Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:18][C@H:17]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:23]([O:22][C:20]([NH:19][C:13]12[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CNC2
Yield: 107.5 %

Procedure:
A 10% palladium-carbon catalyst (about 50% wet, 115 mg) was added to a solution of (+)-(1R*,5S*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (575 mg, 1.595 mmol) in methanol (20 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for two hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (388 mg) as a colorless transparent gummy solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([I:16])=[CH:9][N:8]=1)C.O.O.Cl[Sn]Cl>C(O)C>[I:16][C:10]1[CH:9]=[N:8][C:7]2[NH:6][CH2:5][C:4](=[O:3])[NH:13][C:12]=2[CH:11]=1
Reactant: CCOC(=O)CNc1ncc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: O=C1CNc2ncc(I)cc2N1

Procedure:
(5-Iodo-3-nitro-pyridin-2-ylamino)-acetic acid ethyl ester (17 g) was dissolved in ethanol. SnCl2.2H2O was added and the reaction mixture was heated to 80° C. for two (2) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as a rust colored solid (59-77% yield). M.p. 81° C., LCMS: m/z=275.91 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.94 (s, 2H), 6.94 (bs, 1H), 7.12 (d, J=1.8 Hz, 1H), 7.74 (s, J=1.8 Hz, 1H), 10.40 (bs, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][O:19][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(CCCO)CC2)CC1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCC1CCC(C2CCC(CCC)CC2)CC1
Reaction time: 8 h

Procedure:
3-(4′-Propyl-bicyclohexyl-4-yl)-propan-1-ol (5 g, 18.8 mmol) is dissolved in dichloromethane (50 ml) and triethylamine (3.5 ml) and a solution of methacryloyl chloride (2.2 ml, 21.8 mmol) in dichloromethane (30 ml) is added dropwise at 0° C. The reaction is stirred overnight, evaporated, filtered through silica with heptane/ethyl acetate (19:1) and the crude product is crystallised from ethanol to give 2-methyl acrylic acid 3-(4′-propyl-bicyclohexyl-4-yl)-propyl ester as colourless crystals.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].O[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[C:15]([C:12]1[CH:11]=[CH:10][C:9]2[O:5][CH:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][CH:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[C:14]=2[CH:13]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CCC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chloral hydrate (36.4 g.) was added in portions to a stirred solution of p-hydroxypropiophenone (15 g.) in concentrated sulphuric acid (100 ml.). After the addition was completed, the mixture was stirred at room temperature for 3 hours and then kept for 5 days. The reaction mixture was poured onto ice, and the resulting solid product was filtered off, dissolved in diethyl ether (200 ml.) and filtered to remove any metachloral and unreacted starting material. The filtrate was dried, and evaporated to dryness under reduced pressure. Trituration of the residue with petroleum ether (b.p. 60°-80° C.) gave a solid product, which was crystallised from aqueous ethanol to give 6-propionyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 96°-97° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18](=O)[C:19]#[CH:20])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[O-]CC.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Br)c3)nn12
Yield: 46 %

Procedure:
In a similar manner as described in Example 46 from 1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.0 g, 2.8 mmol), N-cyclopentylguanidine hydrochloride and sodium ethoxide (4.1 mL, 21 wt % in ethanol, 3.6 mmol) at room temperature was obtained 4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.60 g, 46%) as a yellow crystalline solid. MS m/z 469 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[Cl:36])[N:29]([CH3:37])[N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:26][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[Cl:36])[N:29]([CH3:37])[N:28]=2)[CH:9]=1)=[O:6]
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (100 mg, 0.38 mmol, 36721-253A) and potassium carbonate (63.1 mg, 0.45 mmol) was stirred at room temp for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.9 mg, 0.28 mmol, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 11) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-benzamide as a white solid. (Yield 33.3 mg).
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[C:29]([CH:35]=O)[C:28]=1[OH:37].C(N(CC)CC)C>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:35][C:29]1[C:30]([CH2:33][OH:34])=[CH:31][N:32]=[C:27]([CH3:26])[C:28]=1[OH:37])[CH3:5]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc(CO)c(C=O)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A clear solution of (carbethoxymethylene)triphenylphosphorane (22.3 g, 64.02 mmol) in THF was added to pyridoxal (13.01 g, 64.0 mmol) in THF at room temperature. The mixture was stirred for one hour, then triethylamine (10 mL) was added and the mixture was stirred until the solution turned to a yellow suspension. The solvent was evaporated, and the crude product purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (20:1) as eluant to give 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-acrylic acid ethyl ester (34) (15.2 g, quantitative yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=3)[CH2:38][CH2:37]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cc(OC)c(OC)c(OC)c4)CC3)nc2c1
Yield: 97 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 3.55-3.87 (m, 10H), 4.12 (s, 4H), 6.67 (d, J=8.4 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.25 (s, 1H), 7.34 (s, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 8.21 (d, J=3.6 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1
Reactant: CCOC(=O)C=C(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CCCCOC1CCCCO1)CCCc1cccnc1

