Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[K+].I[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>O.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: Oc1ccccc1F
Reactant: CC(C(=O)O)c1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(Oc2ccccc2F)cc1
Temperature: 180 °C

Procedure:
2-Fluorophenol (2.35 g.) was fused with potassium hydroxide (1.7 g.) and a few drops of water by heating to 180° C. 2-(4-Iodophenyl)propionic acid (2.76 g.) and copper powder (0.1 g.) were then added and the melt ws heated at 160°-170° C. for 1 hour. The cooled solid was partitioned with methylene chloride (50 ml.) and 2.5N sodium hydroxide (50 ml.). The aqueous layer was acidified with hydrochloric acid, the resulting gum was extracted into ether, and the ether extract was extracted with saturated potassium carbonate solution. This aqueous extract was acidified with hydrochloric acid and the product isolated in ether. After evaporation the resulting solid was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68° C. and eluting with ethyl acetate. Recrystallization from petroleum ether b.p. 62°-68° C. gave 2-[4-(2-fluorophenoxy)phenyl]propionic acid, m.p. 106°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:17]=1
Reactant: C[O+](C)C
Reactant: COc1cccc(C=CC2CCCCC(=O)N2)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C=Cc2cccc(OC)c2)CCCC1

Procedure:
The product of Example 163 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:6]
Reactant: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2ncc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50 equiv) was added to the reaction, and it was stiffed for 30 min at 25° C. To this was added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv) dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The mixture was extracted with 3×25 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/ethyl acetate (1:30) as eluent. The product (˜100 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (35% CH3CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:42]([C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH2:46])[CH3:43]>>[CH2:42]([C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH:46][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1)[CH3:43]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: CCc1ccccc1N
Product: CCc1ccccc1NC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 2-ethylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: [NH3:1].Cl.[C:3]1([CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19](Cl)=[O:20])[CH:16]=3)[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH2:1])=[O:20])[CH:16]=3)[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 ml of conc. aqueous ammonia and 50 ml of tetrahydrofuran were added, in batches, 20.0 g (64.9 mMol) of 2,3-dihydro-2-(phenylmethyl)-1H-isoindole-5-carboxylic acid chloride-hydrochloride and the mixture was stirred overnight at ambient temperature. The precipitate formed was suction filtered, washed thoroughly with water and dried at 50° C. in a circulating air dryer. The desired compound was obtained in a quantitative yield in the form of colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C(O)(=O)C>>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: C=CC(=O)OC
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Solvent: CC(=O)O
Product: COC(=O)CCNc1cc(-c2noc(C)n2)ccc1CNC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 80 °C
Yield: 29.5 %

Procedure:
A suspension of compound 1g (130 mg, 0.34 mmol) in methyl acrylate (1.0 mL, 11.1 mmol), and acetic acid (0.5 mL, 8.7 mmol) was sealed in a pressure tube under argon and heated at 80° C. overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was purified by preparative tlc (silica gel, 40% v/v ethyl acetate/hexane) to give compound 15a (47 mg, 30%). ESI-MS m/e 469.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:26]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][C:12]([NH:14][C:15]4[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[N:11][CH:10]=3)=[CH:5][CH:4]=2)=[N:2][N:28]=[N:27]1
Reactant: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(-c4nnn[nH]4)cc3)o2)c1
Temperature: 120 °C
Yield: 89.3 %

Procedure:
N-(3-((5-(4-cyanophenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 7 (0.12 g, 0.338 mmol) was dissolved in anhydrous DMF (10 mL), Sodium azide (0.088 g, 1.35 mmol) and ammonium chloride (0.072 g, 1.35 mmol) were added to above solution. Resulting suspension was heated at 120° C. for overnight (14 hours). Reaction was cooled down and water was added. Resulting (precipitated) solid was filtered, washed with water, methanol, and water. This was further purified by dissolving into DMSO and re-precipitated with addition of water. Resulting solid was filtered, washed with water, methanol and dried under high vacuum to yield N-(3-((5-(4-(1H-tetrazol-5-yl)phenyl)oxazol-2-yl)amino)phenyl)methanesulfonamide 41 (0.12 g, 90%) as a white solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3F)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][CH:35]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:41]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][CH:28]([O:27][CH3:26])[CH2:29]4)=[CH:39][CH:38]=3)[CH3:42])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)o2)c(C)c1
Reaction time: 2 h

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-N-methylmethanamine (45 mg, 0.19 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. The fraction collected was dissolved in DCM (5 mL) and shaken with PL-MIA resin for 2 h, and the beads were filtered and washed with DCM (10 mL). The combined filtrates were concentrated in vacuo and the residue purified using prep method D to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([O:11][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])[CH2:26][CH2:25]1)[CH3:10]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:33]([NH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][C:15]2[N:14]([CH2:13][CH2:12][O:11][CH2:9][CH3:10])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:25][CH2:26]1)=[S:34]
Reactant: Nc1ccncc1N
Reactant: CCOCCn1c(CC2CCN(CCN=C=S)CC2)nc2cccnc21
Solvent: C1CCOC1
Product: CCOCCn1c(CC2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3.3 parts of 3,4-pyridinediamine, 11.2 parts of 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]-pyridine and 90 parts of tetrahydrofuran was stirred overnight at reflux temperature. The reaction mixture was evaporated, yielding 14.5 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]thiourea as a residue (compound 138).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:27]=3)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)C>O1CCOCC1>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)=[CH:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Yield: 46.8 %

