Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:23])[N:12]([CH2:16][C:17]1C=C[CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrCCCC=C>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:23])[N:12]([CH2:13][CH:14]=[CH2:15])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCN(CC=C)C(=O)OCc1ccccc1
Temperature: 40 °C
Yield: 104 %

Procedure:
To a suspension of NaH (1.83 g, 76.33 mmol of 90% NaH) in DMF was added benzyl allyl-carbamic acid benzyl ester (7.3 g, 38.2 mmol) in a dropwise fashion. The mixture was stirred at room temperature for approximately 10 minutes whereupon 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added in a dropwise fashion. The reaction was heated to 40° C. for approximately 4 hours whereupon the reaction was partitioned between dichloromethane and water. The organic layer was washed with water (2×'s), brine, dried (MgSO4), filtered and concentrated. Column chromatography of the residue (10% ethyl acetate:hexanes) provided 10.3 grams of the title compound as an oil: MS(EI) 260 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([C:4]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccccc4Cl)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2-chlorobenzenesulfonyl chloride (78 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.69 (m, 2H), 7.57 (m, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.12 (br s, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.77 (br d, J=12.0 Hz, 2H), 2.75 (t, J=10.8 Hz, 2H), 2.06 (s, 1H), 1.84 (d, J=10.8 Hz, 2H), 1.31 (m, 2H). MS m/z (ESI) 448 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:19])([CH2:13]4)[CH2:11]3)[CH2:5][CH2:4]1.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30])=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]23[CH2:18][CH:14]4[CH2:13][C:12]([NH:19][CH2:21][C:22]([N:24]5[CH2:28][CH2:27][CH2:26][C@H:25]5[C:29]#[N:30])=[O:23])([CH2:11]2)[CH:16]([CH2:15]4)[CH2:17]3)[CH2:5][CH2:4]1
Reactant: CN1CCN(CC23CC4CC(C2)C(N)(C4)C3)CC1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(CC23CC4CC(C2)C(NCC(=O)N2CCC[C@H]2C#N)(C4)C3)CC1
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a stirred solution of the hydrochloride (0.33 g, 0.92 mmol) obtained in Step II, in DMSO (3.7 mL) at room temperature under nitrogen atmosphere (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.92 mmol) and K2CO3 (0.76 g, 5.53 mmol) were added. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(4-methylpiperazin-1-yl) methyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.12 g) in 47% yield. m/z (M+1) 386; 1H NMR (CDCl3+CD3OD) 300 MHz δ 4.78 (d, J=5.7 Hz, 1H), 3.85-3.50 (m, 4H), 3.30-3.10 (m, 5H), 2.85-2.70 (m, 8H), 2.52-2.45 (m, 2H), 2.38-2.20 (m, 4H), 2.10-1.90 (m, 4H), 1.70-1.40 (m, 5H), 1.40-1.27 (m, 1H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
The next steps in this process comprise reacting (FIG. 5, compound 3) with Me2NCH(OMe)2 in DMF to form (FIG. 5, compound 4), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine, which is the amino-protected form of (FIG. 5, compound 3); reacting (FIG. 5, compound 4) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (FIG. 5, compound 4) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin -4-yl}-N,N-dimethyl-formamidine (FIG. 5, compound 5), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (FIG. 5, compound 5) with N-Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (FIG. 5, compound 6); removing the silyl and amino-protecting groups by reacting (FIG. 5, compound 6) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester to provide (FIG. 5, compound 7); and finally, reacting (FIG. 5, compound 7) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (FIG. 5, compound 8) as a final product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18](O)=O)=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.B#B>O1CCCC1>[CH3:18][C:17]1[N:16]=[CH:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:21])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: O=C(O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: B#B
Solvent: C1CCOC1
Product: Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.010 mole of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid in tetrahydrofuran is added dropwise to a 0.02 molar solution of diborane in tetrahydrofuran chilled in an ice bath. The mixture is allowed to warm to room temperature and stand overnight. The mixture is poured onto ice and extracted with methylene chloride. The methylene chloride extract is washed with water and dried (MgSO4). The solvent is removed under reduced pressure to give the product of the example.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13].[CH:18]1([O:23][C:24]2[CH:25]=[C:26]3[CH:32]=[CH:31][NH:30][C:27]3=[N:28][CH:29]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[K+].O>CO>[CH:18]1([O:23][C:24]2[CH:25]=[C:26]3[C:32]([CH:8]([OH:9])[C:7]4[C:2]([F:1])=[C:3]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:4]=[CH:5][C:6]=4[F:10])=[CH:31][NH:30][C:27]3=[N:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: c1cc2cc(OC3CCCC3)cnc2[nH]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(OC4CCCC4)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (10, 102 mg, 0.32 mmol) in methanol (1.5 mL) was added 5-cyclopentyloxy-1H-pyrrolo[2,3-b]pyridine (P-0001, 65 mg, 0.32 mmol, prepared as described in Example 12) and potassium hydroxide (54 mg, 0.96 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a solid (11, 102 mg, 68%). MS (ESI) [M+H+]+=466.2.
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:10][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:28]([O:27][C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:10][C:4]=2[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)OC(C)(C)C)cc3C2)cc1
Reaction time: 0.42 h
Yield: 62.6 %

