Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.[OH-].[Na+]>C(Cl)Cl>[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40]([N:2]([CH3:1])[C:3]2[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=2)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1
Reactant: CNc1cnc(SC)nc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2C)n1
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of 1.30 g (5.3 mmol) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-amine and 1.36 ml (7.95 mmol) N-ethyldiisopropylamine in 15 ml CH2Cl2 a solution of 1.30 g (5.3 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 5 ml CH2Cl2 were added and the reaction mixture stirred for 24 hrs. at RT. The reaction mixture was poured onto 50 ml 0.5 N NaOH-solution. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 10:1) to give 2.30 g (82%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide as a white solid, m.p. 124-125°, MS (ISP): 528.2 (M+H+).
Reaction SMILES: Br[CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:20].[Na+]>CC(C)=O>[I:20][CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc2cc(OC)ccc2c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 0.1 moles of ethyl α-bromo-6-methoxy-2-naphthylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:35][C@@H:34]([C:36]2[CH:47]=[CH:46][C:39]3[O:40][C:41]([CH3:45])([CH3:44])[O:42][CH2:43][C:38]=3[CH:37]=2)[O:33][C:32]1=[O:48])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][O:14][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:35][C@@H:34]([C:36]3[CH:47]=[CH:46][C:39]4[O:40][C:41]([CH3:44])([CH3:45])[O:42][CH2:43][C:38]=4[CH:37]=3)[O:33][C:32]2=[O:48])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(SC2CCCC2)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A solution of [3-(cyclopentylthio)phenyl]methanol (270 mg) in dry DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion on mineral oil, 57 mg) and the mixture stirred for 1 h. 2-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (0.4 g) in dry DMF (2 ml) was then added and the mixture stirred for 18 h. Phosphate buffer solution (pH6.5) was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with 10% to 20% ethyl acetate-cyclohexane to give the title compound (0.23 g). LCMS RT=4.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15]1
Reactant: COc1ccccc1CCl
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: COc1ccccc1CN1CCN(CCO)CC1
Yield: 80 %

Procedure:
2-Methoxybenzyl chloride (16 g) and 1-(2-hydroxyethyl)piperazine (13 g) in ethanol (50 ml) were heated under reflux for 4 hours. The solvent was removed under vacuum and the resulting oil was passed through a pad of silica gel eluting with 10% methanol-ammonia in dichloromethane to give 1-(2-hydroxyethyl)-4-[(2-methoxyphenyl)methyl]piperazine as a colourless oil (80%), 13C nmr (CDCl3) 157.4, 130.3, 127.8, 125.2, 119.8, 110.0, 59.5, 57.6, 55.2, 54.8, 52.7 and 52.4 ppm. This material (15 g) was treated at 0° C. with thionyl chloride (15 ml). The mixture was then heated at reflux for 2 hours. Toluene was added and the mixture was evaporated under reduced pressure. The resulting solid was collected and washed thoroughly to give the dihydrochloride of the title compound as a white solid, m.p. 276°-279° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1([Cl:7])[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].CS[C:12]1[N:13]([CH2:22][CH2:23][CH3:24])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][S:18][C:16]=2[N:17]=1>O1CCCC1>[Cl:1][C:2]1([Cl:7])[CH2:4][CH:3]1[CH2:5][O:6][C:12]1[N:13]([CH2:22][CH2:23][CH3:24])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][S:18][C:16]=2[N:17]=1
Reactant: CCCn1c(SC)nc2sccc2c1=O
Reactant: OCC1CC1(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(OCC2CC2(Cl)Cl)nc2sccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a sulfonation flask, 2.8 g (0.02 mol) of 2,2-dichlorocyclopropanmethanol are added to 40 ml of absolute tetrahydrofurane and under stirring 0.6 g (0.015 mol) NaH-dispersion is carefully added. After stirring for 1 hour at room temperature, a solution of 2.4 g (0.01 mol) 2-methylsulfanyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one in 20 ml tetrahydrofurane was added within 2 minutes. After stirring for 4 hours at room temperature the solvent is removed in a water-jet vacuum and the residue is taken up in TBME and the mixture washed repeatedly with water. The TBME-phase is concentrated in the water-jet vacuum and subsequently the excess 2,2-dichlorocyclopropylmethanol destined in high vacuum. 3.0 g of 2-(2,2-dichloro-cyclopropylmethoxy)-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are obtained in the form of a white powder having a melting point of 64-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6][C:5]2=O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[Cl:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cn[nH]c2ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Product: Clc1cnnc2ccc(Br)cc12
Temperature: 0 °C
Yield: 43 %

Procedure:
A solution of Example 34C (0.4 g, 1.8 mmol) in POCl3 (2.5 mL) was heated to 100° C. for 2 hours, and poured slowly onto ice. The aqueous layer was cooled to 0° C. and adjusted to pH 5-7 with 50% NaOH. The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product (0.190 g, 43%).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21](O)[CH3:22])[CH:20]=1>ClCCl.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21]([F:11])[CH3:22])[CH:20]=1
Reactant: CC(O)c1cc(Br)ccc1Cl
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(F)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (4.5 g, 20.34 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanol (3.99 g, 16.95 mmol) in dichloromethane (50 mL) at 0° C. The resulting solution was stirred at 0° C. for 3 h. The reaction mixture was quenched with a 5% solution of aquous sodium bicarbonate (100 mL) and the resulting bubbling biphasic reaction mixture was vigorously stirred at 0° C. for 15 m. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane twice. The combined organic layers were washed with 1M hydrochloric acid, dried and concentrated by rotary evaporation. The product was purified by flash chromatography on silica gel (hexanes) to yield the title compound (2.65 g, 11.16 mmol, 65.8% yield) as a clear oil: 1H NMR (CDCl3): δ 7.65 (d, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.88 (dq, 1H), 1.61 (dd, 3H).
