Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.[OH:29][C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:35]([C:34]1[C:30]([O:29][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)=[N:31][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:36]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)s1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A mixture of ethyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (4.63 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.07 g), anhydrous potassium carbonate (1.52 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless crystals (5.50 g, yield 87%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 156-157° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([F:15])[CH:3]=1.Cl>CO.O>[NH2:9][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([F:15])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1c(O)c(Br)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Bromo-4-fluoro-2,3-dinitrophenol (4.4 g, 16 mmol) was stirred in methanol (88 mL) and 12.0 M hydrogen chloride in water (40 mL), followed by addition of stannous chloride dihydrate (11 g, 47 mmol) and the mixture was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated and concentrated. Purification on silica gel eluting ethyl acetate in hexanes gave the amine product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]2[CH:19]3[CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23][CH:18]3[N:6]3[CH2:7][CH:8]([CH3:17])[N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (100 mg, 0.22 mmol) in DMF (10 mL) was added 2,4-dichlorophenyl boronic acid (63 mg, 0.33 mmol) and Na2CO3 (58 mg, 0.55 mmo, in 0.4 mL of H2O). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(PPh3)4 (35 mg, 0.03 mmol) and the mixture was stirred at 100° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 29% yield) MS [M+H]+ 517.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH:7][CH:8]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH:8]([OH:7])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][CH2:12]1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN1CCN(N)CC1

Procedure:
A solution of hydroxylamine-O-sulfonic acid (0.17 g, 1.5 mmol) in 1:1 tetrahydrofuran-water (10 mL) is added dropwise to a mixture of 1-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine (3.0 g, 7.3 mmol) and sodium hydroxide (0.29 g) in 1:1 tetrahydrofuran-water (30 mL) at 15° C. over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 15° C. for 2 hours. Three additional portions of NaOH (0.29 g each) are then added to the mixture. The reaction mixture is extracted with dichloromethane, dried over NaOH, concentrated and chromatographed to afford 1-N-Amino-4-N-[2'-hydroxy-3'-octadecyloxypropyl]-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[O:6][C:7]3[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=3[C@@H:9]3[CH2:13][C@@H:12]([CH2:14][N:15]4[CH2:20][CH2:19][N:18]([C:21](=[O:26])C(F)(F)F)[CH2:17][CH2:16]4)[O:11][N:10]3[C:4]=2[CH:3]=1.[C:33](=[O:36])([O-:35])[O-].[K+].[K+].C[OH:40]>O>[C:21]([OH:26])(=[O:40])[C:33]([OH:35])=[O:36].[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[O:6][C:7]3[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=3[C@@H:9]3[CH2:13][C@@H:12]([CH2:14][N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[O:11][N:10]3[C:4]=2[CH:3]=1
Reactant: O=C(N1CCN(C[C@@H]2C[C@H]3c4ccccc4Oc4ccc(Cl)cc4N3O2)CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: [K+]
Solvent: O
Product: Clc1ccc2c(c1)N1O[C@H](CN3CCNCC3)C[C@H]1c1ccccc1O2
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of (±)-cis-1-[(11-chloro-3,3a-dihydro-2H-dibenz[b,f]isoxazolo[2,3-d][1,4]-oxazepin-2-yl)methyl]-4-(trifluoroacetyl)piperazine (7.1 g), prepared following the procedure of example 7, and potassium carbonate (4.2 g) in methanol (300 ml) and water (43 ml) was stirred at RT for 2 hours. The solvent was evaporated. The residue was treated with water, extracted with CH2Cl2 and the separated organic layer was evaporated. The residue (5.1 g) was purified by flash chromatography over silica gel (eluent: CH2Cl2 /CH3OH 9/1, 8/2 to 7/3) and the pure fractions were collected and evaporated. The residue (4.2g) was converted into the oxalic acid salt (2:3) in C2H5OH at room temperature, yielding 3.9 g (47%) of (±)-cis- 11-chloro-3,3a-dihydro-2-(1-piperazinylmethyl)-2H-dibenz[b,f]isoxazolo[2,3-d][1,4]oxazepine ethanedioate(2:3); mp. >250.0° C. (comp. 3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([I:17])=[C:13]([CH:16]=1)[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([I:17])=[C:13]([CH:16]=1)[CH2:14][O:15][C:18](=[O:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cc(OCc2ccccc2)ccc1I
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 12 h

