Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:13]([F:14])=[C:12]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][C:9]=1[OH:18].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][O:18][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[C:13]([F:14])[C:8]=1[F:7])[CH3:24]
Reactant: CCOC(CBr)OCC
Reactant: OCCc1ccc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(CCO)c(F)c1F)OCC
Temperature: 90 °C

Procedure:
Cesium carbonate (0.99 g) was added to a solution of 2,3-difluoro-4-(2-hydroxyethyl)phenol (example 77, step b) (0.44 g) and 2-bromo-1,1-diethoxyethane (0.4 mL) in DMF (10 mL). The resulting suspension was heated at 90° C. for 18 h. The reaction was allowed to cool and poured into water (100 mL). The aqueous mixture was extracted with diethylether (3×100 mL). The combined organic solutions were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography eluting with isohexane to 1:1 ethyl acetate:isohexane gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 0.49 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F

Procedure:
reacting 2,6-difluoroaniline with bromine in chloroform to yield 4-bromo-2,6-difluoroaniline;
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36]O)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1.[CH2:40]([N:42](CC)[CH2:43][CH3:44])[CH3:41].O>ClCCl>[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36][N:42]4[CH2:43][CH2:44][CH2:41][CH2:40]4)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1
Reactant: CCN(CC)CC
Reactant: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.21 mL) was added to a stirred solution of N-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0° C. The mixture was stirred for 1 h at 0° C. and 1 h at room temperature. Water was added and the organic phase was separated, (Na2SO4), filtered and concentrated in vacuo. The residue was treated with dichloromethane (10 mL) and pyrrolidine (0.73 mL) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacu. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (147 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[NH2:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:37][CH2:38][CH2:39]O>C1COCC1.C(OCC)(=O)C>[I:25][CH2:39][CH2:38][S:37][C:29]1[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=1[NH2:27]
Reactant: II
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc([N+](=O)[O-])ccc1SCCI
Reaction time: 0.08 h

Procedure:
To a stirred solution of triphenylphosphine (1.81 g, 6.93 mmol) and imidazole (1.887 mL, 13.86 mmol) in THF (15 mL) at 0° C. was added iodine (1.759 g, 6.93 mmol). After stirring for 5 minutes, 2-(2-amino-4-nitrophenylthio)ethanol (990 mg, 4.62 mmol) was added as a solution in THF (5 mL). The resulting mixture was stirred at 0° C. for 1 hour, then diluted with ethyl acetate and washed with water (3×) and brine. The organic phase was dried, filtered, and concentrated then chromatographed in 4:1 hexanes:ethyl acetate giving the desired compound (1.18 g, 79%) as an orange solid. 1H NMR (DMSO-d6) δ 7.55 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1H), 5.89 (brs, 2H), 3.38-3.26 (m, 4H); EI-MS (m/z, %): 324 (M+, 46), 196 (81), 154 (100), 126 (95).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>O1CCOCC1.C(OCC)(=O)C>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[CH:16]=[CH:17][N:18]=[C:3]1[C:2]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[N:11]2
Reactant: FC(F)(F)c1ccc2c(c1)nc(Cl)c1nccn12
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2ccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
To a solution of 4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline (2.00 g; 7.36 mmol; 1 eq) in anhydrous dioxane (250 mL), 3-aminopropanol (6.2 mL; 81.0 mmol; 11 eq) is added, under argon atmosphere. Complete conversion was achieved after 17 hours of stirring under reflux. The initially cloudy yellow solution turns first orange and then becomes translucid. The reaction mixture is cooled to room temperature and diluted in ethyl acetate (500 mL). The organic phase is washed three times with a solution of saturated sodium hydrogenocarbonate (3×330 mL). The organic phases are combined, dried over sodium sulfate and concentrated under vacuum to provide pure title compound (1.94 g; 6.25 mmol; 85%) as a grey powder.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:27])[O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:28]Br>CO>[CH:25]1[C:26]2[CH:14]([CH2:13][O:12][C:11](=[O:27])[NH:10][CH:7]3[CH2:6][CH2:5][CH:4]([C:1](=[O:3])[CH2:2][Br:28])[CH2:9][CH2:8]3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: BrBr
Solvent: CO
Product: O=C(NC1CCC(C(=O)CBr)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.77 g (21 mmol) of 9H-fluoren-9-ylmethyl (4-acetylcyclohexyl)carbamate (cis compound) is dissolved in 100 mL of methanol at ambient temperature and combined with 1.09 mL (21 mmol) of bromine. The mixture is stirred for 16 hours at ambient temperature, cooled, and the crystals precipitated are suction filtered. Yield: 6.35 g (50%); NMR: LG201641.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C([O:12][C:13](=O)[CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[C:20]=1[F:26])[C:15](=O)[CH3:16])C>>[F:26][C:20]1[C:21]([NH2:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:14]1[C:13](=[O:12])[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[C:15]=1[CH3:16]
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)C(Cc1cccc(N)c1F)C(C)=O
Product: COc1ccc2c(C)c(Cc3cccc(N)c3F)c(=O)sc2c1

