Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[C:42]1([CH:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+]>CN(C)C=O.COC(C)(C)C>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][N:32]1[C:31]2[CH:41]=[C:27]([CH2:26][O:25][CH:10]3[CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:50]5[CH2:51][CH2:52][CH:48]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH2:49]5)=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11]3)[CH:28]=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CN4CCC(c5ccccc5)C4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The stirred solution of 0.0435 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0155 g of 3-phenylpyrrolidine in 0.5 ml of N,N-dimethylformamide is admixed at 0° C. with 0.0076 g of sodium hydride dispersion (60% in oil). The reaction mixture is stirred at 0° C. over 15 minutes, then at room temperature for 1 hour, and subsequently diluted with 80 ml of tert-butyl methyl ether. The mixture is washed with 20 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=4.72.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].Cl[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:4][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)[C:2]#[CH:3]
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: C#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1nc(C(=O)OCC)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
0.20 g of propargyl alcohol was dissolved in 20 ml of tetrahydrofuran, and 0.13 g of 60% sodium hydride was added at room temperature. The mixture was stirred at room temperature for 1 hour. After 0.50 g of ethyl 2-chloro-1,3-thiazole-4-carboxylate was added, the reaction mixture was stirred at room temperature for 3 hours. After aqueous saturated ammonium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.33 g of ethyl 2-(2-propynyloxy)-1,3-thiazole-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12]2[C:13](O)=[N:14][C:15]([NH2:19])=[N:16][C:17]=2[CH3:18])[CH:6]=1)[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12]2[C:13]([Cl:24])=[N:14][C:15]([NH2:19])=[N:16][C:17]=2[CH3:18])[CH:6]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2O)c1
Product: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2Cl)c1
Temperature: 100 °C

Procedure:
The product from step (i) (1.9 g) was added to phosphorous oxychloride (30 mL) and the mixture was heated at 100° C. for 15 h. The mixture was allowed to cool and the phosphorous oxychloride evaporated under reduced pressure. The residue was diluted with water (10 mL) and the pH of the mixture was adjusted to pH ˜7 using sodium bicarbonate. The mixture was then heated at 50° C. for 2 h and the aqueous was extracted with EtOAc. The combined organic phase was dried and evaporated under reduced pressure to give the subtitle compound as a pale yellow solid 1.65 g that was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: CCCCCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 67.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and amylamine (0.016 g, 0.184 mmol) gives the title compound (0.0426 g, 67.5%) TOFMS ES+ 344.2 (M+H)+, HRMS calcd for C19H26N3O3 344.1974 (M+H)+, found 344.1963time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.1 min, 100% purity.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=2)[N:11]([C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])=[O:35])=[C:29]([O:44][CH3:45])[CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:45][O:44][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)[NH:8][CH2:9][CH2:10]2)=[O:46])[CH:32]=[CH:31][C:30]=1[NH:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH3:43])=[O:35]
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
A solution of 7-(-2-ethoxycarbonyl-ethyl)-4-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.3 g, Reference Example 2) in dichloromethane (3 ml), at 0° C., was treated dropwise with trifluoroacetic acid (0.5 ml). After stirring for 2 hours at 0° C. a further portion of trifluoroacetic acid (0.5 ml) was added and stirring was continued for a further hour at 10° C. The reaction mixture was poured on crushed ice (50 ml), the pH of this mixture was adjusted to 8 by dropwise addition of sodium hydroxide (20 ml, 1N) and then the mixture was extracted twice with dichloromethane (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (235 mg) was subjected to flash chromatography on silica (0.040-0.063 mm) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound (170 mg) as a white foamy solid. 1H NMR, 300 Hz, (CD3)2SO: δ1.2 (t, 3H); 2.3 (s, 3H); 2.6 (t, 2H); 2.8 (t, 2H); 3.25 (m, 2H); 3.7 (t, 2H); 3.85 (s, 2H); 3.9 (s, 3H); 4.1 (q, 2H); 5.8 (broad s, 1H); 6.4 (dd, J=8 Hz and 1.5 Hz, 1H); 6.5 (d, J=1.5 Hz, 1H); 6.7 (dd, J=8 Hz and 1.5 Hz, 1H); 6.85 (d, J=1.5 Hz, 1H); 7 (ddd, J=8, 8 and 1.5 Hz, 1H); 7.2 (m, 3H); 7.7 (broad d, J=8 Hz, 1H); 8 (d, J=8 Hz, 1H); 8.25 (s, 1H); 8.35 (s, 1H). MS (CI, NH3): MNH4+ 548, MH+ 531.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:38]=[C:39]=[O:40])(=[O:37])=[O:36])=[CH:31][CH:30]=1>O1CCCC1>[CH:18]1([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:6]4[CH:7]=[C:2]([NH:1][C:39]([NH:38][S:35]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)(=[O:36])=[O:37])=[O:40])[CH:3]=[CH:4][C:5]=4[O:24][CH2:25][CH2:26][CH3:27])=[N:9]3)=[C:15]([CH3:23])[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=NS(=O)(=O)c1ccc(F)cc1
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Product: CCCOc1ccc(NC(=O)NS(=O)(=O)c2ccc(F)cc2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of example 54 using 150 mg (0.408 mmol) of the amino compound from example 44A and 411 mg (2.04 mmol) of 4-fluorobenzenesulfonyl isocyanate in 12 ml of tetrahydrofuran, which are reacted overnight.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C(F)(F)F)[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([Br:25])[CH:6]=1)C.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br:25][C:7]1[CH:6]=[C:5]([C:4]([N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(Br)c(OCCO)c(-c2ccccc2)c1

