Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13](OC)([O:16]C)[CH2:14]Br.[H-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:14][C:13](=[O:16])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CBr)(CBr)OC
Reactant: N#CCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cccc(Br)c2)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-bromophenylacetonitrile (7.55 g, 38.5 mmol) and 1,3-dibromo-2,2-dimethyoxypropane (10.09 g, 38.5 mmol) in dry DMSO (100 ml) was added in two portions sodium hydride (3.23 g of 60% dispersion in oil, 81 mmol) while the mixture was cooled in a water bath. The mixture was stirred at RT for 10 minutes, and heated at 60° C. in an oil bath for 6 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and the solvent removed. The residual red oil was eluted through a short pad of silica, eluent 10% EtOAc/Hexane. The resulting ketal was dissolved in acetone (100 ml) and 1N aqueous HCl (10 ml) and heated at reflux for 6 hours under a nitrogen atmosphere. The solvent was removed and the residue was neutralized by treatment with aqueous NaHCO3 and extracted with EtOAc. The solvent was removed and the residue was chromatographed (SiO2, eluent 10% EtOAc in hexane) to give a yellow oil which solidified on drying under vacuum.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([OH:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[OH:41][CH:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(OCC(O)CN)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1ccc(OCC(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(NC(C)=O)cc4)cc3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 1-amino-3-(4-methoxy-phenoxy)-propan-2-ol according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 1.95–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.85–3.95 (m, 2 H), 4.10–4.20 (m, 1 H), 5.70 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.80–6.95 (m, 6 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 10.38 (s, 1 H); MS (ES) m/z: 569.6 (MH+); HRMS Calcd. for C29H37N4O6S (MH+): 569.2434. Found: 569.2418.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14](CC3C=CC(OC)=CC=3)[C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C1(S)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(-c2ccnc(Cl)n2)s1)c1ccccc1

Procedure:
A solution of N-[5-(2-Chloro-pyrimdin-4-yl)-thiophen-2-ylmethyl]-N-(4-methoxybenzyl)-benzamide (25 mg, 0.055 mmol) in 0.25 mL CH2Cl2 was treated with trifluoroacetic acid (0.25 mL) as co-solvent and PS-thiophenol resin (3 eq.) at 40° C. for 15 h. The material was filtered and concentrated to a yellow solid (16 mg, 88%). The crude material was used in the next step.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].[Na+].O>C(O)C>[C:10]1([CH:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 68.9 %

Procedure:
To a solution of 140 g (0.71 mol) of deoxybenzoin and 170 g (1.7 mol) of ethyl acrylate in 2 L of absolute ethanol at ambient temperature was added in portions 20 mL of 50% aqueous sodium hydroxide. An additional 170 g (1.7 mol) of ethyl acrylate was then added over a 15 min. period. The mixture was stirred vigorously for 2.5 h, poured into 1 L of water and extracted with 3×1 L of ether. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. The filtrate was concentrated to near dryness, triturated with 1.5 L of pentane, filtered and the filtrate allowed to stand at -20° C. giving 145 g (69%) of ethyl 4,5-diphenyl-5-oxopentanoate as a white solid (top 45°-57° C.).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([Br:19])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(Br)cc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL), at 65° C., was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 1 h, a solution of 1,3-dibromo-5-fluorobenzene (1.26 mL, 10.0 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 3 days. The mixture was allowed to cool to ambient temperature then poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL) and loaded onto an SCX-2 cartridge, which was then washed with acetonitrile and eluted with 2N ammonia in methanol. Concentration of the basic methanolic fraction in vacuo gave the title compound (1.88 g, 54%). 1H NMR (CDCl3, 400 MHz): 7.22 (t, J=1.6 Hz, 1H), 6.98 (d, J=1.7 Hz, 2H), 4.31-4.23 (m, 1H), 2.69-2.59 (m, 2H), 2.37-2.18 (m, 5H), 2.01-1.92 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.3 min, M+H+=350.
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH:32]=O.O>C1COCC1>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[C:32]#[CH:3]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (bromomethyl)triphenylphosphonium bromide (3.3 g, 7.6 mmol) in THF at 0° C. was added potassium tert-butoxide (2.12 g, 18.9 mmol). The reaction was stirred for 30 minutes and a solution of 2-chloro-6-fluorobenzaldehyde (1 g, 6.31 mmol) in THF was added. The reaction was allowed to warm to room temperature overnight and water was added. The solution was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to give 1-chloro-2-ethynyl-3-fluorobenzene (41).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[CH:4][CH:3]=1.ONC(C1C2C=CNC=2C=CC=1)=N.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[C:31](O)=O)[CH3:26].C(OC1C=C(C=CC=1OCCC)C(O)=O)CC>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:9]=[C:31]([C:30]3[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH3:39])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: N=C(NO)c1ccc(Br)cc1
Agent: CCCOc1ccc(C(=O)O)cc1OCCC
Agent: N=C(NO)c1cccc2[nH]ccc12
Product: CCOc1ccc(-c2nc(-c3ccc(Br)cc3)no2)cc1OCC
Yield: 58 %

