Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH:11]([CH:13]([CH3:18])[C:14](OC)=O)=[O:12].C[O-].[K+]>CO>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:11](=[O:12])[C:13]([CH3:18])=[CH:14][N:9]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)C=O
Reactant: N=C(N)c1ccc(Cl)s1
Agent: CO[K]
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: Cc1cnc(-c2ccc(Cl)s2)[nH]c1=O
Reaction time: 144 h

Procedure:
2.0 g 5-Chlorothiophene-2-carboxamidine hydrochloride and 1.7 g methyl 2-formylpropionate are added to a 25% solution of potassium methoxide in methanol containing 6.2 g of KOMe. The mixture is stirred for 6 days, then the methanol is evaporated and the residue dissolved in water. Upon addition of hydrochloric acid the product precipitates as a white solid (m.p.>250° C.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:12]([NH2:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:14][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cccc(Br)n1
Yield: 92.2 %

Procedure:
By the reaction in the same manner as in Example 55-(i) using 6-bromopicolinic acid (3.06 g), ethylamine hydrochloride (2.49 g), triethylamine (6 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.61 g) and 1-hydroxybenzotriazole (2.66 g), the title compound (3.20 g) was obtained as a colorless oil.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:34][C:35]([NH2:37])=[O:36])[CH:27]=[CH:26]1.C(O[K])(C)(C)C>C1COCC1>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([C:4]3[C:3](=[O:23])[NH:37][C:35](=[O:36])[C:34]=3[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:33]=3[N:25]([CH3:24])[CH:26]=[CH:27]4)=[CH:7][NH:8]2)=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(OCc6ccccc6)ccc45)C(=O)NC3=O)c21
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a suspension of (6-benzyloxy-1H-indol-3-yl}-oxo-acetic acid methyl ester (1.0 g, 3.2 mmol) and 2-(1-methyl-1H-indol-7-yl)-acetamide (608 mg, 3.2 mmol) in 15 ml THF was added 3.5 equiv. of tBuOK in THF at 0° C. (11.3 ml of 1.0 M solution in THF) under N2. The mixture was stirred at r.t overnight, quenched with conc. HCl 5.0 ml, and neutralized with 5 N NaOH to PH=8. The mixture was extracted with ethyl acetate, and the extract was washed with saturated NaHCO3, brine and water, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography with Hexane:Ethyl acetate (1:1) to yield the title compound (700 mg) as orange solid, 74% yield. MS(m/z): 448.2 (M++1), 446.1 (M−−1); 1HNMR (DMSO-d6) 11.62 (s, 1H), 11.07 (s, 1H), 7.77 (d, J=1.80 Hz, 1H), 7.57 (m, 1H ), 7.26 (m, 5H), 7.21 (d, J=2.40 Hz, 1H), 6.94 (tri, J=6.00 Hz, 1H), 6.84 (m, 2H), 6.44(d, J=2.40 Hz, 1H), 6.16 (s, 1H), 4.97 (s, 2H), 3.62 (s, 3H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[CH3:22][C:23]1[N:24]=[C:25]([C:31]2[N:32]=[N:33][N:34]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH:35]=2)[S:26][C:27]=1[C:28](O)=[O:29].N1C=CC=C(CN)C=1>>[CH3:22][C:23]1[N:24]=[C:25]([C:31]2[N:32]=[N:33][N:34]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)[CH:35]=2)[S:26][C:27]=1[C:28]([NH:8][CH2:12][C:11]1[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=1)=[O:29]
Reactant: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 65 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 65% yield: mp 204-205° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.94-8.83 (m, 2H), 8.52 (br s, 1H), 8.43 (br s, 1H), 7.78-7.66 (m, 3H), 7.58-7.51 (m, 2H), 7.38-7.29 (m, 1H), 5.77 (s, 2H), 4.45-4.39 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 157.9, 155.0, 149.3, 148.6, 142.3, 140.6, 135.7, 135.2, 129.3, 129.5, 126.3, 126.2, 125.3, 124.1, 123.9, 53.1, 41.1, 17.5; Ms (ES+) m/z 459.3 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(F)cc2F)cc1
Yield: 87.6 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (120 mg, 0.31 mmol, prepared in example 2) and 2,4-difluorophenylboronic acid (60 mg, 0.38 mmol) were treated as described in example 6 to afford 103 mg (89%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH2:1]([N:8]([CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[C:22](=[O:23])[CH2:21][Cl:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2nccs2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)N(Cc1ccccc1)Cc1nccs1
Reaction time: 1 h

Procedure:
A stirred solution of N-benzyl-N-2-thiazolylmethylamine (204 mg, 1.0 mmol) in 5 mL of dichloromethane was cooled to 0° C. The solution was treated with 5 mL of saturated, aqueous NaHCO3 followed by the addition of chloroacetyl chloride (0.088 mL, 1.1 mmol). The biphasic mixture was stirred vigorously for 1 hour and poured into a separatory funnel. The layers were separated and the aqueous layer extracted with an additional 5 mL portion of dichloromethane. The combined organic phases were dried (Na2SO4), filtered, and concentrated to provide the title compound which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)O1>O1CCOCC1.C(=O)(O)[O-].[Na+].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>[N+:12]([C:4]1[CH:3]=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 128.1 %

