Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:50][CH2:51][C@@H:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[OH:53]>>[OH:53][C@H:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:51][NH:50][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:40][CH:39]=3)[C:33]2=[O:49])=[N:25][C:24]=1[CH3:23])=[O:30]
Reactant: NC[C@H](O)c1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NC[C@H](O)c1ccccc1
Yield: 67 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with (R)-(−)-2-amino-1-phenylethanol, the title compound was obtained as a white powder in 67% yield: mp 149-151° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 9H), 6.24 (br s, 1H), 4.92-4.89 (m, 1H), 4.44 (s, 2H), 4.28-4.02 (m, 2H), 3.85-3.41 (m, 2H), 3.57-3.38 (m, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 157.5, 155.4, 152.8, 148.9, 141.7, 134.3, 129.7, 128.5, 127.8, 125.8, 121.4, 117.6, 73.5, 47.8, 47.2, 42.0, 41.7, 17.1; MS (ES+) m/z 521.3 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.O>ClCCl>[CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14][Cl:18])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cnc(SCc2ccccc2)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.18 g of 2-benzylsulfanyl-5-hydroxymethyl-thiazole dissolved in 5 ml of dichloromethane, 0.4 ml of thionyl chloride dissolved in 5 ml of dichloromethane are added dropwise at 0° C. to. The reaction mixture is then allowed to warm to room temperature and stirred for 0.5 hour. After the addition of 5 ml of water, the organic phase is washed twice with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent in vacuo, chromatography on silica gel (ether:hexane; 1:4) yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14](C(O)=O)CCC(=O)O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.93 (1); Glu 1.22 (1); Arg 1.08 (1)
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>C(OC(=O)C)(=O)C.C1(=O)OC(=O)C=C1>[CH2:6]=[CH:1][CH2:2][CH2:3][CH:14]1[C:15](=[O:16])[O:17][C:12](=[O:18])[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)OC(C)=O
Product: C=CCCC1CC(=O)OC1=O
Temperature: 215 °C

Procedure:
Into a 5 liter/3 neck Pyrex flask equipped with a condenser, addition funnel, thermometer, gas inlet tube, mechanical stirrer, and heating mantle was weighed 2200 grams of polybutene having a molecular weight of about 432 and an unsaturation content of 99.6. Into the addition funnel was placed 3.3 grams of paratoluene sulfonic acid dissolved in 6.6 grams of acetic anhydride and 450.5 grams of maleic anhydride (4.24 moles) which was melted and kept in a liquid state with heat lamps. The polymer in the flask is stirred and heated to a temperature of about 215° C. under a nitrogen atmosphere. The melted maleic anhydride catalyst mixture was added dropwise to the stirred polymer at a rate such that the reaction mixture temperature could be maintained between 210° to 215° C. without flooding the condenser. The addition under these conditions required 4 hours. During the addition, two drops of anti-foam fluid was added to reduce foaming. After the addition of the maleic anhydride the reaction mixture was maintained at 215° C. for 21 hours. The reaction mixture at the end of this period was increased to 235° C. The condenser was replaced with a distillation head and air cooled condenser. The nitrogen flow through the gas inlet tube was increased to 4 SCFH and the unreacted maleic anhydride was thus stripped from the reaction mixture for 2 hours. The mixture was cooled and filtered. The product polybutenyl succinic anhydride obtained had an activity of 67%, the balance of the material being unreacted polybutene with a viscosity of 336 SUS at 100° C. The infrared spectrum displayed carbonyl absorptions at 1870 (medium), 1790 (strong), and 1710 (weak).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([O:41]CC3C=CC=CC=3)=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: [H][H]
Reactant: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)cc1OC
Yield: 97.4 %

Procedure:
N-[5-[2-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-1-hydroxyethyl]-2-(phenylmethoxy)phenyl]methanesulfonamide, trifluoroacetate salt (220 mg, 0.38 mmol) was hydrogenated using 10% Pd/C (120 mg) and MeOH (25 mL, AR grade) at 40 psi of hydrogen in a Parr apparatus for one hour at room temperature. The catalyst was filtered through Celite and washed with MeOH. The filtrate and MeOH washings were combined and concentrated to afford 178 mg (0.37 mmol, 96% yield) of the title compound as a pale yellow crystalline powder. The title compound is a racemic mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][C@@H:18]3[CH2:33][OH:34])=[O:16])[N:12]=[C:11]2[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:42]([O:44]C1C=C(N2C=C(C(N3CCN(C(OCC4C=CC=CC=4)=O)C[C@@H]3C(OC)=O)=O)N=C2C2C=CC(C)=CC=2)C=CC=1)[CH3:43].[BH4-].[Li+]>CO>[C:42]([O:34][CH2:33][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:15]([C:13]1[N:12]=[C:11]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:14]=1)=[O:16])(=[O:44])[CH3:43]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3CO)nc2-c2ccc(C)cc2)c1
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3C(=O)OC)nc2-c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Reaction time: 1 h

