Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NC1CCCC1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of N-cyclopentyl-2-nitrobenzenesulfonamide (23 g, 85.2 mmol) in methanol (500 mL) was added palladium on carbon (10%). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford the product 2-amino-N-cyclopentylbenzenesulfonamide (20 g, yield 97.8%). 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.74 (dd, 1H, J=1.2 Hz, 8.0 Hz), 7.30-7.34 (m, 1H), 6.75-6.82 (m, 2H), 4.86 (br s, 3H), 3.50-3.53 (m, 1H), 1.67-1.69 (m, 2H), 1.55-1.62 (m, 2H), 1.42-1.50 (m, 2H), 1.22-1.36 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:2](=[O:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[O:6])[CH3:5].[CH:8]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH3:25])[C:17]([C:26](=[S:28])[NH2:27])=[CH:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH3:25])[C:17]([C:26]3[S:28][CH:2]=[C:3]([C:4](=[O:6])[CH3:5])[N:27]=3)=[CH:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Reactant: CC(=O)C(=O)CCl
Solvent: CCO
Product: COc1cccc2c(-c3nc(C(C)=O)cs3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.9 %

Procedure:
A solution of 1-chloro-2,3-butanedione (0.717 g, 5.95 mmol) in ethanol (3 ml) was added dropwise to a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (prepared as in Example 16; 1.20 g, 3.97 mmol) in ethanol (12 ml) at room temperature, and then the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained residue was mixed with dichloromethane (50 ml) and washed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane to afford 1-{2-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]thiazol-4-yl}ethanone as a brown solid (1.11 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 1-(4-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (25 mg, 0.06 mmol) in DMF (4 mL) was added 60% NaH (10 mg, 0.25 mmol) in one portion. The mixture was stirred under Ar at room temperature for 30 min. Then, 3-fluoropropyl bromide (20 μl, 0.27 mmol) was added. After stirring at room temperature for overnight, the mixture was quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (11 mg, 40%). 1H NMR (CDCl3) d 2.01-2.22 (m, 2 H, CH2), 3.15, 3.17 (two s, total 3 H, N-methyl), 3.60-3.76 (m, 2 H, N--CH2), 4.22-4.76 (qt, J=77.7, 47.1, 5.7 Hz, 2 H, CH2F), 7.36-7.47 (m, 1 H, aromatic), 7.50-7.81 (m, 4 H, aromatic), 7.82-7.99 (m, 2 H, aromatic), 7.83-8.16 (m, 2 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0435.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].Cl.[CH3:32][OH:33]>[OH-].[Na+]>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:33][CH3:32]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl

Procedure:
82 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 0.5 ml MeOH and 0.5 ml 2 M aqueous sodium hydroxide solution were heated to 120° C. for 3 min using a microwave reactor. The reaction mixture was acidified with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 36 mg 2-{[1-(5-chloro-6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24]([CH3:25])=[O:38])[S:23][C:19]=4[CH:18]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 3.8 mmol) from the previous step and meta-chloroperbenzoic acid (0.82 g, 4.75 mmol) in DCM (38 mL) was stirred at 0° C. for 2 h. The mixture was diluted with DCM and washed sequentially with aq Na2S2O3, saturated aq NaHCO3, and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.58 g, 96%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.44-7.47 (m, 2H), 7.31-7.40 (m, 5H), 7.12 (d, J=8.7 Hz, 1H), 6.97 (m, 1H), 5.49 (s, 2H), 5.11 (s, 2H), 3.08 (s, 3H); LCMS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH2:1](N(C)CCO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14]1>>[CH2:1]([CH2:18][NH:13][CH2:14][CH2:15][N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: CN(CCO)Cc1ccccc1
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCCc2ccccc2)CC1

Procedure:
The title compound was prepared by mesylation of N-benzyl-N-methyl ethanolamine, which was then reacted with biphenyl-2-ylcarbamic acid piperidin-4-yl ester in an alkylation reaction.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:17][CH2:16][CH2:15][S:14][C:13]=2[CH:18]=1)([O-:8])=[O:7]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:17]1[CH2:16][CH2:15][S:14][C:13]2[CH:18]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=[CH:11][C:12]1=2)=[O:4]
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 110 °C

