Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[N:10][N:9]=[N:8]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=2[S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:16][CH:15]=1>O>[CH2:25]([C:23]1[S:22][C:21]([S:29]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])(=[O:30])=[O:31])=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:8]3[N:9]=[N:10][CH:11]=[N:7]3)=[CH:19][CH:18]=2)[CH:24]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: c1nnn[nH]1
Reactant: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
KOH (112.2 mg, 2.00 mmol, crushed pellets) was added to DMSO (10 mL, dried over 4 A molecular sieve) and stirred for 5 min. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture, which was then stirred for 2 h. 3-(4-Bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (130 mg, 0.292 mmol, see step (b) above) was added, the mixture was cooled briefly and stirred for an additional hour before water (50 mL) was added. The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2×50 mL) and brine (0 mL). The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified on column chromatography using hexane:acetone (3:1) as eluent to give the sub-title compound (28.6 mg, 0.066 mmol, 23% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]2[NH:14][C:13](=[O:18])[N:12]([CH3:11])[C:16]2=[O:17])=[CH:5][CH:4]=1
Reactant: CN1C(=O)CNC1=O
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=C2NC(=O)N(C)C2=O)cc1
Yield: 41 %

Procedure:
Prepared according to the procedure described in Example 93 using 4-methoxybenzaldehyde (3.4 g, 25 mmoles) and 3-methyl hydantoin (3.0 g, 21 mmoles). Recrystallization from acetonitrile gave the pure product (2.0 g), mp 221°-222° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl.O>[OH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
168.3 g (1.22 mol) of potassium carbonate are added to a solution of 61.6 g (406 mmol) of 4-piperidinemethanol hydrochloride in a mixture of 406 ml of chloroform and 406 ml of water, followed by 42.55 ml (440 mmol) of ethyl chloroformate dissolved in 160 ml of chloroform. The mixture is stirred for 3 h at 20° C., the organic phase is separated off, the aqueous phase is extracted with dichloromethane, the organic phases are combined to form a single phase, washed with water and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. 76 g of an oil is obtained, this being used without further treatment in the following stage.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[C:4]([CH2:11]Br)[CH:3]=1.C1C[O:16]CC1.[OH-].[Li+].Cl>O.CO>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH2:11][OH:16])[CH:3]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1sc(Br)cc1CBr
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(Br)cc1CO
Temperature: 90 °C

Procedure:
In a 15 mL microwave reaction vial, was added methyl 5-bromo-3-(bromomethyl)thiophene-2-carboxylate (700 mg, 2.23 mmol), THF (4 mL) and MeOH (1 mL). To above solution was added lithium hydroxide (53.4 mg, 2.23 mmol, 1.0 eq) in water (1 mL). The reaction was heated in microwave reactor for 30 min at 90° C. The reaction was cooled down to r.t., neutralized with 1N HCl, extracted with EtOAc, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+.
Reaction SMILES: [CH:1]1([CH:4]([OH:31])[CH2:5][S:6]([N:9]2[CH2:30][CH2:29][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Ca+2].[CH3:38]I>[Ag]=O>[CH:1]1([CH:4]([O:31][CH3:38])[CH2:5][S:6]([N:9]2[CH2:10][CH2:11][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:29][CH2:30]2)(=[O:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC(O)C1CC1)CC2
Reactant: CI
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: COC(CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
A mixture of 8-(2-cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, 30 mg, 0.07 mmol), dry calcium sulfate (33 mg, 0.26 mmol) and silver oxide (60 mg, 0.26 mmol) in methyl iodide (1 mL) was stirred at room temperature for 48 h. The reaction mixture was filtered through Celite® and washed with methylene chloride. The filtrate was concentrated to dryness under reduced pressure to give the crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) which afforded the desired product as a white solid (12.5 mg, 40%). MS (ESI): 477.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].CCN(C(C)C)C(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41]([S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:43][C:37]=2[S:36][CH2:35]1>C(Cl)Cl>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@@H:3]([CH2:2][NH:1][S:44]([C:41]3[CH:42]=[CH:43][C:37]4[S:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=4[CH:40]=3)(=[O:46])=[O:45])[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@H](CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (225 mg, 0.703 mmol) in DIPEA (188 μL, 1.05 mmol) and DCM (7 mL) at 0° C. was added 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (210 mg, 0.845 mmol) in one portion. The solution stirred for 0.5 h and was concentrated. The resulting residue was purified by column chromatography (silica, 2-4% MeOH in DCM (1% NH OH)) yielding the title compound (290 mg, 75%) as a white foam: LC/MS (ES) m/e 548 (M+H); H NMR (CD OD, 400 Hz) δ 8.65 (s, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.45-7.48 (m, 2H), 7.20 (d, J=9.1 Hz, 1H), 4.28-4.31 (m, 1H), 4.14 (s, 3H), 3.55 (s, 2H), 3.42-3.46 (m, 2H), 3.21-3.23 (m, 1H), 3.05-3.15 (m, 1H), 2.91-3.05 (m, 2H), 2.86-2.90 (m, 2H), 2.51-2.62 (m, 2H), 2.33-2.4 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4C=CC=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.C[N:30]1[C:34](CO)=[N:33]C=N1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[N:24]([CH3:25])[N:33]=[CH:34][N:30]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: Cn1ncnc1CO
Reactant: FCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cn1ncnc1COc1nn2c(-c3cc(CF)on3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from the product of Example 66 part c (150 mg, 0.5 mmol) and 2-methyl-1,2,4-triazole-3-methanol (61 mg, 0.53 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) using the procedure given in Example 1 using lithium bis(trimethylsilyl)amide (0.59 ml, 1.0M in tetrahydrofuran) as the base (80 mg, 43%), mp 250-252° C.; 1H NMR (360 MHz, d6-DMSO) δ 4.01 (3H, s, CH3), 5.76 (2H, d, J=47 Hz, CH2), 5.83 (2H, s, CH2), 7.70 (1H, d, J=3.5 Hz, Ar—H), 7.96 (1H, m, Ar—H), 8.02 (1H, s, Ar—H), 8.13 (1H, m, Ar—H), 8.25 (11H, d, J=7.8 Hz, Ar—H), 8.59 (1H, d, J=7.9 Hz, Ar—H); MS (ES30) m/e 381 [MH]+; Anal. Found. C, 52.31; H, 3.36; N, 28.64. C17H13N8O2F.0.15CH2Cl2 requires C, 52.40; H, 3.41; N, 28.51%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[H][H]>ClCCl.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(CO)nc2c(N)nc3c(c21)CCCC3

