Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28][CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:29][S:28](=[O:40])[CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:18][CH:19]=3)[N:12]=2)=[CH:30][CH:31]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (103 mg, 0.24 mmol) was dissolved in DCM (3 mL). mCPBA (61.8 mg, 0.36 mmol) was added and the reaction was stirred at rt for 2 h. Water was added and the product was obtained by separating the organic phase and evaporating the solvent. The crude product was purified using preparative HPLC yielding 4-(4-fluorobenzyl)-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (21.0 mg, 18.9%). MS (ES+) m/z 448.1 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][NH:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][NH:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)([OH:5])=[O:3]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC3CC3C(=O)OCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CC3C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 24.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethoxycarbonyl)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (33 mg, 0.049 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.246 mL, 0.246 mmol). The mixture was heated to 85° C. for 22 h then was cooled to rt. An additional 0.25 mL of 1N NaOH was added to the mixture and it was again heated to 85° C. After stirring the mixture over the weekend, the reaction mixture was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. 1H NMR still showed impurities present, so the mixture was purified a second time by prep HPLC. The fractions containing the product were combined and concentrated under reduced pressure to give the title compound (8.3 mg, 0.012 mmol, 24.15% yield) as a white solid. LCMS: m/e 628.6 (M+H)+, 1.66 min (method 2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
23.8 g of 4-cyanophenol in 150 ml of dimethylformamide were added dropwise to a stirred suspension of 6 g of 80% sodium hydride in 100 ml of dimethylformamide and the mixture was then stirred for a further 1 hour. 39 g of ethyl bromoisobutyrate were added dropwise and the mixture was heated to 100° C. for 76 hours. The solvents were removed by evaporation and the residue was partitioned between diethyl ether and water. The organic phase was washed in succession with 2M sodium hydroxide solution and sodium chloride solution and then evaporated to give 9.4 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in the form of a colourless viscous liquid of boiling point 115°-117° C./0.05 mmHg.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH2:16][OH:17].[I-:18].[K+]>S(=O)(=O)(O)O.C(O)(=O)C>[I:18][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH2:16][OH:17]
Reactant: Nc1ccc(C(F)(F)F)cc1CO
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: OCc1cc(C(F)(F)F)ccc1I
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2-Iodo-4-(trifluoromethyl)aniline (8.0 g, 27.9 mmol), methanol (5 mL) and triethylamine (10 mL) were dissolved in dimethylformamide (50 ml) and, under a carbon monoxide atmosphere, tetrakis(triphenylphosphine)palladium (1.6 g, 1.4 mmol) was added and the mixture was stirred at 50° C. for 5 days. The solvent was evaporated and work-up according to a conventional method gave a crude product of methyl 2-amino-5-(trifluoromethyl)benzoate. The obtained crude product was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (1.0 g, 26.3 mmol) was added under cooling, and the mixture was stirred for 2 hrs. Water (1 ml), 30% aqueous sodium hydroxide solution (1 ml) and water (3 mL) were sequentially added, the precipitate was filtered off, and the filtrate was concentrated to give a crude product of [2-amino-5-(trifluoromethyl)phenyl]methanol. Sodium nitrite (59 mg, 0.86 mmol) was dissolved in conc. sulfuric acid (0.77 mL) and, after cooling, a solution of a crude product (0.15 g, 0.78 mmol) of [2-amino-5-(trifluoromethyl)phenyl]methanol in acetic acid (1.72 ml). After stiring for 30 min. 10% aqueous potassium iodide solution (4.64 mL) was added. After stirring with heating at 70° C. for 30 min, the mixture was worked-up according to a conventional method, and the obtained crude product was purified by silica gel column chromatography (5% to 7.5% ethyl acetate/hexane) to give the title compound (96 mg, 0.32 mmol, 40%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[OH:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26](C)([O-])C.[K+].C(I)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[C:21]([O:24][CH2:25][CH3:26])[CH:20]=[CH:19][CH:18]=3)[CH:23]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 37 g (0.116 mol) of 7-(4-benzyl-piperazin-1-yl)-naphthalen-1-ol and 15 g (0.134 mol) of potassium tert.butoxide in 150 ml of dimethylformamide is stirred for 30 minutes at ambient temperature and then slowly combined with 11 ml (0.135 mol) of ethyl iodide. It is then stirred for 14 hours at ambient temperature. Then the reaction mixture is concentrated by evaporation and the residue is extracted with dichloromethane and water. It is filtered through aluminium oxide, dried over sodium sulphate and the solvent is distilled off. The residue is recrystallised from isopropanol.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]([C:15]1[S:16][C:17]([S:30][CH3:31])=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7].[Li]CCCC.CN(C)[CH:40]=[O:41]>C1COCC1>[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]([C:15]1[S:16][C:17]([S:30][CH3:31])=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:40]=[O:41])[CH:24]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