Procedure:
5-bromo-6-(2-hydroxyethoxy)-N-methyl-N-(8-phenyloctyl) [1,1′-biphenyl]-3-carboxamide was prepared as a colorless oil (0.200 g, 56%) from 3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.87-7.54 (m, 5H); 7.38-7.12 (m, 6H); 3.65 (m, 4H); 3.50 and 3.03 (2bt, 2H); 3.03 (2s, 3H); 2.58 (m, 2H); 1.98 (bs, 1H); 1.60 (m, 4H); 1.40-1.22 (m, 8H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:3][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:2])=[O:19])=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Product: C=C(OC(=O)c1ccc(C(C)(C)C)cc1)c1ccccc1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A mixture of 4.16 g (21.62 mmol) of acetophenone trimethylsilylenol, 4.33 g (22.01 mmol) of 4-tert-butylbenzoyl chloride and 136 mg of mercuric chloride was heated at 100° C. for 2 h. The mixture was then left to cool, water was added over the reaction crude and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. A 2.12 g sample was purified by flash chromatography (hexane:dichloromethane 3:1) giving 1.17 g of 1-phenylvinyl 4-tert-butylbenzoate. Yield 57%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])=O)[C:9]=2[S:31][CH3:32])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1COCC1>[C:26]([C:25]1[S:42][C:21]([C:10]2[C:9]([S:31][CH3:32])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[N:23][N:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CSc1c(C(=O)NNC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CSc1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 77.9 %

Procedure:
To a solution of hydrazide (9) (70 mg, 0.136 mmol) and Lawesson's reagent (137 mg, 0.339 mmol) in THF (5 mL) was irradiated in a microwave reactor (Biotage Initiator™) for 50 minutes at 155° C. The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=4/1) to obtain 54 mg (78%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C:17](=O)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([SH:23])[CH2:21][SH:22].B(F)(F)F.CCOCC.O>C(O)(=O)C.C(OCC)(=O)C.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:16][C:17]2([S:23][CH2:20][CH2:21][S:22]2)[CH2:18]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCS
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2
Yield: 79.1 %

