Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To 3-iodo-4-methylaniline (500.0 mg, 2.145 mmol) was added dichloromethane (DCM) (10 mL) followed by N,N-diisopropylethylamine (DIPEA)(520 μL, 3.0 mmol) and 3-(trifluoromethyl)-benzoyl chloride (0.36 mL, 2.4 mmol). The reaction was stirred at 25° C. for 16 hours and was transferred to a separatory funnel and partitioned between water and dichloromethane (DCM). The organic phase was sequentially washed with 0.1N HCl, saturated aqueous NaHCO3, water, then saturated aqueous NaCl. The washed organic phase was then dried over MgSO4 and filtered and concentrated to leave the crude product. The crude product was triturated with hexanes to leave the product as an off-white solid, (797 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 8.04 (d, 1H), 7.84 (bs, 1H), 7.81 (d, 1H), 7.63 (m, 1H), 7.58 (dd, 1H), 7.22 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=274 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33](OCC)=[O:34])[C:28](OCC)=[O:29])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:28]([OH:29])[C:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)=[C:33]([OH:34])[N:16]=2)=[N:6]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccncc1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: Cc1ccccc1
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1-c1ccncc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
3.27 g (12.1 mmol)1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximid-amide from example III were suspended in 40 ml toluene, reacted with 2.88 g (12.1 mmol) diethyl 2-(4-pyridinyl)malonate (commercially available by Mercachem) and stirred overnight at 140° C. For purification the deposited solid is sucked off and dried under high vacuum.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=[CH:12][C:3]1=2.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:14][CH2:15][N:16]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:17][CH2:18]3)=[CH:10][CH:11]=[CH:12][C:3]1=2
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCCO2
Agent: Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4OCCCO5)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride (J. Med. Chem. 1988, 31, 1934–1940) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 451.2 (Exact Mass: 450.23).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]2[CH:22]=[C:23]([O:26][C@@H:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C@@H:30]([NH2:37])[CH2:29][CH2:28]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CCN(C(C)C)C(C)C.[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57](=O)[O:58]CC(Cl)(Cl)Cl)[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:49])[CH3:48]>O1CCOCC1>[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57]([NH:37][C@@H:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:27]([O:26][C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[S:10][CH2:9][CH2:8][O:7][CH:2]5[CH2:3][CH2:4][CH2:5][CH2:6][O:1]5)=[N:18][N:19]=4)[CH:22]=3)[CH2:28][CH2:29]2)=[O:58])[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(-c4ccccc4SCCOC4CCCCO4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(-c5ccccc5SCCOC5CCCCO5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A solution of Example 20 step b (60 mg, 0.11 mmol), DIPEA (26 μL, 0.15 mmol) and 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (56 mg, 0.138 mmol) in dioxane (5 mL) was heated at 80° C. for 20 h. The reaction was allowed to cool to RT, partitioned between H2O-DCM, the organic phase dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC using MeOH in DCM (0 to 5%) to give the title compound as a yellow foam (38 mg, 45%). LCMS (Method 3): Rt 4.09 min, m/z 772 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.Cl[C:12]1[N:17]=[CH:16][C:15](/[C:18](/[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[C:19](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:20][CH3:21])=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:12]2[N:17]=[CH:16][C:15](/[C:18](/[C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[C:19](\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[CH2:20][CH3:21])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: CN1CCN(CCO)CC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCN(C)CC2)nc1)c1ccccc1
Yield: 121.1 %

Procedure:
Following the same procedure as described in example 3, 2-(4-methylpiperazin-1-yl)ethanol (430 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (160 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.17-7.22 (m, 2H), 7.00-7.15 (m, 5H), 6.97 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.03 (d, J=8.8 Hz, 1H), 4.27 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.48-2.57 (m, 12H), 2.32 (s, 3H), 0.92 (t, J=7.6 Hz, 3H); m/z=444 [M+1]+.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([Mg]Cl)[CH2:8][CH2:9][CH3:10]>C1COCC1>[CH3:4][CH:3]([CH2:2][CH:1]([OH:6])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:5]
Reactant: CC(C)CC=O
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of isovaleraldehyde (5.o g, 58 mmol) in dry THF (15 ml) was added to a stirred 2M THF solution of n-butylmagnesium chloride (30 ml, 60 mmol) at 0° C. under argon. The mixture was allowed to warm up to room temperature and was stirred overnight. The reaction was quenched by the addition of aqueous ammonium chloride (50 ml) and extracted with diethyl ether (200 ml). The organic extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 2-methyloctan-4-ol (6.4 g, 77%) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[O:27])=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c2c1C
Temperature: 25 °C

