Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:36]([O:37][CH3:38])=[CH:35][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:36]([O:37][CH3:38])=[CH:35][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Yield: 58 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. The product was isolated as a white solid (8 g, 58%), mp: 149.5-151.5° C., MS (ESI+): 547 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 7.26 (m, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.65 (t, 2H), 2.90 (m, 3H), 2.77-2.69 (m, 15H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[NH:13][C:14](=[O:26])[C:15]([C:24]#[N:25])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[C:24]([C:15]1[C:14](=[O:26])[N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:12]([C:7]2[C:8]3[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[N:17][C:16]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1c(-c2ccccc2)nc(-c2cccc3c(Br)cccc23)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(-c2cccc3c(Br)cccc23)nc(-c2ccccc2)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105.6 %

Procedure:
1,6-Dihydro-2-(5-bromo-1-naphthalenyl)-6-oxo-4-phenyl-5-pyrimidinecarbonitrile (4.0 g, 9.9 mmol) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil, washed with hexane, 0.6 g, 14.9 mmol) in dry THF (80 mL). After 5 minutes the mixture became a homogeneous solution. Neat t-butyl bromoacetate (2.9 g, 14.9 mmol) was added in one portion and the mixture was refluxed for 18 hours. Additional t-butyl bromoacetate (0.4 g, 2.0 mmol) was added and reflux was continued for 2 hours. The reaction mixture was cooled to room temperature and quenched with water. The mixture was partitioned between water (50 mL) and CHCl3 (100 mL), and the aqueous layer was extracted with CHCl3 (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give an orange foam (5.4 g). The material was purified by radial preparative thin-layer (Chromatotron) chromatography with elution by EtOAc/hexanes (20:80) to give the pure product (3.0 g, 59%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].Cl>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][CH:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[C:37]2=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:22])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A portion (5.2 g; 20 mmol) of the methyl 4-Boc-piperazine-2-acetate product from the previous step was combined with 60 mL of THF and 60 mL of 1 N NaOH (aqueous) and stirred at room temperature for 6 hours to saponify the methyl ester. The reaction was cooled to 0° C., adjusted to pH 9-10 with 10% HCl(aqueous), and 5.2 g (20 mmol) of FMOC-Cl was added. The reaction was stirred at room temperature for 6 hours, (adding 1 N NaOH (aqueous) to maintain pH 9-10) 1 hour, then acidified with 10% HCl to pH=1. The reaction was extracted twice, the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 8.56 g of the desired 4-Boc-1-Fmoc-piperazine-2-acetic acid (the compound of formula (XXIV)); 1H NMR (CDCl3) δ 1.4 (s,9), 2.5-3.0 (m,5) 3.9-4.2 (m,6), 4.5 (m,1), 7-25 (t,4), 7.32 (t,4), 7.48 (d,4), 7.75 (d, 4).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][CH2:23][CH:22]([CH3:27])[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: CC(C)CCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCCC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-methylpentylamine (Example 433, Part A) (0.272 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the sasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.335 g, 36.5%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+, found 359.2087, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>CO>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:43]=[CH:44][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCN)Cc4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of HCl/dioxane at 0° C. was added to (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 0.075 mmol) in MeOH (1 mL). The reaction mixture was stirred at 25° C. for 1 hour. After removal of the solvent, the crude product was purified by preparative HPLC to afford (R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (32 mg, 90%). MS (ESI) m/e (M+H+) 429.2. 1H NMR: δ=8.56 (s, 1H), δ=7.23-7.56 (dd, 4H), δ=4.51 (s, 2H), δ=3.97-4.19 (m, 4H), δ=3.70 (m, 1H), δ=3.61 (m, 4H), δ=3.40-3.43 (t, 2H), 8=2.96-3.15 (m, 4H), δ=2.42 (m, 1H), δ=1.89 (m, 1H), δ=1.21-1.22 (d, 3H).
Reaction SMILES: [Cl:1]Cl.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>CO>[Cl:1][C:5]1[C:4]([OH:3])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: ClCl
Reactant: O=C(O)c1cccc(O)c1
Solvent: CO
Product: O=C(O)c1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
Chlorine gas (10.3 g; 147 mmol) was slowly bubbled through a cold solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, while maintaining the temperature below -60° C. After approximately thirty minutes, the chlorine gas was flushed out with nitrogen and the reaction mixture was allowed to warm to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recyrstallization from 50 mL of water followed by recrystallization from 130 mL of benzene containing 10 mL of acetone to provide the desired titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[CH3:7].[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:7][C:6]1[O:5][C:4]([C:8]([NH:15][C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([O:12][CH3:11])=[O:20])=[O:10])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)O)oc1C
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc(C)c(C)o1
Yield: 27 %

