Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.O>[Br:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[N:18]=1
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(Br)cccc43)n2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCC(Nc2nccc(-n3ccc4c(Br)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (5.8 g) and LiOH.H2O (1.65 g) in THF (100 mL), EtOH (40 mL) and H2O (30 mL) was stirred at RT overnight. The reaction mixture was then acidified with citric acid (7.54 g in 20 mL H2O), and stirred at RT for 1 h. The precipitate was filtered, washed with water, then Et2O, and dried to provide 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclo-hexanecarboxylic acid (5.27 g, 97%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:30][CH2:27][CH:28]=[CH2:29]
Reactant: C=CCN
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Solvent: C1COCCO1
Product: C=CCNc1c([N+](=O)[O-])ccc(Oc2ccc(C#N)cc2)c1Cl
Reaction time: 30 h

Procedure:
A mixture of 4 gm of 2-chloro-4-nitro-3-phenoxy-1-(4-cyano-phenoxy)-benzene, 10 ml of dioxane and 2 gm of allylamine was allowed to stand at room temperature for 30 hours. Thereafter, the dioxane was distilled off, the residue was taken up in chloroform, the resulting solution was extracted with dilute sodium hydroxide, the organic phase was dried with sodium sulfate, the chloroform was distilled off, and the residue was recrystallized from ethanol. 3.5 gm (97.2% of theory) of the yellow crystalline title compound, m.p. 85°-87° C., were obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (5-methoxy-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M29) (254 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (96 mg).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]>>[CH3:10][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([C:25]3[C:24]4[CH:36]=[CH:37][N:38]([S:39]([C:42]5[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=5)(=[O:41])=[O:40])[C:23]=4[C:22](=[O:49])[N:21]([CH3:20])[CH:26]=3)=[C:3]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Cn1c(=O)[nH]c2c(Sc3ccccc3)c(Br)ccc21
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c([nH]c(=O)n5C)c4Sc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-1-methyl-4-(phenylthio)-1,3-dihydro-2H-benzimidazol-2-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C29H25N4O4S2 (M+H)+: m/z=557.1. found: 557.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:46](Br)[CH2:47][CH:48]=[CH2:49]>CN(C=O)C.O>[CH2:49]([N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:10])[CH2:48][CH:47]=[CH2:46]
Reactant: C=CCCBr
Reactant: COc1cccc(C(=O)c2nc(-c3ccccc3)c[nH]2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCn1cc(-c2ccccc2)nc1C(=O)c1cccc(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
(3-Methoxyphenyl)(4-phenyl-1H-imidazol-2-yl)methanone (278 mg, 1.00 mmol) was dissolved in DMF (3 ml), and thereto were added potassium carbonate (207 mg, 1.50 mmol), 18-crown-6 (26.4 mg, 0.100 mmol), 3-butenyl bromide (162 mg, 1.20 mmol), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to azeotropic distillation with toluene to give the title compound (309 mg, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([P:14]([CH2:18][CH3:19])([CH2:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH2:16]([P:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH2:18][CH3:19])=[O:15])[CH3:17]
Reactant: CCP(=O)(CC)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCP(=O)(CC)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by diethylchlorophosphate (1.16 mL, 8.01 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium surf ate. After filtered, the filtrate was concentrated in vacuo to yield 1.5 g of N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine in 88% yield as an oil. MS m/z M+H=323, M+NH4 =340. H1 -NMR (in CDCl3) δ=1.32 (t, 6H, 2×CH3), 1.48 (s, 9H, Boc), 3.1 (m, 4H, piperazine), 3.37 (t, 4H, piperazine), 4.05 (m, 4H, 2×OCH2). The obtained N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine (1.5 g, 4.66 mmol) was dissolved in I 0 mL of 10% trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain 1.6 g of N-diethylphosphorylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=223, H1 -NMR (in MeOH-d4) δ=1.35 (m, 6H, 2×CH3), 3.19 (m, 4H, piperazine), 3.37 (m, 4H, piperazine), 4.05 (m, 4H, 2×OCH2).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([CH:10]2[CH2:9][C:8]([CH3:23])([CH3:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 102.1 %

