Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.ClC1C=CC(Cl)=CC=1C1(C#N)CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:12]#[N:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc2ccccc2c1
Agent: N#CC1(c2cc(Cl)ccc2Cl)CCCC1
Product: N#CC1(c2ccc3ccccc3c2)CCCC1
Yield: 75.5 %

Procedure:
1-Naphthalen-2-yl-cyclopentanecarbonitrile (211) (25.0 g, 75.46%) was synthesized as a white solid from naphthalen-2-yl-acetonitrile (210) (25.0 g, 149.7 mmol) and 1,4-dibromobutane (17.8 mL, 149.7 mmol) following the procedure described for 1-(2,5-dichlorophenyl)-cyclopentanecarbonitrile (198).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[C:5]([S:11][CH3:12])[N:4]=1.C([Li])CCC.CCCCCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].C(OCC)(=O)C>C1COCC1>[CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][C:8]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9]2)=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1nc(SC)n2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(SC)c2s1
Temperature: -60 °C

Procedure:
5,7-Bis(methylthio)imidazo[5,1-b]thiazole (1.66 g) was dissolved in 50 ml of THF under an argon atmosphere. The solution was cooled to −60° C. A 1.6 N n-butyllithium/n-hexane solution (5.76 ml) and 2.29 ml of tri-n-butylstannyl chloride were added dropwise in that order to the solution, and the temperature of the mixture was raised to −40° C. over a period of one hr. Ethyl acetate (100 ml) was added to the reaction solution, and the mixture was washed with 100 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and was filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to prepare 2.31 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CCCBr
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Product: CCCN1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 242° C. (HCl); MS m/z (rel. intensity, 70 eV) 290 (M+, 34), 261 (bp), 218 (22), 190 (20), 70 (37).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6](#[N:9])[CH:7]=[CH2:8]>O>[C:6]([CH2:7][CH2:8][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])#[N:9]
Reactant: CNCCO
Reactant: C=CC#N
Solvent: O
Product: CN(CCO)CCC#N
Temperature: 75 °C
Reaction time: 2.75 h

