Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[S:6][CH:7]=1.[CH3:19]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][N:9]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][Br:1])[CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: O=S(=O)(NCc1cc(CBr)cs1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(Cc1cc(CBr)cs1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 4-bromomethylphenylsulphonyl-2-thienylmethylamine (10.0 g, 28.9 mmol), dimethylsulphate (2.75 ml, 28.9 mmol) and potassium carbonate (19.96 g, 144 mmol) in acetone (100 ml) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate, washed with water and brine, dried, filtered and evaporated. Chromatography of the residue (1:2 ethyl acetate/hexane) gave N-methyl 4-bromomethylphenylsulphonyl-2-thienylmethylamine (1.60 g, 15%) as a colourless oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27](F)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(C3CCCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(C4CCCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An opaque brown solution of Intermediate 1d (171 mg, 1.05 mmol) and sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol) in dry DMF (2 mL) was stirred at RT under Argon for 30 min. Intermediate 34b (219 mg, 1.00 mmol) was added, and the resulting dark solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge, and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left a brown oil. Flash chromatography (silica 25 g, 2-10% [2M NH3 in MeOH] in DCM) gave a yellow oil. Freeze-drying from MeCN-water (1:2, 3 mL) left the title compound as a pale yellow solid (203 mg, 56%). LCMS (Method 3): Rt 2.29 min, m/z 363 [MH+].
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][OH:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][O:27][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCc1c(Cl)cncc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1cncc(Cl)c1COC1CCCCO1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Dihydropyrane (3.01 mL, 33.2 mmol) and p-toluenesulfonic acid monohydrate (5.06 g, 26.6 mmol) were added to a stirred solution of (3,5-dichloro-pyridin-4-yl)-methanol (1.97 g, 11.06 mmol) in DCM (40 mL). After stirring for 1 d at 40° C. the solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and saturated NaHCO3 solution (50 mL). After extraction of the aqueous layer with DCM (2×50 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane and EA) to give the title compound. MS (m/z): 261.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39]>>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH:39][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: CN(C)CCN
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN(C)CCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.035 g, 0.067 mmol) with N,N-dimethylethylenediamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.85-7.45 min) afforded N1-[2-(dimethylamino)ethyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.008 g, 0.014 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 10.20 (br, 1H), 8.22 (m, 2H), 7.96 (d, 1H), 7.80 (d, 1H), 7.45 (t, 1H), 7.31 (m, 3H), 6.90 (br, 2H), 4.96 (s, 2H), 3.40 (m, 2H), 2.75 (m, 2H), 2.07 (s, 6H); MS: (M−H)− 579.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C@@H:7]1[C:22]([CH3:29])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CNN>C(Cl)Cl>[NH2:11][C@H:8]1[C@@H:7]([C:22]([CH3:29])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:6]([CH2:5][C:4]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:3]=2[O:2][CH3:1])[C:9]1=[O:10]
Reactant: CCOC(=O)C=C(C)[C@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1Cc1ccc(OC)cc1OC
Agent: CNN
Solvent: ClCCl
Product: CCOC(=O)C=C(C)[C@@H]1[C@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Yield: 93.2 %