Procedure:
The title compound was synthesized using 3-methyloxy-benzenethiol and 2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester under the same conditions as in the manufacturing example for compound 5d-0-4S1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCON=C(C(=O)O)c1csc(N)n1
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A solution of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10 g.) in a mixture of tetrahydrofuran (39 ml.), methanol (39 ml.) and 1 N sodium hydroxide (75.8 ml.) was stirred at 35° to 40° C. for 5 hours. After the resultant solution was concentrated under reduced pressure, the aqueous residue was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetic acid (synisomer, 6.2 g.), mp 161° C. (dec.)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][C:3]=1[CH3:19].[N+:20]([O-])([O-:22])=[O:21].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[CH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(-c2[nH]c3ccccc3c2C)cc(C)c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2C)cc(C)c1O
Temperature: 0 °C

Procedure:
5.0 g of 2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was added to 100 ml of concentrated sulfuric acid, and the mixture was stirred at 0° C. Then, a solution of 1.76 g of sodium nitrate in 50 ml of concentrated sulfuric acid was added dropwise, and the mixture was stirred for 15 minutes. The reaction mixture was poured into ice-water, and extracted with ether. The resulting crude product was purified by silica gel column chromatography. Recrystallization from ether-hexane gave 2-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-5-nitroindole.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: CC(Cl)Cl
Product: O=C(Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1)C1CCCCC1
Yield: 53.7 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), cyclohexanecarbonyl chloride (0.056 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 79 mg of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylcyclohexanecarboxamide. MS (ES) m/z 351.2; HPLC purity 100% at 210-370 nm, 11.3 min.; 99.5% at 252 nm, 11.3 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H30N2O+H+, 351.24309; found (ESI, [M+H]+), 351.2443.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:4]=1[C:16]([O:18][CH3:19])=[O:17].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>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>[C:8]([C:7]1[C:3]([CH2:2][C:27]2[CH:28]=[C:29]3[C:24]([CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)=[C:4]([C:16]([O:18][CH3:19])=[O:17])[S:5][C:6]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)#[N:9]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
Reactant: OB(O)c1ccc2ccncc2c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccncc2c1
Temperature: 90 °C
Yield: 70.6 %

Procedure:
A mixture of methyl 3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.128 g, 0.371 mmol), isoquinoline-7-boronic acid (101 mg, 0.584 mmol), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.0185 mmol) and cesium carbonate (0.242 g, 0.742 mmol) was suspended in 1,4-dioxane (8.0 mL, 100 mmol) and Water (0.60 mL, 33 mmol) under N2 atmosphere in a 20 mL vial. The vial was capped and heated to 90° C. for 1 hour. The mixture was cooled to room temperature and concentrated in vacuum. The residue was suspended in DCM and filtered over a celite pad. The filtrate was chromatographed in a silica gel column using MeOH/DCM (0/100 to 3/97) to afford a solid product (103 mg, 66.4%). LC/MS: (FA) ES+ 394. 1H NMR (400 MHz, d-chloroform) δ 9.20 (s, 1H), 8.47 (d, J=5.77 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=5.77 Hz, 1H), 7.60 (d, J=5.77 Hz, 1H), 7.44-7.48 (m, 1H), 4.60 (s, 2H), 3.86 (s, 3H), 3.84 (m, 4H), 3.59 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18].C(N(CC)CC)C>C(#N)C>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg, 1.49 mmol) and 2-amino-N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL of acetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The suspension was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The resulting residue was chromatographed over 50 g of flash silica using dichloromethane/methanol 9:1 as the eluant to provide the desired product as a light yellow solid (310 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H), 0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m, 2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m, 1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[C@@H:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][C:10]2[NH:11][C:17](=[O:26])[C:18]3[C:19]([CH:25]=2)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C@@H:4]([CH2:12][OH:13])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCCN1C[C@H](O)C[C@@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCCN3C[C@H](O)C[C@@H]3CO)cc12

Procedure:
(3R,5R)-5-Hydroxymethylpyrrolidin-3-ol and 4-bromobutyronitrile are reacted in the presence of potassium carbonate in N,N-dimethylformamide to give 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile. In the same manner as in Example 1b (e) and using 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][C:5]([Cl:18])=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[C:5]([Cl:18])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1OCc1c(F)cccc1Cl
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cccc(Cl)c1COc1cc(Cl)cnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-5-chloropyridine (0.82 g, 0.0028 mol), 4-chlorophenyl isothiocyanate (0.56 g, 0.0033 mol) and toluene (10 ml) was heated under reflux for 16 hours, then cooled and diluted with ether to induce crystallisation of the product, which was triturated with ethanol. Yield 0.68 g (54%), m.p. 158°-160 ° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:37]>CC(C)=O>[ClH:1].[ClH:37].[ClH:1].[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]4[NH:18][C:17]5[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=5[N:15]=4)[C:7]=3[O:23][CH3:24])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1c(SCCCN2CCN(c3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 73 %

