Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1>C(N(CC)CC)C>[N:58]1([CH2:57][CH2:56][NH:55][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 g) and dimethylformamide (500 mL) were stirred and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 g), 1-(2-aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL) were added. The mixture was stirred for 2 hours at ambient temperature. The solid product was collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by stirring in ethanol (500 mL) for one hour at 64° C. and cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (101.5 g, 77% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.60 (m, 4H, 2×CH2), 2.40, 2.44 (2×s, 6H, 2×CH3), 2.50 (m, 4H, 2×CH2), 2.57, 3.35 (2×m, 4H, 2×CH2), 7.53, 7.70, 7.73, 7.76 (4×m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrrole NH). MS m/z 396 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.COC1(OC)CCCCCC1>C(Cl)Cl>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:25][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Agent: COC1(OC)CCCCCC1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCC1
Yield: 557.9 %

Procedure:
A solution of the compound 8 (450 mg, 1.20 mmol) and p-toluenesulfonic acid hydrate (20.0 mg, 0.105 mmol) in a mixture of methylene chloride (1 mL) - toluene (0.1 mL) was concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), to which was added 1,1-dimethoxycycloheptane (1.51 g, 12.0 mmol). The reaction mixture was heated under reflux over 1 hour and concentrated to a small quantity. A drop of triethylamine was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hexane was added thereto, the mixture was filtered to remove the insoluble matter, and the filtrate was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the compound 10 (275 mg, 47%) as oil. Rf 0.64 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30](Br)=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Sn](CCCC)(CCCC)C=C)[CH2:36]CC>[N+](CC)(CC)(CC)CC.[Cl-].C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([CH:35]=[CH2:36])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cnc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A mixture of compound 4-3 (100 mg 0.193 mmol), Tributyl-vinyl-stannane (92 mg, 0.58 mmol), K2 CO3 (27 mg, 0.193 mmol), Et4NCl (31.8 mg 0.193 mmol) and Pd(PPh3)2Cl2 (10 mg) in THF (5 mL) was heated at 100° C. in microwave system under N2 atmosphere for 45 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 78 mg of 4-5.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CS(C)=O.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:36]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOc1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 96 %

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (3.42 grams, 0.02 moles), with KOH pellets (1.37 grams, 0.02 moles, 85%), and with 15 mL of DMSO. The mixture was stirred at 100° C. under nitrogen until all of the KOH had dissolved (about 2 hours). The dark solution was cooled to 70° C., then the 1-chlorohexadecane (5.22 grams, 0.02 moles) was then added all at once. An exotherm to about 80° C. was observed. The reaction mixture was then stirred at 75° C. for about 7.5 hours, then it was poured into about 500 mL of water; solids separated. After stirring at room temperature for about 2 hours, the mixture was filtered. The solids were washed on the filter with a little water, then they were air dried to give 7.58 grams of waxy white solid. The yield was 96%; mp=35-37° C. Structure was confirmed by IR, GC/MS, and 1H- and 13C-NMR analyses.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CC(F)(F)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Intermediate 19 (0.88 g, 5.64 mmol) was dissolved in THF (12 mL) and (carbethoxymethylene)triphenylphosphorane (1.96 g, 5.64 mmol) was then added. The solution was stirred at 50° C. for 12 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel using n-hexane/AcOEt (5:1) as eluent. The title compound was obtained (1.10 g, 89%) as pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:19]([NH:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:20])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NC1CCCC1
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NC1CCCC1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclopentyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 46%); 1H-NMR (DMSO-d6): δ1.30-1.70 (m, 6H), 1.90 (m, 2H), 4.40 (sextet, 1H, CH), 6.55 (br, 2H, NH2), 6.65 (s, 1H, H-4), 8.15 (br d, 1H, NH), 11.2 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:12]=1.[CH:29]([N:32](C(C)C)CC)(C)[CH3:30].BrCC#N>CS(C)=O>[NH2:17][C:15]1[C:14]([NH:18][CH2:30][C:29]#[N:32])=[C:13]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(SCc2cccc(F)c2F)c1N
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CS(C)=O
Product: N#CCNc1c(N)nc(SCc2cccc(F)c2F)nc1SCc1cccc(F)c1F

Procedure:
A solution of the product of example 1 step a) (5.0 g), diisopropylethylamine (2.8 ml) and bromoacetonitrile (1.1 ml) in DMSO (50 ml) was heated at 100° C. for 5 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a black oil which was purified by silica gel flash column chromatography, eluting with 10:1 dichloromethane:ethyl acetate, to give the subtitled compound as a pale orange solid (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1N.Cl.N([O-])=O.[Na+].[Cu][C:20]#[N:21]>O.C(Cl)(Cl)Cl>[C:20]([C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13])#[N:21]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(OC)c1C#N
Reaction time: 0.5 h