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromathane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dicholomethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na); Rf=2.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.COC(OC)[N:16]([CH3:18])C.O.[NH2:22]N>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[N:16][NH:22][C:10]=2[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn[nH]c2C)cc1
Temperature: 25 °C

Procedure:
To p-Methoxy phenylacetone (1 eq) was added dimethylformamide dimethylacetal (1.5 eq) and the mixture was stirred at reflux overnight. The reaction was cooled to room temperature and diluted with ethanol. Hydrazine hydrate was added (3 eq) and all was heated to 85° C. over night. Once cooled the reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 4-(4-methoxy-phenyl)-5-methyl-1H-pyrazole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.II.[Cl:13]Cl>>[Cl:13][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClCl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: II
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 99 %

Procedure:
141 G of 4-fluoronitrobenzene, 3.8 g of ferric chloride and 0.2 g of iodine were charged and then heated. At a temperature of 60° to 70° C., chlorine gas was blown into the liquid until the starting material could not be detected (over 12 hours) to complete the reaction. Subsequently, the reaction mixture was washed three times with 100 g each of warm water followed by liquid separation to obtain 174 g (yield: 99%) of 3-chloro-4-fluoronitrobenzene. Analytical value thereof by gas chromatography was as follows:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([NH:17][C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:25])[F:24])[CH:12]=3)[CH2:19]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: FC(F)(F)c1cccc(NC2CCCNC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(NC2CCCN(c3ccc(Cl)nn3)C2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 4.5 parts of 3,6-dichloropyridazine, 4.9 parts of N-[3-(trifluoromethyl)phenyl]-3-piperidinamine, 6.4 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue Was crystallized from 2-propanol. The product was filtered off (the filtrate was set aside) and dried, yielding 1.2 parts (16.8%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine: mp. 92.6° C. (compound 146). The filtrate, which was set aside, was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 2.6 parts (32.9%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine monohydrochloride; mp. 173.5° C. (compound 147).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
4-Methoxypyridine-N-oxide hydrate (1 g, 6.99 mmol) dissolved in dichloromethane (4 ml) was added with trimethylsilyl cyanide (1 ml, 7.69 mmol) and subsequently added dropwise with N,N-dimethylcarbamoyl chloride (0.8 ml, 9.09 mmol) under ice cooling. The reaction solution was warmed to room temperature, stirred for 1 hour, and then added further with trimethylsilyl cyanide (0.2 ml, 1.40 mmol). The reaction solution was stirred for 19 hours, then added with 10% potassium carbonate (2 ml). The mixture was diluted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting crystals were washed with hexane to obtain 560 mg (60%) of the title compound as pink crystals without purification.
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:16][O-:17].[Na+]>C(COC)OC.CO.C(OCC)(=O)C>[CH3:16][O:17][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: Cc1ccccc1-n1c(Cl)nn(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nn(C)c(=O)n1-c1ccccc1C
Yield: 95 %

Procedure:
8.25 g 5-chloro-2,4-dihydro-2-methyl-4-(2-methylphenyl)-3H-1,2,4-triazol-3-one was dissolved in 80 mL 1:1 dimethoxyethane/methanol under N2. 14.0 mL sodium methoxide (30% solution in methanol) was added and the solution was heated at reflux for 3 h. The mixture was allowed to cool, diluted with ethyl acetate, washed with water, then saturated aqueous NaCl. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (50-70% ethyl acetate/hexanes as eluent) and triturated with 50% diethylether/hexanes to afford 6.7 g of the title compound of Step C (95% pure). 1H NMR (CDCl3) δ 7.35-7.27 (m,3H), 7.18 (d,1H), 3.94 (s,3H), 3.46 (s,3H), 2.22 (s,3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:34](=[O:36])[CH3:35])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 15 h