Procedure:
A suspension of 7-bromo-4-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (5.00 g, 13.8 mmol) in propionitrile (80 mL) and DMF (20 mL) was de-oxygenated with Ar for 25 min. The mixture was treated with tert-butyl acrylate (8.1 mL, 55 mmol) and (i-Pr)2EtN (5.1 mL, 29 mmol) and was de-oxygenated with Ar for 15 min. Pd(OAc)2 (0.32 g, 1.43 mmol) and P(o-tol)3 (0.85 g, 2.79 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (3.54 g, 63%) as a white solid: MS (ESI) m/e 410 (M+H)+.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:4])[CH3:3]
Reactant: COc1cc(NC(C)=O)ccc1C(C)(C)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)ccc1C(C)C
Yield: 99.2 %

Procedure:
N-[4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenyl]-acetamide (16.4 g) in 100 ml glacial acetic acid was stirred at room temperature under N2, and palladium on activated carbon (3 g 10 Wt %) was added, followed by 5 g of ammonium formate. The reaction mixture was heated to reflux. After 30 minutes 5 g ammonium formate was added, and after 45 minutes another 8.5 g ammonium formate was added. Reflux was continued for another hour, then the reaction mixture was cooled, and filtered through Celite. The filtrate was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over magnesium sulfate. Evaporation under reduced pressure gave N-(4-Isopropyl-3-methoxy-phenyl)-acetamide (15.1 g, 99%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[CH:22][C:23]5[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=5[CH:32]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[OH:33][CH:34]([CH2:37][OH:38])[CH2:35][NH2:36]>>[OH:33][CH:34]([CH2:37][OH:38])[CH2:35][NH:36][C:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:10][CH2:1][O:2][C:3]=5[CH:4]=4)[C:17]([F:18])=[CH:16][N:15]=3)=[CH:32][C:24]=2[CH:25]=1)=[O:29]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Reactant: NCC(O)CO
Product: O=C(NCC(O)CO)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2,3-dihydroxypropylamine gave N2-[2-(N-2,3-dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.86 (d, 1H, J=4.2 Hz), 7.35 (t, 1H, J=1.2 Hz), 7.24 (d, 1H, J=3 Hz), 7.15 (m, 2H), 7.07 (dd, 1H, J=2.1 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.59 (m, 1H), 4.40 9s, 1H), 4.23 (s, 4H), 4.03 (t, 1H, J=5.7 Hz), 3.67 (d, 2H, 3.6 Hz), 3.65 (d, 2H, J=4.2 Hz); 19F NMR (CD3OD): −47578; LCMS: ret. time: 15.72 min.; purity: 99%; MS (m/e): 486 (MH+).
Reaction SMILES: [F:1][CH:2]([F:11])[P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:5]([O:4][P:3]([C:2]([F:1])([F:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])(=[O:7])[O:8][CH2:9][CH3:10])[CH3:6]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOP(=O)(OCC)C(F)F
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(F)(F)P(=O)(OCC)OCC
