Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9](=[O:23])[C@@H:10]([NH2:22])[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])[CH3:12].[OH:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]#[C:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:41](O)=[O:42])[CH:35]=[CH:34]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[C@H:10]([NH:22][C:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([C:30]#[C:29][C@@H:27]3[CH2:28][C@H:26]3[CH2:25][OH:24])[CH:32]=2)[CH:37]=1)=[O:42])[C:9]([O:8][CH3:7])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a stirring suspension of (S)-methyl-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate (6.3, 1.6 g, 4.9 mmol) and 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 3.8 mmol) in ACN (10 mL) at 0° C. was added triethylamine (2.1 mL, 15 mmol), followed by the portionwise addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL) and the reaction mixture was stirred at 0° C. for 75 min. The reaction was concentrated under reduced pressure to yield a residue, which was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2×), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4), which was carried through to the next step without further purification.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[FH:13]>>[C@H:11]1([F:13])[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]1[OH:10]
Reactant: F
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](F)[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 98.9 %

Procedure:
In the same way as described in Example 3, 1 g of D-mannose was reacted with 10 g of hydrogen fluoride. About 1 g of α-D-mannosyl fluoride ws isolated and identified by comparison with authentic material (cf. Barnett 35 al., loc. cit. in Example 3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)#[N:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:25])=S.[Na+].[Na+]>CO.O>[C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)(=[O:25])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C#N)c2C1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Temperature: 55 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
To a solution of 26.7 g (108 mmol) of tert-butyl 8-cyano-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 490 ml of methanol are added 80 ml (864 mmol) of concentrated aqueous 32% sodium hydroxide and 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution. The reaction medium is heated at 55° C. for 2 hours. 4 times 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution are then added every 2 hours and heating is then continued at 55° C. for 18 hours. The medium is then treated with an aqueous solution of 30 g (190 mmol) of sodium thiosulfate in 250 ml of water and the reaction mixture is stirred for 1 hour and then partially concentrated under reduced pressure. The product is extracted with 350 ml and then twice 100 ml of dichloromethane, and the organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in a mixture of dichloromethane and ethyl acetate and then precipitated by slow concentration to give 21.1 g of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after drying in an oven at 60° C. under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.[Cl:19][C:20]1[C:21]([O:31][CH3:32])=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>ClCCl.C(N(CC)CC)C>[Cl:19][C:20]1[C:21]([O:31][CH3:32])=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2c(N)cccc2C1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C(=O)OC(C)(C)C)C3)cc1Cl
Yield: 72.7 %

Procedure:
To a solution of 5-amino-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (1 g, 4 mmol) in dichloromethane (30 ml) and triethylamine (3 ml) was added 5-chloro-2,4-dimethoxybenzoyl chloride (1.03 g, 4.4 mmol). After stirring at room temperature for 2h the reaction mixture was diluted with dichloromethane (75 ml) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate/petrol to afford the title compound as a colourless crystalline solid (1.3 g).
Reaction SMILES: S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[Cl:15][C:16]([Cl:44])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([Cl:43])([Cl:42])[C:36]([O:38]C(C)C)=[O:37])[C:17]([O:19]C(C)C)=[O:18]>>[Cl:15][C:16]([Cl:44])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([Cl:42])([Cl:43])[C:36]([OH:38])=[O:37])[C:17]([OH:19])=[O:18]
Reactant: CC(C)OC(=O)C(Cl)(Cl)CCCCCCCCCCCCC(Cl)(Cl)C(=O)OC(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCC(Cl)(Cl)C(=O)O
Temperature: 3 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3 g. of a mixture of 96-98% sulphuric acid and oleum (1:1 w/w) cooled to 3° C. are added dropwise to the dry diisopropyl 2,2,15,15-tetrachlorohexadecane-1,16-dioate. The mixture is stirred for 10 minutes at 3° C., a colour change to orange thereby taking place. A further 2 g. of the acid mixture are added dropwise until the ester has completely dissolved and then stirred for 15 minutes at 3° C. The solution is cooled to -78° C. and a mixture of ice/dichloromethane added thereto. The frozen mixture is dissolved by slowly warming to ambient temperature while stirring with a porcelain spatula, the solution thereby becoming colourless. After separation of the phases, the aqueous phase is extracted with dichloromethane and the combined organic extracts are dried over anhydrous sodium sulphate. After removal of the solvent, there are obtained 150 mg. (yield 90% of theory) of a colourless solid; m.p. 113.5°-114.5° C., after recrystallisation from cyclohexane.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].C([O-])(C)(C)C.[K+].[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32]I)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCC.O1CCCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]1
Reactant: Fc1ccccc1F
Reactant: CCCCC[C@H]1CC[C@H](CCI)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCc2cccc(F)c2F)CC1
Reaction time: 0.17 h

