Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[Cl:42][C:43]1[CH:44]=[C:45]([N:50]=[C:51]=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49].ClCCl>O>[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][C:51]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]4)[N:17]=[C:16]4[C:12]=2[N:13]=[CH:14][N:15]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]3)=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Nc5ccc(Cl)c(Cl)c5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reaction time: 2 h

Procedure:
80 mg of product obtained in stage 4 of example 41 are mixed with 37.3 mg of 3,4-dichlorophenyl isocyanate and 5 ml of dichloromethane. Stirring is carried out for 2 hours at ambient temperature, 0.5 ml of water are added and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 35 mg of expected product are obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1OC(F)(F)F.[OH2:38].[NH2:39][NH2:40].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:20][C:19]([F:22])([F:21])[O:38][C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:40][N:39]=1
Reactant: NN
Reactant: O
Reactant: O=C(Cc1ccccc1OC(F)(F)F)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3OC(F)(F)F)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(2-trifluoromethoxyphenylacetyl)-1,8-naphthyridin-2(1H)-one (420 mg, 0.80 mmol) produced in Synthesis Example 23 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 155 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(2-trifluoromethoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (233 mg, yield 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]=[C:13]([CH3:17])[C:14]([OH:16])=[O:15].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>CCCCCC.C(OCC)(=O)C.ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:15][C:14](=[O:16])[C:13]([CH3:17])=[CH:12][C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[NH2:1])=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(N)c(C=C(C)C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
Into 20 ml of dichloromethane, 0.82 g (3.5 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid and 0.97 g (7 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved, and 40 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. While this mixture was stirred under cooling with ice, 0.81 g (4.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC/HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of the reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. After this solution was washed and dried, the solvent was evaporated, whereby a syrupy crude product was obtained. This product was refined by a silica gel column chromatography (n-hexane/ethyl acetate=2/1), whereby 0.15 g of the aimed compound was obtained as a yellow crystal (yield: 12%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH:23]([CH3:25])[CH3:24])[C:14]=2[CH:26]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:26][C:14]1[C:15]([CH:23]([CH3:25])[CH3:24])=[N:16][C:17]2[C:22]([C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (12.620 gm, 38.0 mmol) in CH2Cl2 (20 ml) was added over a 10 minute period to a cold (-10° C.) solution of 4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (7.394 gm, 25.2 mmol) and triphenylphosphine (19.86 gm, 75.7 mmol) in CH2Cl2 (140 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to 50 ml. The residue was triturated with Et2O and the precipitated triphenylphosphine oxide was removed by filtration. The filtrate was stripped and the residue was chromatographed (flash, Merck SiO2, 10% EtOAc in hexane) to give 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1 -methylethyl)quinoline as a light yellow foamy oil (11.556 gm, 102% theory).
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:15]=C=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[CH:1]1([CH2:7][C:8]#[N:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(O)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1CCCCC1
Temperature: 0 °C

Procedure:
A solution of the cyclohexylacetic acid (20.0 g, 141 mmol) in CH2Cl2 (80 mL) was heated to reflux and a solution of chlorosulfonyl isocyanate (20.9 g, 148 mmol) in CH2Cl2 (18 mL) was added dropwise over 40 minutes. After the addition was complete, stirring was continued at reflux for 65 minutes. The mixture was cooled to 0° C., and DMF (21.1 g, 288 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred 18 hours. The mixture was poured over ice, the organic layer separated, and the aqueous layer extracted with CH2Cl2 (50 mL). The combined organic layers were washed with water (3×50 mL), brine, dried (Na2SO4), filtered through a plug of Florosil and concentrated. The nitrile was obtained as 14.6 g (85%) of an oil of sufficient purity for use in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[NH:17][N:16]=NN=3)=[CH:10][S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+].C>C(OCC)(=O)C>[CH3:19][C:18]1[O:20][C:13]([C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:12][S:11][CH:10]=2)=[N:17][N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2cscc2-c2nnn[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cscc2-c2nnc(C)o2)cc1

Procedure:
A mixture of 5-(4-(4-methylphenyl)-3-thienyl)-tetrazole (3.3 g, 13.2 mmol) and acetic anhydride (50 ml) was heated at reflux temperature for 1 h. The resulting solution was evaporated in vacuo to give an oily residue which was dissolved into ethyl acetate (100 ml). The organic solution was vashed with a sodium bicarbonate solution (100 ml), treated with activated charcoal and dried (MgSO4). Filtration and evaporation in vacuo afforded 3.4 g of 5-methyl-2-(4-(4-methylphenyl)-3-thienyl)-[1,3,4]- oxadiazole as an oil.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(Cl)Cl>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:35](=[O:38])[CH:36]=[CH2:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 995.1 %

