Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution (20 mL) of ethyl 2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (390 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (3.5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-red oil (yield 330 mg, 95%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12]1([CH3:14])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: CC(C)=O
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 47 %

Procedure:
A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric a-id (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])[CH2:11]2)[CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])#[N:27].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:30][C:29]=1[F:37])#[N:27]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 69.8 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (300 mg, 0.82 mmol), (4-cyano-3-fluorophenyl)boronic acid (176 mg, 1.07 mmol, 1.3 equiv), Pd2(dba)3 (56 mg, 0.061 mmol, 0.075 equiv), tricyclohexylphosphine (34.5 mg, 0.123 mmol, 0.15 equiv) and K3PO4 (296 mg, 1.39 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and brine (20 mL). The organic was dried (Na2SO4), filtered and concentrated in vacuo to give a residue. This crude material was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc to afford the title compound (258 mg). LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:46][CH2:45][CH2:44]4)([CH3:42])[C:30]([O:32]CC4C=CC(OC)=CC=4)=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[N:1]1[CH:2]=[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:44][CH2:45][CH2:46]4)([CH3:42])[C:30]([OH:32])=[O:31])[CH2:18]3)[CH2:14][CH2:15]2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COc1ccc(COC(=O)[C@@](C)(C2CCC2)N2C[C@H](CN3CCC(c4cnc5ccccn45)CC3)[C@@H](c3cccc(F)c3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@](C(=O)O)(C1CCC1)N1C[C@H](CN2CCC(c3cnc4ccccn34)CC2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
To 26 mg of α-(R)-(3-(S)-((4-(imidazo[1,2-a]pyridin-3-yl)-piperidine-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-cyclobutylpropanoic acid, 4-methoxy-benzyl ester (from Step C) was added 2 mL of TFA and 0.3 mL of anisole. The reaction was stirred at r.t. for 1 hour. The reaction mixture was concentrated and the residue was purified by flash chromatography with 10% MeOH in CH2Cl2, followed by 15% MeOH and 1% NH4OH in CHCl3 to provide 23 mg of a foamy solid. 1H NMR (500 MHz, CD3OD): δ1.63-1.81 (m, 4H), 1.93-2.15 (m, 5H), 2.33(t, J=15.6 Hz, 2H), 2.44(m, 1H), 2.86(m, 1H), 3.00(d, J=13.8 Hz, 1H), 3.15-3.89(m, 13H), 7.11 (m, 1H), 7.28 (m, 2H), 7.39-7.48 (m, 2H), 7.75 (s, 1H), 7.85 (m, 2H) 8.32 (d, J=6.9 Hz, 1H). ESI-MS 505 (M+H); BLC A 1.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](F)(F)F)=CC=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=O)CCCC1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:27]4)=[O:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: O=C=NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (180 mg, 0.73 mmol), diisopropyl(ethyl)amine (189 mg, 1.46 mmol), and cyclopentyl isocyanate (97 mg, 0.88 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:2]2[C:3]3[N:4]([N:9]=[C:10]([NH2:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(Br)c2nc(N)nn2c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(B(O)O)c1
Product: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(N)nn2c1

Procedure:
Prepared in analogy to example 160b, starting from 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid. The title compound was obtained as an off-white solid (yield: 99%) after precipitation from diethyl ether. MS ISP (m/e): 354.4 (80) [(M+H)+], 298.4 (100), 237.2 (99).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].[C:25]([O:28][C:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])[CH3:26]>C(#N)C>[CH2:1]([N:3]([CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:28][C:25](=[O:27])[CH3:26])([CH3:35])[CH3:36])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(=O)OC(C)(C)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 5-acetoxy-1-bromo-5-methylhexane (Step V) to give the titled product, a compound of Formula I'. The mass spectrum had M+ at m/z 442.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Si:20]([O:27][CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:29][CH:30]=[O:31])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1>[Si:20]([O:27][CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:29][CH:30]([OH:31])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(CC=O)O[Si](C)(C)C(C)(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(CCCCCCC/C=C\C/C=C\CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 45 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A suspension of Mg (165 mg, 6.77 mmol) in THF (1 mL) was treated with a solution of linoleyl bromide (2.03 g, 6.15 mmol) in THF (1.5 mL) in one portion. The suspension was heated (45° C.) and stirred (4 h). The newly generated Grignard was then treated with a solution of (11Z,14Z)-3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienal (5) (2.0 g, 4.73 mmol) in THF (8 mL) and stirred (2 h). The reaction mixture was quenched by the addition of H2O, extracted with ether, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (2%→3% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-21-((tert-butyldimethylsilyl)oxy)octatriaconta-6,9,29,32-tetraen-19-ol (6)(2.44 g, 77%) as a pale yellow oil. Rf 0.59 (10% EtOAc-hexanes), FW 673.22, C44H84O2Si.