Procedure:
A suspension of methyl-2-amino-3-methoxybenzoate (Intermediate 36, 2.27 g, 12.5 mmol) in water (10 mL) and con. HCl (2 mL) was cooled to 0 deg. C. and a solution of sodium nitrite (1.04 g, 15 mmol) in water (10 mL) was added dropwise. The resulting solution was stirred cold for 30 min. then added to a suspension of copper(I)cyanide (3.4 g, 38 mmol) in water (100 mL). The resulting suspension was heated at 60 deg. C. for 3 h, cooled, chloroform was added and the mixture was filtered through celite. The organic layer was dried (MgSO4), the solvent was evaporated and the residue was flash chromatographed eluting with 0-50% hexane-ethyl acetate affording Intermediate 37 (0.56 g, 23.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (s, 6 H), 7.20 (d, J=8.35 Hz, 1 H), 7.61 (t, J=8.13 Hz, 1 H), 7.68 (d, J=7.47 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:16])[CH:14]=[O:15].O>ClCCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[C:6]2[O:12][C:14](=[O:15])[CH:13]([OH:16])[C:7]=2[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 81.7 %

Procedure:
A mixture of 49.8 g (0.30 mol) of 2-tert-butyl-4-methylphenol, 48.9 g (0.33 mol) of 50% aqueous glyoxylic acid and 0.15 g (0.79 retool) of p-toluenesulfonic acid monohydrate in 90 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. The reaction mixture is afterwards cooled to +5° C and the precipitate is isolated by filtration and washed with cold 1,2-dichloroethane. The filter residue is dried under a high vacuum at room temperature, affording 54.0 g (82%) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one, m.p. 152-160° C (compound (102), Table 1).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:8])[CH3:4].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:20])[C@H:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)Cc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1cnc2ccccc2c1)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of 0.637 g (2 mmol) of 3-(3-quinolyl)alanine ethyl ester dihydrochloride, 0.35 g (2 mmol) of N-(tert-butoxycarbonyl)glycine, 0.56 mL (4 mmol) of triethylamine and 16 mL of chloroform was added at 0° C., in one portion, 0.42 g (2 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred overnight and the precipitate which formed was removed by filtration. The filtrate was washed twice with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using first 1:1 methylene chloride/ethyl acetate and then 1:3 methylene chloride/ethyl acetate as eluents, to give 0.73 g (9.9%) of the title compound as a colorless oil. TLC Rf =0.52 (ethyl acetate); NMR (CDCl3) δ 8.64 (1H, d), 7.9-8.1 (2H, m), 7.9-7.4 (4H, m), 7.1 (1H, bd), 5.46 (1H, bt), 4.9 (1H, m), 4.15 (2H, q), 3.8 (2H, bd), 3.3 (2H, m), 1.37 (9H, s) 1.2 (3H, t). The product has the formula: ##STR115##
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[C:10]1([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]#N)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+].[OH2:27]>O(CC)CC>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:23]([CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH2:19]1)=[O:27]
Reactant: O
Reactant: N#CC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
To 7 parts of magnesium is added dropwise a solution of 50 parts of 1-bromo-2-methylbenzene in 140 parts of 1,1'-oxybisethane so that the mixture is refluxing. The whole is stirred for 15 minutes at reflux. The Grignard-complex is cooled to 10° C. and there is added dropwise a solution of 30 parts of 1-(phenylmethyl)-4-piperidinecarbonitrile in 70 parts of 1,1'-oxybisethane. Upon completion, stirring is continued for 4 hours at room temperature. The reaction mixture is decomposed with a solution of 40 parts of ammonium chloride in 400 parts of water. The organic phase is separated, dried, filtered and evaporated, yielding 31 parts of (2-methylphenyl) [1-(phenylmethyl)-4-piperidinyl]methanone as an oily residue.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:51][CH2:52][CH3:53])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]>C(O)(=O)C>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:51][CH2:52][CH3:53])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 101.7 %