Procedure:
To a solution of didodecylamine 66 (25 g, 70 7 mmol) and diisopropylethylamine (18 g, 141 mmol) in anhydrous CH2Cl2 (700 mL) at −10° C., a solution of acryloyl chloride (7.68 g, 85 mmol) in CH2Cl2 (100 mL) was added dropwise over a period of 20 min. After the completion of the addition the reaction mixture was stirred for 4 h at 0° C. after which the TLC of the reaction mixture showed the completion of the reaction. The reaction mixture was washed with satd. NaHCO3 solution (200 mL), water (200 mL), brine (100 mL) and dried over NaSO4. Concentration of the organic layer provided the product 71 (28.4 g, 100%) which was used as such in the next step. 1H NMR CDCl3 δ 0.94 (t, J=6.5 Hz, 6H), 1.05-1.69 (m, 40H), 3.15-3.60 (dt, 4H), 5.64 (d, 1H), 6.36 (d, 1H), 6.63 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5](=[O:17])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.Br[C:22](Br)([CH2:25][CH3:26])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-:35]>CC(C)=O>[Br:35][CH2:24][CH2:23][CH2:22][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5](=[O:17])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1
Reactant: [Br-]
Reactant: CCC(Br)(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(OCCCCCBr)c1

Procedure:
This compound (42) was prepared from 3′-hydroxy-3,4-methylenedioxy-chalcone, 12 (2.7 g, 10 mmol), dibromo pentane (4.1 mL, 30 mmol) and potassium carbonate (2.76 g, 20 mmol) in dry acetone (100 mL) using the identical procedure as described for 39. Yield 2.7 g (64%); mp 87-88° C.; MS (FAB) 417/419 (M++1); IR (KBr) 1652; 1H NMR (200 MHz, CDCl3) δ 7.73 (d, J=15.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.34 (d, J=15.6 Hz, 1H), 7.16 (s, 1H), 7.14-7.10 (m, 2H), 6.02 (s, 2H), 4.05 (t, J=6.2 Hz, 2H), 3.50 (t, J=6.7 Hz, 2H), 2.02-1.78 (m, 4H), 1.71-1.59 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].CCO.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34]Cl.C(N(C(C)C)CC)(C)C>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[C:26]=1[NH:32][C:33](=[O:36])[CH2:34][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5](=[O:10])[CH2:6]1
Reactant: COc1ccccc1OCC(O)CN1CCNCC1=O
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1=O

Procedure:
To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 (0.7 g, 0.36 mmol) and diisopropylethyl amine (0.76 g, 0.36 mmol). The reaction mixture was heated at reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 14: Mass spectrum (M+1)=442.34
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[N:42]1([CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:52]2[CH2:51][CH2:50][N:49]([CH2:48][CH2:47][N:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)[CH2:54][CH2:53]2)=[O:40])[CH:34]=1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1CCN(CCN2CCNCC2)C1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CCN4CCCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using template 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid (44) and 1-(2-pyrrolidinoethyl)-piperazine as described in general procedure D. LCMS: 536 [M+H].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.I[CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:32]([CH3:34])[CH3:33])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
Sodium Hydride (60% dispersion in oil, 190 mg, 5.2 mmol) was added to an ice-cold solution of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (2) (1.5 g, 3.69 mmol) in 350 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2-Iodo-propane (941 mg, 5.54 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was partitioned between ether (200 mL) and water (350 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×70 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (10% EtOAc/Hexane) to obtain 908 mg (55%) of 3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): Rotamere 95/05: 7.54 ppm (dd, 2H, Haro); 7.49-7.35 ppm (m, 3H, Haro); 7.29-7.25 ppm (m, 2H, Haro); 7.15 ppm (d, 1H, Haro); 7.05 ppm (d, 1H, Haro) 5.09 ppm (hex, 1H, N—CH(CH3), major rotamere); 3.99 ppm (hex, N—CH(CH3), minor rotamere); 3.89 ppm (s, 3H); 1.40 ppm (d, 3H, N—CH(CH3), major rotamere); 1.28 ppm (d, N—CH(CH3), minor rotamere); 1.09 ppm (d, 3H, N—CH(CH3), major rotamere); 1.01 ppm (d, N—CH(CH3), minor rotamere).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])=[O:7])=[C:15]([B:17]([OH:22])[OH:18])[CH:16]=1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1B(O)O)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-N,N-diisopropylbenzamide (1.0 g, 35 mmol) and triisopropyl borate (0.79 g, 4.2 mmol) in THF (20 mL) was added a freshly prepared solution of LDA in THF (4.6 mL, 4.6 mmol) dropwise at 20° C. over a 1 hour period under nitrogen. The reaction mixture was stirred overnight, quenched with saturated aqueous NH4Cl solution (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated to afford {5-bromo-2-[(diisopropylamino)carbonyl]phenyl}boronic acid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[ClH:1].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: c1ccc2c(c1)CCNC2
Product: COc1ccc2c(N3CCc4ccccc4C3)ccnc2c1
Product: Cl

