Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:26])([F:25])[F:27])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([CH3:37])=[CH:39][CH:40]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 11 (60 mg, 0.118 mmol) in CH2Cl2 (2.0 mL) stirred at room temperature was added 4-methyl-benzoyl chloride (24.1 mg, 0.153 mmol), followed by Et3N (18 mg, 0.117 mmol). The reaction mixture was stirred at room temperature for 1 h. More 4-methyl-benzoyl chloride (24 mg, 0.153 mmol), and Et3N (18 mg, 0.117 mmol) were added. After another hour, the reaction mixture was purified by SiO2 chromatography directly (EtOAc:heaxanes/1:4) to afford 12 (52 mg, 70%). MS (ESI): 628 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>CC(C)=O.O>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][CH:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CSCCC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CSCCC(NC(=O)c1ccccc1F)C(=O)O

Procedure:
To a clear solution of D,L-methionine (10 g, 67.02 mmol) and NaOH (4.0 g, 100.53 mmol) in acetone (100 ml)/ H2O (100 ml) was added 2-fluorobenzoyl chloride dropwise with stirring between each addition. Basicity was maintained by adding 2N NaOH when necessary. After addition was completed, the reaction mixture was acidified to pH 2 with 6N HCl and extracted into EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated to give provide 2-(2-fluorobenzoylamino)-4-methylsulfanyl-butyric acid (intermediate XIIa, 13.6 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and ethyl trans-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate. 1H NMR (400 MHz, MeOD) δ ppm 8.51 (d, J=8.84 Hz, 1 H), 8.36 (s, 1 H), 7.89 (d, J=8.08 Hz, 1 H), 7.40 (d, J=8.84 Hz, 1 H), 7.08 (t, J=2.02 Hz, 1 H), 6.97 (dt, 1 H), 4.53 (s, 2 H), 4.06-4.20 (m, 6 H), 3.92 (s, 3 H), 3.35-3.36 (m, 1 H), 3.29-3.31 (m, 1 H), 3.20 (s, 3 H), 2.44-2.68 (m, 2 H), 2.14 (d, J=10.61 Hz, 2 H), 1.91-1.98 (m, 2 H), 1.57-1.77 (m, 4 H), 1.30 (q, 9H). MS (ES+): m/z=734.84 [MH+]. HPLC: tR=1.74 min (UPLC TOF, polar—3 min).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:30])(=[O:29])[NH:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)C>[N:6]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:30])(=[O:29])[NH:26][CH2:27][CH3:28])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: CCNS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Yield: 116.6 %

Procedure:
To the resulting 1-(4-formylpiperazin-1-yl)-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline (0.45 g) were added ethanol (20 ml) and a 8N aqueous solution of sodium hydroxide (651 ml), and the mixture was heated under reflux in nitrogen atmosphere for 1.5 hr. The solvent was evaporated, and to the resulting residue were added water and ethyl acetate. The organic layer was separated. Then it was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(piperazin-1-yl)-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline (0.49 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1N1CCCCC1
Temperature: 125 °C
Reaction time: 84 h
Yield: 89.3 %

Procedure:
A mixture of 150 mg (0.623 mmol) 1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in the previous step) and 272 μL (3.12 mmol) of morpholine were heated with stirring under Ar at 125° C. for 84 h. After cooling to rt, the mixture was poured into water (40 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL) and then dried (Na2SO4) Concentration afforded 162 mg (89%) of the title compound as an orange resin: Mass spectrum (ESI, m/z): Calcd. for C15H21N3O3, 292.2 (M+H), found 292.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.[Li+].[I-].Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: Oc1ccc(C#Cc2ccccc2)cc1

Procedure:
A procedure similar to that described1 was used. A sample of 1-methoxy-4-(phenylethynyl)-benzene (0.4 g, 1.9 mmol) was added collidine (3 mL), LiI (1.5 g) and the solution heated under reflux for 5 h (>95% conversion). The solution was poured into water acidified with HCl, extracted with ether (3×50 mL) and dried (MgSO4). The ether was evaporated and the residue chromatographed (PE) eluting the title compound 0.3 g (80%): mp 125°-128° C. (cyclohexane) (lit2 mp 91°-92°C., lit3 mp 83°-84° C.); 1H NMR (300 MHz, DMSO-d6) δ 6.80 (d, J=8.77 Hz, 2H, C2H), 7.37 (d, 2H, C3H), 7.35-7.42 (m, 3H), 7.46-7.50 (m, 2H), 9.92 (s, 1H, OH); 13C NMR (300 MHz, DMSO-d6) δ 87.32 (acetylenic C), 89.98 (acetylenic C), 112.42 (sp2C), 115.74, 122.90 (sp2C), 128.20, 128.66, 131.06, 133.00, 158.06 (COH); IR (CDCl3) 3596 (OH), 3066 (w), 3039 (w), 2217 (w, acetylenic stretch), 1605, 1512, 1429 (w), 1328 (w), 1261 (s), 1219, 1171 (s), 1140 (w), 1099 (w), 834, 805 (w) cm-1. MS (EI) m/e 194 (M+, 100), 165 (29.4), 97 (11.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([NH:12][C:13]1[CH:19]=[CH:18][C:17](=[O:20])[C:16]([NH2:21])=[CH:15][CH:14]=1)=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([NH:12][C:13]1[CH:19]=[CH:18][C:17](=[O:20])[C:16]([NH:21][C:23](=[O:25])[CH3:24])=[CH:15][CH:14]=1)=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C=C(Nc1ccc(N)c(=O)cc1)C(=O)OCC
Product: CCOC(=O)C=C(Nc1ccc(NC(C)=O)c(=O)cc1)C(=O)OCC

