Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]([CH3:21])([CH3:20])[C:10](ON1C(=O)CCC1=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C@H:24]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)[C:25]([N:27]1[CH2:45][CH2:44][CH2:43][C:29]2([C:33](=[O:34])[N:32]([CH3:35])[CH2:31][CH:30]2[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:28]1)=[O:26].CCN(C(C)C)C(C)C>C1COCC1.O>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH:30]2[C:29]3([CH2:43][CH2:44][CH2:45][N:27]([C:25](=[O:26])[C@H:24]([NH:23][C:10](=[O:11])[C:9]([N:8]([CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:21])[CH3:20])[CH2:46][O:47][CH2:48][C:49]4[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=4)[CH2:28]3)[C:33](=[O:34])[N:32]([CH3:35])[CH2:31]2)=[CH:41][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc(COC[C@@H](N)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(COC[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoate (80 mg, 0.254 mmol) and 7-((R)-2-amino-3-(4-methylbenzyloxy)propanoyl)-4-(4-fluorophenyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one (115 mg, 0.254 mmol) in THF (3 ml) was added DIPEA (0.044 ml, 0.254 mmol) and the mixture stirred at RT overnight. The mixture was diluted with water (10 ml) and extracted with EtOAc (50 ml). The extracts were dried (MgSO4) and concentrated. The residue was applied to a 12 g silica cartridge which was eluted with ethyl acetate. The appropriate fractions were combined and concentrated to give tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(4-methylbenzyloxy)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate as a foam.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4](F)[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH-].[Na+].C(OCC)(=O)C.FC1C(F)=CC(F)=C(C(O)=O)C=1C(O)=O>O.[Zn].C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([F:13])=[C:6]2[C:11]([O:10][C:8](=[O:9])[C:7]=12)=[O:12]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC(=O)c2c(F)c(F)cc(F)c21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
5.5 g (25 mmol) of tetrafluorophthalic anhydride were added under nitrogen to a solution of 3.58 g (89.5 mmol) of sodium hydroxide in 30 g of water. The mixture was then heated at 100° C., and 6.54 g (0.1 mol) of zinc dust were added. The course of the reaction was monitored by GC(TLC), and the reaction was complete after 12 hours. 50 ml portions of water and ethyl acetate were added and the voluminous solids were filtered off with suction and washed four times with 50 ml portions of water. The colorless filtrate was brought to a pH of 1 and extracted using ethyl acetate. Drying of the organic phases over MgSO4, filtration and removal of the solvent in vacuo gave 4.72 g (22.2 mmol; 89%) of colorless powder which could be identified as 3,4,6-trifluorophthalic acid (melting point 156°-160° C). Azeotropic dehydration in boiling xylene gave 3,4,6-trifluorophthalic anhydride.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Fc1ccc(OCCCCCBr)cc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccc(F)cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound and 5-(4-fluorophenoxy)-pentyl bromide (1.1 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(4-fluorophenoxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH2:4].[CH:22]1([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:26]2[C:31]3=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]3[N:29]=[C:28](S(C)(=O)=O)[N:27]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH2:13][CH2:14]2)=[CH:7][C:6]([CH:19]([F:21])[F:20])=[CH:5][C:3]=1[NH:4][C:28]1[N:27]=[C:26]([N:25]([CH:22]2[CH2:24][CH2:23]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:31]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:30]2[N:29]=1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: Nc1cc(C(F)F)cc(N2CCN(C3COC3)CC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nc(Nc3cc(C(F)F)cc(N4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 76.8 %

Procedure:
A mixture of 2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline (50 mg, 0.157 mmol), 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (94 mg, 0.236 mmol) and cesium carbonate (103 mg, 0.315 mmol) in DMF (1574 μl) was stirred at 40° C. for 72 h. The reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organics were washed with 10% LiCl solution and concentrated. Column chromatography (12 g SiO2, 0 to 100% EtOAc-hexane gradient elution) afforded 2-((2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (76.7 mg).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([N:21]3[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][CH3:28])[CH2:22]3)=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH2:27]([O:26][C@H:23]1[CH2:24][CH2:25][N:21]([C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=3)[N:17]=[C:16]([CH3:20])[CH:15]=2)[CH2:22]1)[CH3:28]
Reactant: CCO[C@H]1CCN(c2cc(C)nc3cc(OCc4ccccc4)ccc23)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCO[C@H]1CCN(c2cc(C)nc3cc(O)ccc23)C1
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
A solution of 93 mg (0.23 mmol) of (S)-7-Benzyloxy-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline hydrochloride, product of example 28, dissolved in 7 ml of MeOH was treated with 48 mg of palladium on charcoal (10%) and then hydrogenated at RT for 1.5 h until HPLC analysis indicated the completion of the reaction. The catalyst was filtered off, washed with water, and the solution was concentrated in vacuo. The residue was triturated with n hexane/diethyl ether, the solid obtained was filtered off by suction and dried in a high vacuum to give 67 mg (90%) of (S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride as an off-white solid. ISP mass spectrum, m/e: 273.3 (M+1 calculated for C16H20N2O2: 273).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].CC1C=CC(NC(=O)C)=C(O[CH2:26][CH:27]2[CH2:29][O:28]2)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:10][C:11](=[O:13])[CH3:12])=[C:2]([O:1][CH2:26][CH:27]2[CH2:29][O:28]2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(C)cc1OCC1CO1
Reactant: COc1ccc(NC(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(NC(C)=O)c(OCC2CO2)c1

