Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:15]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNC(=O)CCNC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)CCN(c1nc(Cl)ncc1Br)C1CCCC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.825 g, 8.00 mmol), 3-(cyclopentylamino)-N-ethyl-propanamide (Intermediate 141; 1.48 g, 8.00 mmol) and triethylamine (1.2 mL, 8.16 mmol) were combined in acetonitrile (50 mL) and heated at 100° C. for 4 hours. The solvent was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to give the title compound as a brown oil, (2.14 g, 71%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-methyl-benzoyl chloride (0.46 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was triturated in Et2O (50 mL) for 18 h then filtered and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide as a white solid (0.85 g, 70% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.48 min (96.54%); mp: 194-196° C.; 1H NMR (DMSO-d6) δ 1.97-2.14 (m, 1H, CHH), 2.36 (s, 3H, CH3), 2.44-2.71 (m, 2H, M01), 2.78-3.04 (m, 1H, CHH), 4.63 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.30 (d, J=7.9 Hz, 2H, Ar), 7.75-7.86 (m, 4H, Ar), 7.90 (d, J=7.6 Hz, 1H, Ar), 9.14 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.96, 21.99, 30.93, 42.57, 49.01, 121.95, 123.53, 127.27, 128.91, 129.77, 131.14, 131.60, 133.42, 141.37, 147.73, 166.30, 166.99, 167.13, 169.80, 172.72; LCMS: MH=406; Anal Calcd for C22H19N3O5+0.1H2O: C, 64.89; H, 4.75; N, 10.32. Found: C, 64.72; H, 4.70; N, 10.15.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:9]([Cl:27])=[CH:8][C:7]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[CH:12][C:11]=3[Cl:13])[C:16]2=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1C(Cc2c(Cl)cc(-c3ccsc3)cc2Cl)CCN1C1CCCCC1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.485 g, 3.31 mmol), thiophene-3-boronic acid (1.2 g, 9.39 mmol) tetrakis(triphenylphosphine)palladium (0.362 g, 0.3.13 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 5.5 mL) gives the title compound. Purify the crude material over silica gel (4/1 hexane in ethyl acetate) to yield 1.109 g (87%) of the title compound: mass spectrum (m/z): 410(M+2).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:33](Cl)Cl>C(OC)(OC)OC.C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:29][CH:33]=[N:31][N:30]=4)=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)NN)cc3)ncnc21
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(-c4nnco4)cc3)ncnc21
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of N-Cyclopropyl-3-[6-(4-hydrazinocarbonyl-phenyl)-purin-9-yl]-4-methyl-benzamide (8.0 mg, 0.019 mmol) in 0.5 mL of trimethyl orthoformate was added three drop of acetic acid. The reaction mixture was stirred at 120° C. in microwave for 10 minutes. Then 0.5 mL of methylene chloride and 3 mL of hexanes were added. The product was collected by filtration to give a colorless solid (6.0 mg, 73%). HPLC tR=2.12 min; MS m/z 438 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C>[N:15]1([C:2]2[N:7]=[C:6]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:12]([CH3:14])[CH3:13])[N:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: CC(C)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CC#N
Product: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1[N+](=O)[O-]

Procedure:
Combine 29 g (0.12 mol) of 2,4-dichloro-5-nitro-6-(2-propyl)-pyrimidine with 42 g (0.62 mol) of imidazole in 500 mL of acetonitrile, and stir at room temperature for 24 h. Remove the solvent under vacuum, slurry the residue in 500 mL of CH2Cl2 and wash with 4×500 mL 10% K2CO3. Dry the organic portion over MgSO4, treat with charcoal, filter and concentrate the filtrate to dryness under vacuum to afford 2,4-bis(1H-imidazol-1-yl)-5-nitro-6-(2-propyl)pyrimidine.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19].[NH2:46][C:47]1[C:48]([CH3:56])=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:50](=[O:51])[C:49]1[CH:53]=[CH:54][CH:55]=[C:47]([NH2:46])[C:48]=1[CH3:56])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reactant: Cc1c(N)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(N)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
EDC.HCl (42 mg) was added to a solution of the compound obtained in Step 2 of Example 1 (94 mg), 3-amino-2-methylbenzoic acid (30 mg), and HOBt (27 mg) in DMF while cooling with ice, and the mixture was stirred overnight. EtOAc was added and the mixture was washed with 5% Na2CO3 (×2) and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2—MeOH) and reprecipitated from a mixture of CH2Cl2 and n-hexane to obtain the title compound (77 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17](O)=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N2CCCC2CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part B: To a solution of 4.00 g (14 mmol) of 1-[(4-methoxyphenyl)sulfonyl]-2-carboxypyrrolidine from part A in 50 mL of anhydrous tetrahydrofuran at 0 C under a nitrogen atmosphere, was slowly added over 15 minutes, 20 mL (20 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether. After stirring at room temperature for 2 hours, the solution was cooled in an ice bath, and quenched by the slow sequential addition of 0.8 mL of water, 0.8 mL of 10% sodium hydroxide and 2.4 mL of water. The resulting suspension was filtered through celite and the celite washed with ethyl acetate. The combined organic filtrates were stripped, the residue disolved in ethyl acetate, which was washed with 5% KHSO4, saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford 3.66 g of crude material. This was chromatographed on 200 g of silica gel using 40%-75% ethyl acetate/hexane to yield pure 1-[(4-methoxyphenyl)sulfonyl]-2-(hydroxymethyl)pyrrolidine, m/e=278 (M+Li).
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[Na].[C:6]1([CH2:16][OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>COCCOC>[C:6]1([CH2:16][O:17][CH2:3][S:2][CH3:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CSCCl
Reactant: OCc1cccc2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Product: CSCOCc1cccc2ccccc12
Yield: 50 %

