Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1.CO.[Ni]>[CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
N2,N4-Dibenzyl-3-nitro-6-trifluoromethyl-pyridine-2,4-diamine (15.9 g, 35.6 mmol) was dissolved in a mixture of THF (100 ml) and MeOH (200 ml). Raney Nickel (3.18 g, 20 wt %) was added and the mixture was stirred at room temperature under 80 psi H2 for 1 hour. The mixture was filtered through celite to remove the catalyst and the filtrate was concentrated in vacuo to give an oil. Trituration in MeOH with a small amount of water gave a precipitate which was collected by filtration, washed with cold MeOH and dried in vacuo to give the title compound (9.02 g) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 mL, 0.65 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and was then diluted with CH2Cl2 (25 mL) and washed with sat. NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 provided the title compound mixed together with diacylated material. This material was dissolved in CH2Cl2 and triturated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether (10 mL) and air dried to give impure product (120 mg) as a yellow solid. This solid was purified by crystallisation from CH3CN to give the title compound (47 mg, 0.092 mmol, 16%) as a yellow solid. All the residues were combined, concentrated in vacuo and crystallised from CH3CN to give a second crop of the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. Total yield of title compound=73 mg, 24%; 1H NMR: (CDCl3) 1.87-1.99 (1H, m), 2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79 (1H, s), 7.20 (1H, d), 7.23-7.32 (2H, m) partially obscured by CDCl3 peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46 (1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES+ MH+ 512.26.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])C=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:12][O:6][C:4](=[O:5])/[CH:2]=[CH:3]/[C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:29]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
To a solution of trimethylphosphonoacetate (13 mL, 82 mmol) in 36 mL of THF at 0° C. was added lithium bis(trimethylsilyl)amide (82 mL of 1M THF solution, 82 mmol). This solution was stirred for 20 min, and a solution of 3-cyclopentoxy-4-methoxybenzaldehyde (15 g, 68 mmol) in 30 mL of THF was then added dropwise via addition funnel. When reaction was judged complete by TLC analysis, the reaction was diluted with ethyl acetate:hexanes (1:1), and the organic layer was washed with H2O and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford (E)-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-en-oate as a pale yellow solid (17.2 g, 92%). 1H-NMR (300 MHz): δ 3.79 (s, 3), 3.86 (s, 3), 6.28 (d, 1, J=16), 7.52 (d, 1, J=16).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([C:16](=[O:17])[C:5]=2[CH:4]=1)=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=3)#[N:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=3[C:16](=[O:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1[nH]c(=O)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.85 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042 mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for two days and the reaction mixture washed with alkali to obtain an 11-oxo-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrid-2(1H)one product which is recovered and purified by conventional procedures.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C[N:11](C)C1C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)c1ccccc1
Reactant: c1cc(C2CC2)ccn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1cc(C2CC2)ccn1
Yield: 12 %

Procedure:
Reflux 4-cyclopropyl-pyridine (600 mg, 5 mmol), N,N-dimethylaniline (1.4 mL, 11 mmol) and NaNH2 (50% in toluene, 468 mg, 6 mmol) at 150-160° C. under nitrogen in toluene for overnight. Cool the mixture and dilute with water and ethyl acetate. Extract the organic layer by minimal amount of water. Dry the organic layer (combination of anhydrous MgSO4, Na2SO4 and K2CO3), concentrate and purify by silica gel column chromatography to obtain the title compound in 12% yield. LCMS (ES), m/z 135 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>O1CCCC1>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([O:11][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCC(CC(O)C(=O)O)N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(CC(O)C(=O)OCc2ccccc2)N1

Procedure:
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.1 g), triethylamine (1.2 g), N-N-dimethylaminopyridine (1.5 g), and benzyl chloroformate (17 g) in 40 ml tetrahydrofuran is heated at reflux for 16 hours. After cooling and filtering off the triethylamine-hydrochloride, the solution was concentrated and chromatographed on SiO2 (elution with methanol:chloroform; 3:97) to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, benzyl ester mp 95°-96° C. NMR (CDCl3) and 7.37 (s, 5H), 7.93 (d, 1H), 5.40 (s, 1H), 1.70 (m, 2H). IR (KBr) 3330, 3200, 1733, 1691, 1497, 1456, 1389, 1351, 1287, 1216.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29]O)=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][Cl:35])=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CO)ccc54)ccc3o2)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CCl)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(hydroxymethyl)indole-3-carbonitrile (0.66 g) and thionyl chloride (0.5 ml) in chloroform (20 ml) was stirred at room temperature for 3 hours. After neutralization with aqueous sodium hydrogen carbonate, the resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.67 g).
Reaction SMILES: P(Cl)(Cl)(OC1C=CC=CC=1)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:30]=[N+:31]=[N-:32])=[O:19])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)O)cc1N1CCN(C)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N=[N+]=[N-])cc1N1CCN(C)CC1
Reaction time: 12 h

