Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[N:23]OCC)[CH:20]=4)[NH:15][N:14]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:32][N:31]([CH2:30][C:29]1[N:23]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:12]=[CH:11][CH:10]=2)[NH:27][N:28]=1)[CH3:33]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CC4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclopropyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (377 mg, 0.89 mmol), N-amino-2-(dimethylamino)acetamide (315 mg, 2.69 mmol) and sodium methoxide (515 μL of a 25% w/w in methanol) in anhydrous methanol (5.0 mL) with a reaction time of 24 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a light orange solid. Further purification by preparatory TLC using 50% methanol in ethyl acetate afforded the title compound (145 mg, 40% yield) as an off-white powder. 1H NMR (DMSO-d6) δ 8.8 (br d, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.14–8.05 (m, 2H), 7.84 (d, 1H), 7.7–7.6 (m, 2H), 3.55 (s, 2H), 2.92–2.85 (m, 1H), 2.2 (s, 6H); ES-MS (m/z) 402 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])(O)[O:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[O:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1(c2cc(F)ccc2F)CC(c2ccccc2)N(Cc2ccccc2)O1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)N(Cc3ccccc3)O2)c1
Reaction time: 0.5 h

Procedure:
A mixture of (2E)-1-(2,5-difluorophenyl)-3-phenylprop-2-en-1-one (1-1) (500 mg, 2.05 mmol, 1 equiv) and N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was heated at reflux in ethanol (10 mL) for 4 h. Additional N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was added and the mixture was heated at reflux for 16 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenylisoxazolidin-5-ol (1-2); LRMS m/z (M+H) 368.3 found, 368.1 required. Methanesulfonyl chloride (0.093 uL, 1.20 mmol, 1.11 equiv) was added to a solution of (1-2) (400 mg, 1.09 mmol, 1 equiv) and triethylamine (0.455 mL, 3.27 mmol, 3.00 equiv) in dichloromethane (30 mL) at 0° C. and the resultant mixture was warmed to 23° C. and stirred for 30 min. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenyl-2,3-dihydroisoxazole (1-3) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.46-7.21 (m, 11H), 7.02 (m, 2H), 5.76 (t, 1H, J=3.0 Hz), 5.12 (d, 11H, J=2.8 Hz), 4.41 (d, 1H, J=12.8 Hz), 4.10 (d, 1H, J=12.8 Hz). LRMS m/z (M+H) 350.3 found, 350.1 required.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH2:26]([NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)[CH2:27][CH3:28]>>[OH:1][CH:3]([CH2:4][N:29]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)[CH2:26][CH2:27][CH3:28])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Reactant: CCCNCCc1ccc(OC)c(OC)c1
Product: CCCN(CCc1ccc(OC)c(OC)c1)CC(O)COc1ccc(-c2nc3ccc(OC)cc3c(=O)n2C)cc1

Procedure:
This compound was prepared analogous to Example 2 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one and N-propyl-2-(3,4-dimethoxyphenyl)-ethylamine.
Reaction SMILES: [CH2:1](C1C=CC=C(CC)C=1N)C.[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25][CH3:1])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCc1cccc(CC)c1N
Product: CCc1cc(C(=N)NO)cc(CC)c1O

Procedure:
The title compound is prepared from commercially available 2,6-diethylaniline following literature procedures (G. G. Ecke, J. P. Napolitano, A. H. Filbey, A. J. Kolka, J. Org. Chem. 22 (1957) 639-642; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]>N1CCCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCc2c(c[nH]c2C=C2C(=O)Nc3cccc(C4CCNCC4)c32)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 57.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (58.4 mg, 0.27 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (48 mg, 0.27 mmol) and piperidine (1 drop) in ethanol (1 mL) was stirred at room temperature for 7 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C([O-])(=[O:19])C.[Na+]>C(O)(=O)C>[OH:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 g of 4-bromomethyl-2'-cyanobiphenyl (EP 253,310), 150 g of sodium acetate and 2.5 litres of glacial acetic acid are heated to reflux overnight and the mixture is then concentrated in a high vacuum. The residue is taken up in ethyl acetate, extracted with water, sodium bicarbonate and brine and the solvent is evaporated on a rotary evaporator. The crude product is dissolved in 3.1 litres of ethanol, treated with 430 ml of 2N NaOH and stirred overnight at room temperature. The reaction mixture is concentrated, taken up in ethyl acetate, washed with water and sodium carbonate and concentrated. The residue is suspended in hexane, filtered off with suction, washed and dried at 60° in a high vacuum for 20 hours. 4-Hydroxymethyl-2'-cyanobiphenyl is obtained as a white powder. 1H-NMR (DMSO): 4.58 ppm (d, 2 H), 5.3 ppm (t, 1 H), 7.6-8 ppm (aromatics, 8 H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[O:21])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:5]1=[O:36])(=[O:3])[CH3:2].[CH3:37]I>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[O:21])=[C:13]([N:15]([CH3:37])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:5]1=[O:36])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(NS(C)(=O)=O)c2)C1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(N(C)S(C)(=O)=O)c2)C1=O

