Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]([O:17][C:18](=[O:35])[NH:19][C@@H:20]([C:29](=[O:34])N(OC)C)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:16])([CH3:15])[CH3:14].OS([O-])(=O)=O.[Na+]>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:29](=[O:34])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1F)C(=O)Cc1ccccn1
Temperature: 15 °C

Procedure:
To a solution of 2-picoline (0.54 mL, 5.5 mmol) in 20 mL of THF at −52° C. is slowly added a 1.5 M solution of n-butyllithium in hexanes (3.6 mL, 5.5 mmol). The reaction is then warmed to 15° C. and is then immediately re-cooled to −52° C. To the reaction is added a solution of [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.6 g, 1.8 mmol) in 4 mL of THF. The reaction is then is poured into 8 mL of a 2M solution of NaHSO4 in water. The solution is adjusted to pH7 by addition of pH7 buffer and the product is extracted into ether. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:14][N:13]=[CH:12]1)[C:5]#[N:6].N1C=CN=C1.[Br-].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][C:15]1[N:11]([CH2:10][C:9]2[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=2)[CH:12]=[N:13][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2CCCO)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: N#Cc1ccc(Cn2cncc2CCCO)c(-c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-4-[5-(3-hydroxypropyl)-imidazol-1-ylmethyl]benzonitrile (1.02 g, 3.2 mmol) that is prepared by alkylation of imidazole from Example 21 with bromide described in Example 1C followed by removal of the silyl protecting group by analogy to the first step in Example 3C in DME (10 mL) is added phenylboronic acid (586 mg, 4.8 mmol), aqueous Na2CO3 (2M, 4.8 mL, 9.6 mmol), and PS—PPh3-Pd (O) resin (0.13 mmol/g, 1 g). The reaction mixture is run in a microwave at 130° C. for 20 min. The mixture is partitioned between EtOAc and brine. The organic layer is washed with brine, dried over Na2SO4 and concentrated to give oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10](S(C2C=CC=CC=2)(=O)=O)[C:11]([OH:13])=[O:12])=[CH:3]1>C(O)C.[Na].[Hg]>[CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[C:4]([CH2:10][C:11]([OH:13])=[O:12])=[CH:3]1
Reactant: CC1(C)C=C(C(C(=O)O)S(=O)(=O)c2ccccc2)C(C)(C)CC1
Agent: [Hg]
Agent: [Na]
Solvent: CCO
Product: CC1(C)C=C(CC(=O)O)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84.9 %

Procedure:
20.6 g of 3,3,6,6-tetramethyl-α-(phenylsulphonyl)-1-cyclohexen-1-acetic acid are dissolved in 800 ml of ethanol and the solution is treated at 0° C. with 107.1 g of sodium amalgam (5%). The mixture is stirred at room temperature for 4.5 hours, the solution is decanted off from the mercury, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried, evaporated and filtered over silica gel (eluting agent hexane/ether 1:1). After recrystallization from hexane, there are obtained 10.2 g of 3,3,6,6-tetramethyl-1-cyclohexen-1-acetic acid in the form of colorless crystals, m.p. 50°-54° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O1CCCC1.C(=O)(O)[O-].[Na+]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (600 mg, 1.097 mmol) in tetrahydrofuran (15 mL) N-butyl-N,N-dipropylbutan-1-aminium fluoride (1.207 mL, 1.2067 mmol) was added at room temperature. After 1 h, LCMS showed the reaction was complete. Aqueous sodium bicarbonate solution was added (5 ml). The solvent was removed in vacuo and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give a colorless solid which was purified with flash column chromatography to give the desired product (371 mg, 87%): MS(ESI)[M+H+]=547.4.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>CCO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To a solution of ethyl (1RS, 3RS)-1,3-di-(3,4-methylenedioxyphenyl)indane-2-carboxylate (75 mg, 0.17 mmol) in EtOH (20 ml) was added NaOH (0.10 g, 2.5 mmol). The resulting mixture was allowed to stir at room temperature for 3 d, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. The mixture was then heated at reflux for 36 h, allowed to cool and was concentrated under reduced pressure. To the residue was added concentrated HCl, and the solid which formed was collected by filtration and dried. The solid was triturated with boiling hexanes to afford the title compound as a white solid (50 mg, 73%); m.p. 182-185° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>COCCOCCOC>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH2:18][CH2:19]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)o1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: FC(F)(F)c1cccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5-Phenyl-2-furoyl)-4-(3-trifluoromethylphenyl)-piperazine (6.0 g, 0.015 mole) and sodium borohydride (1.28 g, 0.034 mole) were stirred in diglyme (25 ml), under nitrogen, and redistilled boron trifluoride etherate (6 ml, 0.045 mole) in diglyme (20 ml) added dropwise with continuous stirring. The resultant clear solution was stirred at room temperature for 3 hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 ml), followed by 5NHCl (20 ml) and the mixture heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4N NaOH) and extracted via diethyl ether. The dried ether extract (MgSO4) was evaporated to give an oil which failed to crystallise. The product was converted to the hydrochloride and then reconverted to the free base as in Example 40. The base was obtained as a mobile oil which on very strong cooling crystallised, m.p. 56° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:11][C:10]=2[CH:23]2OCC[O:24]2)[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[S:11][C:10]=2[CH:23]=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc(C3OCCO3)c(-c3cccc(OC)c3)c2C)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COc1ccc(-c2sc(C=O)c(-c3cccc(OC)c3)c2C)cc1
Yield: 96.9 %