Procedure:
Prepared in a similar manner to example 4 using 4,5-dimethyl-furan-2-carboxylic acid and D-leucine methyl ester. Yield: 27%. 1H NMR (500 MHz, CDCl3): δ 0.96 (t, 6H), 1.66 (m, 3H), 1.96 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 4.78 (m, 1H), 6.51 (d, 1H), 6.89 (s, 1H). MS (M+H, 268).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C1COCC1.[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[C:35]([O:37][CH:38]3[CH2:43][CH2:42][N:41]([C:44](N4C=CN=C4)=[O:45])[CH2:40][CH2:39]3)[N:34]=[CH:33][N:32]=1)[CH2:26][CH2:25]2)(=[O:21])=[O:20])[CH3:18]>O>[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([O:37][CH:38]3[CH2:39][CH2:40][N:41]([C:44]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:45])[CH2:42][CH2:43]3)[CH:36]=1)[CH2:26][CH2:25]2)(=[O:20])=[O:21])[CH3:18]
Reactant: OC1CCC1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Cyclobutanol (90 μL, 1.15 mmol) and potassium tert-butoxide (50 mg, 0.446 mmol) were added to a THF (2.5 mL) suspension of the 5-(ethylsulfonyl)-1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)indoline (109 mg, 0.226 mmol) produced in Reference Example 31, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:ethyl acetate=50:50, V/V; (ii) ethyl acetate]. The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (34.6 mg, yield: 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:13][C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Oc2ccc(CO)cc2F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cc(F)cc(C#N)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-fluoro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]([N:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:22]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[C:19]([N:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[O:20]
Reactant: O=Cc1ccco1
Reactant: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1NCc1ccco1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.9 %

Procedure:
2-Furaldehyde (0.20 g) and tert-butyl 3-[{[2-amino-4-(trifluoromethyl)phenyl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (0.33 g) were dissolved in acetic acid (5.0 ml), sodium triacetoxyborohydride (0.31 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10→10:0) was concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred for 30 min. The reaction mixture was concentrated and purified by HPLC to give the object compound (12.2 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]([CH3:46])([CH3:45])[CH2:26][CH2:27][NH:28][C:29](=[O:44])[C@H:30]([CH3:43])[CH2:31][C@H:32]([OH:42])[C@@H:33]([NH2:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:34]([C@H:33]([NH:41][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)[C@@H:32]([OH:42])[CH2:31][C@H:30]([C:29](=[O:44])[NH:28][CH2:27][CH2:26][C:25]([CH3:24])([CH3:45])[CH3:46])[CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
To a solution of 3-methanesulfonyl benzoic acid (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.39 mmol) in 2:1 dichloromethane/DMF (3.0 ml) was added (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (100 mg, 0.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic phase was separated and washed with further 1M hydrochloric acid, dil. aq. NaHCO3 and brine. It was dried over MgSO4, filtered and evaporated to afford the crude product which was triturated with ether to afford the title compound (63 mg, 39%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:7]=2)[N:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:12]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)n1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCN(C)CC2)n1
Temperature: 130 °C
Yield: 42 %