Procedure:
A solution of 1.385 g of ethyl 3-[3-(3-pyridyl)propyl]-7-(2-tetrahydropyranyloxy)-hept-2-enoate in 30 ml ethyl acetate is hydrogenated in a Parr apparatus at 3 atmospheres (=3.04 bar) pressure and room temperature in the presence of 5% Pd/C catalyst for 13 h to yield ethyl 3-[3-(3-pyridyl)propyl]-7-(2-tetrahydropyranyloxy)-heptanoate; NMR (CDCl3): delta 2.2 (ddd,2H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1.[CH3:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:19][N:20]([CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1)[CH3:21]
Reactant: COc1cc(-c2nnc(CCl)o2)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(CN(C)C)o2)ccc1N
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To 2-(chloromethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,3,4-oxadiazole (0.399 g, 1.48 mmol) in dioxane (10 mL) was added dimethylamine (1.87 mL, 40% weight in H2O, 14.8 mmol). The reaction was heated at 60° C. overnight. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. The residue was taken up in EtOAc (20 mL) and Pd on carbon was added in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite® and concentrated to provide the title compound of step D (0.326 g, 1.32 mmol, 89% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18-2.23 (m, 6H), 3.67-3.72 (m, 2H), 3.76-3.82 (m, 3H), 5.47-5.56 (m, 2H), 6.64-6.72 (m, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.30 (dt, J=8.1, 2.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:54])=[N-]>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([O:27][CH3:54])=[O:26])[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid (695 mg) prepared in Example 2 in ethyl acetate (200 ml) was added excess ethereal solution of diazomethane and the mixture was stirred for 30 minutes at room temperature. The resulting solution was evaporated to dryness and the residue was triturated in diethyl ether to give methyl 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronate (700 mg), mp. 124°-128° C. (dec.).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32](/[C:35](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:36]/[CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:37]/[CH:36]=[C:35](/[C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)\[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:21]([Cl:26])[CH:20]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(O)c(Cl)c1
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)c(Cl)c1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (756 mg, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (786 mg, 3.0 mmol), 3-chloro-4-hydroxyphenyl-acetic acid ethyl ester (537 mg, 2.5 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (15 ml), the mixture was stirred for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent: toluen) to give 640 mg (66%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NC1CC1
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Yield: 59 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (2.00 g (10.4 mmol)) and cyclopropylamine (2.0 ml) was heated under reflux for 60 hours, and the excess cyclopropylamine was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with aqueous 1% sodium hydroxide, saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:10) as eluent to give 1.30 g (59%) of 4-chloro-N-cyclopropyl-2-nitroaniline as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[C:4]2[CH:3]=1.C(OCC)(=O)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:39][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:5]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 5,7-dichloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (148 mg, 0.35 mmol) in cyclopentylamine (5 mL) was heated at 80° C. for 3 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by chromatography (4:1 hexanes/ethyl acetate) gave N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (141 mg, 85%) as a yellow foam. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.84 (d, 1H), 7.51 (d, 2H), 6.99 (d, 2H), 6.65 (d, 1H), 6.09 (d, 1H), 6.02 (d, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 2.63 (s, 3H), 2.15 (m, 2H), 1.81-1.69 (m, 6H). MS m/z 466 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=O)[CH3:4].[NH2:8][C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:10](Br)[C:11]#[N:12]>C(O)(=O)C.O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[NH:8][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:4][C:10]=2[C:11]#[N:12])=[CH:19][CH:18]=1
Reactant: N#CC(Br)=C(N)c1ccc(Cl)cc1
Reactant: CC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of trifluoroacetone (3.36 g, 2.7 mL,0.03 mol) in acetic acid is added dropwise at 100° C. to a solution of β-amino-α-bromo-p-chlorocinnamonitrile, (E)- or (Z)- (5.15 g, 0.02 mol) in acetic acid over 41/2 hours. The reaction mixture is heated at 100° C. overnight, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a gum. The gum is flash chromatographed using silica gel and a 15% ethyl acetate in heptane solution to give the title product as a yellow solid (1.8 g, mp 129°-131° C.) which is identified by 1H and 19FNMR spectral analyses.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]([NH2:14])=[CH:8][CH:7]=1.[OH-].[Na+]>Cl>[Cl:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:13])[N:1]=[N:14][C:9]2=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: CNc1nc(Cl)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nnc2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
NaNO2 (350 mg, 5.08 mmol) was added to a stirred solution of 6-chloro-N2-methylpyridine-2,3-diamine (Step 102.2) (800 mg, 5.08 mmol) in 2N HCl (8 mL) at 0° C. and the resulting mixture was stirred for 10 min at 0° C. The reaction was basified with 2N NaOH and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (50% EtOAc/hexane) to afford the title product (545 mg, 3.23 mmol, 64% yield) as beige solid. tR: 0.69 min (LC-MS 2); ESI-MS: 168/170 [M+H]+ (LC-MS 2); Rf=0.46 (50% EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (s, 3H) 7.44-7.62 (m, 1H) 8.62 (d, J=8.6 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[N:14]([CH2:17][C:18]([CH3:26])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:15]=[N-:16]>>[CH3:26][C:18](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[N:16]=[N:15]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCc2c[nH]c(N)n2)nn1
Yield: 88 %