Procedure:
Mix 1-bromo-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (175 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dioxane and saturated sodium bicarbonate solution (3:1, 10 mL), stir the mixture at 120° C. for 1.5 hrs. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=20:1) to afford the product as a yellow solid (310 mg, 82.8%). MS: (M+23): 395.2.
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S. 9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:3]1=[O:15].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)C>[C:11]([O:10][C:8]([NH:7][C@H:4]1[CH2:5][CH2:6][N:2]([N:1]=[C:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[CH2:27][CH2:26]2)[C:3]1=[O:15])=[O:9])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(N)C1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(N=C2CCN(c3ccncc3)CC2)C1=O
Yield: 111.8 %

Procedure:
A solution of (3S)-1-amino-3-(tert-butoxycarbonylamino)-2-pyrrolidone (1.84 g) and 1-(4-pyridyl)-4-piperidone (1.51 g) in ethanol (30 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino]-2-pyrrolidone (3.57 g) as a syrup.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[CH:49]=[N:50][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:53]=2)=[O:47])=[CH:44][N:43]=[CH:42]1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=3)([C:48]3[CH:49]=[N:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.85 mL, 4.62 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.00 g, 4.65 mmol, Intermediate 47: step d) in dry THF (30 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (1.26 g, 4.92 mmol, Intermediate 36: step c) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred for 2 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and DCM. The separated aqueous phase was further extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated to provide the title compound as crude white solid. MS m/e 607.2 [M+H]+ Example 62A was purified by chiral HPLC (ChiralPak AD, 50:50 methanol/ethanol) to provide two enantiomers, Example 62B and Example 62C. The first eluting enantiomer was Example 62B: 1H NMR (500 MHz, CDCl3) δ ppm 8.80 (d, J=1.8 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.8, 2.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.05 (s, 1H), 6.15 (s, 1H), 4.30 (s, 2H), 4.07 (s, 3H), 3.29 (s, 3H); MS m/e 607.2 [M+H]+ and the second eluting enantiomer was Example 62C: 1H NMR (500 MHz, CDCl3) δ ppm 8.80 (d, J=1.7 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J=8.2, 1.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.8, 2.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.06 (s, 1H), 6.16 (s, 1H), 4.30 (s, 2H), 4.07 (s, 3H), 3.30 (s, 3H); MS m/e 607.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:13]=2)[NH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.Cl>C1COCC1.CO>[C:27]([O:26][C:24](=[O:25])[NH:23][C@H:4]([CH2:3][OH:2])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:13]=2)[NH:8][CH:7]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccc(O[Si](C)(C)C(C)(C)C)cc12)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1c[nH]c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
To a solution of Example 400B (1.50 g, 3.3 mmol) in THF (15 mL) was slowly added LiAlH4 powder (127 mg, 3.3 mmol) in several portion at rt. After the addition, the reaction mixture was becoming sticky and the stirring stopped. The temperature of the mixture arises to ˜50° C. Ether (30 mL) was added and the mixture was stirred for 20 min. Methanol (2 mL) and diluted HCl was added slowly and the mixture was extracted with ether. The organic phase was washed with water and concentrated. The residue was separated by flash chromatography (20-60% EtOAc in hexane) to give the desired product (982 mg, 70%). MS (DCI) m/z 421 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(OO)(=O)C.[CH:17](=[O:21])[CH2:18][CH2:19]C.OO>C1(C)C=CC=CC=1.C(O)(=O)C.Cl[Cu]>[CH2:17]([O:21][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:18][CH3:19]
Reactant: CCCC=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl[Cu]
Agent: CC(=O)OO
Agent: OO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g 2,2,6,6-tetramethyl-piperidin-4-ol (intermediate product of Ciba Specialty Chemicals Inc.) are suspended in 7 ml of toluene. 2.3 g of a 40% solution of peracetic acid in acetic acid are added at 0° C. and the reaction mixture is stirred at room temperature for 3 h. 4.2 ml butanal and 2.4 ml of a 30% aqueous hydrogen peroxide solution are added, followed by 50 mg CuCl after 15 min. The reaction mixture is stirred for 1.5 h at room temperature to give a greenish emulsion. The two phases are separated and the organic one is washed with 10% ascorbic acid solution, water, diluted sodium carbonate sol., diluted sodium chloride sol., and saturated sodium chloride sol. The organic phase is dried over sodium sulfate and finally evaporated to complete dryness under vacuum to afford 1.3 g product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCNC2)c1