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of diethyl difluoromethanephosphonate (1.0 g, 5.316 mmol) in THF (50 mL) 2 M LDA (626 mg, 5.847 mmol) was added at −78° C. and stirred for 30 min. Tetradecyl bromide (1.474 g, 5.316 mmol) in THF (10 mL) was added to the mixture at −78° C. and the reaction mixture was stirred overnight. THF was evaporated and the residual oil was purified by flash chromatography using 30% ethyl acetate in hexane as eluent to give 817 mg (40%) of compound 10 as colorless oil. 1H NMR (CDCl3): δ4.26 (m, 4H), 2.05 (m, 2H), 1.56 (m, 2H), 1.37 (t, J=6.9 Hz, 6H), 1.25 (br s, 22H), 0.87 (t, J=6.6 Hz, 3H); MS: [M+23Na] at m/z 407.2.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([C:19]#[C:20][C:21]2[S:22][C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.FC(F)(F)C(O)=O>O1CCCC1.CCOC(C)=O>[C:13]1([C:19]#[C:20][C:21]2[S:22][C:23]([C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][N:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc(C#Cc2ccccc2)s1)N1CCCCC1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
N,N-Carbonyldiimidazole (790 mg, 4.87 mmol) (Fluka Chemie AG) was added to a solution of 2-phenylethynyl-thiazole-5-carboxylic acid (1.00 g, 4.36 mmol) [Intermediate 1] in tetrahydrofuran (17.4 mL) and stirred for 60 minutes. Piperidine (3.03 g, 35.6 mmol) and trifluoroacetic acid (295 μL, 3.83 mmol) were added and the mixture was stirred for 20 hours. The yellow solution was diluted with 150 mL of EtOAc and washed with 3.7 M HCl solution (5×30 mL), water (1×30 mL), 1.0 M K2CO3 (4×30 mL), water (2×30 mL), brine (1×30 mL), dried (Na2SO4) and concentrated to give a light tan solid (94% pure by LC/MS). The sample was further purified by silica gel chromatography over a 40 g SiO2 column using a gradient elution from 25% EtOAc in hexanes to 30% EtOAc in hexanes over 30 minutes to give title compound (2-phenylethynyl-thiazol-5-yl)-piperidin-1-yl-methanone (797 mg, 62%) as a light yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.63-7.59 (m, 2H), 7.46-7.36 (m, 3H), 3.69-3.67 (m, 4H), 1.78-1.62 (m, 6H). LCMS (Method 1), RT=1.41. Calculated [M+H]+=297; Observed [M+H]+=297.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])O
Reactant: COc1cc(C(=O)O)ccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-3-methoxybenzoic acid (2.33 g) and sulfuric acid (0.2 mL) in methanol (20 mL) was heated under reflux for 10 hr, and allowed to cool to room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, the solvent was evaporated under reduced pressure, and water was added to the residue. The resultant precipitate was collected by filtration to give the title compound (2.31 g).
Reaction SMILES: P([Cl:9])(OCC)(OCC)=O.[CH3:10][O:11][CH2:12][C@H:13]([NH:38][C:39]([C:41]1[S:45][C:44]([CH3:46])=[N:43][CH:42]=1)=[O:40])[C:14]([NH:16][C@@H:17]([CH2:35][O:36][CH3:37])[C:18]([NH:20][C@@H:21]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([C@@:24]1([CH3:27])[CH2:26][O:25]1)=[O:23])=[O:19])=[O:15]>ClCCl.O.Cl[Ti](Cl)(Cl)Cl>[Cl:9][CH2:26][C@:24]([OH:25])([CH3:27])[C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:38][C:39]([C:41]1[S:45][C:44]([CH3:46])=[N:43][CH:42]=1)=[O:40])[CH2:12][O:11][CH3:10])[CH2:35][O:36][CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CCl
Temperature: 25 °C
Reaction time: 9 h
Yield: 60.6 %