Procedure:
5-(1-((2-Chloropyrimidin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (50.0 mg, 0.114 mmol) was dissolved in DMSO (0.5 ml) and 1-methylpiperazine (0.127 ml, 1.142 mmol) was added. The reaction was heated at 130° C. overnight and purified by prep-HPLC (MeCN/H2O 20%-50% MeCN, containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford the desired compound as a yellow solid (24 mg, 42%). MS (ES+) C22H22F3N9O2 requires: 501. found 502 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.33-8.24 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 6.32 (d, J=4.9 Hz, 1H), 5.33 (s, 2H), 3.84-3.70 (m, 4H), 2.64 (s, 3H), 2.47-2.38 (m, 4H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([O:19][C:21](=[O:23])[CH3:22])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20]
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Reaction time: 4 h

Procedure:
Mix 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one with pyridine (3 cc) and acetic anhydride (1 cc) and keep at room temperature for 4 hours. Add ethanol (1 cc) and remove low-boiling material under reduced pressure (0.1 mm) to leave a red gum which crystallizes from a mixture of ethyl acetate and light petroleum. Recrystallize from methanol to obtain crystals of 13β-methyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, melting partially at 161°-166° with resolidification at about 220° and finally melting at 260°-265° (decomp.); infrared absorption peaks at 5.75 μ and 8.27 μ, with absence of an absorption band due to a hydroxy group; ultraviolet absorption peak at 307.5 mμ (ε24,000).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[OH:22])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:24][C:25]1[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(O)C1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-chloromethyl-4-(β-trimethylsilyl-ethoxymethoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-[4-(2-trimethylsilyl-ethoxy-methoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 530 [M-(C2H4 +CH2O)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC1(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CCC1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5(C)CCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-(1-methylcyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.45 M) was added palladium 1,1-bis(diphenylphosphion)-ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (49% yield) as a yellow solid. MS (ESI) m/z 499.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][S-:21].[Na+]>CCO>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][S:21][CH3:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]2
Reactant: C[S-]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCBr
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCSC
Yield: 97.6 %

Procedure:
A solution of ethyl 1-(3-bromopropyl)-5-chloro-1H-indole-2-carboxylate (38.5 g, 0.112 mol) and sodium methanethiolate (9.4 g, 0.135 mol) in 500 mL of EtOH was stirred at RT for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with 200 mL of water and then extracted with EtOAc (100 mL×2). The combined organic layers were washed with 100 mL of brine and 100 mL of water, and then dried over Na2SO4 and concentrated in vacuo to afford 34.1 g of the crude ethyl 5-chloro-1-[3-(methylsulfanyl)propyl]-1H-indole-2-carboxylate, which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][C:6]([OH:8])=O)[CH3:3].ClC(OC)=O.C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[C:37](/[CH:41]=[CH:42]/[CH2:43][NH2:44])[CH:38]=[CH:39][CH:40]=2)=[CH:31]1>C(Cl)Cl>[S:30]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[C:37](/[CH:41]=[CH:42]/[CH2:43][NH:44][C:6](=[O:8])[CH2:5][N:4]([CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2][CH3:3])[CH:38]=[CH:39][CH:40]=2)=[CH:31]1
Reactant: CCN(C/C=C/C#CC(C)(C)C)CC(=O)O
Reactant: NC/C=C/c1cccc(-c2ccsc2)c1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C/C=C/C#CC(C)(C)C)CC(=O)NC/C=C/c1cccc(-c2ccsc2)c1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
100 mg of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)glycine hydrochloride was dissolved in 10 ml of methylene chloride, and 34 μl of methyl chloroformate and 0.1 ml of triethylamine were added under ice cooling. The mixture was stirred for 30 minutes, and a methylene chloride solution(5 ml) of 90 mg of (E)-3-[3-(3-thienyl)phenyl]-2-propenylamine was added, then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [silica gel column, hexane→hexane/ethyl acetate=5/1] to give 24 mg (yield 17%) of the captioned compound as a pale yellow oil.