Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([N+:12]([O-])=O)=[CH:10][N:11]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1>CO.[Pd]>[NH2:12][C:9]1[S:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[N:11][CH:10]=1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ncc([N+](=O)[O-])s1
Agent: [Pd]
Solvent: CO
Product: Cn1nc(C(F)(F)F)cc1-c1ncc(N)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
A mixture of 2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-5-nitro-1,3-thiazole (65, 350 mg, 0.13 mmol) and Pd/C in 4 ml MeOH was stirred under H2 balloon at r.t. for 4 h before filtered thru celite. The filtrate was concentrated to dryness to give 8.1 mg 5-amino-2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole (66) as brown thick oil which was used directly used for next step reaction.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.[2H]C(Cl)(Cl)Cl.[2H]C([2H])([2H])O[2H]>>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][NH:31][C:25]2[N:24]=[C:23]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[CH2:16][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[S:12]([CH3:15])(=[O:13])=[O:14])[CH:28]=[CH:27][N:26]=2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(N)cc1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]OC([2H])([2H])[2H]
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(N)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Amino-ethyl)-phenylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 455. CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.9 (d, 1H) 7.5 (d, 1H) 7.4 (m, 1H) 7.2 (m, 3H) 7.1 (d, 2H) 4.4 (s, 2H) 3.7 (m, 2H) 3.2 (m, 4H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m, 2H).
Reaction SMILES: NC1N(C2C=CC=CC=2OC)N=CC=1C#N.[O:17]1[CH2:22][CH2:21][CH:20]([NH:23][NH2:24])[CH2:19][CH2:18]1.CO[C:27](=[C:29]([C:32]#[N:33])[C:30]#[N:31])[CH3:28]>>[NH2:33][C:32]1[N:23]([CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[N:24]=[C:27]([CH3:28])[C:29]=1[C:30]#[N:31]
Reactant: COC(C)=C(C#N)C#N
Reactant: NNC1CCOCC1
Agent: COc1ccccc1-n1ncc(C#N)c1N
Product: Cc1nn(C2CCOCC2)c(N)c1C#N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(tetrahydro-2H-pyran-4-yl)hydrazine and 2-(1-methoxyethylidene)malononitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 4.20 (m, 1H), 4.05 (m, 2H), 3.50 (m, 2H), 2.18 (s, 3H), 2.09 (m, 2H), 1.77 (m, 2H). MS: (M+H m/z 207.0).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][CH2:22][CH2:23]Br.CC(C)=O>O>[Cl:20][CH2:21][CH2:22][CH2:23][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2CO3 (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99°-101° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:38])[CH2:10][C@H:11]([O:36][CH3:37])[C@@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si](C(C)(C)C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.FC(F)(F)C(O)=O>O>[CH3:25][C@H:15]([CH2:14][C@H:13]([O:26][CH3:27])[C@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[C@@H:11]([O:36][CH3:37])[CH2:10][C@@H:9]([CH3:38])[CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:16][OH:17]
Reactant: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C[C@@H](C)CO)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)COC(=O)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 127.4 %

Procedure:
Bis-t-butyldimethylsilyloxy ether 25 (3.67 g, 6.36 mmol) was dissolved in asolution composed of 54 ml of tetrahydrofuran, 18 ml of water, and 0.9 ml of trifluoroacetic acid. The mixture was stirred at 25° C. for 5 hr. The mixture was partitioned between 200 ml of methylene chloride and 100 ml of saturated sodium bicarbonate solution. The aqueous phase was extracted with 2×200 ml of methylene chloride. The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield 3.75 g of an oil. The oil was purified by chromatography on 190 g ofsilica gel eluting with hexanes:ethyl acetate (4:1) to give 2.675 g of primary alcohol 26. This material was homogeneous by both 1H and 13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[CH3:15].C(N(CC)CC)C.[CH3:23][C:24]1[C:25](Cl)=[N:26][C:27]([Cl:31])=[N:28][C:29]=1[CH3:30]>CN(C)C=O>[CH3:23][C:24]1[C:25]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH:8]2[CH3:15])=[N:26][C:27]([Cl:31])=[N:28][C:29]=1[CH3:30]
Reactant: COc1ccc(OC)c2c1CCNC2C
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Yield: 72.9 %

Procedure:
After 5,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline(10 g, 4.82 mmol) and triethylamine (0.67 ml, 4.82 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.71 g, 4.02 mmol) in dimethylformamide, 1.02 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 72.8%)
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[C:20]([F:22])[CH:21]=[C:16]3[C:15]([F:24])([F:23])[C:14]2=[O:25])[CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[C:20]([F:22])[CH:21]=[C:16]3[C:15]([F:24])([F:23])[C:14]2=[O:25])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(F)cnc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(F)cnc32)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.1 %