Procedure:
2-Chloroacetyl chloride (4.08 mL, 50.9 mmol) was added dropwise to a solution containing 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (5 g, 25.5 mmol) in toluene (30 mL). The mixture was refluxed at 110° C. for 20 minutes. The mixture was quenched with saturated sodium bicarbonate solution (100 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (4×100 mL). The crude material was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated to give a yellow-brown solid. 1H-NMR (DMSO-d6) δ 8.12 (d, J=2.7 Hz, 1H), 7.94 (dd, J=2.7, 9.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 4.63 (s, 2H), 3.96 (t, J=5.1 Hz, 2H), 3.32 (t, J=5.4 Hz, 2H, overlap with solvent peak); ESI-MS (m/z, %): 273 (MH+, 100), 295 (40).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:13][CH:14](O)[CH3:15]>>[CH:14]([O:7][C:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)=[O:8])([CH3:15])[CH3:13]
Reactant: CC(C)O
Reactant: O=C(O)c1c[nH]cn1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1c[nH]cn1

Procedure:
To imidazole-4-carboxylic acid (CAS#1072-84-0, 3.0 g, 26.7 mmol) in propan-2-ol (60 mL) is added thionyl chloride (15.9 g, 13.4 mmol) and the solution is refluxed overnight. The volatiles are removed in vacuo and the residue is partitioned between ethyl acetate and 4M aqueous sodium hydroxide. The organic layer is dried-over Na2SO4, filtered and concentrated to afford imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 155.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[CH2:17][OH:18].O1C[CH2:22][CH2:21][CH2:20]1.[H-].[Na+].C(Br)C=C>O>[CH2:22]([O:18][CH2:17][C:12]1[C:13]2[C:8](=[C:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH:21]=[CH2:20]
Reactant: C1CCOC1
Reactant: OCc1cccc2c(-c3ncccn3)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOCc1cccc2c(-c3ncccn3)cccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet is added 2.35 gm of the 5-pyrimidyl-1-naphthylcarbinol and 100 ml of anhydrous tetrahydrofuran. The system is cooled to 0° C. and after cooling 0.26 gm sodium hydride is added. The system is stirred for an additional 20 minutes and 1.1 ml of allyl bromide is added. The system is allowed to come to room temperature over 1/2-hour and is stirred there for an additional 2 hours. Afterwards, the system is heated at reflux for 17 hours. At this time, water is added to the system and the product extracted with methylene chloride. The methylene chloride is then washed with water and dried over sodium sulfate. The methylene chloride is removed by stripping to give the 5-pyrimidyl-1-naphthylcarbinol allylether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: [H][H]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]4[NH:23][N:22]=[N:21][N:19]=4)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Yield: 56.4 %

Procedure:
From 7 g (0.025 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 30), 8.45 g (0.13 mol) of sodium azide and 6.95 g (0.13 mol) of ammonium chloride in 250 ml of dimethylformamide heated at 125°-128° C. under a nitrogen atmosphere, following the procedure of Example 34, there is obtained 4.6 g of 2-butyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 281° C. (dec) after recrystallization from dimethylformamide-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:22]O>>[CH3:22][O:16][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)c2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 7 h

Procedure:
4,6-Dimethoxy-1-naphthalenecarboxylic acid (98.5 g, 0.425 mole, described in Example 61) was added to an ice-cooled solution of SOCl2 (59.5 g, 0.5 mole) in anhydrous methanol (225 ml). The mixture was heated at reflux for 18 hr. Another portion of SOCl2 (35.5 ml) was added and the reflux was continued for another 7 hr. The mixture was extracted with diethyl ether. The ether extract was washed with water and then aqueous NaHCO3 solution, dried (Na2SO4) and concentrated to dryness. The solid residue was crystallized from methanol (720 ml) to give 64.5 g of 4,6-dimethoxy-1-naphthalenecarboxylic acid methyl ester; mp 102°-104° C.; NMR (CDCl3) δ3.9 (s, 6H), 4.0 (s, 3H), 7.7 (m, 5H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=O)[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]>C(OCC)C.C1COCC1>[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)[C@H](NC(=O)C(F)(F)F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC=C1CCN(c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (5.59 g, 15.8 mmol) (dried on vacuum overnight before use) was suspended in ethyl ether (65 mL). The suspension was cooled to −15° C. Potassium tert-butoxide (1.0 mol/L) in THF (12.6 mL, 12.6 mmol) was added slowly and the bright orange suspension was stirred at −25° C. to −10° C. for 1 h while the color persisted. 2,2,2-Trifluoro-N-[(4R)-1-(2-methyl-4-nitro-pyrazol-3-yl)-5-oxo-azepan-4-yl]acetamide (1.38 g, 3.95 mmol) was dissolved in THF (12 mL) and added to the ylide at −15° C. The mixture was slowly allowed to warm to room temperature and stirred overnight then quenched with saturated ammonium chloride, and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give 2,2,2-trifluoro-N-[(4R)-5-(methoxymethylene)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16]I.[OH-].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13](=[O:14])[CH3:15])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(=O)C(C)c1ncc(C(F)(F)F)cc1Cl
Yield: 9.9 %