Procedure:
1000.0 grams (13.31 moles) of 2-methylaminoethanol was placed in a 3000 milliliter 3-neck flask equipped with a stirrer, a condenser, an addition funnel, and a thermometer. 50.0 grams of distilled water was charged to the flask, and 705.4 grams (13.31 moles) of acrylonitrile was charged to the addition funnel (875.2 ml). The acrylonitrile was added dropwise slowly over 55 minutes, during which time the flask was air-cooled and the contents of the flask increased in temperature to about 75° C. The maximum temperature of the flask contents during the addition of the acrylonitrile was about 81° C. After the addition of acrylonitrile was completed, the flask contents were held at 75° C. while agitation was continued for another 2.75 hours. The contents were then allowed to cool to room temperature. The flask was then heated to 80° C. under 5 mm Hg vacuum, to remove residual water and acrylonitrile. The flask contents then comprised 1697.8 grams of product; GC analysis showed that 96.4% of this was the desired reaction product.
Reaction SMILES: [CH:1]([C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2)=O.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:17]/[N:16]=[CH:1]/[C:3]1[N:4]2[C:8]([C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:11]=1)=[CH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(C=O)n2cccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(/C=N/O)n2cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-formylindolizine-8-carboxylate (203 mg, 1.0 mmol) and NH2OH.HCl (105 mg, 1.5 mmol) in THF (30 mL) and H2O (8 mL) at rt was added NaOAc (164 mg, 2.0 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was extracted with EA (2×40 mL). The organic layers was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CCN1CCN(c2ccc(N)cc2)CC1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CCN1CCN(c2ccc(Nc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
The compound from step 2 (554 mg, 2.11 mmol) and iodobenzene (430 mg, 2.11 mmol) were dissolved in toluene (15 ml) and the following reagents were added: Pd2(dba)3 (58 mg, 0.063 mmol), PtBu3 (128 mg. 0.63 mmol) and NaO-t-Bu (202 mg, 2.11 mmol). The reaction mixture was stirred at ambient temperature overnight and then filtered. The filtrate was loaded onto a silica gel column and eluted with 1% MeOH in CH2Cl2 to yield the title compound as a yellow solid (85 mg, 11.9%): MS (ESI) m/z 340 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.56 (t, J=7.2 Hz, 2H), 2.64 (t, J=4.8 Hz, 4H), 2.77 (t, J=7.2 Hz, 2H), 3.13 (br, 4H), 3.69 (s, 3H), 6.82-7.21 (m, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[F:35][C:36]([F:51])([S:47](F)(=[O:49])=[O:48])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][S:47]([C:36]([F:35])([F:51])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:42])([F:41])[F:40])(=[O:49])=[O:48])=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (100.0 mg, 0.2629 mmol) and triethylamine (55.0 L, 0.395 mmol) in acetonitrile (1 mL) was added 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonyl fluoride (60.0 L, 0.341 mmol). The mixture was stirred for 1 hour at room temperature then partitioned between water (25 mL) and ethyl acetate (25 mL). The organic was rinsed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (12 g) and ethyl acetate:hexane solvent gradient. The title compound was isolated as a pale yellow foam (0.128 g, 73%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.71-7.64 (m, 3H), 7.29-7.25 (m, 2H), 7.11 (s, 1H), 7.08 (t, J=7.0 Hz, 1H), 3.10 (s, 3H). MS=663 (MH)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]=O)[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3].C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH3:39][N:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH2:45][NH2:46]>>[CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:46][CH2:45][C:41]3[N:40]([CH3:39])[CH:44]=[CH:43][N:42]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3]
Reactant: Cn1ccnc1CN
Reactant: CCCN(CCC)CCCCN1CCc2cc(C=O)ccc2C1
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCCN(CCC)CCCCN1CCc2cc(CNCc3nccn3C)ccc2C1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that the compound 22 was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and [(1-methyl-1H-imidazol-2-yl)methyl]amine was used in place of {[4-(methyloxy)phenyl]methyl}amine to obtain ({2-[4-(dipropylamino)butyl]-1,2,3,4-tetrahydro-6-isoquinolinyl}methyl)[(1-methyl-1H-imidazol-2-yl)methyl]amine (compound 23-a). The same procedure as a series of reactions of Example 17 was carried out, except that the obtained compound 23-a was used in place of the compound 16, to obtain the title compound having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[C:12]([CH2:25][OH:26])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[CH3:59][N:60]1[CH:64]=[C:63]([NH2:65])[CH:62]=[N:61]1>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:65][C:63]4[CH:62]=[N:61][N:60]([CH3:59])[CH:64]=4)=[O:21])=[CH:18][N:17]=3)=[C:12]([CH2:25][OH:26])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: Cn1cc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(F)c(F)c4)noc3CO)nc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
To a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) in THF (3 mL) were added 1-hydroxybenzotriazole hydrate (43.1 mg, 0.28 mmol), N-ethyldiisopropylamine (120 μL, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.0 mg, 0.28 mmol) and 1-methyl-1H-pyrazol-4-ylamine (26.8 mg, 0.28 mmol). The reaction mixture was stirred overnight at room temperature. Chromatography (silica, ethyl acetate:heptane=2:1 to 9) afforded the title compound (3.5 mg, 3%) as a colourless oil. MS: m/e=442.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:20]([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](=[O:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (3.13 g, 8.15 mmol) in dichloromethane (150 ml) was added Dess-Martin periodinane (5.18 g, 12.2 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (40 mL). The mixture was extracted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (40 mL×3), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 60% dichloromethane/hexanes) to afford 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (2.8 g, 90%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 382.8.
Reaction SMILES: I[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:19]([C:23]1[CH:28]=[C:27]([SH:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.C(Cl)Cl>[C:30]([C:25]1[CH:26]=[C:27]([S:29][CH2:2][C@H:3]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=1[OH:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CI)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(C)(C)O1
Yield: 91.8 %