Procedure:
Benzyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of 4.10 g (7.04 mmol) of 1-benzyl 3-methyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylate from Step A in 75 mL of anhydrous methanol at 0° C. under a nitrogen atmosphere was added 460 mg (21.1 mmol) of lithium borohydride. An additional 460 mg (21.1 mmol) of lithium borohydride was added to the reaction mixture every hour for 3 hours and stirred for one hour after the final addition. The reaction was quenched with a saturated aqueous ammonium chloride solution (50 mL) followed by concentration in vacuo to remove the methanol. The residue was diluted with water (15 mL) and extracted with dichloromethane (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on a Biotage® purification apparatus (silica gel, 65% ethyl acetate in hexanes) to yield the title compound as a colorless solid. LC/MS 555.2 (M+1).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][C:54]([CH2:60][CH2:61][N:39]3[C:38](=[O:42])[CH:37]=[C:36]([O:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([Br:27])=[CH:33][N:32]=4)[CH:41]=[N:40]3)=[CH:55][CH:56]=2)[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccc(Br)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 15b from 1.13 g (4.00 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 25b) and 1.73 g (4.00 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Br)=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1.[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:23]([CH3:24])[CH3:22])=[N:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1
Reactant: CNC
Reactant: Cn1nc(-c2cccc(Cl)c2)nc1-c1ccccc1CBr
Solvent: c1ccccc1
Product: CN(C)Cc1ccccc1-c1nc(-c2cccc(Cl)c2)nn1C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4. g. of 1-methyl-3-(3-chlorophenyl)-5-(2-bromomethylphenyl)-1,2,4-triazole in 50 ml. of anhydrous benzene, 8.8 ml. of a benzene solution containing 20% of dimethylamine are added maintaining the temperature of about 5°-10° C. The mixture was maintained under stirring for 16 hours and then washed with 10% sodium hydroxide and with an aqueous solution of sodium chloride. The organic solution is dried over sodium sulfate and then evaporated. The crude product is purified by distillation at 175° C./0.07 mm Hg. Yield 86%.
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH:14]=O)=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2].O.[OH-].[Na+].Cl.[CH3:22][C:23]([CH3:25])=[O:24]>>[CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH:14]=[CH:22][C:23](=[O:24])[CH3:25])=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2]
Reactant: CCC1(C)Cc2c(C)c(C)c(C=O)c(C)c2C1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)Cc2c(C)c(C)c(C=CC(C)=O)c(C)c2C1
Yield: 79 %