Procedure:
120 mg (0.2 mmol) of N-tert-butyl-4-[3-{3-[(diphenylmethylidene)amino]phenyl}-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridin-2-amine were dissolved in 20 ml of 1,4-dioxane and 5 ml of HCl 4M in dioxane were added. After 4 hours the solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to give, after trituration with diethylether, 40 mg (46% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxy-isobutyrate in 50 mL of CH2Cl2 were added 1.2 g (17.6 mmol) of imidazole and 2.1 mL (16.6 mmol) of TMSCl. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H2O. The organic layer was dried over MgSO4, concentrated and passed through a short plug of silica gel eluted with 9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O.C(OCC)C.O>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(C)cc(Br)c1
Temperature: 90 °C
Yield: 94 %

Procedure:
Sulphuric acid (10 drops) was added to 3-bromo-5-methylbenzoic acid (1.18 g, 5.49 mmol) in ethanol (20 ml) and refluxed at 90° C. for 20 hours. After cooling, the mixture was diluted with diethyl ether/water and the organic phase washed with sodium hydrogen bicarbonate (saturated solution), dried (magnesium sulphate) and evaporated to dryness to give the title compound as a pale yellow oil (1.249 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:10])[CH:32]=[CH:31][C:29]=2[N:30]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5cccc(F)c5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-fluorophenyl)urea was prepared from 3-fluorophenyl isocyanate (13 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (14 mg, 29 μmol, 26%). LC/ESI-MS: m/z=491 [M+H]+; m/z=489 [M−H]−; Rt=3.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cc(Cl)cc(Cl)c2)CCNC1
Reaction time: 1 h

Procedure:
Preparation according to Preparation 2: tert-butyl 3-(3,5-dichlorophenyl)-3-hydroxypyrrolidin-1-carboxylate (1.3 g, 3.9 mmol), dichloromethane (10 mL) and trifluoroacetic acid (3 mL). Stirred for 1 h. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 40:60). Yield: 0.57 g. MS m/z (rel. intensity, 70 eV) 233 (M+, 64), 231 (M+, bp), 145 (56), 111 (55), 75 (72).
Reaction SMILES: [CH2:1]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([C:13]1[S:14][C:15]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-dodecylthiophene (5.18 g, 20.5 mmol) in dry THF (90 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 12.3 mL, 30.8 mmol) was then added slowly. This mixture was stirred at −78° C. for additiona 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 31 mL, 31.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane (200 mL), washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (8.35 g, 98.0%), which was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=O)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C(OC([N:28]1[CH2:32][C@H:31]([CH:33]([C:38]([CH3:43])([CH3:42])[CH:39]([CH3:41])[CH3:40])[O:34][SiH:35]([CH3:37])[CH3:36])OS1(=O)=O)=O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.ClCCl>[CH3:37][SiH:35]([CH3:36])[O:34][CH:33]([C:38]([CH3:42])([CH3:43])[CH:39]([CH3:40])[CH3:41])[C@H:31]1[N:9]2[C:10]3[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=[CH:5][C:6]=3[CH:7]=[C:8]2[C:12](=[O:14])[NH:28][CH2:32]1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 0.700 g ethyl 6-(trifluoromethyl)indole-2-carboxylate in 7 ml DMF was added 0.13 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added 1.30 g (R)-5-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for 18 h. The reaction mixture was distributed between 10% citric acid and dichloromethane and the organic phase was purified by chromatography on silica gel with dichloromethane. The product (1.15 g) was taken up in 11 ml TFA was stirred at 0° C. for 45 min. The solvent was evaporated and the residue was taken up in 10 ml methanol. To the resulting solution was added 1.00 g potassium carbonate and the mixture was stirred at room temperature for 3 h. The reaction mixture was purified by chromatography on silica gel with ethyl acetate to yield 0.36 g of the tiltle compound (m.p.: 143–144° C.) and 0.117 g of its desilylated analog (m.p.: 184–185° C.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Yield: 82 %

Procedure:
Using an analogous method to that described in Example 11, 3-amino-5-bromo-2-chloropyridine was reacted with and 4-fluorobenzenesulfonyl chloride to give N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide in 82% yield; 1H NMR Spectrum: (CDCl3) 8.21 (1H, d); 8.15 (1H, d); 7.84 (2H, m); 7.20 (2H, m); 6.97 (1H, br s); Mass Spectrum: M+H+ 365.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:15][CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1.O>C1(C)C=CC=CC=1>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=[N:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:3][CH:2]=1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C(=NC1CN2CCC1CC2)c1ccc(-c2ccccc2)cc1
Yield: 59.3 %

Procedure:
4-Biphenylcarboxaldehyde (160 mg) and 3-aminoquinuclidine (110 mg) were heated under reflux in toluene (50 ml) for 2 hours using a Dean and Stark water separator. The toluene was evaporated and the residue was purified by medium pressure column chromatography on alumina (ICN Alumina N 32-63), eluting with ethyl acetate to give 3-[(biphenyl-4-ylmethylene)amino]quinuclidine (150 mg) as a colourless solid, m.p. 82°-84° C.; microanalysis, found: C, 82.2; H, 7.7; N, 9.6%; C20H22N2 requires: C, 82.7; H, 7.6; N, 9.6%; NMR (CDCl3): 1.35-1.5(1H, m), 1.6-1.8(3H, m), 2.2-2.3(1H, m), 2.8-3.0(4H, m), 3.0-3.2(2H, m), 3.4-3.5(1H, m), 7.3-7.5(3H, m), 7.55-7.65(4H, m), 7.8(2H, dd) and 8.3(1H, s); m/z 291 (M+H).