Procedure:
Hydrogen chloride (4.0 M in 1,4-dioxane, 1.686 mL, 6.74 mmol) was added to a stirred mixture of tert-butyl(trans-3-(3,3,5-trifluoro-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (0.241 g, 0.674 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 2.5 h. Additional 1,4-dioxane (3 mL) was added, and the reaction mixture was stirred for another 20 h. The reaction mixture was concentrated to yield the title compound (0.210 g, 0.715 mmol, 106% yield) as a white solid. M+1: 258.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11]O)[CH2:6][CH2:5]2>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:11])[CH2:6][CH2:5]2
Reactant: ON=C1CCc2cc(F)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
Zinc powder (20.2 g) was added during three hours to the stirred solution of the above oxime (20.2 g) in acetic acid (200 ml) which maintains the temperature at 25°-35° C. The resulting mixture was stirred an additional 12 hours at room temperature. The solids were removed by filtration and the filtrate concentrated in vacuo. The concentrated filtrate was partitioned between water and toluene and the aqueous phase adjusted to pH 12 with ammonium hydroxide and extracted with toluene. Solvent removal in vacuo gave 5-fluoro-1-aminoindan (17.8 g) as a colored oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6](/[CH:14]=[CH:15]/[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN(C)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2cccnc2)CCN(C)C1
Temperature: 5 °C

Procedure:
2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]4[S:31][N:30]=[CH:29][N:28]=4)(=[O:24])=[O:25])=[CH:20][CH:21]=3)[N:16]([CH3:43])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2ccc(F)c(C#N)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-cyano-4-fluorophenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3-cyano-4-fluorophenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.54-7.60 (m, 2 H) 7.91-8.07 (m, 5 H) 8.13 (dd, J=6.13, 2.35 Hz, 1H). m/z (ESI) 413.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C.O>[Cl:1][C:2]1[N:11]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCO
Solvent: O
Product: Clc1nc(N2CCOCC2)c2ccccc2n1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Twenty grams of 2,4-dichloroquinazoline was suspended in 200 ml of ethanol. To this suspension was added 17.4 g of morpholine. A mildly exothermic reaction ensued with the concomitant dissolution of the suspended dichloroquinazoline. When the reaction subsided, after about 10 minutes, the mixture was heated at reflux for 15 minutes, and then was allowed to cool. The reaction mixture then was diluted with 800 ml of water. The solid which precipitated was collected by filtration and was washed with water. After drying, the solid was recrystallized from 1:2 benzene-hexane, to give 18.5 g of 2-chloro-4-morpholinoquinazoline; m.p. 103°-105°. The following analytical data were obtained:
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)C=CC=CC=1.[ClH:23]>C(O)C.[Pd]>[ClH:23].[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[N:22]=2)[CH2:9]1
Reactant: c1ccc(CN2CCOC(c3nc4cnccc4[nH]3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cc2[nH]c(C3CNCCO3)nc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[4-(Phenylmethyl)-2-morpholinyl]-1H-imidazo[4,5-c]pyridine (1.0 g, 3.40 mmol) was hydrogenated in ethanol (30 mL) in the presence of Pd/C (10 wt %, 0.362 g, 0.340 mmol) and 0.2 mL of concentrated hydrochloric acid. After stirring at room temperature overnight, the catalyst was filtered off. The filtrate was concentrated to afford an HCl salt of the title compound (0.8 g) as a yellow oil. LC-MS (ES) m/z=205 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.059 g, 26%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methylphenylboronic acid (0.169 g, 1.24 mmol). mp 157-159° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH2:26])[CH:23]=2)[CH:18]=[N:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:23]=2)[CH:18]=[N:17]1
Reactant: Cn1ncc2ccc(CN)cc21
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cnn(C)c3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-indazol-6-yl)methanamine.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]([NH:18][CH3:19])=[S:17]>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[C:2](=[O:3])[C:1](=[O:5])[N:18]([CH3:19])[C:16]1=[S:17]
Reactant: CNC(=S)Nc1c(C)cccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1N1C(=O)C(=O)N(C)C1=S
Yield: 65.9 %