Procedure:
6.00 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetone (Int-11) (27 mMol) (synthesis according to P10 and comm av.) and 5.75 g of methyl iodide (40.5 mMol) were diluted in 120 mL of dimethoxyethane. 3.03 g of potassium hydroxide were added portionwise at room temperature. After cooling, 100 mL of water were added to the reaction mixture which was extracted twice with 150 mL of ethyl acetate. The organic phase was washed twice with 100 mL of water, dried over magnesium sulfate and concentrated. After purification on silica, 0.67 g (39%) of desired product 3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-one (Int-12) were obtained, [M+1]=252.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH3:13][C:14]([NH:18][CH2:19][CH:20]=[O:21])([CH3:17])[C:15]#[CH:16]>C1C=CC=CC=1>[CH3:13][C:14]([N:18]([CH2:19][CH:20]=[O:21])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])([CH3:17])[C:15]#[CH:16]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: C#CC(C)(C)NCC=O
Solvent: c1ccccc1
Product: C#CC(C)(C)N(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-(1,1-dimethylprop-2-ynylamino)acetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-(1,1-dimethylprop-2-ynyl)-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:35][C:23]1[CH:22]=[C:21]([CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:11])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of (1R)-2-acetyloxy-1-methylethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (18) (12.7 g, 22.1 mmol) in 100 mL of methanol, 10% Pd—C (200 mg) pre-mixed with 10 mL of methanol was added under a nitrogen atmosphere. The nitrogen was exchanged with hydrogen using the evacuation refill cycle method. The mixture was stirred under hydrogen at room temperature for 4 hours. After filtration and washing with methanol, the filtrate was concentrated to afford 8.8 g (100% yield) of the title compound (19). 1H NMR (400 MHz, CDCl3): δ 1.21 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.07 (s, 3H), 2.95 (m, 2H), 4.05 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.48 (dd, J=14, 6.4 Hz, 1H), 5.04 (d, 1H, NH), 5.15 (m, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.74 (d, J=8.0 Hz, 1H). MS (ESI) m/z 420.0 (M+Na)+ and 396.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[I-].[CH3:18][N+:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(OCC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:24]1[CH:23]=[C:22]([CH3:25])[CH:21]=[CH:20][N:19]1[CH3:18]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Cc1cc[n+](C)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C2C=C(C)C=CN2C)c(OC)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5 g, 2.3 mmol) in diethyl ether (10 ml) cooled at −78° C. under nitrogen was added a solution of n-butyl lithium (1.0 ml, 2.5 mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at −78° C. for 2 hours and then 1,4-dimethylpyridinium iodide (2) (0.54 g, 2.5 mmol) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and extracted with diethyl ether (2×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.5 g, 93%) as a brown oil, 1H NMR CDCl3 ??1.7 (s, 3H), 2.7 (s, 3H), 3.8 (s, 6H), 4.45 (dd, 1H, J=2,7) 4.85 (m, 1H), 5.4 (d, 1H, J=4), 6.05 (d, 1H, J=7), 6.45 (d, 1H, J=3), 6.55 (m, 1H), 7.5 (d, 1H, J=9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[N:23]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:27]([OH:28])[C:26]4[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: Cn1nccc1C=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Yield: 59 %

Procedure:
Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 385 mg (59% yield) of the title compound.