Procedure:
A mixture of 0.12 g (0.324 mmol) of tert-butyl [(4R,6S)-6-(iodomethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate, 0.0925 g (0.388 mmol) of 2,6-di-tert-butyl-4-mercaptophenol (See R. J. Laufer, U.S. Pat. No. 3,129,262), 0.067 g (0.49 mmol) of powderly anhydrous potassium carbonate and 0.5 ml of dry N,N-dimethylformamide was stirred for 16 hours at room temperature. The reaction solution was distilled away under reduced pressure. The residue was dissolved in ether, washed with saturated brine solution, dried and distilled away under reduced pressure. The residue was purified by subjecting to silica gel column chromatography [eluent: ethyl acetate-methylene chloride (1:19)]]to give 0.143 g of tert-butyl [(4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate as crystals (yield: 92%). The desired compound was recrystallized from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.C[Si]([C:19]#[N:20])(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:19]#[N:20])[CH:6]=[CH:5]2
Reactant: COc1cc2c(ccc[n+]2[O-])cc1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Product: COc1cc2nc(C#N)ccc2cc1Cl
Temperature: 80 °C
Yield: 76.9 %

Procedure:
A 50 mL flask containing acetonitrile (6.0 mL) was charged with 6-chloro-7-methoxyquinoline 1-oxide (0.25 g, 1.19 mmol), TEA (0.33 mL, 2.39 mmol), and trimethylsilyl cyanide (0.48 mL, 3.58 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The residue was basified using saturated Na2CO3 and the product was extracted with DCM. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to afford 6-chloro-7-methoxyquinoline-2-carbonitrile (0.20 g) MS [M+H+]=219.4.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]2[S:22][C:21]([CH:23]=O)=[CH:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:17]2[S:22][C:21]([CH2:23][N:9]3[CH2:8][CH2:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)([OH:12])[CH2:11][CH2:10]3)=[CH:20][C:18]=2[N:19]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2nccs2)CCNCC1
Product: OC1(c2nccs2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 4-thiazol-2-yl-piperidin-4-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-thiazol-2-yl-piperidin-4-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 408. 400 MHz 1H NMR CDCl3 9.30 (s, 2H); 7.76 (d, 1H, J=3.3 Hz); 7.325 (d, 1H, J=3.3 Hz); 7.31 (s, 1H); 5.23 (s, NH2); 4.07-3.90 (m, 8H); 2.92 (d, 2H, J=11.7 Hz); 2.66 (t, 2H); 2.36 (m, 2H); 1.95 (d, 2H, J=11.6 Hz). LC-MS (m+1)=511.14
Reaction SMILES: [CH2:1]([CH:8]1[C:12]([OH:13])=[CH:11][C:10](=[O:14])[N:9]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[CH2:1]([C@H:8]1[C@@H:12]([OH:13])[CH2:11][C:10](=[O:14])[N:9]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccccc2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of 4-(2-benzyl-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-chlorobenzonitrile (400 mg) and acetic acid (0.60 mL) in acetonitrile (20 mL) was added sodium borohydride (86 mg) at 0° C. in small portions. The mixture was warmed to room temperature, and stirred for 3 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 310 mg, 77%).
Reaction SMILES: [CH2:1]([C:7](C)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:10](=[O:17])([O:14][CH2:15][CH3:16])OCC.[H-].[Na+]>O1CCOCC1>[CH2:1]([C:7](=[O:8])[C:10]([O:14][CH2:15][CH3:16])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)OCC
Reactant: CCCCCCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCC(=O)C(=O)OCC
Yield: 62.5 %