Procedure:
When the product of Step A was substituted for N-hydroxy-1H-indole-4-carboximidamide and 3,4-diethoxybenzoic acid was substituted for 3,4-dipropoxybenzoic acid in Example 43, Step C the similar process afforded the title compound in 58% yield. 1H-NMR (CDCl3) 1.47-1.53 (m, 6H); 4.14-4.24 (m, 4H); 6.97 (d, 1H, J=8.48 Hz); 7.61-7.66 (m, 3H); 7.77 (dd, 1H, J=1.98, 8.42 Hz); 8.00 (d, 2H, J=8.55 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23](Cl)[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C.C1COCC1>[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COCCCOc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxypropan-1-ol (0.500 mL, 5.23 mmol) in t-butanol (5 mL) was added a 60% dispersion of NaH in oil (70 mg, 1.75 mmol). The resulting suspension was permitted to stir for 30 minutes at which time the reaction was placed at 0° C. and charged with 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS#778574-06-4, 300 mg, 1.02 mmol) as a solution in THF (1.5 mL). After 20 minutes the mixture was quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers were then separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel flash chromatography to provide 6-benzyl-2-chloro-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccno4)cc2)CCN3CC(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccno4)cc2)CCN3CC(C)C)cc1
Yield: 50.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (118 mg) in dichloromethane (20 ml) at −78° C. After finishing the dropping, water was added to the mixture, an aqueous solution of saturated sodium bicarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:4), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 328) as yellow crystals, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (72.8 mg) (Compound 329) as yellow crystals.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)=[CH:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([CH:5]3[CH2:6][CH2:7][CH:2]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[S:15]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CC=C(c2ccc3sc(=O)[nH]c3c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4sc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from hydrogenation of 5-(4-oxo-cyclohex-1-enyl)-3H-benzothiazol-2-one (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([OH:22])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 28 %

Procedure:
A solution of 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (200 mg, 0.711 mmol) in CH2Cl2 (5 mL) was added to a mixture of methyl 3-aminobenzoate (107 mg, 0.711 mmol) and pyridine (1 mL) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated and the crude methyl 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (100 mg) was slurried in water (4 mL). LiOH (300 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction was acidified by aqueous 2 M HCl and the white precipitate was collected by filtration, washed with CH2Cl2 (5 mL) and dried. The title compound was obtained in 28% yield (75 mg, over two steps). MS (ESI+) calcd for C16H12ClNO4S2 380.989627, found 380.989527.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([Cl:28])=[CH:34][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(Cl)nc4)cc3c12
Temperature: 80 °C