Reaction SMILES: [ClH:1].C1(C(C2C=CC=CC=2)[N:9]2[CH2:12][CH:11]([N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[C:14]3[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:10]2)C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[NH:9]1[CH2:10][CH:11]([N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[C:14]2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:12]1
Reactant: Fc1ccc(-c2ccn(C3CN(C(c4ccccc4)c4ccccc4)C3)c2-c2ccncc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2ccn(C3CNC3)c2-c2ccncc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
0.45 ml of concentrated hydrochloric acid and 0.12 g of 20% palladium hydroxide on carbon were added to a solution of 1.20 g (2.61 mmol) of 1-(1-diphenylmethylazetidin-3-yl)-3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 21(i) above] in 12 ml of ethanol. The resulting mixture was stirred under a hydrogen atomosphere at 50° C. for 20 hours. After cooling to room temperature, the reaction mixture was then filtered and the filtrate was concentrated by evaporaration under reduced pressure. The residual solid was washed with diethylether to give 0.91 g (yield 95%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3([C:10]([F:13])([F:12])[F:11])[NH:21][CH2:18][CH2:19][NH:20]3)=[N:8][C:4]=2[CH:3]=1
Reactant: NCCN
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.02 g; 3.61 mmol), ethylene diamine (0.74 mL; 11.04 mmol) and para-toluenesulphonic acid monohydrate (0.12 g; 0.603 mmol) were suspended in toluene (80 mL), then heated to reflux with a Dean-Stark trap for 3 hrs. After 3 hrs, ethylene diamine (0.74 mL; 11.04 mmol) was added to the reaction mixture and the reaction mixture was allowed to reflux with the Dean-Stark trap for 18 hrs. The reaction was cooled to room temperature and concentrated in vacuo to a crude brown residue. The crude brown residue was dissolved in ethyl acetate (60 mL), washed with water (3×50 mL) and brine (50 mL), then dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated in vacuo to a crude brown oil, which was purified by column chromatography (SiO2, 50% ethyl acetate/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: OCc1ccncc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. TEA (44 μl, 0.314 mmol, 2 eq.) was added to (3-fluoro-pyridin-4-yl)-methanol (20 mg, 0.157 mmol, 1 eq.) in 1 mL DCM, followed by MsCl (15 μl, 0.188 mmol, 1.2 eq.) The reaction was stirred at 0° C. for 30 minutes. HPLC and LC-MS showed reaction complete. The reaction crude was concentrated down. Ethyl acetate was added and washed with saturated NAHCO3 aqueous solution. The Ethyl acetate layer was concentrated after dried over Na2SO4 to give color oil which was used directly in next step. LC-MS shows 206.1 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([NH:17][C@@H:18]1[C@H:23]2[CH2:24][C@H:20]([CH2:21][CH2:22]2)[C@H:19]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])(=[O:16])=[O:15].[OH-].[K+].Cl>CO.O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([NH:17][C@@H:18]1[C@H:23]2[CH2:24][C@H:20]([CH2:21][CH2:22]2)[C@H:19]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:15])=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (234 mg, 0.50 mmol) was dissolved in methanol (6 ml)/tetrahydrofuran (4 ml). To the solution was added 1 N potassium hydroxide (1.50 ml, 1.50 mmol) under ice-cooling. After the reaction mixture was warmed up to room temperature, it was allowed to react for 16 hr and concentrated to remove the solvent. To the residue were added ethyl acetate (50 ml) and water (10 ml), and then 1 N HCl (2.00 ml, 2.00 mmol), and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:1) containing 0.2% acetic acid) to yield (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1a-2) (203 mg, 0.434 mmol). Yield 87%, oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (109 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 3.3 g of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 85 ml of DMF, 10.6 ml of N,N-diisopropylethylamine and 3.2 ml of 2-(trimethylsilyl)ethoxymethyl chloride. After 5 h at RT, the mixture is poured into 8 volumes of ice-water. The aqueous phase is extracted with 3 times 200 ml of AcOEt, and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. Purification is carried out by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 2.1 g of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in the form of a white solid. MS (E/I): m/z=515 (M+); 1H NMR: −0.12 (s, 9H); 0.87 (t, J=8.0 Hz, 2H); 3.65 (t, J=8.0 Hz, 2H); 6.17 (s, 2H); 7.40 (t, J=8.0 Hz, 2H); 7.77 (m, 1H); 8.41 (broad s, 1H); 8.47 (dd, J=1.5 and 8.5 Hz, 1H); 8.77 (d, J=8.5 Hz, 1H). And, on the other hand, 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (white solid). MS (E/I): m/z=515 (M+); 1H NMR: −0.05 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.92 (s, 2H); 7.38 (t, J=8.0 Hz, 2H); 7.76 (m, 1H); 8.24 (broad s, 1H); 8.34 (dd, J=1.5 and 8.5 Hz, 1H); 8.69 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]2[NH:29][CH2:30][CH2:31][C:26]2=[CH:25][CH:24]=1)CCC>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:18](=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]2[NH:29][CH2:30][CH2:31][C:26]2=[CH:25][CH:24]=1)(=[O:7])[O:5][CH3:6]