Procedure:
Dissolve 1-benzyloxycarbonyl-4-keto-(S)-proline (15.7 g, 60 mmol) in acetic acid (45 ml) and ethyl acetate (45 ml), add 1,2-ethanedithiol (6.2 g, 66 mmol) and stir under nitrogen. Add boron trifluoride etherate (redistilled) and stir 4 hours. Pour the reaction mixture into a mixture of water (175 ml) ethyl acetate (120 ml) and ether (60 ml). Wash the organic layer with water (3×175 ml) then extract twice with 1.0 N sodium bicarbonate (150 ml, then 50 ml). Acidify the aqueous layer to pH 1 with concentrated hydrochloric acid, extract twice with ether (150 ml, then 50 ml). Wash the organic layer with brine, dry over anhydrous magnesium sulfate and concentrate in vacuo to obtain crude 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid as an oil (16.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:23](O)=O>O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([OH:7])=[O:6])=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=3[N:1]=[CH:23]2)=[CH:15][CH:16]=1)([OH:22])=[O:21]
Reactant: O=CO
Reactant: Nc1ccc(Cl)c(C(=O)O)c1NCc1ccc(C(=O)O)cc1
Solvent: O
Product: O=C(O)c1ccc(Cn2cnc3ccc(Cl)c(C(=O)O)c32)cc1
Yield: 100 %

Procedure:
A solution of 3-amino-2-[(4-carboxyphenyl)methyl]amino-6-chlorobenzoic acid (80 mg, 0.24 mmol, prepared as in Example 2 (i-ii)) in 0.5 ml of 98% formic acid was refluxed under argon for 2.5 hours. The reaction mixture was diluted with water and the resulting solid was collected to give 80 mg (100%) of the title compound; mp 291°-292° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[F:19])[N:15]=[CH:14][C:13]([C:21]#[C:22][Si](C)(C)C)=[CH:12]2)[S:6][CH3:7])C.[OH-].[Na+].Cl>C1COCC1>[C:21]([C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH:5]([S:6][CH3:7])[C:4]([OH:27])=[O:3])=[C:18]([F:19])[C:17]=2[CH3:20])#[CH:22]
Reactant: CCOC(=O)C(Oc1cc2cc(C#C[Si](C)(C)C)cnc2c(C)c1F)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#Cc1cnc2c(C)c(F)c(OC(SC)C(=O)O)cc2c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of (7-fluoro-8-methyl-3-trimethylsilanylethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester (3.35 g, 90% purity) from Step 7 in THF (100 ml), a 0.5 M aq NaOH soln (19.5 ml) was slowly added at 0° C. The light yellow mixture was stirred during 2 hrs at 0-10° C., then 2M HCl soln was added (pH 1). The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure yielding (3-ethynyl-7-fluoro-8-methyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid which was used as such for the next step. 1H NMR (DMSO-d6) δ ppm: 13.60 (1H, br s); 8.85 (1H, d); 8.40 (1H, d); 7.560 (1H, d); 6.11 (1H, s); 4.50 (1H, s); 2.59 (3H, d); 2.17 (3H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:25]1[CH2:35]CN2C(=NCCC2)C[CH2:26]1.C(I)(C)C>C(#N)C>[CH:25]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[C@@H:13](/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:14]([OH:16])[CH2:15][C@@H:2]1[OH:1])([CH3:35])[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCC/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CC(C)I
Solvent: CC#N
Product: CCCCCC/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O

Procedure:
The title compound 8 was obtained as a colorless oil (36 mg, 95%), following a procedure similar to that disclosed in Example 5 except that the compound 6 obtained above (33 mg, 0.1 mmole) was dissolved in acetonitrile (1 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (40 μl, 0.3 mmole) and then isopropyl iodide (0.19 μl, 1 mmole) were added thereto.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].C(N(CC)CC)C.O>O1CCOCC1>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a stirred solution of 2,2,2-trifluoroethylamine (1.17 ml, 15 mmol) in dioxane (37 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (3.0 g, 14 mmol) and triethylamine (2.06 ml, 15 mmol). The light yellow suspension was stirred at room temperature for 4 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield 3-nitro-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (3.18 g, 83%) as a light yellow solid. MS (ISP) 283.9 [(M−H)−].
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)Cl.I[CH2:25][CH2:26]CCCCCC.C([Cu])#N.[Li+].[Cl-].CC1(C)N([O])C(C)(C)CC(=O)C1>[Zn].BrCCBr>[CH2:1]([O:7][N:8]1[C:9]([CH3:17])([CH3:18])[CH2:10][C:11](=[O:16])[CH2:12][C:13]1([CH3:14])[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:25][CH3:26]
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCCCCCI
Agent: N#C[Cu]
Agent: CC1(C)CC(=O)CC(C)(C)N1[O]
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Product: CCCCCCCCON1C(C)(C)CC(=O)CC1(C)C
Yield: 36 %