Procedure:
To a stirred mixture solution of 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5 g, 3.56 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.36 g, 97%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=374.0& 376.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:39])[N:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]([CH2:30][CH2:31]O)[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:31][CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22]([NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)=[O:23])[C:25](=[O:39])[N:26]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCO)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN5C(=O)c6ccccc6C5=O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.38 mmol) and phthalimide (0.11 g, 0.76 mmol) in 10 mL of CH2Cl2 was added triphenyl phosphine (0.13 ml, 0.57 mmol), followed by diethyl azodicarboxylate (0.089 ml, 0.57 mmol) via a syringe. The reaction mixture was stirred at RT for 16 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) to give the title compound as a light yellow solid (0.22 g, 88% yield). MS (ESI pos. ion) m/z: 658 (MH+). Calc'd exact mass for C37H28FN5O6: 657. 1H NMR (300 MHz, MeOH) 8.53 (1H, d, J=5.5 Hz), 8.28 (1H, d, J=9.0 Hz), 7.80-7.91 (5H, m), 7.50 (1H, s), 7.48 (2H, d, J=3.0 Hz), 7.26-7.36 (6H, m), 6.49 (1H, dd, J=5.4, 1.0 Hz), 4.27 (2H, t, J=5.5 Hz), 3.97 (3H, s), 3.74 (2H, t, J=5.5 Hz), 2.68 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[Br:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cc(C)no4)cc3)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Br)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4′-(3-Methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.00 g, 2.88 mmol) was dissolved in acetic acid (12 mL) and N-bromosuccinimide (0.563 g, 3.2 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was submitted to standard aqueous workup to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][O:35][C:34]1=[O:38]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][O:35][C:34]5=[O:38])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1OCCN1CCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1OCCN1CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-(2-hydroxyethyl)1,3-oxazolidin-2-one following General Procedure J.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:66][C@@H:67]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:68]([C@@:70]1([CH3:73])[CH2:72][O:71]1)=[O:69].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:15]([NH:66][C@@H:67]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:68]([C@@:70]1([CH3:73])[CH2:72][O:71]1)=[O:69])=[O:16])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.08 h

Procedure:
To (S)-2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoic acid (3.39 mmol assumed) and HATU (1.45 g, 3.82 mmol) in DMF (10 mL) at 0° C. was added (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (1.05 g, 3.47 mmol). The mixture was stirred for 5 min to dissolved the solids and DIEA (2.41 mL, 13.88 mmol) was added. The reaction mixture was stirred at this temperature for 15 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude tert-butyl ((S)-3-(benzyloxy)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C37H45N3O8, found 660.4 (MH+).
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]([CH2:9][OH:10])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl>>[CH2:9]1[CH:8]2[CH:3]([CH2:4][NH:5][CH2:6][CH2:7]2)[CH2:2][O:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C(CO)C1
Agent: Cl
Product: C1CC2COCC2CN1
Temperature: 95 °C
Yield: 59 %

Procedure:
Tert-butyl 3,4-bis(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4 mmol) and concentrated hydrochloric acid (8 mL) were added to a sealed tube (50 mL). The reaction mixture was heated at 95° C. overnight, cooled to room temperature and concentrated in vacuo. The pH was adjusted to 8 by adding aqueous solution of NaOH. The mixture was extracted with CH2Cl2 (30 mL×2). The organic phase was washed with water (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the crude product as yellow oil (300 mg, 52.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 128.2 (M+1).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:8]([NH:15][CH:3]=[CH:4][C:5]#[N:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: N#CC=CO
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: N#CC=CNCc1ccccc1
Yield: 57.1 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) and 43.1 g (0.3 mol) of benzylamine hydrochloride are refluxed for 5 h in 150 ml of acetonitrile. After removal of the solid by filtration and withdrawal of the solvent, the product was dissolved in chloroform and washed with water. Subsequent vacuum distillation yielded 22.6 g of 3-benzylaminoacrylonitrile (57.1%).
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[OH:24])=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:10]2[S:22][N:21]=[C:20]([CH3:23])[C:11]=2[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[N:13][C:8]=1[C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7]
Reactant: CCCCOC(=O)c1nc(-c2cnccn2)c2c(C)nsc2c1O
Reactant: NCC(=O)O
Product: Cc1nsc2c(O)c(C(=O)NCC(=O)O)nc(-c3cnccn3)c12