Procedure:
37.0 g (77.3 mmol) of ethyl rac-cis-1-(2,4-dimethoxybenzyl)-β-methyl-4-oxo-3-phthalimido-2-azetidineacrylate are dissolved in 500 ml of methylene chloride and the solution is treated with 8.2 ml (0.15 mmol) of N-methylhydrazine at 30° C. for 48 hours. The mixture is filtered and the filtrate is evaporated. The residue is taken up in ethyl acetate and filtered. The filtrate is extracted with 200 ml of aqueous hydrochloric acid and the aqueous phase is separated, neutralized with saturated aqueous sodium bicarbonate solution and extracted twice with 200 ml of methylene chloride each time. After drying and evaporation, the crude colourless product is isolated. There are obtained 25.1 g (93%) of ethyl rac-cis-3-amino-1-(2,4-dimethoxybenzyl)-β-methyl-2-oxo-4-azetidineacrylate of melting point 89°-93° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([S:15][CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.C(NCC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:28]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][S:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CSC1c2ccccc2Oc2ccccc21)C(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: O=C(O)[C@H](CSC1c2ccccc2Oc2ccccc21)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A sample of 1.0 g of S-(9H-Xanthen-9-yl)cysteine (3.3 mmole) from Example 4 was dissolved in 10 ml of chloroform. To the solution was added 1.5 ml of water and 1.5 ml of diethylamine. The mixture was cooled to 4° C. by an ice bath and 0.98 g of trityl chloride (3.5 mmole) was added in portions over a period of 30 min. After 2 h of stirring at room temperature. The reaction mixture was separated. The organic phase was washed twice with 4% diethylamine aqueous solution. The organic layer was dried over Na2SO4. The drying reagent was removed by filtration and the filtrate was condensed to dryness by rotary evaporation. The residue was refluxed in 10 ml of a 1:30 mixture of diethyl amine/ethyl alcohol. The resultant diethyl ammonium salt was partitioned between 10 ml of ethyl acetate and 7 ml of 5% aqueous KHSO4 and 7 ml of water. The ethyl acetate layer was separated and was dried over MgSO4 and was concentrated to get 1.4 g of product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (137 mg, 309 μmol) in pyridine (3 mL) was added cyclopropanecarbonyl chloride (68 μL, 742 μmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (9:1, 20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from methanol and ethyl acetate to give the title compound (56 mg, 35%) as pale-red crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH2:11]([Li])[CH2:12][CH2:13]C.CC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:12]([CH3:13])[CH3:11]
Reactant: COc1cccc(OC)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cccc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 1,3-dimethoxybenzene (33 ml) was dissolved in THF (1l). The solution was cooled in an ice bath then n-butyl lithium (200 ml) was added in a dropwise fashion in over a 45 minute period. The resultant mixture was stirred for 2 hours at a temperature of 10° C. The solution was then cooled to 0° C. and acetone (21 ml) was added in a dropwise fashion. Solution was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and the solvent removed. The residue was dissolved in a mixture of ethyl acetate (50 ml) and sulfuric acid (1 ml). The acidic mixture was subjected to a positive hydrogen pressure (30 psi) over a catalytic amount of 5% palladium-on-carbon in a Parr shaker at room temperature for 30 minutes. The solution was filtered and water added. The organic layer was purified by HPLC (eluted with a gradient of 0 to 5% hexane in ethyl acetate) to yield 6.3 g of 1,3-dimethoxy-2-(iso-propyl)benzene. This latter substituted benzene product was refluxed for 3 days in a mixture of 48% hydrobromic acid in water and acetic acid (300 ml to 500 ml). Ether and brine were added to the reaction mixture. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed by HPLC (column eluted with a gradient of 5 to 15% ethyl acetate in hexane). The chromatography yielded 1.82 g of the title product.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[C:15]1([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][C:15]4([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:21](=[O:22])[N:13]=1)([CH2:4]3)[CH2:2]2
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Product: O=C1N=C(NC23CC4CC(CC2C4)C3)SC12CCCCC2

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([C:22]([C:25]4([C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[CH:31]6)[CH2:27][CH2:26]4)=[CH:23][N:24]=3)[CH:21]=2)=[CH:12][C:11]=1[F:38])[CH3:8])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:38][C:11]1[CH:12]=[C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([C:22]([C:25]4([C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[CH:31]6)[CH2:27][CH2:26]4)=[CH:23][N:24]=3)[CH:21]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH:7]([CH3:8])[C:6]([OH:39])=[O:5]
Reactant: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl-2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoate (100 mg, 0.2 mmol) was dissolved in a mixed solvent of methylene chloride (5.0 mL) and trifluoroacetic acid (5.0 mL). The solution was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure. The residue was co-evaporated with toluene three times, and was directly used in next step. LCMS: (M+H)=469. 1.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[N:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:1][CH:2]1[C:7]2[N:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CC1c2nnccc2CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2ccnnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 70.0 mg (0.258 mmol) of tert-butyl 8-methyl-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate (Step F) was added 2 mL of trifluoroacetic acid. The reaction was stirred at ambient temperature for 1 h and concentrated to afford the title compound. LC/MS: 150 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)O.[CH3:23][O:24][C:25]([C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][N:28]=1)=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:23][O:24][C:25]([C:27]1[N:32]=[CH:31][C:30]([N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH:2]([CH3:22])[CH3:1])=[CH:29][N:28]=1)=[O:26]
Reactant: COC(=O)c1ncc(NC(=O)OC(C)(C)C)cn1
Reactant: CC(C)CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ncc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (1.120 g, 3.630 mmol) (prepared as in Example 3.2 Step A) was combined with 5-tert-butoxycarbonylamino-pyrimidine-2-carboxylic acid methyl ester (0.920 g, 3.63 mmol) and dissolved in anhydrous tetrahydrofuran (20 mL). Triphenylphosphine (1.43 g, 5.45 mmol) was added and the reaction was brought to 0° C. Diisopropyl azodicarboxylate (1.43 mL, 6.90 mmol) was added dropwise over 5 min. The reaction was stirred as a yellow solution, allowing the bath to warm to room temperature. At 3 d, the reaction was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave impure (+/−)-5-{tert-butoxycarbonyl-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butyl]-amino}-pyrimidine-2-carboxylic acid methyl ester (1.501 g) as a pale yellow oil. MS (M+1): 544.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](NCC)=[CH:5][CH:4]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(OC(=O)C)(=[O:21])C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][CH2:12][NH:14][C:15](=[O:21])[CH3:16])=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: CCNc1ccc(OC)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (4-methoxy-phenyl)-ethylamine (10 g, Aldrich, U.S.A.) and triethylamine (10.1 mL) in dichloromethane (200 mL) was added acetic anhydride (7.4 g). The mixture was stirred at rt for 3 h and was washed successively with hydrochloric acid (1 M, 100 mL), 10% aqueous potassium carbonate (100 mL) and brine (100 mL). The dichloromethane layer was dried over sodium sulfate and filtered. The filtrate was evaporated to afford N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (13.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](F)=[O:8].[OH-:14].[Na+]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:14])=[O:8]
Reactant: O=C(F)c1cc(Cl)c(F)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cc(Cl)c(F)c(F)c1F

