Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:43])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:43])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M292) (337 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (142 mg, 52%).
Reaction SMILES: C(O[C:6]1[C:11]2[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[C:13]([CH2:15][CH2:16]CC)=[N:14][C:10]=2[C:9](C)=[CH:8][CH:7]=1)CCC>C(Cl)Cl.C(O)C>[CH2:15]([C:13]1[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1)[CH3:16]
Reactant: CCCCOc1ccc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c12
Solvent: CCO
Solvent: ClCCl
Product: CCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(7-n-butoxy-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([OH:37])=O>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35](=[O:37])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[CH:11]=1)[CH3:2]
Reactant: O=C(O)Cc1ccccn1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2ccccn2)c1

Procedure:
[5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and 2-pyridylacetic acid hydrochloride were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(2-pyridin-2-yl-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].C(CS[C:12](=[S:18])SCC(O)=O)(O)=O.[CH:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:20]>O>[CH:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][NH:21][CH:1]=[O:4])=[CH:24][CH:25]=2)=[S:18])=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: [Na+]
Solvent: O
Product: O=CNNc1ccc(NC(=S)Nc2ccc(NNC=O)cc2)cc1
Temperature: 95 °C
Reaction time: 0.08 h

Procedure:
Sodium carbonate (2.1 g, 0.02 mole) was dissolved in water (100 ml). Bis(carboxymethyl)trithiocarbonate (4.5 g, 0.02 mole) was added portionwise with vigorous stirring. The pH of the reaction mixture was adjusted to 9.5 by the addition of sodium carbonate. The mixture was then heated to approximately 95° C. 1-Formyl-2-(4-aminophenyl)hydrazine (6.5 g, 0.043 mole) was added in one portion to the reaction mixture. Stirring was continued for five minutes. The reaction mixture was chilled, the solid was filtered off, washed thoroughly with water and dried. Yield 4.5 g (66%), m.p. 212°-214° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.N1C=CN=C1.[C:17]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=O>[Pd]>[N:24]1([C:17]2[N:19]=[C:23]3[CH:22]=[N:21][C:20]4[N:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]3[CH:2]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Pd]
Agent: c1c[nH]cn1
Product: c1cnc2ncc3nc(-n4ccnc4)cn3c2c1

Procedure:
Prepare by reaction of 2,6-dichloro-3-nitropyridine with excess imidazole followed by hydrogenation with palladium on carbon and cyclization with carbonyldiimidazole to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[CH:7][C:8]2=O)=[CH:4][CH:3]=1>O.Cl.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[OH:11]
Reactant: O=C1C=Cc2ccc(Cl)c(O)c21
Agent: Cl
Agent: [Zn]
Solvent: O
Product: Oc1c(Cl)ccc2c1CCC2
Yield: 69.6 %

Procedure:
3.2 g of 6-chloro-7-hydroxy-1H-inden-1-one in 16.8 ml of water and 67.2 ml of concentrated aqueous hydrochloric acid were stirred and heated with freshly prepared zinc amalgame (from 26.88 g of zinc wool) in an oil bath at 120° C. for 16 hours. The reaction mixture was cooled, decanted and treated with ethylacetate and dichloromethane. The organic layer was evaporated in vacuo. The residue was purified by an acid/base separation yielding 2.08 g of 5-chloro-2,3-dihydro-1H-inden-4-ol, M.S. (C.I.) (M/Z): 169 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1C(=O)[O:7][N:6]=[C:5]1[C:10]1[C:14]2[CH:15]=[C:16]([CH:29]3[CH2:31][CH2:30]3)[C:17]([N:19]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=2[O:12][C:11]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.[OH-].[Na+]>C(O)C>[CH:29]1([C:16]2[C:17]([N:19]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]3[O:12][C:11]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)=[C:10]([C:5]4[NH:4][CH2:3][CH2:2][O:7][N:6]=4)[C:14]=3[CH:15]=2)[CH2:30][CH2:31]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)n3CCCl)c2cc1C1CC1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C3=NOCCN3)c2cc1C1CC1)S(C)(=O)=O
Yield: 47.7 %