Reactant: CCCCOC(=O)CCCCc1ccc2c(n1)NCC2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCC2)OC
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
A solution of dimethyl methylphosphonate (1.35 g, 10.9 mmol) in anhydrous THF (20 mL) was cooled to −78° and treated dropwise with 2.6 M n-BuLi (4.1 mL). After stirring at −78° for 15 min, a solution of ester 23-6 (0.750 g, 2.71 mmol) in THF (10 mL) was added dropwise and the resulting solution stirred for 15 min at −78°, quenched with sat. NH4Cl (25 mL), then extracted with CHCl3 (1×25 mL), and the organic layer was applied to PCTLC (4 mm, 10% MeOH/CHCl3) affording 0.79 g (89% yield) of 23-7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:20])=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:20])=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:10])[C:5]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1Cl
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1NC1CC1
Temperature: 0 °C
Yield: 74.2 %

Procedure:
A solution of 5-bromo-2-chloro-N-(2,6-dichloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (3.00 g, 7.61 mmol) and cyclopropylamine (2.11 mL, 30.5 mmol) in xylenes was heated in a sealed tube at 120° C. for 24 h. The reaction was cooled to 0° C., diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by trituration (Et2O:hexane, 3:1) to give the title compound (2.35 g, 75% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2[Br:21])[CH:12]1[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[OH:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[CH:38]=[CH2:39]>CC(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2[Br:21])[CH:12]1[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:30][CH2:39][CH:38]=[CH2:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(ccc(F)c2Br)C1c1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1C1c2ccc(F)c(Br)c2CCN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of (±)-5-bromo-1-(5-chloro-2-hydroxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (150 mg, 0.28 mmol, 1.00 eq.) and K2CO3 (43 mg, 0.31 mmol, 1.10 eq.) in acetone (0.7 mL), allyl bromide (26 μL, 0.29 mmol, 1.05 eq.) was added. The mixture was heated to 60° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (4 mL). The mixture was extracted with DCM (2×5 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was partially purified by flash master (column: 10 g, flow: 15 mL/min, Heptane to Heptane+10% AcOEt) to yield (±)-1-(2-allyloxy-5-chloro-phenyl)-5-bromo-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[Na+].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].Cl>O.CO>[ClH:1].[ClH:1].[CH:14]([CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1)([CH3:15])[CH3:13]
Reactant: CC(C)C=O
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1NCCc2[nH]cnc21

Procedure:
To a solution of 20 g of histamine dihydrochloride in 54 ml of water and 440 ml of methanol, 19.6 g of sodium hydroxide dissolved in 54 ml of water and 25 ml of isobutyraldehyde are added and the solution refluxed for 24 h. The solution is then acidified with 200 ml of conc. hydrochloric acid and evaporated in vacuo. The residue is taken up in methanol. The methanolic extract is evaporated in vacuo to give 23 g of 4-isopropyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine dihydrochloride, m.p. 238°, from which the free base, m.p. 112°, is obtained by ion-exchange on Amberlite (Trade Mark) IRA 410. A solution of 1.3 g of the base in 10 ml of dioxane is treated with 1.3 g of methyl isothiocyanate and refluxed for 4 h. The solution is cooled and filtered; 1.4 g of 4-isopropyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 240°, are collected.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>CCO>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[(5,5-dimethyl-5,6-dihydronaphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 60 mg, 0.171 mmol) in 2 ml of TBF and 7 ml of EtOH at 0° C. was added NaBH4 (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h. The reaction was quenched by slow addition of cold water. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane, 1:3) to afford the title compound as a red oil.