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:13])[NH2:12])[CH2:7][CH2:6]1)=[O:4].CO[C:16](OC)([N:18]([CH3:20])[CH3:19])[CH3:17]>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[S:13])[N:12]=[C:16]([N:18]([CH3:20])[CH3:19])[CH3:17])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(C)(OC)N(C)C
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1
Product: COC(=O)[C@H]1CC[C@H](C(=S)N=C(C)N(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.72 g, 3.6 mmol) and N,N-dimethylacetamide dimethyl acetal (0.95 g, 7.2 mmol) was stirred at room temperature over night. The solvent was evaporated. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.90 g, 93%) as yellow oil. MS m/e: 271 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([OH:33])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:41][C:42]1([C:45]#[N:46])[CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:16]([F:19])([F:17])[F:18])=[O:30])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:41][C:42]1([C:45]#[N:46])[CH2:44][CH2:43]1)=[O:33]
Reactant: N#CC1(N)CC1
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)O)c(Cl)cc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
6-Chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid (93% pure; 0.116 g, 0.22 mmol) was dissolved in dichloromethane (2.5 ml). N,N-Dimethylformamide (1 drop) and oxalyl chloride (0.058 ml, 0.66 mmol) were successively added dropwise. The reaction mixture was stirred at room temperature for 30 min and at 40° C. for 30 min, and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.5 ml) and added dropwise at room temperature to a solution of 1-aminocyclopropanecarbonitrile hydrochloride (0.052 g, 0.44 mmol) and diisopropylethylamine (0.085 g, 0.66 mmol) in dichloromethane (2.5 ml). The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with saturated ammonium chloride solution and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was chromatographed with water and acetonitrile through RP silica gel and gave 0.033 g (24% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=O.[Cl:32][C:33]1[CH:34]=[C:35]([NH:39][C:40]([NH2:42])=[NH:41])[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[NH:39][C:40]1[N:42]=[C:5]([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:4]=[CH:3][N:41]=1
Reactant: CN(C)C=CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N=C(N)Nc1cccc(Cl)c1
Product: Clc1cccc(Nc2nccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c1

Procedure:
4-(3-Dimethylaminoprop-2-en-1-oyl)-1-triphenylmethylimidazole (Method 3) was treated with 3-chlorophenylguanidine under conditions analogous to those described in Example 7 to give the title compound; m/z: 514.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[CH3:20][O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>>[CH3:20][O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:24][CH2:23]1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Agent: Cl
Product: CO[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=308.5 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and trans-4-methoxycyclohexanamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([Cl:10])[N:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([CH2:6][OH:7])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)nc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Br)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 6-bromo-2-chloronicotinaldehyde (5.40 g, 24.50 mmol) in THF (30 ml) and MeOH (10.0 ml) at 0° C. was added NaBH4 (0.927 g, 24.50 mmol). The mixture was stirred at 0° C. for 2 h. Saturated NH4Cl (50 ml) was added and the mixture extracted with ethyl acetate, dried over (Na2SO4), filtered and concentrated in vacuo to give (6-bromo-2-chloropyridin-3-yl)methanol (5.50 mg, yield: 101%). MS (M+H)+: 224.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: Fc1cccc([Mg]Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccccc1-c1ccccc1P(c1cccc(F)c1)c1cccc(F)c1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