Procedure:
A mixture of Example 10H (61 mg, 0.109 mmol) and 1.0 M sodium hydroxide (0.271 mL, 0.271 mmol) in ethanol (2 mL) was refluxed for 1 hour, cooled and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 1% to 4% methanol in dichloromethane to give the title compound as a solid (26 mg, 47%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.55 (m, 1H) 0.83 (m, 6H) 0.88 (m, 1H) 0.99 (m, 2H) 1.26 (m, 1H) 1.38 (m, 1H) 1.61 (m, 1H) 2.38 (m, 1H) 3.12 (s, 3H) 3.45 (m, 2H) 3.63 (m, 1H) 3.73 (m, 1H) 3.99 (t, J=4.65 Hz, 2H) 7.05 (s, 1H) 7.24 (t, J=3.20 Hz, 1H) 7.40 (m, 2H) 7.83 (s, 1H) 8.00 (m, 2H); MS (ESI+) m/z 500 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]1([C:38](=[O:44])[CH2:39][C:40](=O)[CH2:41][CH3:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:41](/[C:40](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:39]/[C:38](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 40 mg (0.092 mmol) of Intermediate 50 and 17 mg (0.092 mmol) of Intermediate 16 to yield 21 mg of Example 5: TLC (DCM/MeOH, 4/1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.59 (d, 1H, J=9.8), 8.09 (d, 2H, J=9.0), 7.85 (d, 2H, J=8.8), 7.78 (m, 2H), 7.39 (m, 3H), 7.12 (d, 2H, J=8.0), 6.80 (d, 2H, J=8.0), 5.54 (s, 1H), 4.15 (t, 2H, J=6.6), 4.17 (m, 1H), 3.11 (m, 1H), 2.90 (t, 2H, J=6.6), 2.72 (m, 1H), 2.33 (s, 3H), 1.98 (m, 2H), 0.9 (t, 3H, J=7.5); low resolution MS (ES+)m/e 593.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]#[N:20])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12](/[C:18](/[C:19]#[N:20])=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CC#N)cc2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(/C(C#N)=C/c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of 0.231 mmol tert-butyl-7-(cyanomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2 ml ethanol were added 0.278 mmol of NaOEt solution (21%) and 0.254 mmol benzaldehyde. The mixture was stirred at room temperature over night. The mixture was diluted with ethanol and H2O, and a white precipitation observed. The solid was filtered off and washed with ethanol and H2O. The white solid was dissolved in methanol. Evaporation of the solvent gave 64 mg (77%) of solid material.
Reaction SMILES: Cl[CH2:2][C:3]([O:9][C:10](=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:4][O:5][CH2:6][CH2:7][CH3:8].C([O:21][PH:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])C.[K].[I-].[K+].[CH2:31](C(C)=O)[CH3:32]>>[CH2:31]([P:22]([NH:24][CH:25]([CH3:26])[CH3:27])(=[O:23])[O:21][CH2:2][C:3]([O:9][C:10](=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:4][O:5][CH2:6][CH2:7][CH3:8])[CH3:32]
Reactant: CCCON=C(CCl)OC(=O)Nc1ccccc1
Reactant: CCO[PH](=O)NC(C)C
Reactant: CCC(C)=O
Agent: [I-]
Agent: [K+]
Agent: [K]
Product: CCCON=C(COP(=O)(CC)NC(C)C)OC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
1-Chloro-2-(N-phenylcarbamoyloxy)-2-propoxyiminoethane (13.5 grams; 0.05 mole), methyl ethyl ketone (60 ml), potassium ethyl-N-isopropylphosphonamidate (9.4 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N-phenylcarbamoyloxy)-2-propoxyiminoethyl] ethyl-N-isopropylphosphonamidate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[O:16][CH2:17][C:18](=[O:23])[C:19]=1[C:20]([O-:22])=[O:21].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.N1CCC[CH2:37][CH2:36]1>C(O)C>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:17]2[O:16][C:15]([NH:14][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:7][C:2]=3[CH3:1])=[C:19]([C:20]([O:22][CH2:36][CH3:37])=[O:21])[C:18]2=[O:23])=[CH:25]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Cc1cc(CN2CCCC2)ccc1NC1=C(C(=O)[O-])C(=O)CO1
Reactant: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(CN3CCCC3)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a solution of 2-{[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.25 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 129, First step to Third step and 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) in ethanol (10 mL), piperidine (0.014 mL, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature then the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.035 g, y. 10%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:30])([F:31])[C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:25]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 4-(4-trifluoromethyl-phenoxy)-benzylamine (0.133 g, 0.5 mmol), and K2CO3 (0.235 g, 1.7 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[4-(4-trifluoromethyl-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.116 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.81 (s, 2H) 7.01-7.56 (m, 1H), 7.91 (d, 1H). GC-MS: m/z 383 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH3:26])[C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)([OH:12])[CH2:9]1)=[O:7])[CH3:4].[CH3:27]I>C1COCC1>[CH2:3]([N:5]([CH3:26])[C:6]([CH:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]([F:25])[CH:14]=2)([O:12][CH3:27])[CH2:9]1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)C(=O)C1CC(OC)(c2ccc(CN3CCCC3)c(F)c2)C1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% wt, 0.040 g, 1.00 mmol) was added to a solution of Example 14, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethyl-methyl-amide (0.25 g, 0.748 mmol) in THF (5 mL). After stirring for 15 min, all gas evolution ceased and methyliodide (0.06 mL, 0.96 mmol) was added. The resulting mixture was stirred at room temperature for 16 h then quenched with water and extracted into EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated to give the title compound as a light yellow oil (0.13 g): Rf=0.16 (20% MeOH/EtOAc); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[CH2:36]([NH2:38])[CH3:37].C1COCC1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:38][CH2:36][CH3:37])[CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:13][CH2:14]1)(=[O:8])=[O:7]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN(C)C)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (25 mg, 0.05 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added 2M ethyl amine in THF (0.15 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (12 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([OH:53])=O)[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[F:28][C:26]1[CH:25]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:53])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
TSTU (106 mg, 0.33 mmol) was added in one portion to a stirred solution of 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (144 mg, 0.30 mmol, >98% enantiomeric purity, made from the second eluting ester enantiomer from chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—see below) and DIPEA (0.057 mL, 0.33 mmol) at room temperature and the resulting mixture was stirred for 1.5 h. Morpholine (0.052 mL, 0.60 mmol) was then added to the reaction mixture and stirring was continued over the week-end. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one (69 mg, 44%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN(C)S(C)(=O)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 25 °C
Yield: 80 %