Procedure:
A solution of 2-(4-amino-5-oxo-1,3,6-cycloheptatrien-1-ylamino)-2-butenedioic acid diethyl ester (1.7 g, described in Example 1) in acetic anhydride (17 ml) is stirred at room temperature for 16 hr. The solution is evaporated and the residue is dissolved in ethyl acetate. The solution is washed with 1N potassium hydroxide and water, dried over sodium sulfate and evaporated to give a residue of 2-(4-acetylamino-5-oxo-1,3,6-cycloheptatrien-1-ylamino)-2-butenedioic acid diethyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CCC(=O)O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-{2-[(tert-butoxycarbonyl)amino]phenyl}-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in DCM (0.05 M) a large excess (>100 eq) of TFA was added and the solution was stirred at RT for 1 h. The volatiles were removed in vacuo to afford the title compound (quant); MS (ES+) m/z 421 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>[Pd].CO>[NH2:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NCCCO)c(N)c1
Yield: 91 %

Procedure:
A mixture of 70 parts of 3-[(4-methyl-2-nitrophenyl)amino]-1-propanol and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 54 parts (91%) of 3-[(2-amino-4-methylphenyl)amino]-1-propanol as a residue.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[S:4](=[O:15])(=[O:14])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:36](=[O:37])[C:35]2[CH:38]=[CH:39][CH:40]=[C:33]3[C:34]=2[C:29](=[CH:30][CH:31]=[CH:32]3)[C:28]1=[O:41]>CN(C=O)C>[O:41]=[C:28]1[C:29]2[C:34]3[C:33](=[CH:40][CH:39]=[CH:38][C:35]=3[C:36](=[O:37])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][N:3]1[C:2](=[O:1])[C:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=3[S:4]1(=[O:15])=[O:14])[CH:32]=[CH:31][CH:30]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)N(CCCCN1C(=O)c3cccc4cccc(c34)C1=O)C2=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-oxo-2,3-dihydrobenzo[d]isothiazole-6-carboxylic acid 1,1-dioxide (8) (1 mmol) and anhydrous K2CO3 (5 mmol) in DMF was added 2-(4-bromobutyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3b) (3 mmol). The reaction mixture was gently refluxed for overnight, cooled to room temperature and poured into the crushed ice. The resulted solution was acidified with con. HCl and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum to get the crude product. The Crude residue was purified by flash column chromatography using MeOH—CHCl3 (2:8) to obtain the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.34 (m, 6H), 7.91-7.77 (m, 3H), 4.41-4.37 (m, 2H), 4.14-4.08 (m, 2H), 1.89-1.71 (m, 4H). MS (ES−) m/z 477 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH2:32]([O:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][C:40]([CH2:46]Cl)=[CH:41][CH:42]=2)[CH:37]=1)[CH:33]=[CH2:34]>>[CH2:32]([O:35][C:36]1[CH:37]=[C:38]2[C:43]([CH:42]=[CH:41][C:40]([CH2:46][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:24]=[CH:23][S:22][CH:21]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]3)=[CH:39]2)=[CH:44][CH:45]=1)[CH:33]=[CH2:34]
Reactant: C=CCOc1ccc2ccc(CCl)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccsc3)cc2)C(O)C1
Product: C=CCOc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccsc4)cc3)cc2c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-allyloxy-7-chloromethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(7-allyloxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate, from which after cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152 (e) there was obtained tert-butyl (3RS,4RS)-3-(7-hydroxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a yellowish, viscous oil; MS: 604 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13][CH2:12]3)[CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:30]([C:40]([F:43])([F:42])[F:41])[CH:29]=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O.CCOC(C)=O>[N:35]1([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:26]([N:15]3[C:16]4[C:11](=[CH:10][C:9]([O:8][C:4]5[CH:3]=[C:2]([NH2:1])[N:7]=[CH:6][N:5]=5)=[CH:18][CH:17]=4)[CH2:12][CH2:13][CH2:14]3)=[O:25])=[CH:29][C:30]=2[C:40]([F:41])([F:42])[F:43])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Nc1cc(Oc2ccc3c(c2)CCCN3)ncn1