Procedure:
Using N-{5-(3-acetyl-2-oxoimidazolidin-1-yl)-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (93 mg) described in Example 596 and methyl iodide (12.3 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (15 mg) was obtained.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CN(C)[C:18](=[O:21])[CH:19]=[CH2:20].[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[S:23]1[CH:27]=[CH:26][C:25]2[C:18](=[O:21])[CH2:19][CH2:20][C:24]1=2
Reactant: c1ccsc1
Reactant: C=CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCCl
Product: O=C1CCc2sccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Over a period of 10 minutes a solution of triflic anhydride (84.7 g, 0.30 mol) in DCE (300 mL) was added to a cold solution of N,N-dimethylacrylamide (29.8 g, 0.30 mol) in DCE (2700 mL). The mixture was stirred for 15 minutes at 0° C. A solution of thiophene (25.3 g, 0.30 mol) was added and the mixture was refluxed for seven hours. A solution of potassium carbonate (150 g in 200 mL of water) was added. The mixture was extracted two times with DCM dried over sodium sulphate and evaporated under reduced pressure. The compound was purified by silica gel chromatography with ethyl acetate/hexane.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]([CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]([OH:28])=O)[NH:21]4)=[CH:13][O:14][C:10]=2[CH:9]=1)([CH3:3])[CH3:2].[NH2:31][CH:32]1[CH2:37][CH2:36][C:35]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)([OH:38])[CH2:34][CH2:33]1>>[OH:38][C:35]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)[CH2:36][CH2:37][CH:32]([NH:31][C:26]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[C:17]([O:16][CH2:15][C:12]2[C:11]4[CH:29]=[CH:30][C:8]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])=[CH:9][C:10]=4[O:14][CH:13]=2)[CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:33][CH2:34]1
Reactant: CC(C)OCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: CC(C)OCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(2-Isopropoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30e and amine 14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 80 °C

Procedure:
A suspension of EXAMPLE 4C (13.0 g, 29.9 mmol) and LiOH monohydrate (3.78 g, 90.0 mmol) in dioxane (250 mL) and water (100 mL) was heated at 95° C. for 16 hours, concentrated to dryness, treated with water (600 mL), heated to 80° C., and filtered. The filtrate was treated with 1M HCl (90 mL) and the resulting precipitate was collected by filtration and dried to give the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16](N(OC)C)=[O:17])(=[O:3])[CH3:2].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16](=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C(=O)N(C)OC)c(NC(C)=O)c2c1
Reactant: Br[Mg]c1ccccc1
Product: COc1ccc2[nH]c(C(=O)c3ccccc3)c(NC(C)=O)c2c1

Procedure:
The title compound was prepared in an analogous manner to the procedure described in step 3 of Example 125 employing 3-acetylamino-5-methoxy-2-(N-methoxy-N-methylamino)carbonyl indole (step 4) and phenylmagnesium bromide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1.[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+]>CO>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:17]([O-:20])(=[O:19])=[O:18])=[CH:4][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:21]
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)([O-])Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of α-bromo-4-fluoro-3-phenoxytoluene (4.86 g, 17.3 mmol) and sodium sulfite (2.39 g, 19 mmol) in 50% aqueous methanol (20 ml) is heated at reflux for 5 hours and cooled to room temperature. The resultant colorless solid is collected by filtration and washed with chilled 50% aqueous methanol and methanol to obtain 3.4 g of sodium (4-fluoro-3-phenoxyphenyl)methanesulfonate. Another 1.8 g of product is recovered from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:25]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23]C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:25]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[OH:23]
Reactant: COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Into the reaction flask was added 6-chloro-12-methoxy-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene (1.35 g, 3.82 mmol), methylene chloride (20 mL), and 1.0 M of boron tribromide in methylene chloride (19.1 mL). The reaction mixture was stirred at rt overnight. To the mixture was added 1.0 M of sodium bicarbonate in water (30 mL). The precipitate formed was collected by vacuum filtration. The cake was washed with water and methylene chloride, and air dried to provide the desired product (1.25 g, 96%). LCMS for C17H15ClN5O (M+H)+: m/z=340.1.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ccc(N)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NS(C)(=O)=O)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-amino-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])([O-:3])=[O:2].[Br:10]Br.O>CO>[Br:10][CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CC(=O)CCC[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Solvent: CO
Product: O=C(CBr)CCC[N+](=O)[O-]
Reaction time: 2 h
Yield: 55 %

