Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.C(OCC)C.CO>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[N:13]=[C:12]([OH:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOCC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)cc3)c(=O)c12
Temperature: 150 °C
Yield: 68.9 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (0.800 g, 2.16 mM) was stirred in methanesulfonic acid (16 mL) to give an amber solution. This solution was heated to 150° C. for 6 hours and cooled to room temperature. Addition of ethyl ether (250 mL) and methanol (50 mL) gave a tan precipitate. The solid was collected and washed with methanol/ether to give the title compound (0.530 g, 51%) as a tan powder, mp 316-318° C.; MS(CI): 356 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Fc1ccc(Cc2cc(Cl)ncn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccc(F)cc2)ncn1
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.08 g of 2-butyn-1-ol was added, followed by stirring for 15 minutes. Then, 0.2 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(4-fluorobenzyl)pyrimidine was slowly added dropwise, followed by further stirring at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(4-fluorobenzyl)pyrimidine (the present compound (143)).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20]C(=O)C)=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C[O-].[Na+]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Temperature: 70 °C
Yield: 73.6 %

Procedure:
N[4-(Thiazol-2-ylsulfamoyl)-naphthalen-1-yl]acetamide (0.48 g, 1.38 mmol) was dissolved in 0.5 M NaOMe (20 ml) and heated at 70° C. for 16 h. After the solvents were evaporated, a 2:1 EtOH:H2O mixture (6 ml) and a few drops of AcOH were added. While stirring the mixture, a precipitate formed which was filtered and dried under vacuum to give 4-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide (0.31 g, 73%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=306.0; tR=2.04 min.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][C@H:22]2[CH2:42][CH2:41][C:24]3([O:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@@H:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:25]3)[CH2:23]2)[C:18]([OH:20])=O)[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][C@H:22]2[CH2:42][CH2:41][C:24]3([O:28][C@H:27]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@@H:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:25]3)[CH2:23]2)[C:18]([N:4]([O:3][CH3:2])[CH3:5])=[O:20])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (936 mg) in acetonitrile (40 mL) was neutralized with triethylamine (3.35 mL), and 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoic acid (4.33 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.30 g) and 1-hydroxybenzotriazole (612 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.05 g, yield 69%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH2:2][CH2:3][CH3:4].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:14][N:15]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCOC(=O)CCCCCBr
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)CCCCCN(C)c1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 111 g (0.44 mol) of butyl-6-bromohexanoate (Example 21), 50 g (0.46 mol) of N-methylaniline, 63.9 g (0.46 mol) of anhydrous potassium carbonate, 3.6 g (0.022 mol) of potassium iodide, and 500 mL of butanol was heated at reflux with stirring for 60 hours. The resulting suspension was cooled and filtered, and the solid was extracted with ethyl acetate. The extract was combined with the filtrate and the solvents were removed by rotary evaporation. The residue was distilled in vacuo, bp 183°-188° C. (0.1 mm). A slightly yellow oil was obtained, mass 60 g (50%).
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:6])[O:3]CC.O>Cl>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:3])[OH:6]
Reactant: CCOP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: CP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Ethyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (1 g) in 20 ml of 6N hydrochloric acid is heated under reflux overnight. The solution is then poured into water and extracted with methylene chloride. The combined solvent extracts are dried over magnesium sulfate and the solvent is then evaporated off to give P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=O)[CH2:3][CH2:2]1.O.C(N(CC)CC)C>O1CCCC1>[CH:1]1([NH:4][CH2:5][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](CNC2CC2)[C@H](O)C1
Reaction time: 7 h
Yield: 103.5 %