Procedure:
Diethyl chlorophosphate (120 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL). A solution of TiCl4 (1 mg, catalytic) in dichloromethane (2 mL) was added, followed by N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (300 mg, 0.58 mmol) in dichloromethane (10 mL). The reaction mixture was stirred 9 h at room temperature, then diluted with dichloromethane (10 mL) and water (10 mL). The organic layer was separated and washed with brine (5 mL) and dried over MgSO4. It was concentrated to dryness, and the residue purified on silica gel column (dichloromethane:methanol=100:1 to 80:1) to give product as a white solid (200 mg, yield 63%); MS for C25H33ClN4O7S m/z: 570 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].C1N2CN3CN(C2)CN1C3.C(O)(=[O:25])C.Cl>O>[C:6]([C:5]1[CH:4]=[C:3]([C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH:2]=[O:25])#[N:7]
Reactant: CC(=O)O
Reactant: COc1ccc(C#N)cc1CBr
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COc1ccc(C#N)cc1C=O

Procedure:
To 5 g of 3-bromomethyl-4-methoxybenzonitrile, were added 6.2 g of hexamethylenetetramine, 10 ml of acetic acid, and 10 ml of water. The mixture was heated under reflux for 2 hours. After addition of 10 ml of concentrated hydrochloric acid, the mixture was further refluxed for 15 minutes. The reaction mixture was cooled in ice and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed twice with 200 ml of water, then with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of 3-cyano6-methoxybenzaldehyde; m.p. 119°-120° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.4 %

Procedure:
A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C.
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])C.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH:13]1([NH:19][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CCCCC(=O)O
Solvent: O
Product: O=C(O)CCCCC(=O)NC1CCCCC1
Temperature: 80 °C

Procedure:
34.8 g (0.2 mol) of adipic acid monoethyl ester are added dropwise and with stirring to 19.8 g (0.2 mol) of cyclohexylamine. The temperature rises to 60° C. The reaction mixture is heated to 80° C. for 1 h. After cooling, the solution is poured into 200 ml of water and then extracted with 300 ml of ethyl ether. The ether phase is stirred into 150 ml of potassium hydrogen carbonate solution. After separation of the ether phase when settling has taken place, the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid. The precipitate is drained, washed with water, dried and recrystallised in acetonitrile.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16]2
Reactant: ICCCCCI
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)CCC1(CCC(N3CCCCC3)CC1)C2

Procedure:
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of 1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture after cooling is diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)].
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1>O>[N+:6]([C:18]1[C:13]2[N:12]=[N:11][NH:10][C:14]=2[CH:15]=[CH:16][CH:17]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]nnc12
Reaction time: 8 h

Procedure:
To a cooled solution (20° C.) of 1,060 ml. of 23% fuming sulfuric acid and 265 ml. of 90% nitric acid is added in a dropwise fashion a solution of 537 g. of benzotriazole in 1000 ml. of concentrated sulfuric acid. The temperature is not allowed to go above 50° C. At the end of the addition, the reaction mixture is allowed to stand at room temperature overnight. The reaction mixture is then poured over ice and water and a heavy yellow precipitate forms. The solid is collected by filtration, washed with water and dried. The solid, which is a mixture of the 4-nitro (90%) and the 5-nitro (10%) products, is then slurried with 7.5 l. of hot acetonitrile cooled and 537 g. (73%) of 4-nitrobenzotriazole is collected by filtration, m.p. 228°-231° C.