mmol, 75%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (9 g), phosphoryl chloride (2.8 ml), di-isopropylethylamine (11.4 ml) and 1,2-dichloroethane (130 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 7-benzyloxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[N:6]=[CH:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1c2ccncc2NCc2cccn21
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
A solution of 4.2 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 75 ml of ethanol, was treated with 800 mg of sodium borohydride and stirred at ambient temperature for 18 hours. The solvent was then concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate (2×). The combined organics were washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was recrystallized from isopropyl ether:methanol (180:10) to afford 3.1 g (74%) of 10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, m.p. 135°-140° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:8][C:7](=O)[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]1=[O:19].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[CH3:1][N:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:8][C:7](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]1=[O:19]
Reactant: N=C(N)NN
Reactant: Cc1cc(=O)n(C)c2c1C(=O)CC(c1ccsc1)C2
Agent: Cl
Solvent: CCO
Product: Cc1cc(=O)n(C)c2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Yield: 93.4 %

Procedure:
To a mixture of 1,4-dimethyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.1 g) and aminoguanidine hydrochloride (41 mg) were added ethanol (3 ml) and 2N hydrochloric acid (0.2 ml), and the mixture was refluxed for 4 hours and concentrated under reduced pressure. To the residue was added ethanol (1 ml), and precipitated crystals were filtered, washed with ethanol and dried to give 1,4-dimethyl-5-guanidinoimino-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 137) (0.125 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:40])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:27](COCC[Si](C)(C)C)[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[CH:23]=[N:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:40])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[NH:27][C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[CH:23]=[N:22][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCn1cnc2nc(-c3ccc(OCC(=O)Nc4ccc(C#N)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCn1cnc2nc(-c3ccc(OCC(=O)Nc4ccc(C#N)cc4)cc3)[nH]c2c1=O
Yield: 57.2 %

Procedure:
The above compound N-(4-Cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide (0.110 g, 0.20 mmol) was taken in DCM (6 ml) and TFA (3 ml), stirred for 4 hrs at 27° C. The solvent was evaporated and the residue was washed with saturated NaHCO3 followed by water and n-pentane to obtain N-(4-cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide (0.049 g, 58%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.CS(C)=O.[C-:25]#[N:26].[K+]>O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:25]#[N:26])[N:8]=1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)NCCc1cccc[n+]1[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NCCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A mixture of 2-(2-acetylaminoethyl)pyridine N-oxide (70.8 g) and dimethyl sulfate (41 ml) was stirred at ambient temperature for 1.5 hours. To the mixture was added dimethylsulfoxide (420 ml) and potassium cyanide (25.6 g) and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added water and extracted with chloroform. The extract layer was dried over magnesium sulfate and evaporated in vacuo to give 2-(2-acetylaminoethyl)-6-cyanopyridine (74.3 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([NH:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Temperature: 92 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-nitro-benzenesulfonamide (2.20 kg, 9.30 mol), benzylamine (1.5 L, 13.9 mol), triethylamine (2.5 L, 18.1 mol), and acetonitrile (22.0 L) were heated at 92° C. for 20 h. The mixture was then cooled to 40° C., and was then partially concentrated in vacuo. The residue was added to 0° C. water (22.0 L) and the resulting suspension was allowed to warm to 23° C. and stirred for 2 h. The suspension was filtered and the solid was then washed with water (5 L). The washed solid was suspended in absolute ethanol (11 L), and was then filtered and washed with absolute ethanol (5 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-benzylamino-5-nitro-benzenesulfonamide (2.40 kg, 7.81 mol, 84%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.64 (2H, d, J=4.6 Hz), 6.81 (1H, d, J=9.4 Hz), 7.23-7.44 (6H, m), 7.77 (2H, bs), 8.11 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 8.49 (1H, d, J=3.1 Hz). LC-MS (ESI) calcd for C13H13N3O4S 307.06, found 308.2 [M+H+] (100%), 615.2 [2M+H+] (81%).
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[OH:7][C:6]1[CH:8]=[C:9]2[C:11]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][C:23](=[O:24])[O:10]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
Concentrated H2SO4 (65 ml) was added to a mixture of resorcinol (26.7 g, 242.4 mmol) and ethyl benzoylacetate (51.26 g, 266.7 mmol) at 0° C. The resulting suspension was stirred for 24 h at room temperature. Water (2 L) was added and the mixture was stirred for 1 h. The solid was filtered, washed with water (2 L) and dried to give 55.78 g of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:27]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[C:3]([O:23][CH3:24])[CH:4]=2)[CH:9]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH:26]=[CH2:25]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCc2cc(OC)c(O)cc2C1Cc1ccc(OC)c(OC)c1
Temperature: 80 °C