Procedure:
A mixture of [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (15.2 g, 56.2 mmol, U.S. Pat. No. 5,389,640 Example 9), platinum(IV) oxide (7.6 g), and trifluoroacetic acid (75 mL) was hydrogenated at 50 psi (3.5×105 Pa) of hydrogen on a Parr apparatus for 2 days. The mixture was diluted with dichloromethane and filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane and methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and 1:1 saturated aqueous sodium bicarbonate/water (250 mL). Some solid formed that was isolated by filtration. The aqueous layer was extracted with dichloromethane (2×200 mL). The solid was dissolved in methanol and the resulting solution was combined with the organic layers, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica gel, elution with 10% 1 M NH3 in methanol/dichloromethane) to afford 4.98 g of [4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10]O)=[N:8][CH:9]=1)=[O:4].[ClH:13].S(Cl)([Cl:16])=O>C(OCC)(=O)C.CO>[ClH:16].[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10][Cl:13])=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc(CO)n1C
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(CCl)n1C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in ethyl acetate/methanol 6 ml, 1:1) was converted to the hydrochloride by usage of an excess of an etheral solution of hydrogen chloride. After evaporation, the light brown residue was treated with thionyl chloride (1.1 ml, 15 mmol) and stirred for 0.5 h. After evaporation, the title compound was obtained as brown solid (100% yield). MS: m/e=189(M+H+), mp 106-108° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:20][NH2:21])[CH:18]=[CH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:17]([O:20][NH:21][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH:18]=[CH2:19]
Reactant: C=CCON
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCONc1nc(NCCC)nc(NCCC)n1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.00 g, 8.71 mmol), O-allyl-hydroxylamine hydrochloride (1.91 g, 17.42 mmol) and NaOH (0.70 g, 17.42 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was heated at 60° C. for 4 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII, 2.05 g, 88% yield). ESI-MS (m/z) 267 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[CH2:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:25]=[CH2:26])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
Pd(PPh3)2Cl2 (15 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.6 mL) and 3-vinylphenylboronic acid (29 mg, 0.19 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-vinylphenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (3 mg, 6%). 1H-NMR (MeOD): 1.40 (s, 9H), 2.44 (m, 1H), 2.61 (m, 1H), 3.25 (s, 3H), 5.85 (d, 1H), 6.14 (m, 1H), 6.23 (m, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.32 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][CH:16]1[N:21](C(OCC2C=CC=CC=2)=O)[CH:20]([CH:32]2[CH2:34][O:33]2)[CH2:19][CH2:18][CH2:17]1>C(O)(C)(C)C.O>[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH:20]([CH:32]([OH:33])[CH2:34][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:21]1
Reactant: CC1CCCC(C2CO2)N1C(=O)OCc1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1CCCC(C(O)COc2ccc(F)cc2)N1

Procedure:
A solution of a p-fluorophenol in t-butanol is treated with one equivalent of potassium t-butoxide, followed by the compound of Example 35A. The reaction mixture is then refluxed until all epoxide has reacted. The reaction is cooled, diluted with water, and extracted with ethyl acetate. The organic extracts are dried and concentrated. The carbobenzyloxy protecting group is removed by standard hydrogenolysis and the final product purified by chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C@@H:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=1[NH:28][C@@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])=[O:15])[CH3:18]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Yield: 100.2 %