Procedure:
80.0 g (0.61 mole) of 1-nitro-pentane-4-one are dissolved in 250 ml of anhydrous methanol, whereupon 31.5 ml (0.61 mole) of bromine are quickly added under cooling with ice. The reaction mixture is stirred for a further 2 hours at a rate that the internal temperature should not exceed 40° C. To the reaction mixture 250 ml of water are added, the reaction mixture is stirred at room temperature overnight. Next morning the solution is extracted three times with 300 ml of ether each, the etheral solution is washed with a 10 % sodium carbonate solution free of acid, whereupon it is washed three times with 200 ml of water each and 200 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatogaphy on a silica column and eluted with a 3:1 mixture of n-hexane and ethyl acetate. Thus 70.4 g of the desired compound are obtained in the form of a faint yellow liquid, yield 55%. Rf =0.30. IR(film) :2950, 1720, 640 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH2:44][NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[CH:48][CH:47]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:45]([CH2:44][C:32]1[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:31]=1)[C:46]1[CH:47]=[CH:48][C:49]([CH:52]([CH3:53])[CH3:54])=[CH:50][CH:51]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 65.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.94 g) and [(3,4-dibenzyloxyphenyl)methyl](4-isopropylphenyl)amine (2.5 g) as starting materials, 5-benzyloxy-N-[(3,4-dibenzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.64 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-[(3,4-dihydroxyphenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1.[OH-].[Na+]>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Reaction time: 1.5 h
Yield: 54.4 %

Procedure:
2-(Butyloxy)-8-(methoxy)-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (Isomer 2, 1.96 gm) was suspended in methanol (20 ml) and 4N HCl in dioxan (10 ml) added with stirring to give a clear solution. After 1.5 h, the solvents were evaporated to low volume and water added with stirring, followed by neutralisation with saturated sodium bicarbonate. The resulting off-white solid was filtered, washed with water and dried, yield 1.73 gm. Initial attempts to recrystallise from methanol or ethanol were unsuccessful. The recovered material was dissolved in glacial acetic acid (10 ml) with heating but precipitated immediately on addition of water (10 ml). Further addition of acetic acid (4 ml) and heating gave a clear solution, from which the product crystallised on allowing to cool. The solid was filtered, washed and dried, yield 1.06 gm (Crop 1). A second crop was obtained from the filtrate on standing, yield 460 mg, which was dissolved in sodium hydroxide and precipitated by the addition of acetic acid and then the recovered solid was heated in methanol (20 ml) with further additions of methanol (15 ml) to the boiling mixture to give a cloudy solution, which was allowed to cool. The resulting solid was filtered off, yield 257 mg. This was combined with the first batch of solid (Crop 1) and added portionwise to boiling methanol (130 ml) to give a slightly cloudy solution. On allowing to cool with stirring, a white solid crystallised out which was filtered off, washed with methanol and dried, to give the title compound yield 1.02 gm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].ClC(OC(Cl)C)=O>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCCN(Cc3ccccc3)C2)C2CCCCCC2)c1
Agent: CC(Cl)OC(=O)Cl
Product: N#Cc1cccc(N(C(=O)NC2CCCNC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
A mixture of N-(3-cyanophenyl)-N′-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (prepared in Example 60, 2.7 g, 6.98 mmol) and α-chloroethyl chloroformate (1.09 g, 7.65 mmol) was stirred at ambient temperature for 2.5 h, whereupon the reaction was complete as judged by TLC. The solvent was removed by evaporation in vaccuo and was replaced with methanol (40 mL). The reaction was heated at reflux until all of the newly formed intermediate was consumed as indicated by TLC. Evaporation of the solvent gave 2.49 g of N-(3-cyanophenyl)-N′-(piperidin-3-yl)cycloheptylurea; LRMS (M+H)+ m/z 299.
Reaction SMILES: [C:1]([NH:6][CH2:7][CH2:8][NH2:9])([O:3][CH2:4][CH3:5])=[O:2].[C:10]1([CH2:16][CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([NH:6][CH2:7][CH2:8][NH:9][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)NCCNCCCc1ccccc1
Yield: 36 %

Procedure:
A solution of 0.88 g of carboethoxyethylenediamine, 1.33 g of 3-phenylpropyl bromide and 1.0 g of anhydrous potassium carbonate in 10 ml of tetrahydrofuran was heated overnight under reflux. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to alumina column chromatography (25 g). Elution with hexane-ethyl acetate (3:1 v/v) gave 0.54 g of N-carboethoxy-N,,N,-bis(3-phenylpropyl)ethylenediamine (1) and 0.60 g of N-carboethoxy-N'-(3-phenylpropyl)ethylenediamine (2).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:33][OH:34]>C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[N:33][OH:34])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(C=NO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
To 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 5 ml of ethanol, 460 mg of sodium acetate and 290 mg of hydroxylamine hydrochloride, followed by stirring at room temperature for 15 hours and at 70° C. for 12 hours. The solvent was evaporated under a reduced pressure, and water was added to the resulting residue, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 300 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde oxime.