Procedure:
27.7 g. (84 mmol) (-)-7-Hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline in 430 ml. ethanol are mixed with 9.18 g. (75.9 mmol) allyl bromide and 17.6 g. (209 mmol) sodium bicarbonate. The reaction mixture is heated for 3 hours at 80° C., while stirring. After cooling and evaporating in a vacuum, the residue is partitioned between water and methylene chloride. The usual working up and chromatographic purification (silica gel; chloroform) gives 22.0 g. of a pale yellow foam. By crystallisation from isopropanol-diethyl ether, there is obtained (+)-2-allyl-7-hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline in the form of colourless crystals; m.p. 108°-112° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([O:21][CH2:20][CH2:19][NH:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc(CN2CC3(CN(C(=O)OC(C)(C)C)CCO3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Product: O=C1NCC2(CNCCO2)c2[nH]c(-c3ccnc(-c4cc5ccccc5o4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 1—1 using E8 and 2-benzofuraneboronic acid. The crude was purified by semi-preparative HPLC (method A) and isolated as a TFA-salt. MS (ES) C22H19N5O3 requires: 401. found: 402.1[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].[CH:24]1([NH:27][CH2:28][C@@H:29]2[C@H:33]([F:34])[CH2:32][NH:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH:24]1([NH:27][CH2:28][C@@H:29]2[C@H:33]([F:34])[CH2:32][N:31]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:23])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:3][C:2]=3[F:1])[CH2:30]2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)c21
Yield: 37.6 %

Procedure:
Using ethyl 6,7,8-trifluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylate (50.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (29.0 mg), the same procedure was followed as in Example 40 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (25.1 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CCN(CCO)CC2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N2CCN(CCO)CC2)n(C)c(=O)c1O
Reaction time: 10 h

Procedure:
To a solution of 5-benzyloxy-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.2058 g, 0.49 mmol) dissolved in EtOAc (20 mL) was added a small amount of palladium on carbon. The mixture was shaken under H2 at 40 psi for 10 hours, filtered over celite and concentrated to yield the title compound as a yellow waxy solid (0.0483 g, 30% yield). 1H NMR (500 MHz, MeOD) δ: 4.44 (2H, q, J=7.1 Hz), 3.75 (2H, t, J=5.9 Hz), 3.56 (3H, s), 3.22–3.21 (4H, m), 2.78 (4H, bs), 2.68 (2H, t, J=5.9 Hz), 1.41 (3H, t, J=7.2 Hz). HRMS (M+H) calcd for C14H23N4O5: 327.16685. found: 327.1661.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[NH2:16].[N:17]#[C:18]Br.N.C(Cl)(Cl)Cl>CO.O>[NH2:17][C:18]1[NH:16][C:3]2[CH:4]=[C:5]([O:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: CC(C)Oc1cc(N)c(N)cc1OC(C)C
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)Oc1cc2nc(N)[nH]c2cc1OC(C)C
Reaction time: 70 h

Procedure:
A solution of 1,2-diamino-4,5-di-isopropoxybenzene (2.24 g.) in methanol (40 ml.) was added to a mixture of cyanogen bromide (1.6 g.) in water (40 ml.). The mixture was stirred at 20°-25° C. for 70 hours and then basified by addition of an excess of aqueous ammonia solution (density 0.88). The mixture was then separated by filtration and the filtrate evaporated. The residue which was obtained was mixed with water (50 ml.) and chloroform (50 ml.). The chloroform phase was separated, dried (MgSO4) and evaporated. The residual gum obtained, was purified by chromatography on a column of silica gel (40 g.) using methanol-chloroform (1:3 v/v) as eluant, to give 2-amino-5,6-di-isopropoxybenzimidazole as a sticky solid (1.2 g.), having characteristic absorption bands at ν 3400, 3320, 3080, 1660 and 1565 cm-1, in the infra-red (IR) spectrum.