Procedure:
Methylthiomethyl 1-naphthylmethyl ether was prepared by the reaction of chloromethyl methyl sulfide with the sodium salt of naphthalene-1-methanol in DME in the presence of sodium iodide as described for analogous reactions by E. J. Corey and M. C. Bock in Tetrahedron letters 38 3269(1975); yield 50%, b.p. 105°-115° C./0.01 mmHg. 1H NMR (CDCl3): δ2.17 (Me), 4.70 (CH2S), 5.01 (CH2Naph), 7.1-8.2 (Naph).
Reaction SMILES: [C:1]([C@@H:3]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[NH:23][C:24]([C:26]1[N:27]([CH3:35])[C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)#[N:2].C(O)(=O)C>C(OCC)(=O)C>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C@H:3]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23][C:24]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:16])[C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc([N+](=O)[O-])cc2)cc2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(N)cc2)cc2ccccc21
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To 120 mg (0.25 mmol) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-nitro-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide dissolved in 5 mL ethyl acetate was added 20 mg activated carbon on charcoal (10% Wt.) and 0.7 mL glacial acetic acid. The reaction mixture was hydrogenated under normal atmosphere (H2 balloon) for two hours, filtered through a cake of celite, washed with water and 10% NaOH aqueous solution, dried over magnesium sulfate, and concentrated to provide 80 mg of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-(4-amino-benzyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-amide. HPLC: 92% pure, yield: 71%, MS: 444 (M+H+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:8]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O(CC)CC>[N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc2sc3nccn3c2c1
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccc2c(c1)N1CCN=C1S2)C(=O)OCC
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of 5.5 parts of imidazo[2,1-b]benzothiazol-6-amine and 7.5 parts of diethyl 2-(ethoxymethylene)propanedioate is stirred for 30 minutes at 110° C. The solid product is suspended in 1,1'-oxybisethane. It is filtered off and dried, yielding 10 parts (95%) of diethyl 2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)aminomethylene]propanedioate; mp 140° C.
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:4]=1[Br:3]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1Br

Procedure:
Methyl iodide (13 g, 91.5 mmol) is added to slurry of 2-bromo-5-iodobenzoic acid (23 g, 70.4 mmol) and K2CO3 (14.6 g, 106 mmol) in DMF (50 mL) at room temperature. After TLC shows complete consumption of the starting material, the reaction is diluted with Et2O and washed three times with a saturated aqueous solution of NaCl. The combined aqueous layers are extracted once with fresh Et2O and once with EtOAc. The organic layers are combined, dried with Na2SO4, filtered and concentrated to an oil. The oil is diluted with a minimal amount of Et2O and filtered through a plug of silica. The silica is rinsed with a 20% ether/hexanes mixture. The eluents are concentrated in vacuo to give 2-bromo-5-iodobenzoic acid methyl ester as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:8]2(=[O:24])=[O:23])[CH2:31]1
Reactant: CC1CNCC(C)N1
Reactant: O=S1(=O)N(CCCCCBr)c2ccccc2N1c1ccccc1F
Product: CC1CN(CCCCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC(C)N1
Yield: 99.5 %

