Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5]CC)=O.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[CH:21]([NH:24][C:3](=[O:5])[CH:2]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][CH:13]=1)[Cl:1])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: CC(C)N
Solvent: CCOCC
Product: CC(C)NC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 5 g. (0.016 moles) of ethyl α, 2'-dichloro-4-biphenylylacetate and 5.5 ml. of anhydrous isopropylamine are stirred over Linde 4A molecular sieve for 16 hours at room temperature. The reaction mixture is taken up in ether and washed 3 times with 15 ml. of 10% hydrochloric acid. The ether layer is dried over sodium sulfate, filtered, and the ether is removed. The residue is triturated with n-hexane and the precipitate is collected to obtain N-isopropyl α, 2'-dichloro-4-biphenylylacetamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[NH:7][C:8](=[O:10])[CH3:9].CN(C)[C:16]1[O:17][C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1>C(O)(=O)C.O>[Cl:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([N:1]2[C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[NH:21][C:16]2=[O:17])=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc(N)c(F)cc1Cl
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Yield: 78.1 %

Procedure:
A mixture of 5′ -amino-2′-chloro-4′-fluoroacetanilide (1.0 g, 4.9 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (1.0 g, 4.9 mmol) in acetic acid is refluxed for 90 minutes and diluted with water. The resultant aqueous mixture is filtered to obtain the title product as an off-white solid (1.4 g, mp 264-266° C.) which is identified by 1H, 13C and 9F NMR spectral analyses.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:37][CH2:36][CH2:34][OH:35])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NCCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), ethanolamine (18 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (43 mg, 81% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a stirred solution of 2-chloro-5-nitrophenol (2 g, 11.62 mmol), cesium carbonate (5.66 g, 17.44 mmol) in DMF (20 mL) was added tert-butyl 3-bromopropylcarbamate (4.13 g, 17.44 mmol) followed by tetrabutylammonium iodide (0.214 g, 0.581 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC and LC-MS. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (200 mL) and washed with brine (2×200 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give tert-butyl 3-(2-chloro-5-nitrophenoxy)propylcarbamate (2.2 g, 57.4%) as a light-brown solid. LC-MS (M−100)+=230.7 1H NMR (400 MHz, CDCl3) δ ppm 7.82-7.76 (2H, m), 7.52 (1H, d, J=8.4 Hz), 4.99 (1H, s), 4.20 (2H, t, J=5.6 Hz), 3.41-3.37 (2H, q, J=6.0 Hz), 2.12-2.01 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([OH:22])=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:32].[CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([O:22][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(O)CCCN1CCCCC1
Reactant: C=CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: C=CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC

Procedure:
2-Allyl-5,5-diethyl-8-(3-methyl-2-octyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-piperidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts to produce the desired product.
Reaction SMILES: CN.CN(C)CCCN.CN(C)CC[CH2:14][NH:15][C:16]1[C:21]2[CH:22]=[N:23][C:24]3[N:28]([CH2:29][CH3:30])[N:27]=[CH:26][C:25]=3[C:20]=2[N:19]2[N:31]=[CH:32][N:33]=[C:18]2[N:17]=1>>[CH2:29]([N:28]1[C:24]2[N:23]=[CH:22][C:21]3[C:16]([NH:15][CH3:14])=[N:17][C:18]4[N:19]([N:31]=[CH:32][N:33]=4)[C:20]=3[C:25]=2[CH:26]=[N:27]1)[CH3:30]
Reactant: CCn1ncc2c1ncc1c(NCCCN(C)C)nc3ncnn3c12
Agent: CN
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(NC)nc3ncnn3c12

Procedure:
By substituting methylamine for the 3-dimethylaminopropylamine in the procedure of Example 1 (c), 8-ethyl-N-methyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo-[1,5-a]pyrimidin-5-amine is obtained, m.p. > 300°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[N:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[N:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2nn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2nn1

Procedure:
Ethyl 6-nitrocinnolin-3-yl carboxylate (150 mg.) was dissolved in ethanol (20 ml.), and 30% w/w palladium on charcoal catalyst (20 mg.) was added. The solution was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure until the theoretical uptake had taken place. The catalyst was filtered off and the ethanol solution was evaporated to dryness, yielding a yellow solid. This solid was purified by chromatography on a column of Kieselgel 60 (E. Merck, Darmstadt) using ethyl acetate as eluent. The appropriate fractions were combined and evaporated to dryness to give ethyl 6-aminocinnolin-3-yl carboxylate, m.p. 204°-206° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CN(C)C=O>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:26][C:25]1[CH:27]=[CH:28][C:22]([Cl:21])=[CH:23][CH:24]=1)=[O:15]
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1N
Yield: 27.7 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (5.5 mL, 63.05 mmol), 4-methoxy-3-nitrobenzoic acid (11.30 g, 57.32 mmol), dimethylformamide (1.0 mL, 1.29 mmol), and 4-chloroaniline (14.6 g, 114 mmol) to afford the product (4.4 g); m.p. 191-192° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([OH:13])[CH3:12].Cl>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][C:9](=[NH:10])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cccnc1Cl
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)Cc1cccnc1Cl
Reaction time: 24 h