Procedure:
To a solution of ethyl-3-methyl-4-hydroxy-5-tert-butyl-benzofuran-2-carboxylate 12a (0.760 g, 2.75 mmol) in 30 mL dry (4A sieves) 1,2-dichloroethane at 5° C. under nitrogen was added a solution of thiophene-2-carbonyl-chloride (806 mg, 5.49 mmol) in 5 mL 1,2-dichloroethane followed by the portionwise addition of AlCl3 (0.733 g, 5.59 mmol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature and then refluxed for 1.5 hours. The reaction mixture was then cooled and poured into 100 mL ice cold 2N HCl. The organic layer was removed and the aqueous layer extracted with methylene chloride (3×30 mL). The combined organic layers were washed with 5% NaHCO3 (50 mL), water (50 mL) and saturated NaCl (50 mL) and dried over Na2SO4. Concentration followed by flash chromatography (30% EtOAc in hexane) afforded compound 13 as an oil sufficiently pure for further use; 1H NMR d 1.41 (3H, t, J=6 Hz), 1.55 (9H, s), 2.90 (3H, s), 4.42 (2H, q, J=6 Hz), 7.19 (1H, dd, J=4 Hz), 7.75 (2H, d, J=4 Hz), 7.90 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][NH:9]C(=O)OCC2C=CC=CC=2)[CH2:4]1)[CH3:2]>[Pd].CO>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][NH2:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCN1CC[C@@H](CN)C1
Yield: 90.9 %

Procedure:
Palladium on carbon (10%, 0.3 g) was added to a solution of benzyl N—((S)-1-ethylpyrrolidin-3-ylmethyl)carbamate (Intermediate 170, 1.8 g) in methanol (20 mL) and the resultant mixture was stirred under an atmosphere of hydrogen for 24 hours. The mixture was filtered and the filtrate was evaporated to dryness to give ((S)-1-ethylpyrrolidin-3-yl)methylamine (0.8 g) as a colourless oil, which was used without further characterisation.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:25]([S:39](Cl)(=[O:41])=[O:40])=[CH:24]2.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:31])=[O:32])[C:25]([S:39]([N:17]1[CH2:18][CH2:19][N:14]([C:12]3[S:13][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[CH:8]=4)=[CH:10][N:11]=3)[CH2:15][CH2:16]1)(=[O:41])=[O:40])=[CH:24]2
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: Cc1cc(-c2cnc(N3CCNCC3)s2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2cnc(N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5n4S(=O)(=O)c4ccccc4)CC3)s2)ccn1
Reaction time: 3 h

Procedure:
A saturated solution of hydrochloride in methanol (12 ml) was added to 1-(t-butoxycarbonyl)-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine (400 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated under reduced pressure, whereby 1-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained as a white solid. In a solution of the resulting hydrochloride in methylene chloride (12 ml) was dissolved 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (522 mg), followed by the addition of diisopropylethylamine (538 μl) at room temperature. After stirring for 3 hours, a saturated aqueous solution (50 ml) of sodium bicarbonate was added to the reaction. mixture to separate it into layers. The water layer was extracted with methylene chloride (2×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=7:1), whereby the title compound (240 mg) was obtained as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCCCCCCCCO
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCCCCCCCCCCCCCCCO)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-hydroxy-benzaldehyde (0.24 g, 2mmol) and 1,16-dihydroxyhexadecane (0.51 g, 2 mmol), triphenylphosphine (0.53 g, 2 mmol) in dry THF (20 ml) at −15° C. under an argon atmosphere was added a solution of diisopropylazodicarboxylate (0.4 g, 2 mmol) in dry THF (7.5 ml) over a period of 40 minutes. The mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure, diethyl ether was added and the white solid formed was removed by filtration. The filtrate was evaporated to dryness and the residue purified by chromatography on a column of silica gel which was, eluted with petroleum ether (b.p. 40-60° C.):tetrahydrofuran (THF) (10:1 by volume) to yield the title compound which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=2)=[O:31])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)n(C)n1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=455.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 2.19 g (8.75 mmol) 3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid in 50 ml MeOH/THF 3/2 are added 0.2 g Pd/C (10% Engelhard 4505) and the reaction is stirred at rt under hydrogen (1 atm) for 18 h. After filtration through celite the solvent is evaporated at reduced pressure to give the product.
Reaction SMILES: O.O.O.O.O.[S:6]([O-])([O-])(=O)=S.[Na+].[Na+].O.Cl.[CH3:15][C:16]1[C:21]([OH:22])=[C:20]([CH2:23]Cl)[C:19]([CH:25]=[CH2:26])=[CH:18][N:17]=1>C(O)C>[CH3:15][C:16]1[C:21]([OH:22])=[C:20]([CH2:23][SH:6])[C:19]([CH:25]=[CH2:26])=[CH:18][N:17]=1
Reactant: O=S([O-])([O-])=S
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CS
Temperature: 75 °C