Procedure:
At ambient temperature, add a solution of 5.3 g (0.025 mol) of phenyl dichlorophosphate in 100 ml of dichloromethane to a solution of 5 g (0.02 mol) of 4-methoxy-3-(4-methyl piperazin-1-yl)benzoic acid [J. Med. Chem., 37 (15), 2255 (1994)] and 3.25 g (0.05 mol) of sodium azide in 4.05 ml of pyridine. After stirring for 12 hours, wash the organic phase with 100 ml of water, separate off the organic phase, dry it over magnesium sulphate and evaporate off the solvent in vacuo at 30° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.N>C(O)C.[Pd]>[CH3:17][C:4]1[C:5]2[N:6]([C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:9][N:10]=2)[N:7]=[CH:2][CH:3]=1
Reactant: Cc1cc(Cl)nn2c(-c3ccccc3)nnc12
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1ccnn2c(-c3ccccc3)nnc12
Yield: 85 %

Procedure:
6-chloro-8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x240 is dissolved in ethanol (300 ml), and 10% Pd/C (0.9 g) and 25% aqueous ammonia (60 ml) are added. The mixture is hydrogenated in the Parr apparatus under hydrogen pressure 2.5 atm at room temperature for 1h10. The reaction mixture is filtered through a Celite layer, which is washed with ethanol. The combined filtrates are evaporated, and the residue is dissolved in dichloromethane. The solution is washed with brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure to afford 2.9 g of 8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]CC)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(SCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
A solution of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylate (20 mg, 0.033 mmol) in tetrahydrofuran (0.33 mL) was placed in a microwave reaction vial followed by ethanol (0.17 mL) and 1 N sodium hydroxide (0.050 mL). The tube was sealed then heated to 100° C. for ten minutes. The reaction mixture was then concentrated and the residue partitioned between tetrahydrofuran and brine. 1 N hydrochloric acid (0.050 mL) was added. The organic layer was separated and concentrated to yield 17 mg (94%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylic acid as an orange solid. 1H NMR (400 MHz, d6-DMSO): δ 8.57 (d, J=9 Hz, 1H), 8.35 (s, 1H), 8.20-8.10 (m, 3H), 7.76 (d, J=8 Hz, 2H), 7.63 (d, J=7 Hz, 2H), 7.58-7.7.54 (m, 1H), 7.42 (d, J=8 Hz, 2H), 3.95 (s, 2H), 3.24 (septet, J=7 Hz, 1H), 1.16 (d, J=7 Hz, 6H). HRMS (ESI) C29H22Cl2N2O3S calculated: 549.0806 [M+H]+, found: 549.0813 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[N:26]=[CH:25][C:24]2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]3[N:35]=[CH:36][CH:37]=[C:38](Cl)[C:21]=3[C:20]=2[CH:19]=1.BrC1N=CC2N(COCC[Si](C)(C)C)C3N=C(Cl)C=CC=3C=2C=1>O1CCCC1.O.C(OCC)(=O)C>[Br:17][C:18]1[N:26]=[CH:25][C:24]2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:22]3[N:35]=[CH:36][CH:37]=[C:38]([O:1][C@@H:2]4[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]4)[C:21]=3[C:20]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2c(Cl)ccnc21
Agent: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2ccc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccnc3c2c2cc(Br)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (64 mg, 0.32 mmol) in tetrahydrofuran (1.2 mL) was added sodium hydride as 60% dispersion in mineral oil (13 mg, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before a mixture of 6-bromo-4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole with 6-bromo-2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (4:1, 60 mg, 0.1 mmol) was added in one portion, and the reaction mixture was stirred at this temperature for 10 minutes before being warmed to 40° C. for 2 hours. The cooled reaction mixture was then diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-65% ethyl acetate in heptane) to afford the title compound as a colorless oil, which was used in the next step without any further purification (60 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=O)C=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C1N=C[N:23](C(N2C=NC=C2)=O)C=1.Cl.[NH2:34][CH2:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[C:38](=[O:54])[N:39]([CH:46]1[CH2:51][CH2:50][C:49](=[O:52])[NH:48][C:47]1=[O:53])[C:40]2=[O:45].C(N(CC)CC)C>CN(C=O)C.O>[O:53]=[C:47]1[CH:46]([N:39]2[C:38](=[O:54])[C:37]3[C:41](=[CH:42][CH:43]=[CH:44][C:36]=3[CH2:35][NH:34][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)[N:23]=3)=[O:20])[C:40]2=[O:45])[CH2:51][CH2:50][C:49](=[O:52])[NH:48]1
Reactant: CCOc1cc(-c2cccc(C(=O)O)c2)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cccc(C(=O)NCc3cccc4c3C(=O)N(C3CCC(=O)NC3=O)C4=O)n2)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.1 %