Procedure:
Following a procedure similar to that described in Example 35(c), 255 mg of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was detritylated by treatment with 75% v/v aqueous acetic acid, to give 170 mg of the title compound as an amorphous solid. The Nuclear Magnetic Resonance Spectrum of this compound was identical with that of the compound obtained as described in Example 40(c).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:53])[CH2:51][OH:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]([OH:53])[CH2:51][OH:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.5 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethane-1,2-diol 7b (0.9 g, 1.22 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.82 mL, 6.1 mmol) and 10% Pd/C (36 mg, 0.12 mmol) in turn. The mixture was stirred at room temperature under H2 for 5 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound 7 as a white solid (94 mg, 9.43%, HPLC: 99.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 467.3[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40 (m, 2H), 7.29 (dd, 1H), 7.09 (d, 2H), 6.83 (m, 2H), 5.27 (d, 1H), 4.95 (d, 1H), 4.89 (d, 1H), 4.88 (d, 1H), 4.55 (t, 1H), 4.00 (m, 5H), 3.66 (m, 3H), 3.45 (m, 2H), 3.37 (m, 2H), 1.30 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH2:11][C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([CH3:38])[C:20]([C:21]3[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)=[C:14]2[CH:13]=1.C(N(CC)CC)C.O>C1COCC1>[CH3:38][C:19]1[C:20]([C:21]2[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:14]2[CH:13]=[C:12]([CH2:11][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][N:15]2[N:18]=1
Reactant: Cc1nn2ccc(CO)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn2ccc(COS(C)(=O)=O)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (815 mg, 4.49 mmol, 4.3 equiv) is added at room temperature under an atmosphere of argon to a solution of 3-(5-hydroxymethyl-2-methyl-pyrazolo[1,5-a]pyridin-3-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (400 mg, 1.04 mmol) and of triethyl amine (0.314 ml, 2.25 mmol, 2.2 equiv) in anhydrous THF (10 ml). The reaction mixture is stirred for 1 hour at room temperature. Water is added, and the mixture is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue (450 mg, 94%) is used directly in the next transformation.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]>O1CCOCC1.Cl>[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24]([N:2]([CH3:3])[CH3:1])[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Reactant: CNC
Agent: Cl
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(N(C)C)n1
Reaction time: 0.5 h

Procedure:
3.0 g of dimethylamine are introduced at 20°-30° C., with cooling, into a solution of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea in 80 ml of dioxane. After the formed suspension has been stirred for a further 30 minutes, it is taken up in 500 ml of 0.1N hydrochloric acid, and the product which has precipitated is separated by filtration; yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-dimethylamino-6-methoxy-1,3,5-triazin-2-yl)-urea, m.p. 171°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.CO[CH:34](OC)[CH2:35][NH2:36].Cl>CC(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]2[CH:34]=[CH:35][N:36]=[C:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1
Reactant: COC(CN)OC
Reactant: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(Br)cc(CC)c1-n1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.6 %

Procedure:
In a 250 mL round-bottom flask added N-(4-bromo-2,6-diethylphenyl)benzamide (7.64 g, 23 mmol), phosphorus pentachloride (4.79 g, 23 mmol), and phosphorus oxychloride (40 mL). The reaction was heated up to reflux under nitrogen. After 2.5 h, the reaction mixture was cooled and phosphorus oxychloride was distilled off using short path distillation apparatus. 2-propanol (40 mL) and 2,2-dimethoxyethanamine (48.4 g, 460 mmol) was added. The reaction was stirred at room temperature for 4 h. Concentrated hydrochloric acid (40 mL) was added carefully, and the reaction was heated to reflux overnight. The solution was decanted from black solid and neutralized with 10% sodium hydroxide solution, extracted with ethyl acetate. The organic layers were dried over magnesium sulfate. The residue was purified by silica gel column chromatography eluting with 20 and 30% ethyl acetate/hexanes. 6.75 g (83% yield) of product was obtained after purification.
Reaction SMILES: ClC1C=CC(Cl)=CC=1OC1N=CC=CC=1C(O)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[F:36])[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O.CC1CCC2C(=CC=CC=2)N1.[NH:48]1[C:57]2[C:52](=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH2:50][CH2:49]1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[F:36])[O:23][C:24]1[C:25]([C:26]([N:53]2[C:52]3[C:57](=[N:48][CH:49]=[CH:50][CH:51]=3)[CH2:56][CH2:55][CH2:54]2)=[O:28])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Reactant: c1cnc2c(c1)NCCC2
Agent: CC1CCc2ccccc2N1
Agent: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Product: O=C(c1cccnc1Oc1ccc(F)c(Cl)c1)N1CCCc2ncccc21

Procedure:
The title compound was prepared in analogy to Example 67 replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (Example 77, Step 1) and 2-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-[1,5]naphthyridine ([CAS RN 13993-61-8]). MS (ISN): 383.9 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][CH2:12]C[C:10]2[CH:9]=[C:8]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3].N([C@H]1C2C(=CC(C=O)=CC=2)[O:27]CC1)=[N+]=[N-]>>[N:1]([C@H:4]1[C:5]2[C:10](=[CH:9][C:8]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:27][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(C=O)ccc21
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Product: [N-]=[N+]=N[C@@H]1CCOc2cc(CN3CCCCC3)ccc21

Procedure:
Using the same procedure described for (20), and using (R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde afforded (R)-1-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)piperidine (26) MS m/z: 273.6 (M+H) (Calc'd for C15H20N4O−272.35); and