Procedure:
Was prepared from N-(2-hydroxy-4-methoxyphenyl)acetamide according to the method described for N-[4-methyl-2-(2-oxiranylmethoxy)phenyl]acetamide using cesium carbonate instead of potassium carbonate.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C@H:31]1[CH2:35][CH2:34][N:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][CH:36]([N:33]5[CH2:34][CH2:35][C@H:31]([F:30])[CH2:32]5)[CH2:37][CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: F[C@H]1CCN(C2CCNCC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC[C@H](F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.1 g, 0.255 mmol), 4-((S)-3-fluoropyrrolidin-1-yl)piperidine (0.053 g, 0.307 mmol) and 4 Å molecular sieves (0.25 g) in DCE (4 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.109 g, 0.51 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 40:60) to give 565 as a white solid (0.121 g, 87%). LCMS (Method I): RT=2.26 min, [M+H]+ 548.2 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.00 (m, 1 H), 7.65-7.61 (m, 1 H), 7.26-7.21 (m, 2 H), 5.16 (dt, J=56.0, 5.5 Hz, 1 H), 4.50-3.96 (m, 4 H), 3.82 (s, 3 H), 3.79-3.74 (m, 4 H), 3.75 (s, 2 H), 3.32-3.19 (q, J=7.4 Hz, 2 H), 2.89-2.74 (m, 4 H), 2.69-2.55 (m, 1 H), 2.37-2.28 (m, 1 H), 2.15-1.97 (m, 4 H), 1.90-1.74 (m, 3 H), 1.45-1.34 (m, 2 H), 1.34 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[C:8]([CH3:10])([CH3:9])[CH:7]1[C:11]#[N:12])=[O:5])[CH3:2].O.CN(C)C=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[C:8]([CH3:9])([CH3:10])[CH:7]1[C:11]#[N:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C#N)C1(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C(C#N)C1(C)C
Yield: 61 %

Procedure:
A mixture of 71.7 g (0.3 mol) of 3,3-dimethyl-2-cyano-cyclopropane-1,1-dicarboxylic acid diethyl ester, 6 ml of water and 100 ml of dimethylformamide was heated to the boiling point under reflux for 20 hours. For working up, the mixture was diluted with toluene, washed twice with 300 ml of water each time, dried and distilled. 30.6 g (61% of theory) of 3,3-dimethyl-2-cyano-cyclopropane-1-carboxylic acid ethyl ester of boiling point 87°-95° C./2 mbar were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:5][CH2:6]2)=[O:36])[CH2:39][CH2:38]1
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(NCC1CCN(C(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+].CCOC(C)=O>COCCOC.CCCCCC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Br)c[nH]1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(Br)ccc1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
The mixture of 5-bromo-2(1H)-pyridone (200 g) and MeI (324 g) and K2CO3 (318 g) in DME (2 l) was heated at 80° C. with stirring for 2 hours. The above mixture was cooled to room temperature. The precipitated salt was removed by filtration and washed with DME. Evaporation of solvent in the filtrate in vacuo gave oily residue. The residue was portioned to EtOAc and water. The organic layer was separated. Aqueous layer was extracted with EtOAc twice. The combined organic solution was dried over MgSO4. Evaporation of solvent in vacuo gave crystal residue. The residue was pulverized with IPE and n-hexane (1:3, 1000 ml). The precipitate was collected by filtration and dried in vacuo to give 5-bromo-1-methyl-2(1H)-pyridone as white powder (182.5 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>C(Cl)Cl>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][S:41]([C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)(=[O:43])=[O:42])=[CH:16][CH:15]=1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: COc1ccc2nccc(-c3ccc(CCN)cc3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)cc3)c2n1
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a stirred solution of 2-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)phenyl]ethylamine hydrochloride salt (0.10 g, 0.26 mmole), from Example 1a, in dry CH2Cl2 (25 mL) at RT was added triethylamine (0.11 mL, 0.78 mmole) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride (69 mg, 0.26 mmole). After 24 h, the reaction contents were concentrated. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.10 g, 75%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.06 (d, J=4.5 Hz, 1H), 8.57 (d, J=9.0 Hz, 1H), 8.26 (d, J=4.6 Hz, 1H), 8.10 (d, J=9.1 Hz, 2H), 7.73 (m, 3H), 7.45 (d, J=9.0, 1H), 7.17 (m, 2H), 4.25 (s, 2H), 4.06 (s, 3H), 3.77 (m, 2H), 3.31 (m, 2H). LC-MS (ES) m/e 507 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OC)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COc1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc1F
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F
Yield: 5.4 %