Procedure:
A solution of 0.21 mol of n-butyllithium in 130 ml of hexane is added to a mixture of 0.25 mol of 1,2-difluorobenzene, 0.20 mol of potassium tert.-butanolate and 200 ml of tetrahydrofuran at -100° C. After the mixture has been stirred for 10 minutes, a mixture of 0.2 mol of 2-(trans-4-pentylcyclohexyl)-ethyl iodide, 0.2 mol of dimethylaminepropyleneurea and 50 ml of tetrahydrofuran is added at -90° C. After the mixture has been stirred at -40° C. for 1 hour, customary working up gives the ethane derivative of boiling point 135° C./0.5 mm Hg, in addition to a little 1,4-di-(2-trans-4-pentylcyclohexyl)-ethyl)-2,3-difluorobenzene as a by-product, of C 64° C. N 106.7° I.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]3([O:28][CH3:29])[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3)[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(OC(=O)C)C>[CH3:39][C:38]1[CH:40]=[CH:41][C:35]([S:32]([O:27][CH2:26][C@@H:19]2[C@@H:20]([OH:25])[C@H:21]([OH:24])[C@@H:22]([OH:23])[C@@:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([CH2:9][C:8]4[CH:30]=[CH:31][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=4)[CH:11]=3)([O:28][CH3:29])[O:18]2)(=[O:34])=[O:33])=[CH:36][CH:37]=1
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1.2 g, 2.66 mmol) in leutidine (18.6 mL, 159.8 mmol), was added tosyl chloride (3.0 g, 15.98 mmol) at 0° C. The reaction mixture was stirred at r.t. for 12 h. After the completion of reaction as monitored by TLC, the reaction mixture was diluted with ethylacetate (50 mL) and washed with 5% HCl (3×10 mL). The organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.7:9.3 MeOH:DCM) to provide title compound (1.42 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2
Reactant: COC(=O)c1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(N)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of Example 71A (10.33 g, 44.5 mmol) in acetic acid/water (3/1) (320 mL) was treated with iron powder (5.06 g, 90.7 mmol). After stirring for 16 hours at room temperature, the reaction mixture was filtered the filtrate concentrated under reduced pressure to approximately half the original volume. The mixture was then extracted with dichloromethane (3×200 mL). The organic fractions were combined, dried (MgSO4), and the filtrate concentrated under reduced pressure to afford crude material. A precipitate formed in the aqueous phase after sitting for several hours. This was filtered to afford additional crude material. The crude material was purified by column chromatography (2% methanol/CH2Cl2) to provide the title compound. MS (ESI+) m/z 203 (M+H)+; MS (ESI−) m/z 201 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.92 (s, 3H), 6.34 (s, 2H), 6.96 (dd, J 1.0, 7.8, 1H), 7.31 (d, J 8.1, 1H), 7.51 (t, J 7.9, 1H), 8.82 (s, 1H), 9.15 (s, 1H); Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.99; N, 13.85. Found: C, 65.03; H, 4.95; N, 13.65.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:7]=2[N:8]=1)[CH:19]=[CH2:20]
Reactant: C=CCNc1nc(Cl)nc2c(C(C)C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(C(C)C)c2n1
Yield: 89.3 %

Procedure:
70 mg (0.26 mmol) of 4-allylamino-2-chloro-7-isopropylthieno[3,2-d]pyrimidine and 239 mg (4.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (30 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 67 mg (yield: 89.3%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:11][NH2:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C[O:14][C:15](=O)[N:16]=[C:17](SC)[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][NH:8][C:7]=1[N:11]1[C:15](=[O:14])[NH:16][C:17]([CH:18]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: CCOC(=O)c1c[nH]nc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.9 %

Procedure:
A solution of 0.140 g of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester, 0.236 g of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 1d) and 0.209 ml of triethylamine in 6 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in 7 ml of methanol, and then 0.251 g of sodium cyanotrihydroborate, 0.086 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (0.152 g) as a light green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.[F:29][C:30]([F:34])([F:33])[CH2:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:31][C:30]([F:34])([F:33])[F:29])=[CH:24][N:23]=1
Reactant: FC(F)(F)CI
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(OCC(F)(F)F)cn2)c1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 mmol) was used in Procedure L with excess trifluoroethyl iodide. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.64 (40% ethyl acetate/hexanes); MS (Q1) 490 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[C:8]1/[C:9](=[O:23])[CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:11](=[O:13])[CH2:12]/1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])[C:9]1=[O:23]
Reactant: [H][H]
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\c3sccc3C)C2=O)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C2C(=O)CC(Cc3sccc3C)C2=O)c(C)c1