Procedure:
9-Bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (500 mg, 1.130 mmol) was dissolved in ethanol (15 ml) and toluene (15.00 ml). (Dichlorobis)palladiumtriphenylphosphine (79 mg, 0.113 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298 mg, 1.242 mmol) and Na2CO3 (2 M, 1.135 mL) were added and argon was bubbled through the solution for several minutes. The solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulftate, filtered and concentrated. The crude residue was purified via a chiral AD column which afforded the title compound. 1H NMR (500 MHz, CD3OD, δH) 10.68 (s, 1 H), 8.56 (d, 1 H, J=1.8 Hz), 8.30 (dd, 1 H, J=8.4, 3.0 Hz), 8.04 (dd, 1 H) J=9.0, 1.8 Hz), 7.68-7.64 (m, 1 H), 7.63-7.60 (m, 2 H), 7.54 (d, 1 H, J=8.4 Hz), 7.38 (td, 1 H, J =9, 1.2 Hz): [M+1]+ 475.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[N:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[NH:45][N:44]=[N:43][N:24]=2)=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)C1=C(COCC#N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nnn[nH]2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 81.2 %

Procedure:
A solution of [4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxyacetonitrile (3.52 g) and tri-n-butyltin azide (3.00 g) in dioxane (100 ml) was heated under reflux for 21.5 hours and then evaporated. The residual oil was taken up in diethyl ether (200 ml) and dry hydrogen chloride was bubbled through the stirred solution in a slow stream for 50 minutes. The resulting precipitate was collected, washed with diethyl ether and dried to give the title compound (3.14 g), m.p. 112°-114° C.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:16][C:7]1[CH:2]=[CH:3][C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:5]([CH:6]=1)[CH:8]=[O:9]
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@H](C)Oc1ccc(C)cc1C=O
Yield: 90.8 %

Procedure:
A mixture (S)-(4-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (100 mg, 0.485 mmol), Dess-Martin periodinane (247 mg, 0.582 mmol) in DCM (5 mL) was stirred at rt for 1 h. It was then diluted with EtOAc and washed with sat. NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-5-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (90 mg, 91%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 6.87-6.78 (m, 2H), 5.88 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.21-5.10 (m, 2H), 4.59 (sxt, J=6.1 Hz, 1H), 2.63-2.51 (m, 1H), 2.51-2.42 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.C(N(CC)CC)C>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 1.2 g (3 mM) of 2-methoxy-3-octadecylcarbamoyloxypropylamine IV a1 in 24 ml of dichloromethane and 0.5 ml (3.6 mM) of triethylamine is added 0.75 g (3.93 mM) of 4-chlorobutanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature overnight. The product is isolated with dichloromethane extraction and dichloromethane layer is washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:2) mixture as an eluent. The product is recrystallized from dichloromethane-n-hexane to give 1.28 g (2.305 mM) of 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane III a5 as colorless crystals in 77% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([N:8]([CH3:9])[S:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:23])=[O:22])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.15 g (3.75 mmol)) in DMF (5.0 ml), 4-chloro-N-methyl-2-nitroaniline (0.34 g (1.82 mmol)) was added with stirring at room temperature. To the resulting mixture, after 30 minutes' stirring at room temperature, 5-chloro-2-thiophenesulfonyl chloride (0.67 g (3.11 mmol)) was added. The reaction mixture was stirred at room temperature for 24 hours and then poured into water and extracted with chloroform. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with acetone-hexane (1:4) as eluent, to give 0.11 g (16%) of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CC[N:27]([CH:31]([CH3:33])C)[CH:28](C)C.N1CCC1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:27]4[CH2:28][CH2:33][CH2:31]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and azetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.88 (1H), 6.69 (1H), 4.49 (m, 4H), 3.24 (m, 2H), 2.40 (m, 2H), 2.04 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 3H), 1.27-1.30 (m, 2H). m/z: 394 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:25][C:26](=[O:28])[CH3:27])[CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Yield: 77.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.009 moles), triethylamine (1.4 ml, 0.010 moles), and 1-chloro-2-propanone (0.8 g, 0.009 moles) in ethanol (50 ml) is stirred and heated to reflux. After 20 hours the mixture is cooled and the precipitate filtered off, rinsed with ethanol, and dried to give the product (1.9 g), mp 128°-129° C.