Procedure:
Oxalyl chloride (8.4 g; 0.066 mol) was added dropwise to the stirring solution of N-(2,6-dimethyl phenyl)-N′-methylthiourea (6.4 g; 0.033 mol) in methylene chloride (100 mL). The mixture was heated at reflux for 2 hours then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour. The solvent was concentrated. The precipitated solid was collected by filtration and dried to give 5.4 g of 1-(2,6-Dimethylphenyl)-3-methyl-2-thioxo-4,5-imidazolidinedione, m.p. 144–146° C. Mass spectrum; (El, M.+) m/z248. 1H-NMR (DMSO-d6; 300 MHz): δ 7.30 (t, 1H), 7.18 (d, 2H), 3.33 (s, 3H), and 2.08 ppm (s, 6H).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:15]#[C:16][CH3:17].S(Cl)([Cl:30])=O>ClCCl>[CH2:14]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:30])=[O:24])=[CH:21][CH:20]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC#CCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
2.8 ml (14.2 mmol) of dicyclohexylamine are added to a solution of 2.7 g (14.2 mmol) of 4-but-2-ynyloxybenzoic acid diluted in 30 ml of dichloromethane. After stirring for 30 min at ambient temperature, the reaction medium is cooled to 0° C. and 1.0 ml (14.2 mmol) of thionyl chloride is slowly added. The mixture is then stirred at ambient temperature for 1 h 30 min, then the dicyclohexylamine salts are precipitated by adding 50 ml of diethyl ether. After filtration of the reaction medium, the filtrate is concentrated under vacuum. 2.9 g (100%) of 4-but-2-ynyloxybenzoyl chloride are obtained in the form of a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]1.C[Sn](C)(C)[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1.C(N(CC)CC)C.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][N:13]1[CH2:14][CH2:15][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)C1
Reactant: C[Sn](C)(C)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(-c4cncnc4)cc23)C1
Yield: 17.2 %

Procedure:
A mixture of 5-bromo-3-(N-methylpyrrolidin-3-yl)1H-indole (0.450 g, 1.86 mmol), 5-trimethylstannylpyrimidine (0.518 g, 1.86 mmol), bis(triphenylphosphine)palladium(II) chloride (0.100 g), triethylamine (0.84 mL, 6.03 mmol, 3.2 eq), lithium chloride (0.254 g), and 2,6-di-tert-butyl-4-methylphenol (3.0 g) in anhydrous N,N-dimethylformamide (8 mL) was heated at reflux under nitrogen for 4 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide] afforded the title compound (0.089 g, 0.32 mmol, 17%) as an off-white solid: mp, 140.0-143.0° C.; TLC Rf =0.20 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (CD3OD) δ9.05 (s, 2H), 9.03 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.39 (dd, J=1.6 and 8.5 Hz, 1H), 7.16 (s, 1H), 4.90 (s, 1 exchangeable H), 3.78-3.66 (m, 1H), 3.16 (t, J=8.7 Hz, 1H), 2.92-2.84 (m, 1H), 2.72-2.59 (m, 2H), 2.42 (s, 3H), 2.42-2.33 (m, 1H), 2.10-1.99 (m, 1H); 13C NMR (CD3OD) d 156.6, 155.9, 138.9, 137.7, 129.0, 125.4, 123.2, 121.4, 119.7, 118.7, 113.6, 63.5, 57.1, 42.6, 36.3, 33.2; FAB LRMS (m/z, relative intensity) 279 ([MH]+, 100); HRMS calculated for C17H18N4 278.1533, found 278.1520.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.[N:35]1(OC(N(C)C)=[N+](C)C)[C:39]2C=CC=CC=2N=N1.CN>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:35][CH3:39])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 6 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (300 mg, 0.82 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (341 mg, 0.9 mmol) and methylamine (45 mL, 0.9 mmol); (15 mg, 6% yield). RT 7.164 20-100% ODS at 1 mL/min method, ES-MS (m/z) 292 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](O)=[O:18]>>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([F:13])[CH:15]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1ccc(C(=O)Nc2cc(OC)c(Cl)cc2OC)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step a, from 4-chloro-2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 197-199° C.; MS m/e 340 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:35])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:35])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 39.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile (2.6 g, 8 mmol) prepared in Example 68a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.7 g, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[CH3:23]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:31][C:28]3[N:29]=[CH:30][C:25]([O:24][CH2:22][CH3:23])=[CH:26][N:27]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Reactant: CCOc1cnc(N)nc1
Solvent: C1COCCO1
Product: CCOc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2F)nc1
Temperature: 120 °C
Yield: 18.4 %

Procedure:
To a 10 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, Example 96(e)) and 5-ethoxy-2-pyrimidinamine (40.6 mg, CAS 39268-74-1) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (13.6 mg), tris(dibenzylideneacetone)dipalladium(0) (7.12 mg) and sodium tert-butoxide (21.0 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (RS)-2-[4-(5-ethoxy-pyrimidin-2-ylamino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (15 mg, 18%) as a yellow gum. MS (ISP): 441.4 ([M+Na]+), 419.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:12].[OH-].[K+].Cl.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(/C=C/CO)ccc1F
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(/C=C/COCCCN2CCCC2)ccc1F
Yield: 23.6 %

Procedure:
Following the procedure described in example 2, but starting from trans-3-(4-fluoro-3-methylphenyl)prop-2-en-1-ol (710 mg), potassium hydroxide (592 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (802 mg) in dimethylsufoxide (6 mL) affords 280 mg of trans-1-{3-[3-(4-fluoro-3-methylphenyl)allyloxy]propyl}-pyrrolidine.