16.4 g (70 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 80 ml of anhydrous tetrahydrofuran are introduced, in an argon atmosphere with stirring, and a 2M solution of 140 mmol of 3-fluorophenylmagnesium bromide in tetrahydrofuran is added dropwise. The temperature increases in the course of this from 25° to 45° C. The mixture is then stirred for 12 hours at 65° C., cooled to room temperature and 100 ml of water and 100 ml of ethyl acetate are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 25.8 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 19.8 g (71%) of colorless crystals having melting point 161° to 163° C. are obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([C:19](=[O:21])[NH2:20])[CH:14]=[CH:15][C:16]=2[Br:18])[NH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:22]=O>CO.Cl>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([C:19](=[O:21])[NH2:20])=[C:12]2[C:17]=1[C:9]1[CH2:8][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:1][CH2:22][C:10]=1[NH:11]2
Reactant: CCOC(=O)C(N)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Reactant: C=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1Cc2c([nH]c3c(C(N)=O)ccc(Br)c23)CN1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a solution of ethyl 2-amino-3-(4-bromo-7-carbamoyl-1H-indol-3-yl)propanoate (3.45 g, 9.74 mmol) in methanol (68.8 mL) and 1 M aqueous HCl (52.9 mL) was added 37% aqueous formaldehyde (0.790 mL, 9.74 mmol) and the resulting mixture was heated at 80° C. After 1.5 h, additional formaldehyde (0.79 mL) was added and heating was continued. After 3.5 h, additional formaldehyde (0.79 mL) was again added and heating was continued. After 6 h, the mixture was cooled to room temperature, concentrated, and partitioned between a solvent mixture of CHCl3 and iPrOH (3:1) and 1 M NaOH and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to afford the crude product as a light brown solid (3.16 g, 89% yield). LCMS (M+H)+ m/z 365.8, 367.8.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20]O)[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:41]1C=CN=C1.II.[I-].[N-]=[N+]=[N-].[Na+].[N-]=[N+]=[N-]>C(Cl)Cl.CN(C=O)C.CC(=O)OCC.C1COCC1.O>[NH2:41][CH2:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:11](=[O:12])[O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:16]1
Reactant: c1c[nH]cn1
Reactant: O=C(N[C@H]1CC[C@@H](CO)CC1)OCc1ccccc1
Agent: II
Agent: N#N
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (1.53 g, 5.81 mmol), triphenylphoshine on polystyrene (17.43 mmol) and imidazole (559 mg, 8.13 mmol) in dry CH2Cl2 (150 mL) was added iodine (2.38 g, 9.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide (1.94 g, 5.20 mmol) was redissolved in DMF (15 mL) and treated with sodium azide (358 mg, 5.46 mmol). The reaction mixture was heated to 80° C. until completion of the reaction. The mixture was then diluted with EA, washed with brine (3×), dried over MgSO4, filtered and concentrated under reduced pressure. To a mixture of the crude azide (1.50 g, 5.20 mmol) in THF (27 mL) were added polymer-supported Ph3P (2.0 eq.) and water (9 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 0.5M Na2CO3 and the layers separated. The aq. layer was extracted with EA (2×) and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give benzyl (cis-4-(aminomethyl)cyclohexyl)carbamate as a yellow oil. LC-MS-conditions 07b: tR=0.57 min; [M+H]+=263.46.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4](=[O:5])[CH2:12][CH3:13]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCCO1
Solvent: C1CCOC1
Product: CCC(=O)[C@H]1CCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide (20.15 g, 1 equiv) in THF (250 ml) was added ethyl magnesium bromide (44.3 ml of a 3M solution in THF, 1.05 equiv) The reaction was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl solution. EtOAc was added and the organic portion was separated and washed further with saturated NH4Cl solution, dried (MgSO4) and concentrated in vacuo to afford the title compound; NMR (CDCl3) 1.05 (3H, t, CH3), 1.9 (3H, m), 2.2 (1H, m, CH), 2.6 (2H, m, CH2), 3.95 (2H, CH2O), 4.3 (1H, m, CHO).
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])([CH3:11])[CH3:10].N#N.[CH3:20][C:21]([CH3:46])([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH3:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:8][C:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:43](=[O:44])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:26][C:24]([O:23][C:21]([CH3:46])([CH3:20])[CH3:22])=[O:25])([CH3:11])[CH3:10]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
N-Methylmorpholine (3.3 ml) was added to a suspension of L-alanine 1,1 -dimethylethyl ester (4.0 g), N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine (11.4 g), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.8 g) and 1-hydroxybenzotriazole (4.1 g) in dichloromethane (150 ml). The resulting mixture was allowed to stand for 18 hours, and was then poured into distilled water (200 ml). The organic phase was separated, washed with water, saturated sodium hydrogen carbonate, dilute aqueous citric acid, brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to yield N-[N2 -[(1,1-dimethylethoxy) carbonyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysinyl]-L-alanine 1,1-dimethylethyl ester (12.6 g) as a foam.