Procedure:
Through a cooled solution of 2-(2-chloropyridin-3-yl)acetonitrile (Synthesis (6), 528-30, 1992) (1.7 g, 11.1 mmol), ethanol (1.0 mL, 16.7 mmol), and dichloromethane (25 mL) was bubbled HCl gas at 0° C. for 30 minutes. After standing at 4° C. for 24 hours, the reaction mixture was concentrated, and the residue was triturated with diethyl ether. The precipitate was collected and dried to obtain the titled compound. MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:3]1=2.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH:13]=[C:14]([C:17]3[NH:23][N:22]=[N:21][N:18]=3)[CH:15]=[CH:16][C:3]1=2
Reactant: Cn1c2ccc(C#N)cc2c(=O)c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccc(-c3nnn[nH]3)cc2c(=O)c2cccnc21
Reaction time: 20 h
Yield: 72.7 %

Procedure:
A mixture of 5 g of 10-methyl-5-oxo-5H,10H-benzo[b][1,8]naphthyridine-7-carbonitrile, 50 ml of dimethylformamide, 1.45 g of ammonium chloride and 1.8 g of sodium azide is heated with stirring at 110° C to 120° C for 20 hours. After cooling, crystals are filtered off and added to a dilute hydrochloric acid, and the mixture is stirred. The crystals are filtered off, washed with water and recrystallized from dimethylformamide to give 4.3 g of 10-methyl-7-(5-1H-tetrazolyl)-5-oxo-5H,10H-benzo[b][1,8]naphthyridine melting at 321° C with decomposition.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([N:22]1[C:27]([CH2:29][OH:30])([CH3:28])[CH2:26][O:25][CH2:24][C:23]1=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][C:27]1([CH2:29][OH:30])[CH3:28])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(CO)COCC(=O)N1Cc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(CO)COCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (3.46 M solution in toluene; 42 ml) was added to a solution of 4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.77 g) in toluene (100 ml) at 0° C. under nitrogen atmosphere and the whole was stirred at room temperature for 1 hour. Ethanol (20 ml) was added to the mixture at 0° C. and the pH of the mixture was adjusted to 12 by 1N sodium hydroxide solution. The organic layer was separated, added 1N hydrochloric acid and the acidic aqueous layer was separated. This procedure was repeated twice and the combined aqueous layer was made alkaline with 4 M sodium hydroxide solution. It was extracted with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo to give 4-benzyl-3-hydroxymethyl-3-methylmorpholine (9.35 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:18]Br>ClCCl>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13]([Br:18])[C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)COc1cccc2c1CCCC2=O
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methoxycarbonylmethoxy-5-oxo-5,6,7,8-tetrahydronaphthalene (0.5 g) in dry dichloromethane (3 ml) was added bromine (0.14 ml) at 0° C. The mixture was warmed up to room temperature, stirred for 2 hours. The mixture was washed with an aqueous saturated sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (30 ml) using a mixture of dichloromethane--n-hexane. The desired fractions were collected and evaporated in vacuo to give 1-methoxycarbonylmethoxy-5-oxo-6-bromo-5,6,7,8-tetrahydronaphthalene (0.41 g). The crude crystal (50 mg) was recrystallized from ethyl acetate--n-hexane to give 31 mg as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
30 ml of tetrahydrofuran was added to 2.00 g of N-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyl lithium·pentane solution was added thereto under an argon stream at -78° C. Then, 1.41 g of 1-benzyl-4-piperidone was dissolved in 20 ml of tetrahydrofuran, and the solution was added dropwise. After stirring for 2 hours, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 2.07 g of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].Cl.[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:31]([CH3:32])[CH3:30])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Agent: Cl
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and dimethylamine hydrochloride were reacted by a procedure similar to Example 47 to give 249. MS: (ESI+) 441.0
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[O:4]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:17]=[CH:16][N:15]([CH2:25][CH3:26])[N:14]=2)[O:4]1
Reactant: CCI
Reactant: CO[C@@H]1O[C@H](c2nnc[nH]2)[C@H]2OC(C)(C)O[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4H-1,2,4-triazole (Preparation 20) (1.0 g, 4.2 mmol), potassium carbonate (0.57 g, 4.2 mmol) and iodoethane (0.33 ml, 4.2 mmol) in acetone (10 ml) was heated under reflux for one hour. Further iodoethane (0.05 ml, 0.6 mmol) and potassium carbonate (0.1 g, 0.7 mmol) were added and heating under reflux continued for 30 minutes. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:methanol (97:3 by volume) to give the title compound (0.4 g) (TLC data—Rf 0.65 in solvent system dichloromethane:methanol 95:5 by volume).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C1OCCOCCOCCOCCOCCOC1.[C-:27]#[N:28].[K+].C(Cl)(Cl)Cl>CN(C)C=O.[Cu]I.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>[NH2:8][C:5]1[CH:4]=[N:3][C:2]([C:27]#[N:28])=[CH:7][N:6]=1