Procedure:
N-octyloxy-4-oxo-2,2,6,6-tetramethylpiperidine (30.3 g, 36%) is synthesized in the same manner as described above with regard to N-cyclohexyloxy-4-oxo-2,2,6,6-tetramethyl-piperidine, with the exception of the addition of Zn (294.0 mmol, 19.25 g), 1,2-dibromoethane (900 μl), trimethylchlorosilane (1.2 ml), iodooctane (294 mmol, 70.6 g), CuCN (294 mmol, 26.3 g), LiCl (588 mmol, 25.0 g) and 4-oxo-TEMPO (294 mmol, 50.0 g). 1H-NMR (CDCl3): δ=3.69 (t, J=6.5 Hz, 2H, O—CH2), 2.55 (d, J=12.8 Hz, 2H, CH2—CCH3), 2.20 (d, J=12.8 Hz, 2H, CH2—CCH3), 1.54 (m, 2H, CH2—CH3), 1.36 (m, 2H, CH2), 1.28 (m, 14H, CH2 and C—CH3), 1.15 (s, 6H, C—CH3), 0.88 (t, J=6.8 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3) δ=208.4, 77.1, 62.9, 53.3, 32.5, 31.8, 29.6, 29.2, 28.6, 26.4, 22.6, 22.5, 14.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Solvent: O
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{3-chloro-4-[4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (1.2 g) and p-fluorobenzoic acid (0.8 g) in Eaton's acid (5 mL) was heated at 60° C. for 4 h. The resulting red solution was cooled to 0° C., water (30 mL) added and the suspension stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (2×), the combined organic layers washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), concentrated in vacuo and flashed chromatographed on silica gel (25-40% THF/hexanes) to afford the title compound of Step A as a off-white foam, 1.1 g. MS Calc.:481.9; Found:481.8.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>CN(C=O)C.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>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[O:10][CH2:9][C:8]4[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=4[C:6]=3[CH:5]=[C:4]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=23)=[CH:23]1
Reactant: OB(O)c1ccoc1
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccoc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (342.mg, 1.0 mmol), furan-3-boronic acid (224 mg, 2 mmols) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmoles) in DMF (20 ml) is heated at 120° C. with stirring for 4 h. The mixture was filtered through celite, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, filtered, stripped of solvent and purified by silica column chromatography (18%-25% ethyl acetate-hexane) to yield 200 mg (61%) of the title compound as a yellowish solid: mp 216-218° C.; 1H NMR (DMSO-d6): δ 5.00 (2H, s), 6.66 (2H, m), 6.84 (1H, dd, J=8.45 Hz, J=2.35 Hz), 6.93 (1H, dd, J=8.77 Hz, J=2.35 Hz), 7.04 (1H, d, J=2.17 Hz), 7.76 (1H, d, J=8.83 Hz), 7.80-7.85 (3H, m), 8.16 (1H, s), 9.61 (1H, s), 9.71 (1H, s); MS (ESI) m/z 329 (M−H)−, 331 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[C:10]([C:14]([OH:16])=[O:15])=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].[CH3:17]O>>[N+:6]([C:9]1[C:10]([C:14]([O:16][CH3:17])=[O:15])=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7]
Reactant: CO
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Fuming sulfuric acid (4 mL) was added to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (16.0 g, 102 mmol) in methanol (200 mL), and the reaction was stirred at RT for 24 hours. The reaction mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, providing C29 as a white solid. Yield: 17.1 g, 99.9 mmol, 98%. LCMS m/z 170.0 (M−1). 1H NMR (400 MHz, CDCl3) δ 4.05 (s, 3H), 8.40 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=O.[NH3:24]>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[N:6][C:5]([C:3](=[O:2])[NH2:24])=[CH:10][N:9]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(C(N)=O)cn2)CC1
Temperature: 60 °C

Procedure:
3 mmol of 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester (example 1.13(a)) was dissolved in a 7 molar solution of gaseous ammonia in methanol. The reaction vessel was tightly closed and heated overnight at 60° C. Cooling of the reaction mixtures led to crystallisation of the title compound. MS (m/e): 308.4 (MH+, 100%)