Reactant: O=C(Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(c2)CCCN3C(=O)Nc2ccc(CN3CCCC3)c(C(F)(F)F)c2)ncn1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 85 mg (0.35 mMol) 6-amino-4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidine (Step 1.3) and 0.33 mMol (4-pyrrolidin-1-ylmethyl-3-trifluoromethyl-phenyl)-carbamic acid phenyl ester in 2 ml DMSO is heated to 60° C. Then 65 μl (0.38 mMol) diisopropyl-ethyl-amine are added and stirring at 60° C. continued for 3 h. The resulting solution is poured into water containing 30 mg KOH and EtOAc, the aqueous layer separated off and extracted 2× with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAC→EtOAc/(EtOH+1.5% Et3N) 19:1) gives the title compound: MS: [M+1]+=513; HPLC: tARet=8.8; Anal.: C,H,N,F.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[CH:25]=[C:24]([CH3:27])[N:23]=[C:22]([NH2:28])[C:21]=2[N:20]=[C:19]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:22]1[C:21]2[N:20]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[CH:25]=[C:24]([CH3:27])[N:23]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 36-45, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2666.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][O:33][C:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[O:36][N:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:39]([C:37]4[O:36][N:35]=[C:34]([O:33][CH3:32])[CH:38]=4)=[O:40])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: COc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cc(F)c43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light red oil. MS: 570.1 (MH+, 1Cl).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH:27]=[N:28]O)[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1>CC#N.O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]#[N:28])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](C=NO)CC4)c3)ncnc21
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: N#C[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
[A] cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 μL, 0.0000784 mol) was added and the resulting mixture was stirred at rt. After stirring 15 h, LCMS analysis showed formation of the product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm×100 mm C18 column; 45% CH3CN—H2O (0.1% NH4OH), 1 min, to 75% at 6 min; 30 mL/min; detector set at m/z 423; retention time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:18]([C:19](O)=[O:20])=[C:17]([F:22])[C:16]([CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:14]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:12][C:13]1[C:18]([C:19]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:20])=[C:17]([F:22])[C:16]([CH2:23][NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3cccnc23)c1F
Yield: 10.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using quinolin-8-amine (Intermediate-48, 50 mg, 0.34 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 119 mg, 0.41 mmol), oxalyl chloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (132 mg, 1.02 mmol) in CH2Cl2 (5 mL) to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.91 (s, 1H), 8.71 (d, J=8.1 Hz, 1H), 8.48 (d, 1H), 8.16 (t, 1H), 7.78 (d, 1H), 7.67 (t, J=7.2 Hz, 2H), 7.40 (m, 2H), 4.32 (d, 2H), 1.14 (s, 9H); MS (m/z): 414.23 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1.[C:26](O)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C=O)C>[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:26](=[O:28])[CH3:27])[CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1
Reactant: O=C(O)c1cn(CCO)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Yield: 96.7 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.50 g (4 millimole), anhydrous acetic acid 0.7 g (7 millimole), triethylamine 0.5 g (5 millimole) and DMF 5 ml was heated at 90°-100° C. for 3 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum, and acidified with acetic acid. The precipitated crystals were collected by filtration, washed successively with water and ethanol and dried. 1.46 g (97%) of 1-(2-hydroxyethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as yellowish powders.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7]([O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:9])=[O:8].[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].S(=O)(=O)(O)O>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][N:37]([C:29]([C@@H:13]2[CH2:12][C@@H:11]([O:10][S:7]([CH3:6])(=[O:8])=[O:9])[CH2:15][N:14]2[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])=[O:31])[C:36]1=[O:40]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C1NCCN1CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 7.4 %

Procedure:
To a mixture of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (1.2 ml) was added dropwise phosphorus oxychloride (0.58 ml) at -5° C. and the mixture was stirred at 5° C. for 5 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)proline (2.0 g) in tetrahydrofuran (20 ml) under ice-cooling. The solution was stirred at the same temperature for 30 minutes. To this solution were added 3-(2-hydroxyethyl)-2-oxoimidazolidine (1.0 g) and conc. sulfuric acid (0.035 ml) and the mixture was stirred at 45°-50° C. for 2 hours. Ethyl acetate (50 ml) and water (30 ml) was added to the reaction mixture. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (50 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]carbonyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (0.19 g).