Procedure:
The title compound (0.021 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.35 g) using 3-fluoro-4-methoxybenzyl bromide (0.25 g) in place of benzyl chloride. The reaction sequence also provided 3-(4-chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H21ClFN3O, 385.14; found, m/z 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.06-7.02 (m, 1H), 6.90-6.86 (m, 2H), 5.29 (s, 2H), 3.84 (s, 3H), 3.35-3.29 (m, 2H), 2.94-2.92 (m, 4H), 2.88-2.85 (m, 2H), 2.80-2.77 (m, 2H). 13C NMR (125 MHz, CD3OD): 154.2, 152.2, 149.1, 148.1, 143.5, 134.2, 132.9, 131.1, 131.0, 130.5, 129.1, 123.3, 118.7, 115.0, 114.8, 114.4, 56.2, 52.4, 49.9, 28.8, 27.3.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][CH2:4]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][NH:17][C:16](=[O:28])[C:15]=2[C:29]#[N:30])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][N:17]([CH2:2][CH:3]3[CH2:5][CH2:4]3)[C:16](=[O:28])[C:15]=2[C:29]#[N:30])=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
(Chloromethyl)cyclopropane (0.6 ml, 6.36 mmol) was added to a solution of 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one (1.71 g, 5.10 mmol) and potassium carbonate (2.02 g, 14.62 mmol) in N,N-dimethylformamide (5 ml), followed by stirring at a bath temperature of 80° C. for 6 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate (300 ml). The organic layer was washed with water and a saturated aqueous solution of sodium chloride (brine), successively, and was then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby the title compound (1.413 g, 71.5%) was obtained as yellow crystals.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Yield: 97.7 %

Procedure:
A solution of N-tert-butyl-4-nitrobenzenesulfonamide (10.0 g, 39 mmol) in EtOH (100 mL) is stirred for 48 h under a H2 atmosphere in the presence of 10% Pd/C (1.50 g). The resulting mixture is filtered and concentrated to give the desired product as a slightly-coloured solid (8.7 g, yield: 98%).
Reaction SMILES: C([N:3]1CC[CH:6](C(O)=O)[CH2:5][CH2:4]1)C.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(#N)C=C>C(O)(C)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:6][CH2:5][C:4]#[N:3])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCN1CCC(C(=O)O)CC1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC(C)O
Solvent: C=CC#N
Product: CCOC(=O)C1CCN(CCC#N)CC1
Yield: 101.5 %

Procedure:
A solution of piperidine-4-carboxylic acid ethyl ester (ethylisonipecotate) (4.7 g, 30 mmol), acrylonitrile (1.7 g, 31 mmol) in isopropyl alcohol (30 ml) was stirred at room temperature for 15 hours, then evaporated to dryness to afford 1-(2-cyano-ethyl)-piperidine-4-carboxylic acid ethyl ester as an oil (6.4 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH:34][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1
Reactant: COC(=O)CN
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with glycine methyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light yellow foam, MS (ESI+): m/z=447.3 [M+H]+.
Reaction SMILES: O[C:2]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:5][CH:4]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.CCO.CS(O)(=O)=O.[OH-].[Na+]>CO.[Pd]>[N:7]1([CH2:6][CH:4]2[CH2:5][CH:2]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=3)[CH2:3]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc(C2(O)CC(CN3CCCC3)C2)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NCc1ccc(C2CC(CN3CCCC3)C2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirring soluiont of Example 213 (4-(1-Hydroxy-3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzonitrile) (500 mg, 1.9 mmol) in 20 mL of each MeOH and EtOH was added methanesulfonic acid (1.3 mL, 19.5 mmol), followed by 125 mg of 10% palladium/carbon. The reaction vessel was purged several times with N2 and then pressurized with 45 psi H2. After 1 h the reaction mixture was purged with N2 filtered through a plug of Celite and concentrated under reduced pressure. This mixture was re-dissolved in EtOH (20 mL) then 10% Pd/C (125 mg) was added. As before the reaction vessel was purged several times with N2, pressurized with 45 psi H2 and then heated to 50° C. After 2 hours the reaction mixture was purged with N2, filtered through a plug of Celite, and concentrated under reduced pressure to yield viscous oil. This oil was taken up in MeOH and solid NaOH (780 mg, 19.5 mmol.) was added. This mixture was stirred overnight. The solid were then filtered off and the filtrate was concentrated. The HCl salt was made by the first dissolving the residual compound in EtOAc and then a solution of HCl (2N in EteO) was added. The solids was collected and dried under reduced pressure. Purification of this material was accomplished by dry pack method flash column chromatography using a 40 g ISCO column, eluting with a gradient of 10%–40% MeOH/CH2Cl2 with 0.2% NH4OH. The product containing fractions were collected and concentrated to give the title compound (350 mg, 74% yield) as a colorless solid. The HCl salt of the title compound was made treating the title compound in EtOAc with a solution of HCl (2N in Et2O).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1cccc(Cl)c1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 2-chloro-6-methylbenzylamine (650 mg, 4.2 mmol) and Rhodanine (559 mg, 4.2 mmol) in acetonitrile (25 mL) was added DIPEA (1.74 mL, 10 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.22 g, 4.5 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 305 mg (28.5% yield) of 2-(2-chloro-6-methylbenzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H11ClN2OS (M+) 254.0281. found 254.0282.