Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9](O)[CH3:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(Cl)Cl>[N:24]([CH:9]([C:5]1[N:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(C(C)O)ccc1F
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(C)N=[N+]=[N-])ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A 250 ml round bottom flask containing 1-(5-fluoro-6-methylpyridin-2-yl)ethanol (Method 14; 550 mg, 3.54 mmol) was charged with triethylamine (0.75 ml, 5.4 mmol) and anhydrous DCM (8.0 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.32 ml, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, and the volatile components were removed using a rotary evaporator. The residue was treated with sodium azide (466 mg, 7.17 mmol) and anhydrous DMF (5.0 ml), and the slurry was allowed to stir at room temperature. After 2 hours, the mixture was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (Rf in 90:10 hexanes:EtOAc=0.47) to afford the title compound as a colourless oil (567 mg, 89%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[F:25])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[F:25])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of N-tert-butyl-2-(2-fluoro-4-methylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 184 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (421 mg, 284 μL, 3.69 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2-fluoro-4-methylphenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (58 mg, 170 μmol, 92%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.27 (s, 1H), 8.97 (s, 1H), 8.10 (s, 1H), 7.96 (d, J=2.3, 1 H), 7.81 (t, J=8.6, 1 H), 7.70 (s, 1H), 7.10 (d, J=12.4, 1 H), 6.95 (d, J=8.0, 1 H), 2.29 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 342.1 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=O)[NH:10][CH2:9][CH2:8]1.O>O1CCCC1>[S:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=C1NCCSc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNCCS2
Temperature: 0 °C
Yield: 90 %

Procedure:
To a bottle containing a cooled suspension of lithium aluminum hydride (44 g, 1.17 mol) in dry tetrahydrofuran (1.5 L) was added 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol) in portions at 0° C. After being refluxed for 18 hours, the reaction mixture was cooled to 0° C., followed by addition of water (25 mL) dropwise. The reaction mixture was then filtered through a pad of celite and washed with dichloromethane. The filtrate was dried over sodium sulfate and evaporated in vacuo to afford 125 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine (yield was 90%), which was used for the next step without further purification.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]4)=[CH:49][CH:50]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc2C1=O
Yield: 86 %

Procedure:
The compound of example 229 was prepared analogous to compound of example 225 by hydrolysis of compound of example 228.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)C.O1CCCC1.[NH2-].[Na+].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>O>[N+:18]([C:14]1[CH:13]=[C:12]([N:11]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:21])[N:31]([CH2:29][CH3:30])[C:32]2=[O:33])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 5.7 g of 2-(m-nitroanilino)nicotinic acid ethyl ester and 50 ml of dry tetrahydrofuran was added 1.1 g of sodium amide and the solution was stirred for one hour. To this was added dropwise under cooling 2.9 g of ethyl isocyanate and this mixture was reacted at 60°C for 10 hours. After the reaction was complete, the solvent was distilled off from the mixture, and to the residue obtained was added water to precipitate a crude product. This product was collected by filtration and recrystallized from methanol to give 3.4 g of 1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as colorless needles, melting at 210°-211°C.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:30][CH3:31])=[C:8]([CH:29]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=S)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10].S([O-])([O-])=[O:33].[Na+].[Na+].Cl>[OH-].[Na+]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:30][CH3:31])=[C:8]([CH:29]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:33])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10]
Reactant: CCNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCNC(=O)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
0.1 ml (1.16 mmol) of 30% strength hydrogen peroxide solution was added to a solution of 46 mg (0.1 mmol) of 5-chloro-2-methoxy-N-(2-(1-(3-ethylthioureidosulfonyl)piperidin-4-yl)ethyl)benzamide in 2 ml of 0.5 M sodium hydroxide solution at 0° C. After the reaction mixture had been kept at 0° C. for 1.5 hours, 100 mg of sodium sulfite were added, and the mixture was acidified by means of 2 M hydrochloric acid. The precipitated solid was filtered off, washed with water until neutral and reprecipitated from diethyl ether/methanol. 19 mg (43%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: S=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
A solution of 3.45 g of 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one in 80 ml of hexamethylphosphoric acid triamide (HMPT) was treated with 4.24 g of Lawesson reagent and the mixture was stirred at 105° C. for 3.5 h. The reaction mixture was poured into 600 ml of saturated aqueous sodium hydrogen carbonate solution and 2 l of water. After stirring at room temperature for 30 min. the precipitate was filtered off. There were obtained 3.0 g of crude, yellow 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione, m.p. 242° C., which was used in this form for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].F[C:24]1[CH:37]=[CH:36][C:27]2[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:22][C@H:18]([O:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([O:1][C:24]2[CH:37]=[CH:36][C:27]3[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=3[CH:25]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6])[CH2:19][O:20][CH3:21]
Reactant: CN1C(=O)c2ccc(F)cc2OC1(C)C
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OC(C)(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.25 g, 0.82 mmol), 7-fluoro-2,2,3-trimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (172 mg, 0.82 mmol) and potassium carbonate (226 mg, 1.64 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 12 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in DCM, to give the desired compound as a white foam (122 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1.C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:11][CH:10]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)s2)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(CC3SC(=O)NC3=O)s2)c1
Reaction time: 72 h
Yield: 18.5 %