Procedure:
2-[3-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (7.0 g, 18 mmol) and PPTS (1.4 g, 5.6 mmol) were combined in wet acetone (180 mL) and heated at reflux for 2 h. At this time, the cooled solution was concentrated in vacuo and the residue was taken up in ethyl acetate (200 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine (200 mL each), dried (Na2SO4) and concentrated in vacuo to give the title compound (5.9 g, 95%, m.p. 105-08° C.) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.N>C(#N)C>[CH:14]1([C:12]2[C:7]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2CCC2)cc1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)C(C1CCC1)=NCC2
Yield: 48.2 %

Procedure:
A solution of this amide (9 g) in dry acetonitrile (170 ml) containing phosphorus oxychloride (23.7 ml) was heated under reflux for 43 hours. The cooled mixture was then poured onto dilute ammonia solution and this mixture extracted with ethyl acetate (3×150 ml). The ethyl acetate solution was then extracted with dilute hydrochloric acid (3×100 ml). The aqueous acid extracts were basified by addition of aqueous ammonia solution and the mixture extracted with ethyl acetate. The organic extracts were washed with brine and concentrated to give an oil which was distilled at 190° C./0.2 mbar to give 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline as a colourless solid (4 g), mp 44°-46° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:21][CH:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=1[Cl:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:31][C:25]1[C:26]([NH:12][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:13])[F:1])=[CH:9][CH:8]=2)[CH3:11])=[N:27][CH:28]=[N:29][C:24]=1[CH:22]([Cl:21])[CH3:23]
Reactant: CC(N)c1ccc(OC(F)F)cc1
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl

Procedure:
In 50 ml of toluene were dissolved 3.8 g of 1-(4-difluoromethoxyphenyl)ethylamine and 2.3 g of triethylamine, and to the mixture was added 3.5 g of 6-(1-chloroethyl)-4,5-dichloropyrimidine. The mixture was refluxed under heating for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:19]2[CH2:18][CH:17]=[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[CH:11]=3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Cc1cccc(C2=CCNCC2)c1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C2=CCN(c3ccc(Cl)nn3)CC2)c1
Temperature: 70 °C
Yield: 24 %