Procedure:
In a dry flask equipped with a Dean-Stark trap and reflux condenser, ethyl 1-(t-butoxycarbonyl)-3-oxo-4-piperidinecarboxylate (4.19 g, 15.4 mmol) was dissolved in toluene (50 mL). (R)-(+)-a-Methylbenzylamine (1.91 g, 15.8 mmol) and p-toluenesulfonic acid monohydrate (0.019 g, 0.1 mmol) were added and the mixture heated to reflux for 6 hours. The crude reaction mixture was concentrated in vacuo to give the desired amine (5.78 g, 100%) as a thick orange oil. 1H NMR (300 MHz, CDCl3), δ: 7.36 (t, J=3, 2H), 7.33 (t, J=4, 1H), 7.31 (dd, J=3, J′=4, 2H), 4.59 (m, 1H), 4.16 (q, J=7, 2H), 3.59 (m, 2H), 2.34 (m, 2H), 1.58 (bs, 2H), 1.52 (d, J=3, 3H), 1.29 (s, 9H), 1.26 (t, 3H, J=7). MS (ESI), m+/z: (M+H)+=375.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:9])([CH2:7][OH:8])[CH2:5][OH:6].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[NH2:3][C:4]([CH3:9])([CH2:7][O:8][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(N)(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 109.4 %

Procedure:
Sodium hydride (55% in dispersion in oil) (1.141 g) was added portion wise to a solution of 2-amino-2-methyl-propane-1,3-diol (2.50 g) in dry THF (35 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h. tert-Butyldiphenylsilyl chloride (6.54 g) in dry THF (10 ml) was added dropwise 0° C. and the reaction mixture was stirred for 17 hrs at room temperature. The reaction mixture was quenched with water (18 ml) and extracted thrice with ethyl ether. The two layers were separated and the organic layer was washed once with water and then dried over sodium sulphate, filtered and concentrated under reduced pressure to yield 8.94 g of 2-amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propan-1-ol as a crude product which was used as such in Stage 2 described below. 1H NMR (CDCl3) δ ppm: 7.68-7.62 (4H, m); 7.47-7.37 (6H); 3.52 (2H, dd); 3.39 (2H, dd); 1.09 (9H, s); 1.02 (3H, s).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([OH:23])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:3][C:2]#[CH:1])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 15 h

Procedure:
1.73 g (14.6 mmol) of propargyl bromide were added dropwise to a mixture of 3.00 g (9.74 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine, 4.0 g (29 mmol) of potassium carbonate and 100 ml of anhydrous dimethylformamide. The mixture was stirred at 20°-25° C. for about 15 hours and then poured into 400 ml of water. The solution was kept cold for a few hours, and the resulting crystals were then separated off, washed with water and dried under reduced pressure. Yield: 3.1 g (92%) of colorless crystals of melting point 102°-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:6]([F:10])([F:9])[CH2:7][CH3:8])=[CH:4][F:5].S(=O)(=O)(O)[OH:14]>O>[F:5][CH2:4][C:3]([OH:14])([C:6]([F:9])([F:10])[CH2:7][CH3:8])[C:2]([F:11])([F:12])[F:1]
Reactant: O=S(=O)(O)O
Reactant: CCC(F)(F)C(=CF)C(F)(F)F
Solvent: O
Product: CCC(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol may be prepared by fluorinating 3-pentanone to form 3,3-difluoropentane which may then be dehydrogenated to form 3,3-difluoro-1-pentene. CF3 may then be reacted with the 3,3-difluoro-1-pentene to form 2-trifluoromethyl-1,3,3-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-pentene. The 2-trifluoromethyl-1,3,3-trifluoro-1-pentene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[CH:24]([N:27](CC)[CH:28](C)C)(C)C.Cl.CNC>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:27]([CH3:28])[CH3:24])[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.5 g, 1.40 mmol) in anhydrous DMF (5 mL) at room temperature under Ar atmosphere was added N,N-diiso-propylethylamine (0.0.54 mL, 3.09 mmol) and dimethylamine hydrochloride (0.126 g, 1.54 mmol). The resulting solution was stirred at 85° C. for 16 hours at which time the reaction mixture was concentrated to dryness and the residue chromatographed over silica gel eluting with 50% EtOAc in n-hexane to give methyl [4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.505 g, 99% yield) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[C:26]([CH2:32][CH2:33][Cl:34])[CH:25]=1>C1COCC1>[CH3:14][N:13]([CH3:15])[C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][C:26]=3[CH2:32][CH2:33][Cl:34])=[O:30])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1sc(Br)cc1CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3sc(Br)cc3CCCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of [(R)-1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amine (349 mg) and triethylamine (0.25 mL) in THF (4 mL) a solution of 5-Bromo-3-(2-chloro-ethyl)-thiophene-2-carbonyl chloride (489.6 mg) in THF (3 mL) added dropwise. The mixture was stirred for 2 h at room temperature. Then the solvent was removed in vacuum and then water and ethyl acetate were added to the residue. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 456.84 (C19H23BrClN3OS); MS (ESI): 456, 458 (M+H+).