A solution of 2 M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added dropwise at 0° C. to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol) (Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0° C., then cooled to −78° C. and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5 mmol) was added. The mixture was stirred for 5 mins then N,N-dimethylformamide (0.30 mL, 3.8 mmol) was added at −78° C. and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3×20 mL), dried over Na2SO4 and evaporated. The crude solid was purified by elution from a 20 g SPE with 50% EtOAc/hex to give 0.33 g (75%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.48 (s, 1H), 8.26 (m, 1H), 8.10 (m, 1H), 8.06 (s, 1H), 7.71 (s, 1H), 2.50 (s, 3H), 1.51 (s, 9H). Mass spectrum (ESI, m/z) calcd. for C18H20N2O5S3 440.1, found 440.8 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](O)(=[O:24])=[O:23])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N:41]1C=CC=CC=1>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](=[O:24])(=[O:23])[NH2:41])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: c1ccncc1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)O)cc1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
1.2 g of 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulpho-biphenyl are stirred with 10 ml of pyridine at 60° C. for 1 hour. The solution is then evaporated down, the residue is stirred with acetone and suction filtered. It is then taken up in 15 ml of thionylchloride and stirred for 1 hour at 60° C. After evaporation the residue is taken up in 10 ml of dimethylformamide and stirred into 10 ml of dimethylformamide saturated with ammonia. After 15 minutes stirring at ambient temperature the mixture is evaporated down and chromatographed on silica gel with dichloromethane/ethanol (98:2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Oc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(OC2CCN(Cc3ccccc3)CC2)c1

Procedure:
The title compound was prepared from 1-benzyl-4-hydroxypiperidine and 3,5-difluorophenol, using the same method as that described for preparation 43. The crude compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 95:5, to afford the desired product in 63% yield. LRMS APCI m/z 304 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[C:22]2[C:24]=1[C:15]([CH3:17])=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10](=[O:12])[NH:23]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: COc1cc(OC)c2c(C)c(CCc3ccccc3)c(=O)[nH]c2c1
Temperature: 80 °C

Procedure:
Ethyl 2-(2-phenylethyl)acetoacetate (2.70 g) in xylene (5 ml) was treated with 3,5-dimethoxyaniline (1.60 g) at 150° C. as described in example 19a. Methanesulfonic acid (4.0 ml) was added at room temperature and the mixture heated at 80° C. for 1 hour. The product was isolated as described in example 19a. Yield 1.38 g (41%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[NH:30])[NH2:29])[CH2:23]1.CC(C)([O-])C.[K+]>C(O)C.O>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:3][N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:30]=1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1cccnc1
Reactant: CC1CCCN(C(=N)N)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1occc1-c1nc(N2CCCC(C)C2)ncc1-c1cccnc1
Temperature: 25 °C
Yield: 8.4 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(3-pyridinyl)-2-propen-1-one (256 mg, 1 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (267 mg, 1.5 mmol) in ethanol (5 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate and isohexane to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(3-pyridinyl)pyrimidine (28 mg, 8%). A solution of 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(3-pyridinyl)pyrimidine (28 mg, 0.084 mmol) in dichloromethane (1 ml) was treated with hydrogen chloride (1M in diethyl ether, 0.1 ml). The solvent was evaporated and the residue co-evaporated with dichloromethane (×2). The resulting solid was dried to give the title compound as a solid (24 mg, 77%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.75-8.73 (2H, m), 8.45 (1H, s), 8.17 (1H, d), 7.86-7.82 (1H, m), 7.45 (1H, d), 5.87 (1H, d), 4.65-4.59 (2H, m), 3.02-2.95 (1H, m), 2.71-2.65 (1H, m), 2.38 (3H, s), 1.91-1.18 (5H, m), 0.92 (3H, d).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]([NH2:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:26][C:27]([NH2:29])=[O:28])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
A mixture of 1-benzyl-3-(4-chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.05 mmol), 2-bromo-acetamide (8 mg), and Na2CO3 (15 mg) in acetone (2 mL) was stirred at 25° C. for 16 h. After concentration, purification by flash chromatography (2 M NH3/MeOH in CH2Cl2) provided the desired compound (6 mg). MS (ESI): exact mass calculated for C22H23ClN4O, 394.16; found, m/z 395.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 2H), 2.76-2.74 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH2:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[NH:26])[CH2:20][CH3:21].C(N(CC)CC)C>C(#N)C>[C:13]1([C:4]2[N:3]=[C:2]3[N:26]=[C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[O:22][CH2:19][CH2:20][CH3:21])[NH:27][C:8](=[O:10])[C:7]3=[CH:6][N:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1-c1nc2nc(-c3ccccc3)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 28 reaction of ethyl 4-chloro-2-phenyl-5-pyrimidine carboxylate (1.05 g) with 2-propoxybenzamidine (from sodium, 0.10 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.40 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product which was recrystallized from methanol to yield the title compound, 0.52 g, m.p. 203-4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O>C(O)CCCC>[CH2:9]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:14][CH2:13][CH2:12][CH2:17][CH3:16])=[O:6])[CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCCO
Product: CCCCCNc1cc(C(=O)OCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (6 g), n-pentanol (60 ml), and conc. sulphuric acid (0.5 ml) was refluxed for 24 hours. After cooling, the precipitated n-pentyl 3-pentylamino-4-phenoxy-5-sulphamyl-benzoate was isolated by filtration and recrystallized from n-pentanol. After drying in vacuo, the compound was obtained with a melting point of 138°-139° C.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:7](=[O:8])[O:6][CH2:5][C@@H:4]1[CH2:9][C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1.Cl.[OH-:17].[Na+:18].Cl>O>[CH3:1][CH2:2][C@@H:3]([C:7]([O-:6])=[O:8])[C@H:4]([CH2:5][OH:17])[CH2:9][C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1.[Na+:18]
Reactant: CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pilocarpine hydrochloride (3.92 g; 16.00 moles) was dissolved in distilled water (4 ml) and the solution was cooled to about 0° C. To the solution 18 ml of ice cold 2M NaOH were added in four portions. The solution was left standing at about 0° C. for one hour. After neutralizing excess NaOH with 5 ml of 1M HCl, the solution was evaporated under reduced pressure. The residue was dissolved in 60 ml of absolute ethanol and mixed for 10 minutes at 60° C. After cooling to 4° C. undissolved NaCl was removed by filtration. The filtrate was evaporated under reduced pressure, whereby 3.93 g of sodium pilocarpate were obtained as a white, extremely hygroscopic substance.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[C:24]([Br:25])=[CH:23][C:14]2[O:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[O:18][C:13]=2[CH:12]=1>>[Br:25][C:24]1[C:11]([Br:10])=[CH:12][C:13]2[O:18][C:17]([F:20])([F:19])[C:16]([F:21])([F:22])[O:15][C:14]=2[C:23]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC1(F)Oc2cc(Br)c(Br)cc2OC1(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Br)c(Br)cc2c1OC(F)(F)C(F)(F)O2
Temperature: 5 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A precooled mixture of 19 ml of nitric acid and 26 ml of concentrated sulphuric acid is slowly added dropwise at 5° C. to 73 g (0.2 mol) of 6,7-dibromo-2,2,3,3-tetrafluoro-benzo (1.4)dioxane. The mixture is subsequently stirred at 5° C. for 4 hours, poured onto ice and extracted thoroughly with ether, the extract is washed with water and sodium hydrogen carbonate solution (until neutral), and dried over magnesium sulphate, and the ether is removed. 72 g (88% of theory) of 6,7-dibromo-5-nitro-2,2,3,3-tetrafluoro-benzo(1.4)dioxane having the melting point 91° to 92° C. are isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>CN(C)C1C=CN=CC=1.O1CCCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:34]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 1.45 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 1.86 mL of triethylamine and 162 mg of 4-dimethlaminopyridine in 150 mL of tetrahydrofuran at 20° C. is added 1 g of 1-fluoro-2-isocyanato-4-methylbenzene. The reaction is stirred for 3 hours 30 minutes at 60° C., and then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of water and dichloromethane. The organic phase is washed with 1N HCl solution and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 2.13 g of a white powder of 1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.Cl[C:21](=[O:27])[C:22](OCC)=[O:23].O>ClCCl>[CH:1]1([CH2:4][N:5]2[C:22](=[O:23])[C:21]([OH:27])=[N:12][C:11]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]2=3)[CH2:2][CH2:3]1
Reactant: Nc1cccnc1NCC1CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=c1c(O)nc2cccnc2n1CC1CC1
Yield: 33 %

Procedure:
To 1.6 g (9.8 mM) of N2-(cyclopropylmethyl)pyridine-2,3-diamine and 1.7 ml (9.8 mM) of diisopropylamine in 20 ml of dichloromethane were added, drop by drop, under stirring; at room temperature, 1.1 ml (9.8 mM) of ethyl chloro(oxo)acetate. The reaction mixture was stirred at room temperature for 16 h and water was added. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography using dichloromethane/methanol (95/5) as eluant, which afforded after evaporation 700 mg of 4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one as a solid. Yield: 33%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CCNCc1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(Cc1ccco1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
Ethyl 3-[(furan-2-ylmethyl)amino]propionate (10.8 g) prepared in the step 2 and 18.3 mL of triethylamine were dissolved in 180 mL of methylene chloride, 7.14 g of ethyl chloroformate was added by slowly dropping thereinto under cooling with ice and the mixture was stirred at room temperature for 5 hours. Water (200 mL) was added to the reaction solution and the mixture was subjected to extraction with methylene chloride. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom. The residue was purified by silica gel column chromatography to give 13.77 g of the objective compound as yellow liquid.