Temperature: 29 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 3-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (400 mg, 0.83 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL) at 29° C. The mixture was stirred for 2 h at 29° C. The mixture was concentrated and the residue was purified by prep-HPLC to give the title compound (79.1 mg, Yield 25.0%). 1H NMR (CD3OD, 400 MHz): δ 7.75-7.93 (m, 2H), 7.45-7.62 (m, 2H), 7.17-7.37 (m, 4H), 4.45-4.74 (m, 2H), 4.40 (dd, J=6.3, 3.3 Hz, 1H), 3.71-4.04 (m, 2H), 3.49-3.70 (m, 5H), 3.35-3.49 (m, 3H), 3.08-3.32 (m, 3H), 2.52 (qd, J=6.6, 4.2 Hz, 1H), 2.09-2.27 (m, 1H). LCMS (m/z): 380.2 (M+1).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[C:24]2[O:29][CH3:30])(=[O:17])=[O:16]>CC(O)=O.C1COCC1>[CH3:30][O:29][C:24]1[C:23]2[C:28](=[C:19]3[C:20](=[CH:21][CH:22]=2)[C:11]2[C:10](=[CH:9][CH:14]=[CH:13][CH:12]=2)[S:15](=[O:17])(=[O:16])[NH:18]3)[N:27]=[CH:26][CH:25]=1
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccccc3N)cccc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Temperature: 5 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
t-Butyl nitrite (120 μl, 1.1 mmol) added was added to a solution of 2-amino-N-(4-methoxy-quinolin-8-yl)benzenesulfonamide 571 (254 mg, 0.77 mmol) in AcOH/THF (1:1; 10 ml) at 0° C. and the mixture was stirred at 5° C. for 2 h. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent followed by preparative HPLC (acidic conditions 1) to give the title compound (16 mg, 6%).
Reaction SMILES: C(OP([C:9](OC)(OC)[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1([CH3:52])[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:50]=O)[CH:39]=2)[O:34]1.Cl[Sn](Cl)(Cl)Cl>C1COCC1.CCCCCC.C(OCC)(=O)C.ClCCl>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([C:11]2[CH:50]=[CH:38][C:37]3[CH:36]=[C:35]4[C:40]([C:41]([C:43]5[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=5)=[CH:42][C:33]([CH3:52])([CH3:32])[O:34]4)=[CH:39][C:9]=3[CH:10]=2)=[CH:22][CH:21]=1)[CH3:20]
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)cc1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(c2ccc(C)cc2)=CC(C)(C)O4)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (−78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol) in THF (9 mL) was added n-BuLi in hexane (1.6 M solution, 2.8 mL). The mixture was gradually warmed to ambient temperature over 30 minutes and stirred for 5 minutes. To this mixture was added 2,2-dimethyl-4(tol-4-yl)-chrom-3-en-6-al (Compound Q, 260 mg, 0.93 mmol) in THF (1 mL) at ambient temperature and the mixture was stirred for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (10 mL) dried and the solvent was removed by evaporation. The residual material was subjected to flash chromatography on silicagel to obtain the E and Z olefinic compounds, which were dissolved in dichloromethane (5 mL) and cooled to −50° C. A solution of SnCl4 in dichloromethane (150 mg in 0.7 mL) was added to the olefinic compounds. The reaction mixture was gradually warmed to −10° C. over 3 hours and then quenched with methanol and water. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine and dried. Solvent was removed under reduced pressure and the residue purified by chromatography on silicagel to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].C(O)(=O)C.[I:20]N1C(=O)CCC1=O.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:20])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2ccccc2F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2ccccc2F)cc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
2-Chloro-2′-fluorobiphenyl-4-ol (Preparation 76, 430 mg, 1.93 mmol) was dissolved in DCM, and cooled to 0° C. Acetic acid (5 mL), N-iodosuccinimide (434 mg, 1.93 mmol) were added followed by concentrated sulphuric acid (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with heptane:ethyl acetate 7:3 to give the title compound (620 mg, 92%) as oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2.CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33]Cl.O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([O:21][CH2:31][O:32][CH3:33])[CH2:8]3)[CH2:3]2
Reactant: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCO[C@H]1CC[C@]2(C)[C@H](CC[C@@H]3C[C@]4(C)C(=O)CC[C@H]4C[C@H]32)C1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a solution of compound 22 (120 mg, 0.41 mmol) in dried dichloromethane (15 mL) was added DIPEA (130 mg, 1.0 mmol), chloromethyl methyl ether (121 mg, 1.5 mmol), and DMAP (10 mg) at room temperature. After 16 h, water was added and the product extracted into dichloromethane (100 mL×2). The combined extracts were dried, filtered, and removed. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 24 (138 mg, 100%): 1H NMR (CDCl3) δ 4.60 (s, 2H), 3.79-3.78 (m, 1H), 3.31 (s, 3H), 0.80 (s, 3H), 0.76 (s, 3H); 13C NMR (CDCl3) δ 220.9, 94.4, 71.5, 55.0, 54.5, 47.7, 45.8, 39.8, 39.6, 36.1, 35.6, 34.7, 33.4, 32.6, 31.7, 28.7, 26.2, 24.1, 23.9, 13.5, 11.3.