Procedure:
When 5-chloro-2,3,4-trifluorobenzoyl fluoride is briefly treated with aqueous sodium hydroxide solution then, after acidification and drying, crystals of 5-chloro-2,3,4-trifluorobenzoic acid are obtained, melting point: 123°-4° C.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17](N)[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][N:24]([CH3:29])[S:25]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Reactant: CN(C)S(=O)(=O)Cl
Product: CCC1(c2c[nH]c3c(S(=O)(=O)N(C)C)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and dimethyl sulfamoyl chloride, the title compound is prepared as in example 15. 0.16 g (29%). LC-MS m/z 402.1 (M++1).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:3]([C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:7][C:6]=2[CH3:24])=[O:4])[CH2:27]1
Reactant: NC1CCOC1
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NC1CCOC1
Yield: 43 %

Procedure:
As described for example 68c, 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (80 mg, 0.24 mmol) was converted, using 3-amino-tetrahydrofuran instead of isopropylamine, to the title compound (40 mg, 43%) which was obtained as a light yellow solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#N.[OH-:14].[Na+].C([OH:18])C>O1CCOCCOCCOCCOCCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([OH:18])=[O:14]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)(C#N)c1ccc(F)cc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Product: CC(C)(C(=O)O)c1ccc(F)cc1Br
Yield: 93 %

Procedure:
Mix 2-(2-bromo-4-fluoro-phenyl)-2-methyl-propionitrile (1 g, 4.13 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) (100 mg, 1% wt) with sodium hydroxide (10 M, 20 mL, 200 mmol) in ethanol (5 mL). Heat the mixture to reflux for 3 h. Quench the reaction with 1 N HCl. Extract the product with chloroform. Dry the organic phase over sodium sulfate and concentrate to give an oily residue. Purify the residue by FCC (10% methanol in DCM as eluant) to give the title compound as a yellow solid (1 g, 93%). MS (ES) m/z 260/262 [M+1]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1Cc2ccccc2C1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1Cc2ccccc2C1)c1cnc2ccccc2n1
Yield: 53 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.32 g, 1.7 mmol), 2-aminoindan (0.20 g, 1.5 mmol), pyridine (3 mL), and water (30 mL) yielding 0.23 g (53%) of (221):
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([CH:19]=[CH:20][C:21](O)=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.Cl>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)[CH2:20][C:21](=[O:22])[O:5]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Reactant: Oc1cccc(O)c1
Agent: Cl
Product: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Yield: 64 %

Procedure:
Condensation of resorcinol with 3-(1-naphthyl)acrylic acid in the presence of hydrochloric acid/hydrogen chloride (method of J. D. Simpson and H. Stephen, J. Chem. Soc. (London) 1936, 1382) gave the desired dihydrocoumarin, m.p. 203.5-206.5, in 64% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccccc2)c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
10% Palladium on carbon (2.0 g) was added to a solution of 3-nitro-N-phenyl-benzamide (20 g, 83 mmol) in ethanol (225 mL) and the mixture was hydrogenated at 45 psi for 2 hours. The mixture was filtered through diatomaceous earth and concentrated to give a colorless solid (mp 118-120° C., 16 g, 90%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.ClC1N=C(C(O)=O)C=CC=1OCC1CC1.[CH3:35][C:36]1([CH3:41])[CH2:40][O:39][CH2:38][NH:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:37]3[C:36]([CH3:41])([CH3:35])[CH2:40][O:39][CH2:38]3)=[O:14])[CH:9]=[CH:8][C:7]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH2:2][CH2:3]1
Reactant: CC1(C)COCN1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(OCC2CC2)c(Cl)n1
Product: CC1(C)COCN1C(=O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using the mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (24 mg, 37%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 361.1370 [MH+].