Procedure:
To a solution of benzyl(3R,4S)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (14.5 g, 47.6 mmol) in 116 mL of dehydrated tetrahydrofuran, 122 mL of a tetrahydrofuran solution of borane-tetrahydrofuran complex (1.17 mol/L, 143 mmol) was added dropwise over 20 minutes at an internal temperature of 40 to 44° C. The mixture was stirred at the same temperature for 7 hours. Subsequently, the reaction mixture was cooled to an internal temperature of 25° C. or below. At an internal temperature of 15 to 25° C., 14.5 mL of water was added dropwise and the mixture was stirred for 20 minutes. At an internal temperature of 10 to 18° C., 39.8 mL of triethylamine (286 mmol) was added dropwise and the mixture was stirred for 5 minutes. The mixture was then refluxed for 15 hours. Subsequently, the mixture was allowed to cool and concentrated under reduced pressure. To the resulting residue, 44 mL of water was added and the mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of water and extracted with 60 mL of 2 mol/L hydrochloric acid. The aqueous layer was cooled in a water bath under stirring and 60 mL of a 2 mol/L sodium hydroxide solution was added at an internal temperature of 20 to 28° C. to adjust the pH to about 12. This mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of 28% brine. To the organic layer, 20.2 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. Subsequently, the mixture was filtered through a cotton plug and washed with 22 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The product was dried at room temperature under reduced pressure for 1 hour to give 14.3 g of a crude product of the title compound as a pale yellow oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].N1C=CC=CC=1.[C:20]1([C:33](Cl)=[O:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:10][C:33]([C:20]2[C:32]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:34])[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(-c2cnccn2)c1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2cnccn2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a suspension of 3-(pyrazin-2-yl)aniline (0.12g) and pyridine (0.17ml) in dichloromethane (3ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.16 g) in dichloromethane (3 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyrazin-2-yl)phenyl)-9H-fluorene-1-carboxamide (0.193 g; 76.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:14]1C=CC(Br)=CC=1.[Li]CCCC.CCCCCC.C1(=O)CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C1CCCC1
Product: OC1(c2ccc(Br)cc2)CCCC1
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to 1-(4-bromo-phenyl)-cyclobutanol (described in example S97) using 3 g of 1,4-dibromobenzene (12.7 mmol), 7.95 ml of a 1.6 molar solution of n-BuLi in hexane (12.7 mmol) and 1.24 ml of cyclopentanone (14.0 mmol). The isolated residue was purified by flash column chromatography (1:4 diethyl ether/pentane) to give 1.2 g of 1-(4-bromo-phenyl)-cyclopentanol (39%) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].O1COCO[CH2:13]1.FC(F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.CCOCC>C1COCC1>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:13])[C:6]2=[O:11]
Reactant: C1OCOCO1
Reactant: O=C1CCc2c(O)cccc21
Agent: C[NH2+]c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1Cc2c(O)cccc2C1=O

Procedure:
To a solution of 4-hydroxy-1-indanone (1 g; 6.7 mmol) in THF were added, at ambient temperature and under argon, powdered 1,3,5-trioxane (1.2 g; 13.4 mmol) and N-methyl-N-phenylammonium trifluoroacetate (2.9 g; 13.4 mmol). The suspension was refluxed for 4 hours. Ether was added to the mixture and the resulting precipitate was filtered off. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (8/2) to give 4-hydroxy-2-methylene-1-indanone as a beige solid (0.76 g; 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.N1C=CC=CC=1.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39].C(O)(=O)C>ClCCl.O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:29])[F:30])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCS(=O)(=O)Cl
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(NS(=O)(=O)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [3-(4-aminobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.051 g), pyridine (0.019 mL) and dichloromethane (0.5 mL) at 0° C. was treated with ethanesulfonyl chloride (0.013 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water, and then acidified by the addition of glacial acetic acid. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure to afford title compound as a yellow gum (0.051 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:21]=[N-:22])=[CH:16][C:15]=2[OH:23])=[CH:8][N:7]=1.[I-:26].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([I:26])[C:17]([N:20]=[N+:21]=[N-:22])=[CH:16][C:15]=2[OH:23])=[CH:8][N:7]=1
Reactant: [I-]
Reactant: COC(=O)COc1ccc(NC(=O)c2ccc(N=[N+]=[N-])cc2O)cn1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)c2cc(I)c(N=[N+]=[N-])cc2O)cn1
Reaction time: 0.17 h