Procedure:
6-Methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-one (2.24 g, 6.6 mmol) was taken up in thionyl chloride (25 ml) and treated with DMF (5 drops). The resulting solution was then heated at reflux for 1 hour followed by cooling to ambient temperature. The excess thionyl chloride was removed by evaporation followed by azeotroping with toluene (3×). The residue was basified with saturated aqueous sodium hydrogen carbonate solution (to pH8) and extracted twice with ethyl acetate. The organic solution was washed with water, brine, dried (MgSO4) and evaporated to dryness to give 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (1.90 g, 80%).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:24]([CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:26])=[O:25])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)Cc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.35 g of phenylmethanesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was chromatographed on 30 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated. Recrystallization of the residue from 5 ml of ethyl acetate yielded 60 mg of N-[4-(3-nitro-phenyl)-thiazol-2-yl]-C-phenyl-methanesulfonamide as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][CH2:18][C:19]([O:21]CC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]1([CH2:9][S:8][C:6]2[NH:7][C:2]3[NH:1][C:19](=[O:21])[CH2:18][S:17][C:3]=3[C:4](=[O:16])[N:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CSc2c([nH]c(SCc3ccccc3)nc2=O)N1

Procedure:
To a solution of the product from step b) (0.30 g) in dry toluene (60 ml) was added p-toluene sulphonic acid (50 mg) and the solution heated under reflux for 11 hours. The resultant solid was collected by filtration, washed with ether and dried to give the subtitle compound as a colourless solid (0.290 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](Cl)=[O:29]>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:29]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccc(F)cc1Cl
Yield: 50.9 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.37 mL, 2.7 mmol) and 2-chloro-4-fluorobenzene-1-carbonyl chloride (Acros, 0.25 g, 1.3 mmol) in 15 mL THF were processed using the method described in Example 132 to afford the title compound (0.19 g, 0.56 mmol, 52% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.27 (s, 3H), 3.30 (s, 3H), 3.76 (t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 7.00 (ddd, J=8.5, 7.8, 2.4 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 8.04 (dd, J=8.8, 6.4 Hz, 1H); MS (DCI/NH3) m/z 343 (M+H)+; Anal. calculated for C15H16ClFN2O2S: C, 52.55; H, 4.70; N, 8.17. Found: C, 52.60; H, 4.38; N, 8.06.