Procedure:
A solution of 20 g. of sodium thiosulfate pentahydrate in 15 ml. of water is added to a solution of 18 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride in 100 ml. of 50% ethanol. The mixture is heated one hour at 75° C., cooled and evaporated to dryness to give Bunte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, m.p. 198°-200° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Agent: Cl
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps B-C of Example 82, using (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate in Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6×250 mm, 5 μm. Modifier 0.05% DEA. Mobile Phase: 60/40 CO/ethanol. Flow: 2.35 mL/min. Retention time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH2:6])C.C[O-].[Na+].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]#[N:20].C(O)(=O)C.Cl>CO>[NH:20]1[CH:4]=[CH:5][N:6]=[C:19]1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1
Reactant: N#Cc1cnccn1
Reactant: CCOC(CN)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc(-c2ncc[nH]2)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 453.1 %

Procedure:
2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50° C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) δ ppm: 7.67 (s, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.99 (d, J=2.5 Hz, 1 H), 5.72 (s, 2 H)
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.Cl[C:42]([O:44][CH2:45][CH2:46][O:47][CH3:48])=[O:43]>>[CH3:48][O:47][CH2:46][CH2:45][O:44][C:42]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([NH2:8])=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:43]
Reactant: COCCOC(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COCCOC(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Yield: 72 %

Procedure:
In the same manner as Example 1-D-01, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (40 mg) and 2-methoxy-ethyl chloroformate (0.021 ml) instead of acetic anhydride, a colorless oily crude product (60 mg) of 4-(2-bis-(4-methoxy-benzyl)-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 2-methoxy-ethyl ester was obtained. The obtained colorless oily crude product (60 mg) of 4-(2-bis-(4-methoxy-benzyl)-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 2-methoxy-ethyl ester was subjected to deprotection reaction according to the above deprotection reaction method 2, to obtain 4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 2-methoxy-ethyl ester as a colorless solid (21 mg, 72%).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[CH2:40][OH:41]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][OH:41])=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCC[C@H]1CO
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3CO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (S)-[1-(4-amino-butyl)-pyrrolidin-2-yl]-methanol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.62-3.56 (m, 2H), 3.29-3.23 (m, 2H), 3.02 (m, 1H), 2.78 (m, 1H), 2.83 (m, 1H), 2.51 (m, 2H), 2.24 (d, 3H, J=1.6 Hz), 2.02 (m, 1H), 1.88-1.56 (m, 7H) ppm; MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CS(O[CH:22]([C:37]#[N:38])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:22]([C:37]#[N:38])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:24]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Product: Cc1ccc(OC2C(C(=O)OC(C#N)c3ccc(F)c(Oc4ccccc4)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is reacted with α-cyano-4-fluoro-3-phenoxybenzyl methanesulfonate to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF is added dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydride in oil in 250 ml of THF, and the reaction mixture is left stirring for three hours at RT. It is cooled in an ice bath, a solution of 68.2 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is added dropwise and the reaction mixture is left stirring overnight at RT. It is acidified by adding a pH 2 buffer solution, and the THF is then evaporated off under vacuum. The aqueous phase is extracted with ether, the organic phase is washed twice with a pH 4 buffer solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with toluene and then with a toluene/AcOEt (100:3; v/v) mixture. 50 g of the expected product are obtained.