Reactant: Nc1cnc(Br)cn1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a stirred solution of 5-bromo-2-aminopyrazine (1.0 g) 5.8 mmol), CuI (2.76 g, 14.5 mmol), 18-crown-6 (121 mg; 0.46 mmol), potassium cyanide (943 mg; 14.5 mmol) in dimethylformamide (20 mL) was added Pd(PPh3)4 (196 mg; 0.17 mmol). After stirring at room temperature for 20 minutes the reaction was placed in an oil bath at 155° C. for 2 hours. The reaction was allowed to cool to room temperature and then poured into chloroform (300 mL). A precipitate formed that was filtered and triturated with hexanes to yield an off white solid (60% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(C)c1CO
Reactant: CC(C)(C#N)c1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C)c1COc1cccc(C(C)(C)C#N)c1
Reaction time: 16 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.76 g, 20.3 mmol) and diisopropyl azodicarboxylate (DIAD, 4.7 g, 23.2 mmol) in THF (20 ml) was added drop wise to a solution of 2-(3-hydroxyphenyl)-2-methylpropanenitrile (Step B, 3.2 g, 19.8 mmol) and triphenylphosphine (5.28 g, 20.1 mmol) in THF (50 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 16 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[Cl:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:44])[CH2:27][C:28]1([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>CCCCCC.O1CCOCC1.O1CCCC1>[ClH:22].[CH3:43][O:42][C:36]1[CH:35]=[C:34]([C:28]2([CH2:27][N:26]([CH3:44])[CH2:25][CH2:24][CH2:23][C:11]3([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[S:12][CH2:13][CH2:14][CH2:15][S:16]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:39]=[CH:38][C:37]=1[O:40][CH3:41]
Reactant: COc1ccc(C2SCCCS2)cc1OC
Reactant: COc1ccc(C2(CN(C)CCCCl)CCCCC2)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C2(CN(C)CCCC3(c4ccc(OC)c(OC)c4)SCCCS3)CCCCC2)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2.56 g (0.01 mol) of 2-(3,4-dimethoxyphenyl)-m-dithiane in 20 ml of abs. tetrahydrofuran was cooled to -60° in a sulphonation flask while gassing with dry argon and treated dropwise within 15 minutes with 4.68 ml (0.0075 mol) of a solution of butyllithium in hexane, whereby the temperature was held at -60°. Thereafter, the solution was stirred at -20° for 2 hours, then again cooled to -60° and treated dropwise with a solution of 1.70 g (0.005 mol) of N-(3-chloropropyl)-1-(3,4-dimethoxyphenyl)-N-methylcyclohexanemethanamine in 20 ml of abs. tetrahydrofuran. After 16 hours at -20° and 4 hours at room temperature the solution was poured on to ice-water and the mixture was washed three times with ether. The ethereal extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was chromatographed on silica gel 60 with toluene/ethyl acetate (8:2 ). After evaporation of the solvent there was obtained a colourless oil which was dissolved in a small amount of abs. dioxan and treated with an excess of hydrogen chloride in abs. dioxan, whereby N-[[1-(3,4-dimethoxyphenyl)cyclohexyl]methyl]-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propanamine hydrochloride was obtained as solid white foam.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-])=O)=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:16])[C:6]2=[O:15].Cl.O>CCO.[Fe]>[NH2:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([Br:1])=[C:3]2[C:7]=1[C:6](=[O:15])[N:5]([CH3:16])[CH2:4]2
Reactant: CN1Cc2c(Br)c(F)cc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1Cc2c(Br)c(F)cc(N)c2C1=O
Yield: 49.5 %

Procedure:
A suspension of 4-bromo-5-fluoro-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 31E, 490 mg, 1.70 mmol) in EtOH (10.0 mL) was charged with iron powder (473 mg, 8.48 mmol) and then heated to reflux. After 10 min of reflux, the reaction mixture was charged with 1 M of HCl in H2O (2.03 mL, 2.03 mmol) and stirred at reflux for 10 min. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was quenched with NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to an orange solid. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and then concentrated under reduced pressure to yield a bright yellow solid (218 mg, 50%). 1H NMR (CDCl3, 400 MHz): δ 6.38 (d, J=10.9 Hz, 1H) 5.29 (br. s., 2H) 4.22 (s, 2H) 3.14 (s, 3H). MS (ESI): m/z=260.99 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—3 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[S:5][CH:6]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:4]1[S:5][CH:6]=[C:2]([CH:15]=[O:16])[CH:3]=1)[CH3:10]
Reactant: CCOC(OCC)c1cc(Br)cs1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(OCC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at −78° C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By 1H NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHz, CDCl3): δ □9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).