Procedure:
In an analogous manner as described in general procedure V, 1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with 2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.08 g (88%) of 1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. MS (ES) m/z 447.0;
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=1.[C:22](=[S:24])=[S:23].O>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16]2[S:23][C:22]([SH:24])=[CH:19][C:18](=[O:20])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: S=C=S
Reactant: CC(=O)CC(=O)c1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(S)sc(-c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(3-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warm warmed slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (4.28 g, 72%); m.p. 188° C. (decomp); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.07 (d, 1H, J=1.4 Hz, H-3), 7.36 (d, 1H, J=1.4 Hz, H-5), 7.47–7.52 (dd, 1H, J1=J2=7.9 Hz, Ar-5), 7.69–7.72 (d, 1H, J=7.9 Hz, Ar-4/6), 7.76–7.78 (d, 1H, J=7.9 Hz, Ar-4/6), 7.92 (s, 1H, Ar-2); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1C
Yield: 92 %

Procedure:
To a flask (1000 mL), 120 g of 2-methylphenylacetic acid and 400 mL of anhydrous methanol were added, and then 24 mL of concentrated sulfuric acid was further added with stiffing. The mixture was heated with an oil bath and refluxed. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the solvent was removed by vacuum distillation. The residue was dumped into 400 mL of water and extracted with 400 mL of ethyl acetate. The organic layer was washed with water (2×200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A light yellow oily product was obtained. The light yellow oily product was further distilled under vacuum condition to yield 117.3 g of a colorless oily product (135-140° C., 16 mmHg) with a yield of 92%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: O=Cc1cccnc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1cccnc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and pyridine-3-carbaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.43 (s, 1H), 8.29-8.13 (m, 2H), 7.51-7.43 (m, 2H), 7.23 (d, 1H, J=1.8 Hz), 6.91 (d, 1H, J=1.8 Hz), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1.[CH2:26](C1C=CN=C(N)C=1)[CH2:27]C>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:11]=[CH:12][C:13]([B:16]3[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:14][CH:15]=2)[CH:3]=1)[CH2:26][CH3:27]
Reactant: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: CCCc1ccnc(N)c1
Product: CCCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Yield: 54.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 6, starting from 4-propylpyridin-2-amine, to afford the title compound (371.5 mg, 54.1%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.CO[CH:21]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:29]([O:28][C:26]([N:25]1[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22][CH:21]1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)CC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)C1CCC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
TiCl4 (1.9 mL, 1.9 mmol) as a 1M DCM solution was added to a solution of dimethyl malonate (0.195 mL, 1.70 mmol) in DCM (10 mL) at 0° C. under N2, and the reaction was stirred for 10 minutes. DIEA (0.3 mL, 1.7 mmol) was then added slowly, and the reaction was stirred for an additional 30 minutes at 0° C. A DCM (2 mL) solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (325 mg, 1.4 mmol) was then slowly added dropwise, and the reaction was stirred at 0° C. for 10 minutes. Saturated NH4Cl was then added, and then reaction was diluted with DCM and washed with saturated NaHCO3. The organic fractions were then dried, filtered, and concentrated to give the crude product, which was purified by column chromatography (500:50-500:90 hexanes:EtOAc) to give dimethyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)malonate (0.35 g, 75%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:25][C:26](=[O:39])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@@H:9]([NH:25][C:26](=[O:39])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(=O)OC(C)(C)C)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of {(R)-2-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-3-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester (0.39 g, 0.71 mmol) in DCM (2 ml) is treated with 4M hydrogen chloride in dioxane (1 ml). The reaction mixture is stirred at room temperature for 1.5 hours and then the solvent evaporated. The residue is co-evaporated with ethanol (×2) to afford (E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt. [MH]+ 453.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (4.00 g, 40 mmol, commercially available e.g. from Sigma-Aldrich) was dissolved in Dichloromethane (DCM) (125 mL) and to this was added triethylamine (6.69 mL, 48.0 mmol). This solution was then cooled with ice water. 2-Chloro-4-fluorobenzoyl chloride (8.49 g, 44.0 mmol, commercially available e.g. from Maybridge, Alfa Aesar or ABCR) was then diluted down with Dichloromethane (DCM) (25 mL), before being added via a pressure-equalizing dropping funnel. The solution was allowed to stir at room temperature overnight, and was then washed with sodium bicarbonate (100 ml), the solid was removed, and the remaining solution was washed again with sodium bicarbonate (100 ml) and brine (100 ml), before being dried over magnesium sulphate. The solvent was then removed in vacuo to afford crude product which was triturated with hexane then stirred in ethyl acetate at 80° C., before being filtered and air-dried to give 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (5.179 g).