Procedure:
A mixture of 3′-ethoxy-4′-methoxybiphenyl-3-carboxylic acid (0.55 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (30 mL) was stirred at ambient temperature under nitrogen for 90 minutes. 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 3 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (3×150 mL), dried (MgSO4), and evaporated, providing 0.75 g of the product as a pale yellow solid (69% yield): mp 196-198° C.; 1H NMR (DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 2.05-2.10 (m, 1H), 2.54-2.64 (m, 2H), 2.85-2.98 (m, 1H), 3.83 (s, 3H), 4.18 (q, J=6.3 Hz, 2H), 5.02 (d, J=6.3 Hz, 2H), 5.20 (dd, J=12.7 Hz, d=5.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.74-7.83 (m, 4H), 7.87-7.94 (m, 2H), 8.03 (t, J=7.8 Hz, 1H), 8.16 (d, J=7.7 Hz, 1H), 9.56 (t, J=6.3 Hz, 1H), 11.18 (s, 1H); 13C NMR (DMSO-d6) δ 14.8, 22.0, 31.0, 38.6, 49.0, 55.5, 64.0, 111.8, 119.8, 120.0, 122.0, 122.4, 127.3, 130.1, 131.7, 133.3, 134.9, 138.6, 139.1, 148.2, 149.2, 150.5, 155.1, 164.5, 167.0, 167.8, 169.8, 172.7; Anal. calcd for C29H26N4O7.0.5H2O: C, 63.15; H, 4.93; N, 10.16. Found: C, 63.36; H, 4.80; N, 10.19.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:20][OH:21])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:21][CH2:20][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 93 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (1.4 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (Example 14) (0.68 g), benzene (40 ml) and pyridine (0.26 ml) to yield the title compound (0.73 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][CH2:10][CH2:11][NH2:12]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:11][CH2:10][OH:9])=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: NCCO
Solvent: CC(=O)N(C)C
Product: OCCNc1ccc(Br)cn1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1 g, 5.2 mmol) and 2-hydroxyethylamine (1.59 g, 26 mmol) in 3 ml DMA was heated by microwaves at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc. The organic layers were washed with saturated aqueous NaHCO3 (4×), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH 0 to 5%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: tR 1.66 min (Method A); M+H=217, 219 (Br-pattern) MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCCN2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To a suspension of 5-bromo-2-(pyrrolidin-2-yl)pyridine (2.67 g, 11.8 mmol) in DCM (20 mL) at 0° C. was added DIEA (1.5 eq), followed by CbzCl (1.1 eq). The resulting clear solution was warmed to it and stirred for 2 h. The reaction mixture was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.35 in 50% EtOAc) to afford the titled compound as a brownish oil (3.63 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:72]1[CH2:77][CH2:76][CH:75]([N:78]2[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]2)[CH2:74][CH2:73]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([Cl:35])[CH:21]=3)[C:36](=[O:38])[N:81]3[CH2:80][CH2:79][N:78]([CH:75]4[CH2:76][CH2:77][O:72][CH2:73][CH2:74]4)[CH2:83][CH2:82]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 150 mg (0.25 mmol) (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 89 mg (0.28 mmol) TBTU and 44 μL (0.32 mmol) triethylamine in 1.5 mL DMF was stirred for 1 h at RT. Then 47 mg (0.28 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction solution was stirred for 2 h. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[S:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=3)[N:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCCC1>C1(C)C=CC=CC=1>[Cl:3][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:16][C:14]2[N:15]=[C:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[S:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of thionyl chloride (1.5 ml) in toluene (5 ml) was added to a mixture of 4-(2-phenyl-4-thiazolylmethoxy)benzyl alcohol (4.35 g), tetrahydrofuran (50 ml) and toluene (50 ml) under ice-cooling, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain colorless crystals of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (4.10 g, yield 89%). Melting point: 98–99° C.