Procedure:
To a solution of 4-[1-(3-methylthiophen-2-yl)-meth-(E)-ylidene]-2-(2,4,6-trimethylphenyl)cyclopentane-1,3-dione (100 mg, 0.31 mmol) in methanol (10 ml) is hydrogenated in a H-Cube using 10% palladium on charcoal at 40° C. and 10 bar hydrogen pressure with a flow rate of 0.5 ml/min. The eluate collected is concentrated under vacuum to give a residue which is purified by silica gel column chromatography to give 4-(3-methylthiophen-2-ylmethyl)-2-(2,4,6-trimethylphenyl)cyclopentane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH4+:16].[OH-]>C(Cl)Cl>[NH2:16][S:12]([C:8]1[CH:9]=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 20 ml scintillation vial was added 2,3-dichloro-5-(chlorosulfonyl)benzoic acid (170 mg, 0.587 mmol). To this was added 1.5 ml of DCM and 7 ml of 7M NH4OH. The reaction mixture was stirred vigorously at room temperature overnight. After consumption of the starting material, the reaction solution was concentrated to half volume with a rotary evaporator and acidified with 6M HCl to ˜pH 4.5. The resulting solution was left at room temperature until the product precipitated. The product was collected by vacuum filtration and air dried, yielding 5-(aminosulfonyl)-2,3-dichlorobenzoic acid (80 mg, 50%) as light yellow solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[CH:17]=3)=[CH:12][S:11]2)=[CH:5][C:4]=1C.[CH2:30](N(CC)CC)C>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:28])(=[O:27])[N:24]([CH3:25])[CH3:26])[CH:17]=3)=[CH:12][S:11]2)=[C:5]([CH3:30])[CH:4]=1
Reactant: Cc1cc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)ccc1Cl
Reactant: CCN(CC)CC
Agent: Br
Product: Cc1cc(Cl)ccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 2 (a), from 2-(4-chloro-3-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-4-thiazoline hydrobromide and triethylamine. Melting point 137°-141° C.
Reaction SMILES: [N:1]1[C:11]2[C@@H:10]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@H:9]3[CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[Cl:36].[OH-].[Na+]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([S:37]([N:7]2[CH2:8][C@@H:9]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C@H:10]3[C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)(=[O:38])=[O:39])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNCc3cccnc3[C@@H]2C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H]2CN(S(=O)(=O)c3ccc(Cl)c(Cl)c3)Cc3cccnc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 334B (100 mg, 0.34 mmol) and triethylamine (0.097 mL, 0.69 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 10 minutes. 3,4-Dichlorobenzene-1-sulfonyl chloride (0.52 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at room temperature overnight. A 10% NaOH solution (2 mL) was added; the dichloromethane layer was separated, treated with water (2 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:2]=1>[Pd].C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:2]=1
Reactant: OCCC#Cc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: OCCCCc1cnc2ccccc2c1
Yield: 99.9 %

Procedure:
A solution of 4-(3-quinolinyl)-3-butyn-l-ol (17.0 g, 0.086 mol) is hydrogenated over palladium on carbon (1.0 g) in ethanol (400 mL) at room temperature. After the catalyst is filtered, the solvent is removed under reduced pressure to give 17.3 g of a brown oil. The oil is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give 13.5 g of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([CH3:27])=[N:25][N:26]=2)=[N:10]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([CH3:27])=[N:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Yield: 55.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.04 g, 2 mmol) was reacted with morpholine-3-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)C(C3C=CC=CC=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1)#[CH:32]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:32]2[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:31]=2[C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(-c2ccccn2)cc1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1ccc(-c2cc(-c3ccc(-c4ccccn4)cc3)c(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 210 °C
Yield: 124.6 %

Procedure:
A solution of 2,3,4,5-tetraphenylcyclopentadienone (4) (Morgenroth et al, Tetrahedron 1997, 53, 15349) (1.14 g, 2.96 mmol) and (3) (354 mg, 1.98 mmol) in diphenyl ether (3 mL) was deoxygenated and heated at 210° C. under argon for 3 hours. The reaction mixture was purified by column chromatography over silica using a dichloromethane/light petroleum mixture (1:1) as eluent to give (5) (988 mg, 93%).