Procedure:
The title compound, MS: m/e=291.2 (M+H+), was prepared from 4-chloro-7-methoxy-quinoline and 1,2,3,4-tetrahydroisoquinoline
Reaction SMILES: [OH2:1].[CH3:2][Si:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:31])[O:17][C:18]2[CH:23]=[CH:22][C:21]([Si:24]([CH3:30])([CH3:29])[O:25][SiH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)([CH3:8])[O:4][SiH:5]([CH3:7])[CH3:6].CC(C)=[O:34]>[Pd]>[OH:1][Si:26]([CH3:27])([CH3:28])[O:25][Si:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16](=[O:31])[O:15][C:12]2[CH:11]=[CH:10][C:9]([Si:3]([CH3:2])([CH3:8])[O:4][Si:5]([OH:34])([CH3:7])[CH3:6])=[CH:14][CH:13]=2)=[CH:19][CH:20]=1)([CH3:29])[CH3:30]
Reactant: O
Reactant: CC(C)=O
Reactant: C[SiH](C)O[Si](C)(C)c1ccc(OC(=O)Oc2ccc([Si](C)(C)O[SiH](C)C)cc2)cc1
Agent: [Pd]
Product: C[Si](C)(O)O[Si](C)(C)c1ccc(OC(=O)Oc2ccc([Si](C)(C)O[Si](C)(C)O)cc2)cc1
Yield: 78 %

Procedure:
To a cold (-5° C.) solution of 100 ml of acetone, 4 ml. of water and a catalytic amount of 5% palladium-on-carbon was added slowly 9.0 g of bis[4-(1,1,3,3-tetramethyldisiloxanyl) phenyl]carbonate in 20 ml. of acetone over a period of 8 hrs. After the addition was complete, the palladium-on-carbon was removed by filtration. The filtrate was concentrated on a rotary evaporator at room temperature to a viscous liquid which solidified upon treatment with pentane. There was obtained 7.5 g (78%) of the required compound. The carbonate was recrystallized from benzene and hexane solution to yield the pure compound, m.p. 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)[CH:3]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:22][C:23]1[C:24]([O:15][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:2]([Cl:1])=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccc(F)cc4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
6-Chloro-4′-fluoro-4-(pyridazin-4-yl)biphenyl-3-ol (Preparation 102, 150 mg, 0.50 mmol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 345 mg, 0.75 mmol), and potassium carbonate (207 mg, 1.50 mmol) were suspended in dimethyl sulfoxide (2 mL). The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (2×50 mL) and dichloromethane (3×50 mL). The organic layers were combined, dried over MgSO4, filtered and evaporated. The residue was purified by semi preparative reverse phase HPLC (solvent A: 0.05% formic acid in acetonitrile; solvent B: 0.05% formic acid in water; flow rate: 15 mL/min; gradient 0 min 5% A, 2.5 min 5% A, 22.5 min 95% A, 32.5 min 95% A then return to initial conditions) to afford the title compound (100 mg, 27%) as a glass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=C)=[C:13]2[C:17]=1[N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=2[C:12]([CH:22]=[O:33])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c2c1ccn2S(C)(=O)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)n1ccc2c(C=O)ccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-benzyloxy-1-methanesulfonyl-4-vinyl-1H-indole (1.3 g, 3.9 mmol; Intermediate 84) in dioxane (25 ml), lutidine (900 μl, 7.9 mmol), sodium metaperiodate (3.37 g, 15.8 mmol) (in water (10 ml)) and osmium tetroxide (100 mg, 0.1 mmol) was added (in that order). A precipitate was almost immediately formed, and the mixture was stirred for 1 h at room temperature. Water was added. The precipitate was filtered off, and washed with water. The solid material was extracted with acetonitrile. The acetonitrile-solution was evaporated. The product was purified by strait phase chromatography using Biotage flash-chromatograph 5-40% EtOAc in petroleum ether 40-60° C. Obtained 0.40 mg. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: O1CC1C[N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2.[CH:42]([OH:45])([CH3:44])[CH3:43]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][N:35]([CH2:43][CH:42]([OH:45])[CH2:44][C:7]1([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)[CH2:34][CH2:33]2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1OC)CN(CC(O)CC1(c3noc4cc(F)ccc34)CCNCC1)CC2
Reaction time: 8 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g, 11.6 mmol), K2CO3 (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4 -tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.