Procedure:
According to the procedure indicated in Examples 1), 3) and 6), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-phenylpiperazine and subsequent conversion into the hydrochloride in acetone gives the title compound; colorless crystals; m.p. 105° C., dec.; yield 73%.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:24](OCC)=[O:25]>O1CCCC1>[CH:24]([CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: CCOC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C=O)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-oxohexahydro-1H-azepine-1-carboxylate (commercially available from e.g. Magic Chemicals) (2.0 g, 9.4 mmol) in tetrahydrofuran at −78° C. was treated with a 2M solution of lithium diisopropylamide (4.7 ml, 9.4 mmol) in tetrahydrofuran. After 20 minutes neat ethyl formate (0.7 g, 9.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 2 hours the reaction was quenched, poured into water and extracted several times with ethyl acetate. The combined organic layers were then dried and reduced in vacuo to furnish the title compound which may be used without further purification (D8).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[K+].C1(C)C=CC=CC=1>O=O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: O=O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 45 °C
Reaction time: 0.3 h
Yield: 81.8 %

Procedure:
A stirred mixture of 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (20.0 g, 0.082 mol), potassium cyanide (10.4 g, 0.159 mol) and oxygen-free ethanol (60 mL) was heated at 45° C. A slurry of chloronaphthalenylbis(triphenylphosphine)nickel (i.e. the product of Example 1, a mixture of 1- and 2-isomers) (4.01 g, 5.36 mmol) in oxygen-free ethanol (60 mL) was added in four portions to the reaction mixture. Each addition was completed in about 18 minutes, and after the first addition subsequent additions were begun approximately 50, 75, and 105 minutes after the previous addition was complete. Oxygen-free ethanol (15 mL) was added to the reaction mixture after the second addition to facilitate stirring. After the fourth addition was complete, the reaction mixture was stirred for 5.7 h at 45° C., and then more chloro-naphthalenylbis(triphenylphosphine)nickel (0.5 g, 0.67 mmol) in oxygen-free ethanol (10 mL) was added over 10 minutes. After stirring overnight at 45° C., toluene (100 mL) was added, and the solvent was evaporated under reduced pressure. More toluene (150 mL) was added, and the solvent was again evaporated under reduced pressure. The resulting solid was slurried in toluene (120 mL), filtered, and washed with toluene (100 mL) and water (2×70 mL). The solid was dried overnight in a vacuum-oven at 50° C. to give the title compound as a white solid (12.68 g, 81.8% yield). A portion of the product was recrystallized from acetonitrile to give an analytical sample melting at 204.0-204.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[OH-].[Na+]>C(OCC)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: C=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C=Cc1ccc(OC2CCCCO2)cc1
Reaction time: 20 h

Procedure:
In a 250 ml round-bottomed flask, 15 g (125 mmol) of 4-hydroxystyrene and 0.4 g (2.3 mmol) of p-toluenesulfonic acid monohydrate are dissolved in 120 ml of diethyl ether. Then, at 5° C., 11.6 g (137 mmol) of 3,4-dihydro-2H-pyran are added dropwise over a period of 10 minutes. The mixture is allowed to reach room temperature and is further stirred for 20 hours. 1N NaOH solution is then added and the organic phase is washed twice with water, dried over magnesium sulfate and concentrated to yield 23.3 g (114 mmol, 90% of the theoretical yield) of 4-tetrahydropyran-2-yloxystyrene in the form of a colourless oil that can be used for the copolymerisation without being further purified. 1H-NMR (CDCl3, 100 mHz): δ7.37/d (J=9 Hz)/2H, 7.02/d (J=9 Hz)/2H, 6.52/dd (J1 =18 Hz, J2 =11 Hz)/1H, 5.50/dd (J1 =18 Hz, J2 =2 Hz)/1H, 5.41/m/1H, 5.11/dd (J1 =11 Hz, J2 =2 Hz)/1H, 4.0-3.7/m/1H, 3.7-3.4/m/1H, 2.2-1.2/m/6H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C:5]1[C:6]([NH2:28])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:13]=2)=[N:9][C:10]=1[NH2:11].[H-].[Na+].I[CH3:33].Cl>CN(C)C=O>[NH2:11][C:10]1[C:5]([N:4]([CH3:33])[C:3](=[O:29])[O:2][CH3:1])=[C:6]([NH2:28])[N:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[N:13]=2)[N:9]=1
Reactant: CI
Reactant: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
24 mg (61 μmol) of the compound of Example 1 were initially charged in 1 ml of dimethylformamide, and about 2.7 mg (70 μmol) of sodium hydride (60% in mineral oil) were added. The resulting mixture was stirred at RT for 10 min, 6 μl (9 μmol) of iodomethane were then added and the reaction was stirred overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire mixture was separated by HPLC (Method 5). The appropriate fractions were concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 8 mg (32% of theory) of the target compound.