Procedure:
A mixture of 4.5 parts of 3,6-dichloropyridazine, 5.2 parts of 1,2,3,6-tetrahydro-4-(3-methylphenyl)pyridine, 5.3 parts of sodium carbonate and 72 parts of N,N-dimethylformamide was stirred and heated overnight at about 70° C. The reaction mixture was evaporated and water was added to the residue. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 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 and dried, yielding 2.1 parts (24%) of 3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine: mp. 122.2° C. (compound 28).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:17]3[C:12]([CH3:23])([C:13]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=4[CH2:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:24])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C@@H:17]3[C@:12]([CH3:23])([C:13]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10][C:9]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN2C(=O)CCC3(C)C2=CCc2cc(Cl)ccc23)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)CC[C@@]3(C)c4ccc(Cl)cc4CC[C@H]23)cc1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a stirred solution of subtitle compound from Step B (693 mg) in CH2Cl2 (2.5mL) under a nitrogen atmosphere was added triethylsilane (1.4 ml) The reaction mixture was stirred for 15 minutes. To the solution was added 1.5 mL of trifluoroacetic acid and the reaction mixture stirred at room temperature overnight. The reaction mixture was partitioned between CHCl3 and saturated NaHCO3. The organic phase was dried over Na2SO4 and the solvent removed under vacuum. The residue was purified by chromatography on SiO2 (25% ethyl acetate in hexanes as eluent). The product containing fractions were evaporated under vacuum to afford 459 mg of the subtitle compound as a foam. Melting point 55°-60° C.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].Cl>C(OCC)(=O)C>[CH3:3][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:14])[F:16])[CH:8]=1)(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
To a 250 ml round bottom flask was added tert-butyl 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-carboxylate from the previous step, 60 ml ethyl acetate and 60 ml 3N HCl. The reaction mixture was heated at reflux for 3 hours. NMR showed complete conversion. The volatiles were removed and the residue was dissolved in 50 ml water, washed with 50 ml ether. The aqueous portion was basified with addition of KOH and extracted twice with 60 ml ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated to give 3.5 g colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C1COCC1>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)=[O:34]
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 38.5 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with pivaloyl chloride (0.02 mL, 0.165 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 19 h. Obtained as a sand solid (26 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[SH-:16].[Na+].Cl>O>[CH2:14]([O:13][C:11]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[CH:9][N:10]=2)[C:2]=1[SH:16])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnc2ncnn2c1Cl
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc2ncnn2c1S
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
The product obtained in Step 1 (3.6 g) and sodium hydrosulfide (2.5 g) were dissolved in 50 ml of water, the solution was stirred at room temperature for 20 minutes, its pH was lowered to 1.0 with 6N hydrochloric acid, and the crystals thus formed were collected by filtration, affording 3.0 g of the objective compound as yellow crystals.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1SC.[NH2:16][NH2:17]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[NH:16][NH2:17]
Reactant: CSC1=NCCN1CCO
Reactant: NN
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: COC(C)(C)C
Product: NNC1=NCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)-2-methylthioimidazoline mesylate (35 g, 0.136 mole) is suspended in ethyl alcohol (80 ml) and treated with anhydrous hydrazine (9.3 ml, 0.296 mole). The mixture became clear immediately. The solution is stirred at room temperature overnight and then diluted with t-butyl methyl ether (1 liter). On storage of the mixture in the freezer at -20° C., crystals separated, which are filtered, washed well with t-butyl methyl ether and dried. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 1-(2-hydroxyethyl)-2-hydrazinoimidazoline mesylate, melting point 85°-88° C.
Reaction SMILES: [CH:1]1([CH:7]([OH:16])[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C([O-])(O)=O.[Na+]>ClCCl.O>[CH:1]1([CH:7]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(O)C2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1ccc(C#N)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Dissolve 4-(cyclohexyl-hydroxy-methyl)-benzonitrile (1 g, 4.66 mmol), and triethylamine (1.3 mL, 9.3 mmol) in dichloromethane (20 mL). Cool the mixture to 0° C., add methanesulfonyl chloride (1.49 mL, 5.34 mmol) and stir the solution for 2 h at 0° C. Add water (10 mL) and saturated aqueous NaHCO3 (10 mL). Separate the layers and extract back the aqueous phase with dichloromethane (3×20 mL). Combine the organic layers, wash with water (20 mL), dry over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as a yellow oil (1.29 g, 94%). MS (APCI) m/z: 294 (M+H)+.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][CH:10]=1.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH2:16][C:17]#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: O=CCCc1ccc(CO)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#CCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8.5 g (61.5 mmol) K2CO3 are added to a solution of 5.0 g (30.4 mmol) 3-(4-hydroxymethyl-phenyl)-propionaldehyde in 100 mL MeOH and then a solution of 7.0 g (36.4 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphonate in 50 mL MeOH is added dropwise and stirred for 3 h at RT. The reaction mixture is diluted with 200 mL EtOAc, washed with 80 mL saturated NaHCO3 solution, the aqueous phase extracted with 100 mL EtOAc and the combined organic phases are dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (cyc/EtOAc 3:1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1F
Yield: 49 %

Procedure:
Upon boiling a solution of 6.2 g 2-fluorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour, 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 128° - 130°C (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
3-(2-Bromophenyl)propanoic acid (1) (550 g, 2.4 mol, 1 equiv) was dissolved in 1,2-dichloroethane (5.5 L). Thionyl chloride (437.8 mL, 6 mol, 2.5 equiv) was added to the solution and the mixture was refluxed for 24 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methylene chloride (1 L) and added dropwise to a mechanically stirred suspension of anhydrous aluminum chloride (526.9 g, 3.96 mol, 1.65 equiv) in dichloromethane (1 L) while keeping the reaction temperature below 27° C. The reaction was stirred at room temperature for three hours before being quenched into a five gallon bucket which was half-full of ice. The resulting mixture was extracted with dichloromethane (3×3 L). The combined organic layers were washed sequentially with saturated brine (2 L) and saturated sodium bicarbonate (2 L). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was dried overnight in a vacuum oven at 30° C. to give compound 2 (435 g, 86% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](O)([CH3:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[ClH:31].CCOCC.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(O)C>[ClH:31].[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[CH2:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC1(O)c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-one (4.88 g, 11.9 mmol) in chloroform (50 ml) was added HCl.ether (1M, 20 ml) solution. A precipitate formed. This mixture was stirred for 18 hours at room temperature. The mixture was basified with triethylamine and washed with brine. The organic solution was dried and concentrated to a crude material. The purification was done by flash chromatography over silica gel column (SiO2, 60 g; eluted with DCM). The pure product thus obtained weighed 3.28 g (70%). Treatment with HCl.ether solution in ethanol gave 1.52 g of white crystals, m.p.=261°-263° C.