Procedure:
A solution of 20.0 g of methyl hexyl ketone in 100 ml of dioxane was dropped into a solution comprising 210 ml of diethyl carbonate, 12.8 g of sodium hydride dispersed in oil at a concentration of 60% by weight and 100 ml of dioxane in an argon atmosphere, and the mixture was refluxed overnight. Then, the solvent was removed and the residue was distilled under a reduced pressure to obtain 20.0 g of ethyl hexylketoacetate having a boiling point of 83° C. under 0.65 mmHg. The yield was 62.5%
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (953 mg, 3.36 mmol) in DCE (50 mL) was added 4-azetidin-3-ylmorpholine (525 mg, 3.69 mmol), trimethyl orthoformate (3.67 mL, 33.58 mmol) and acetic acid (0.19 mL, 3.36 mmol). After stirring at room temperature for 2 h sodium triacetoxyborohydride (1.10 g, 5.03 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with H2O/MeOH then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, gradient 0:100 to 20:80) to give 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidine as a pale yellow solid (856 mg, 62%). LCMS (Method C): RT=2.77 min, [M+H]+ 410
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][CH:8]=[N:7][CH:6]=2.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])=[O:29]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1cnc2cnccc2c1-c1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1cnc2cnccc2c1-c1ccccc1Cl
Yield: 36.4 %

Procedure:
A solution of 3-amino-4-(2-chlorophenyl)-1,7-naphthyridine (169 mg, 0.66 mmol) and 2,4-difluorophenylisocyanate (102 mg, 0.66 mmol) in tetrahydrofuran (50 ml) was refluxed for 8 hours. The mixture was concentrated, and the residue was purified by column chromatography (silica gel; methanol:chloroform=1:9), and recrystallized from hexane to give the title compound (98 mg, 0.24 mmol) as colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1)#[N:2].NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2C(=O)COc3ccc(C#N)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2

Procedure:
tert-Butyl {trans-4-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate (Intermediate 78) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:17])[CH3:16])[C:8]([OH:14])=[C:9]([CH2:12][OH:13])[C:10]=1[CH3:11])([CH3:4])[CH3:3].[CH3:18][CH:19]1OC(C)OC(C)O1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:18][CH:19]1[O:14][C:8]2[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[C:10]([CH3:11])[C:9]=2[CH2:12][O:13]1
Reactant: Cc1c(C(C)(C)C)cc(C(C)C)c(O)c1CO
Reactant: CC1OC(C)OC(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(C)(C)C)cc(C(C)C)c2c1COC(C)O2
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A mixture of 5-(1,1-dimethylethyl)-6-methyl-3-(1-methylethyl)-2-hydroxy-benzenemethanol (7.09 g, 0.03 mol), p-dioxane (150 mL), paraldehyde (13.2 g, 0.3 mol) and p-toluenesulfonic acid monohydrate (0.57 g, 0.003 mol) was heated at reflux for 1.5 hours. The mixture was cooled to 25° C., poured onto water (100 mL) and extracted with hexane (3×50 mL). The extracts were washed with saturated sodium bicarbonate solution (2×50 mL), water (4×50 mL), brine (50 mL) and dried (Na2SO4). Evaporation of solvents and distillation of the residue gave 5.56 g (71% yield, GLC purity 99%) of 2,5-dimethyl-6-(1,1-dimethylethyl)-8-(1-methylethyl)-4H-1,3-benzodioxin, bp 110°-120° C., 0.5 mm; 1H-NMR (CDCl3)δ 1.20 (6H, d, J=7 Hz), 1.40 (9H, s), 1.54 (3H, d, J=5 Hz), 2.20 (3 H, s), 2.9-3.5 (1H, m), 4.80 (2H, s), 5.07 (1H, q, J=5 Hz), 7.10 (1H, s); IR (film)νmax 2940, 1585, 1410 cm-1 ; MS m/e 262, 218, 203, 175, 161; UVλmax (ethanol) 225 (ε=6960), 281 (ε=2040).