Procedure:
To a suspension of (5-(4-azido-2-hydroxybenzoylamino)pyridin-2-yloxy)acetic acid methyl ester (22 mg, 0.064 mmol) in DMF (1 mL) was added sodium iodide (11 mg, 0.07 mmol) and chloramine T (51 mg, 0.22 mol). The reaction mixture turned homogeneous and after 10 minutes, the mixture was poured into water and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue that was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes as eluant). This gave 7.8 mg (26%) of (5-(4-azido-2-hydroxy-5-iodo-benzoylamino)-pyridin-2-yloxy)-acetic acid methyl ester as an off-white solid: 1H NMR (300 MHz, acetone-d6) δ 9.92 (bs, 1H) 8.40 (m, 1H), 8.33 (s, 1H), 8.05 (m, 1H), 6.92 (m, 1H), 6.87 (s, 1H), 4.90 (s, 2H), 3.69 (s, 3H); MS (EI) m/z 467.97 (M−H)−.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:25][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(-c2ccccc2CN[C@H]2CCCc3ccccc32)cc1

Procedure:
[1,1′-Biphenyl]-2-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.CCOC(C)=O.[Pd]>[CH:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1cccc(C2(O)CCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(C2CCC2)c1
Yield: 89 %

Procedure:
A mixture of 1-(3-methoxy-phenyl)-cyclobutanol and 10% Pd/C (60 mg) in ethanol (10 ml) was hydrogenated under 45 psi hydrogen atmosphere for 3 hours. The mixture was diluted with EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-cyclobutyl-3-methoxy-benzene (162 mg, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and pyrrolidine (0.032 ml, 0.39 mmol). Pale yellow solid (60 mg, 71%). LC-MS (ESI): 429 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[NH:13][N:14]=[C:15](Cl)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[I:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][CH2:1][CH2:2][C:3]3[N:13]([N:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=3)[C:7]=2[CH:8]=1
Reactant: C#CCCOc1ccc(I)cc1NN=C(Cl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Temperature: 125 °C
Yield: 73.9 %

Procedure:
To a solution of ethyl 2-{2-[2-(but-3-yn-1-yloxy)-5-iodophenyl]hydrazin-1-ylidene}-2-chloroacetate (3.9 g, 9.27 mmol) in toluene (800 ml) was added triethylamine (13 ml, 9.32 mmol) and the mixture was then stirred under reflux (heating block at 125° C.) for 18 hours. After cooling to ambient temperature water (100 ml) and ethyl acetate (100 ml) were added and the mixture was transferred into a separation flask. The organic layer was separated, washed with brine (200 ml), dried over MgSO4, filtered and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 0-20% ethyl acetate in heptane) provided 2.63 g (74%) of the title compound as crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.43 (3H, t, J=7.17 Hz), 3.09 (2H, t, J=6.03 Hz), 4.45 (2H, q, J=7.17 Hz), 4.53 (2H, t, J=6.10 Hz), 6.81 (1H, s), 6.93 (1H, d, J=8.54 Hz), 7.61 (1H, dd, J=8.54, 2.14 Hz), 8.28 (1H, d, J=2.14 Hz);); M+1=385
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](O)=[O:26].S(Cl)(Cl)=O.C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])/[N:7]([CH2:11][C:12]2([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1cn(CC2(O)CCCCC2)c(=N)s1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1(O)CCCCC1
Yield: 51.4 %

Procedure:
The product of Example 20A (1.3 g, 3.7 mmol), 5-chloro-2-methoxybenzoic acid (0.70 g, 3.7 mmol), thionyl chloride (10 mL) and triethylamine (1.6 mL, 11 mmol) in THF (25 mL) were processed as described in Example 18B and Example 18C to provide the title compound (0.82 g, 1.9 mmol, 50% yield). MS (DCI/NH3) m/z 437 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4)CC3)cccc2n1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
In a 20 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and benzyl bromide (45 mg; 0.27 mmol) in N,N-dimethylformamide and heated to 60° C. for 16 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol to obtain 43.1 mg of title compound. (64% yield).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:6]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(N)cc1

Procedure:
The mixture of 2 g of 4-(4-acetamidophenylamino)-3-n-butylamino-5-sulfamoylbenzoic acid and 50 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. It is cooled, filtered and the filtrate acidified with glacial acetic acid to a pH of 4-5. The mixture is cooled in an ice bath, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-n-butylamino-5-sulfamoylbenzoic acid of the formula ##SPC8##