Procedure:
To a solution of 18.26 g of the 2-ethyl-2,4,5,7-tetramethylindan-6-carboxaldehyde in 58 ml of absolute acetone was added 28 ml of water and 32 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified was 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 19.38 g of the title compound as yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:50]([O:54][C:55]([N:57]([CH:70]([CH3:72])[CH3:71])[CH2:58][C@H:59]([C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)[C:60](O)=[O:61])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:60](=[O:61])[C@@H:59]([C:63]3[CH:64]=[CH:65][C:66]([Cl:69])=[CH:67][CH:68]=3)[CH2:58][N:57]([CH:70]([CH3:72])[CH3:71])[C:55](=[O:56])[O:54][C:50]([CH3:53])([CH3:51])[CH3:52])[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0380 g, 0.118 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0337 g, 0.0986 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 3-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was again concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-(isopropylamino)propan-1-one dihydrochloride (0.030 g, 53%). MS APCI (+) m/z 507.2 detected.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[N:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[N:35]=[C:31]([CH3:30])[S:32][CH:33]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cs1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5csc(C)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B35), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography for three consecutive times (amino phase silica gel, eluent: EtOAc) to yield the title compound as a solid.
Reaction SMILES: [Na][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([S:10][Na])[S:5][N:4]=1.Br[C:13]1[S:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1>CO>[N+:18]([C:15]1[S:14][C:13]([S:2][C:3]2[C:7]([C:8]#[N:9])=[C:6]([S:10][C:13]3[S:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:5][N:4]=2)=[N:17][CH:16]=1)([O-:20])=[O:19]
Reactant: N#Cc1c(S[Na])nsc1S[Na]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CO
Product: N#Cc1c(Sc2ncc([N+](=O)[O-])s2)nsc1Sc1ncc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 4.36 (0.02 mol.) of 3,5-di(sodiomercapto)-4-isothiazole carbonitrile in methanol was added 8.4 g (0.04 mol.) of 2-bromo-5-nitrothiazole. A yellow-brown solid begins to precipitate almost immediately. The reaction mixture is stirred for an additional 2 hours at room temperature (~22° C.). The precipitate is collected by suction filtration, washed with water and methanol and dried in vacuo to yield 6.77 g (79% yield from the isothiazole) of a tan solid, m.p. 197°-199.5° C.
Reaction SMILES: ClC1C=CC=C2C(OC(=O)C=12)=[O:6].[N+:13]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=[O:23])[C:17]=12)=[O:20])([O-:15])=[O:14].ClCl.C1(=O)OC(=O)C2=CC=CC=C12>>[N+:13]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]([C:19]([OH:6])=[O:20])[C:17]=1[C:22]([OH:21])=[O:23])([O-:15])=[O:14]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: ClCl
Agent: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
3-Chlorophthalic anhydride can also be prepared from 3-nitrophthalic anhydride by replacement of the nitro group by chlorine. The 3-nitrophthalic anhydride needed for this is prepared in three process steps by nitration of phthalic anhydride in moderate yield, by isomer separation of the nitrophthalic acids formed, by fractional crystallization and by conversion to the anhydride of the 3-nitrophthalic acid obtained (M. S. Newman, P. G. Scheurer, J. Am. Chem. Soc. 78 (1956), 5005; Organic Syntheses, Coil. Vol. 1 (1932), 399-401). This multistage and complicated route, which additionally gives poor yields, is not very suitable for industrial use.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[C:18](=[O:20])[CH3:19])[CH2:3][CH2:2]1.Cl[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1C=CC=CC=1.C(OCC)(=O)C>[C:18]([C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=1[N:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NC1CCOCC1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)N(c1cc(C(F)(F)F)ccc1C(C)=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a stirred solution of 400 mg (1.39 mmol) 1-(2-(tetrahydro-2H-pyran-4-ylamino)-4-(trifluoromethyl)phenyl)ethanone in benzene (5 ml) was added 360 μl (2.78 mmol) ethyl 3-chloro-3-oxopropanoate at 0° C. The reaction mixture was stirred at 80° C. for 4 h. Then the mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml), brine (20 ml), a sat. aq. Na2CO3 sol. (2×30 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to yield 550 mg (1.37 mmol, 98%) ethyl 3-((2-acetyl-5-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)amino)-3-oxopropanoate, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C.O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][O:8][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOC(=O)c1cc(C)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
A 2 L round-bottomed flask equipped with a mechanical stirrer was charged with 2,5-dimethyl-3-furoic acid (81.0 g, 0.58 mol) and potassium carbonate (95.9 g, 0.69 mol) in DMF (500 mL). An ice bath was used to cool the reaction as 2-methoxyethoxymethyl chloride (72.2 g, 0.58 mol) was added portionwise. The reaction was stirred for 5 h at rt. The mixture was then diluted with water (1.5 L) and extracted with EtOAc (2×600 mL). The combined organics were washed with water (2×900 mL) and saturated sodium chloride solution (1 L), dried over MgSO4, filtered and concentrated to afford compound 803A (103 g, 82%) as a yellow oil. 1H NMR(CDCl3): δ=6.23 (s, 1H), 5.47 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.51 (s, 3H) and 2.20 ppm (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]([OH:16])[CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:24](OC)([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]2[CH2:14][O:15][C:24]([CH3:26])([CH3:25])[O:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 0.83 g (2.48 mmol) of 6-chloro-N-cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-3-sulfonamide, 0.67 mL (5.45 mmol) of 2,2-dimethoxypropane and 47 mg of pTsOH in 5 mL of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of EtOAc, washed with 50 mL of saturated NaHCO3 solution and 50 mL of water, and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.92 g 6-chloro-N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide is obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28]OS(C(F)(F)F)(=O)=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].C[N+](C)(C)C.O>COCCOC>[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)C1CCC(COS(=O)(=O)C(F)(F)F)CC1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)C1CCC(CC(F)(F)C(F)(F)F)CC1
Reaction time: 4 h
Yield: 18.5 %

Procedure:
(Pentafluoroethyl)trimethylsilane (105 mg, 0.548 mmol) was added to a solution of 4-trifluoromethanesulfonyloxymethyl-cyclohexanecarboxylic acid benzyl ester (cis:trans=4:1) (67.0 mg, 0.176 mmol) in DME (0.88 ml) at −30° C., and tetramethylammonium fluoride (21 mg, 0.22 mmol) was then added at −30 to −27° C. over one hour. The mixture was stirred for four hours while warming from −30° C. to 0° C. and further stirred at 0° C. for one hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=150/1) to give 4-(2,2,3,3,3-pentafluoro-propyl)-cyclohexanecarboxylic acid benzyl ester (cis:trans=11:1) (11.4 mg, 18%).