Procedure:
1 g (2.5 mmol) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylidenemethyl)thiophen-2-yl]benzyl}methylcarbamate is placed in 20 ml of dioxane and 0.2 ml of acetic acid. The reaction medium is degassed and placed under 3 atm of hydrogen for 3 days. After filtration through Celite, 0.2 g (20%) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylmethyl)thiophen-2-yl]benzyl}methylcarbamate is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)/C=C/c1ccccc1F
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-fluorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull, 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 351.81; mp: 226.0-228.0° C.; 1H-NMR (DMSO) δ: 8.92-8.87 (1H, m), 8.39-8.29 (1H, m), 8.29 (1H, d, J=16.1 Hz), 7.99-7.79 (4H, m), 7.70-7.51 (4H, m), 7.44-7.31 (3H, m).
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[C:11]1[C:23]([OH:25])=O>>[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[C:11]1[C:23]([Cl:1])=[O:25]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Cl
Reaction time: 8 h

Procedure:
N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (31 μL, 0.23 mmol) was added to a mixture of 1-methyl-4-(BOC amino)pyrrole-2-carboxylic acid (50 mg, 0.21 mmol) in CDCl3 (200 mL). After a few minutes, the 1H-NMR of the reaction mixture showed complete conversion of the acid to the acid chloride. The proton spectrum of this solution of acid chloride did not change on standing overnight at room temperature. 1H NMR (CDCl3): δ 7.35 (br s, 1H), 6.93 (d, J=2 Hz, 1H), 6.46 (br s, 1H), 3.82 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C=O.C([O-])(=[O:15])C.[NH4+].O>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(C=O)cc1
Yield: 61.1 %

Procedure:
13.2 g of p-cyanobenzylamine, 12.0 g of paraformaldehyde, 46.0 g of ammonium acetate, 60 ml of water and 60 ml of acetic acid were mixed and reacted at 100° C. for 3 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and water in an amount equal to the amount of solvent distilled off was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 8.0 g (yield: 62%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C1CCC(=O)O1
Reactant: NC1C=CCCCC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CCC(=O)N1C1C=CCCCC1
Yield: 61 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), succinic anhydride (1.0 g) and acetic acid (10 ml) was heated under reflux for 24 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The oily product thus obtained was purified by column chromatography on silica gel to obtain 1.07 g of N-(2-cycloheptenyl)succinimide [[Compound (214)].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][CH:15]=1.[I-].[Na+].[CH:29]1([C:35]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[N:41]=[CH:40][N:39]([CH2:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[N:38]=2)[OH:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(#N)C.O>[CH:49]1([C@@:35]([OH:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:37]2[N:41]=[CH:40][N:39]([CH2:42][CH:43]3[CH2:48][CH2:47][N:46]([CH2:21][CH2:20][C:17]4[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])=[CH:19][CH:18]=4)[CH2:45][CH2:44]3)[N:38]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CS(=O)(=O)OCCc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
Methanesulfonic acid 2-{4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl}-ethyl ester (Preparation 35, 20.00 g, 53.56 mmol) was dissolved in acetonitrile (80 mL) and stirred at room temperature. Sodium iodide (16.06 g, 107.12 mmol) was added portionwise and the resulting slurry heated to 80° C. for 18 h. The reaction mixture was cooled to 50° C. and further acetonitrile (80 mL) was added. To this mixture was added cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 15.87 g, 53.56 mmol) and diisopropylethylamine (9.79 mL, 56.24 mmol) and heating was continued for 6 hours, then allowed to cool to room temperature. Water (160 mL) was added and the resulting slurry stirred overnight at room temperature. The solid was collected by filtration and washed with acetonitrile (5×20 mL), then dried in vacuo at 45° C. for 8 hours to yield the title compound as a brown solid in 68% yield, 20.9 g,
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:3]([CH2:11][NH:16][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc2c(cc1Cl)OCO2
Reactant: NC1CC1
Product: Clc1cc2c(cc1CNC1CC1)OCO2