Procedure:
4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (0.089 g, 0.4.47 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.085 g, 0.491 mmol) following the general procedure for click reactions outlined above to produce 4-{4-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-butyl}-1H-imidazol-2-ylamine (0.132 g, 79%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), 7.03 (m, 5H), 6.49 (s, 1H), 6.25 (s, 1H), 5.05 (s, 2H), 2.67 (t, 2H), δ 2.73 (t, 2H), δ 1.56 (s, 3H), δ 1.42 (m, 4H) ppm; 13C (75 MHz, CD3OD) δ 147.3, 144.7, 136.4, 132.7, 129.9, 128.9, 128.6, 128.5, 128.3, 127.5, 127.2, 126.9, 108.7, 61.2, 27.4, 27.3, 23.8, 22.8, 14.8 bpm; HRMS (ESI) calcd for C19H24N6(M+) 336.2135, found 336.2134.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br-].[CH2:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:13]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OC2CCCC2)cc1F
Temperature: 70 °C

Procedure:
A suspension of 2.5 g 4′-hydroxy-2′-fluoroacetophenone, 2.0 mL cyclopentane bromide and 7.9 g cesium carbonate in acetonitrile (35 mL) was heated for 1 hour under reflux and then heated at 70° C. for 15 hours. Further, 1.0 mL cyclopentane bromide was added thereto, and the mixture was heated for 3 hours under reflux. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.65 g of the title compound in a crude state (yellow oil) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH3:35])[CH:30]=[C:31]([F:34])[CH2:32]O)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][C:31]([F:34])=[CH:30][C:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, a solution of triphenyl phosphine (0.96 g, 4.25 mmol) in carbon tetrachloride at −5° C. is treated dropwise with a solution of bromine (0.679 g, 4.25 mmol) in carbon tetrachloride, warmed to and stirred at room temperature for 45 minutes, treated with a solution of 4-(p-chlorophenyl)-2-fluoro-4-methyl-2-penten-1-ol, (Z)—(0.81 g, 3.54 mmol) in carbon tetrachloride, refluxed for 2 hours, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered through diatomaceous earth. The filtrate is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless oil (0.736 g, 71% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[C:12](=O)[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[CH3:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][C@@H:11]([CH2:15][CH3:16])[C@H:12]([NH:30][CH3:29])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O
Reactant: CN
Product: CC[C@H](Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)[C@@H](C)NC

Procedure:
The title compound was prepared by a reductive amination as shown above starting with 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic acid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl3)