Procedure:
50 mg of 4-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]butan-1-ol was dissolved in 1 ml of dichloromethane, mixed with 0.34 ml of pyridine and 20 μl of acetyl chloride and stirred for 15 hours. It was mixed with saturated sodium bicarbonate solution, diluted with water, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified using thick-layer chromatography.
Reaction SMILES: [N:1]1([CH2:7][C@H:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[ClH:14].[O:13]=[S:12]1[O:11][C@@H:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:9][O:10]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@@H](O)CN1CCOCC1
Solvent: ClCCl
Product: Cl
Product: O=S1OC[C@H](CN2CCOCC2)O1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (2S)-3-(4-morpholinyl)-1,2-propanediol (0.90 g, 5.6 mmol) in CH2Cl2 (7.5 mL) was cooled to 0° C. and added thionyl chloride (0.81 mL, 11.1 mmol, 2.0 equiv.) was added dropwise. The resulting solution was heated at the reflux temperature for 1 hr, cooled to room temperature and concentrated under reduced pressure to give 4-[(4S)-(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride (1.40 g, 103%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:28]1[N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:25]=[C:26]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[CH:27]=1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 74.1 %

Procedure:
Compound 43 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[3-chloro-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.30 g, 0.59 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.34 g of crude product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C@H:9]2[C@@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:20]([O:15][C@H:14]1[C@@H:13]([CH2:16][O:17][CH2:7][C:6]2[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=2)[O:12][CH:11]=[CH:10][C@H:9]1[O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CO[C@@H]2C=CO[C@H](CO)[C@@H]2O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2C=CO[C@H](COCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 3-O-(4-methoxybenzyl)-D-galactal (2.28 g, 8.56 mmol) and benzyl bromide (3.75 mL, 3.68 mol equiv; freshly passed through basic alumina) in DMF (30 mL) under N2 at 0° C. was treated with NaH (1.37 g, 4.0 mol equiv) in two portions. The reaction was stirred 0.5 h at 0° C. and 1 h at rt. The reaction was carefully poured into 50 g of crushed ice, diluted to 100 mL with water, then extracted with EtOAc-hexanes (1:1, 100 mL×3). Organic extracts were washed with water (100 mL×2), dried (Na2SO4) and concentrated. Flash chromatography with 15% EtOAc-hexanes gave 3.58 g (94%) of the title compound as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41].[OH-].[Na+]>C(#N)C.O>[C:40]([NH:44][C:45]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(-c2ccc(NC(=O)NC(C)(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-[1-methyl-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in ACN (1 mL) are added DIEA (65 μL, 0.372 mmole) and tertbutylisocyanate (21 μL, 0.182 mmole). The reaction mixture is heated overnight at 80° C. Water is added as well as 1N NaOH to pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over MgSO4, filtered, and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (98:2:0.2) to (95:5:0.5), and the residue is submitted to a preparative TLC on silica gel eluting with (CH2Cl2:MeOH:NH4OH) from (9:1:1) to give 1-tert-butyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-urea melting at 173° C.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[C:3]2[CH:7]=[CH:8][C:9]3[C:14]([C:2]1=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:15]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16].[C:38]1(C)C=CC=C[CH:39]=1>>[CH2:38]([O:17][C:15](=[O:16])[CH2:18][C:4]1[C:3]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]=2[O:1][CH:5]=1)[CH3:39]
Reactant: O=C1COc2c1ccc1ccccc21
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CCOC(=O)Cc1coc2c1ccc1ccccc12

Procedure:
A mixture of naphtho[1,2-b]furan-3 (2H)-one (1.85 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, naphtho[1,2-b]furan-3-yl-acetic acid ethyl ester was obtained as a white oil. Yield: 2.2 g (86%); 255 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1CBr.CCOCC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:15][C:23]1[CH:24]=[CH:25][O:21][CH:22]=1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccco1
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OCc1ccoc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture 2-chloro-5-(thiazol-2-ylamino)phenol (100 mg, 0.44 mmol) and Cs2CO3 (147 mg, 0.44 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (125 mg, 0.48 mmol) at 0°. After 30 min the reaction was heated to RT. Reaction control by TLC showed full conversion after 5 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 62% yield (83 mg).