Procedure:
The title compound was synthesized in analogy Example 3 from 7-hydroxy-3-methyl-4-pyrazin-2-yl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 346.1 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][C:29]=2[CH:30]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:35]([C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C:9]=3[NH:10][C:11]3[C:12]([CH3:20])=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[C:7]#[N:8])=[CH:30][C:29]=2[CH:31]=1)=[O:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)ccc2[nH]ccc12
Temperature: 120 °C
Yield: 76.1 %

Procedure:
A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (2.5 g, 6.7 mmol), 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde (4.35 g, 10 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.34 mmol) in DMF (25 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water, resulting in a suspension. The insoluble material was removed by filtration and the residue was washed thoroughly with ethyl acetate. The organic layer (from filtrate) was washed with water twice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:1) to give 2.0 g (76%) of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a yellow solid. HPLC retention time: 10.7 min.(h); MS: 393.2 (M+H); melting point: 235-237° C.; and HRMS: 393.13484.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7].C(C1C=CC(S(NC2C=CC(C)=CC=2)(=O)=O)=CC=1)(C)(C)C>>[Br:1][CH2:2][C:3]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][OH:11])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCNCCO
Agent: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(CCO)C(=O)CBr

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-ethyl-N-(2-hydroxy-ethyl)-amine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide; in contrast to the general procedure the intermediate 2-bromo-N-ethyl-N-(2-hydroxy-ethyl)-acetamide was isolated before being used in the coupling with the potassium N-tolylsulfonamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]2[CH2:20]CC[CH2:17]2)[C@H:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]([CH3:20])[CH3:17])[C@H:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Solvent: CC(C)=O
Product: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C

Procedure:
Intermediate C-1 was prepared similarly to the synthetic methods used to prepare Intermediate A with the exception that acetone was used instead of cyclopentanone in the reductive amination step.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[CH:11][CH:10]=1>ClCCl>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[O:24])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(Cn2cccn2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(=O)NC(Cn2cccn2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (0.7 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (180 mg, 0.32 mmol) in dichloromethane (Intermediate 93) (7 mL) under argon. The resulting solution was stirred at room temperature overnight. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-amino-N-[1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white powder.
Reaction SMILES: ClC1C=C(C=C(NC2CCN(CC3C=C(OCC)C(Cl)=C(OCC)C=3)CC2)N=1)C(O)=O.C[O:33][C:34](=[O:69])[C:35]1[CH:40]=[C:39]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:54]=[C:53]([O:55][CH2:56][CH3:57])[C:52]([C:58]4[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=4)=[C:51]([O:65][CH2:66][CH3:67])[CH:50]=3)[CH2:44][CH2:43]2)[N:38]=[C:37]([Cl:68])[CH:36]=1>>[Cl:68][C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:54]=[C:53]([O:55][CH2:56][CH3:57])[C:52]([C:58]4[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=4)=[C:51]([O:65][CH2:66][CH3:67])[CH:50]=3)[CH2:44][CH2:43]2)[N:38]=1)[C:34]([OH:69])=[O:33]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(=O)OC)cc(Cl)n3)CC2)cc(OCC)c1-c1ccc(F)cc1
Agent: CCOc1cc(CN2CCC(Nc3cc(C(=O)O)cc(Cl)n3)CC2)cc(OCC)c1Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(=O)O)cc(Cl)n3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for 2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinic acid (example 232) from 2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinic acid methyl ester (example 225) and obtained as colorless solid. MS (ISN): 526.1 [M−H].