Procedure:
Synthesized according to typical procedure J from 6-chlorobenzo[1,3]dioxole-5-carbaldehyde and cyclopropylamine.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O: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][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH2:29]([N:36]1[CH:5]=[C:6]([O: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][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=[C:3]1[CH2:2][OH:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(Cc2ccccc2)c(CO)cc1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 50.0 g (0.127 mole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone and 70 mL benzylamine is stirred for 2 hours at 100°-110° C. After cooling to about 50° C., the dark solution is mixed with 400 mL water and stirred. The precipitate thus formed is filtered off, washed, dried and recrystallized from propan-2-ol with thee addition of active charcoal, colorless crystals thereby being obtained; m.p. 120°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2Br)=[CH:5][CH:4]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2Br)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of bromide 34 (1.0 g, 2.02 mmol, 1 eq) and 3-(trifluoromethyl)phenyl boronic acid (575 mg, 3.03 mmol, 1.5 eq, Aldrich, Milwaukee, Wis., USA) in dimethoxyethane (70 mL), was added sodium carbonate solution (9 mL of a 2 M solution) and tetrakis-triphenylphosphine palladium (233 mg, 0.1 eq). The mixture was stirred at 90° C. for 16 h, cooled to room temperature, and concentrated in vacuo. The resultant residue was partitioned between EtOAc and saturated sodium bicarbonate solution, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (0-40% EtOAc/hexane) to give 790 mg (72%) of N-(4-(4-methoxybenzyloxy)-3-(3-trifluoromethylphenyl)benzyl)-4-fluoro-N-methylbenzenesulfonamide (35). 1HNMR (CD3OD, 400 MHz): δ 7.84 (m, 3H), 7.65 (d, 1H), 7.44-7.54 (m, 3H), 7.18-7.30 (m, 5H), 7.04 (d, 1H), 6.85 (d, 2H), 5.02 (s, 2H), 4.14 (s, 2H), 3.80 (s, 3H), 2.63 (s, 3H). MS (ESI): MH+=560.1. HPLC (Method B) tR=4.57 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](P(OC)(OC)=O)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9](=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([OH:20])[CH:22]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (Fluka, Cat. #09659) (0.97 g, 3.3 mmol) and 3-hydroxybenzaldehyde (0.400 g, 3.28 mmol) were combined in methylene chloride (14 mL) at r.t. under nitrogen. To this DBU (0.68 mL, 3.9 mmol) was added and the reaction was stirred at r.t. for 2 h. The reaction was taken up in ethyl acetate, washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an oil. The product was purified by Flash chromatography on a silica gel column eluting hexane: ethyl acetate gradient to give methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)acrylate (0.92 g, 96%) as a clear oil Analytical LCMS (M+H-Boc)+: m/z=193.9.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[N:10][C:9]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[N:17][C:8]1=2.FC(F)(F)C(O)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:9]2[N:10]=[CH:11][C:12](=[O:13])[N:7]([CH2:6][CH:2]=[O:1])[C:8]=2[N:17]=1
Reactant: COc1ccc2ncc(=O)n(CC3OCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.9 %

Procedure:
To 0.21 g of 4-(1,3-dioxolan-2-ylmethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-one, 10 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 5 hours and then left overnight. The solvent was distilled off under reduced pressure. The resultant residue was charged with ethyl acetate and water and adjusted to pH 7.0 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.18 g of (6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde as a light brown foam.