Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:31]=[C:30]([C:32](=[O:34])[NH2:33])[CH:29]=[CH:28][C:10]=1[O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:27].O>CN(C=O)C>[C:32]([C:30]1[CH:31]=[CH:9][C:10]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18][O:19]3)=[CH:14][C:13]=2[Cl:27])=[CH:28][CH:29]=1)(=[O:34])[NH2:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3N)c(Cl)cc21
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(Cl)cc21
Temperature: 68.5 °C
Reaction time: 0.62 h
Yield: 94.4 %

Procedure:
To a solution of isobutyl nitrite (3.92 g, 15.2 mmol) in DMF (100 mL) at 66° C. was added a solution of ethyl 7-(2-amino-4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (5.94 g, 15.2 mmol) in DMF (30 mL) dropwise over 14 minutes. The temperature rose to 70° C. during the addition and gas began to evolve. After 37 minutes of stirring at 68-69° C. the resulting solution was cooled to ambient temperature and poured into a reparatory funnel containing water (1500 mL). The resulting mixture was extracted with ethyl acetate (250 mL) and the organic layer was washed with 1M HCl, and brine, dried over sodium sulfate and concentrated to give 5.39 g of brown solid. The solid was triturated with ether and filtered to provide the desired product (4.86 g, 85%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.C1CCCCC1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step A) (4.0 g, 16 mmol) in tetrahydrofuran (25 mL) was cooled to −78° C., and then treated dropwise with 2 M n-butyllithium in cyclohexane (8.6 mL, 17.2 mmol). The reaction mixture was stirred for a further 30 minutes, and then a solution of hexachloroethane (4.2 g, 18 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was stirred for 1 h, warmed to room temperature, and quenched with water (50 mL). The resulting solution was extracted with dichloromethane, dried (MgSO4), and concentrated under reduced pressure to give 4.38 g of title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3Cl)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-chlorophenyl)-6-hydroxy-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml), 6.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the mixture was subsequently refluxed for 4 hours. After cooling the mixture, water and 50 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 4.6 g of 5-chloro-3-(2-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 162°-163° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 335.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:41][N:42]1C(=O)C[CH2:44][CH2:43]1.CNCCO.[OH2:53]>CCOC(C)=O>[OH:53][CH2:44][CH2:43][N:42]([CH3:41])[C:25](=[O:33])[NH:24][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:34])[N:3]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O
Reactant: CN1CCCC1=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Agent: CNCCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N(C)CCO)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 59 %

Procedure:
A mixture of phenyl (4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (30 mg, 0.05 mmol), NMP (5 mL) and 2-(methylamino)ethanol (5.0 mg, 0.06 mmol) was heated at 40° C. for 1.5 hours. The mixture was cooled to rt, and diluted with EtOAc (15 mL) and water (10 mL). The separated organic layer was washed with water (10 mL×3), followed by washing with brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=20/1), and then washed with ether (5 mL) to give the title compound as a white solid (17 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:26]([Mg]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C[O:38]CC1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CCC1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Temperature: 0 °C

Procedure:
A solution of tert-butyl[1-(4cyanophenyl)cyclobutyl]carbamate (1-2) (16.6 g, 61.0 mmol) in anhydrous THF (300 mL) was cooled to −78° C. while stirring under an atmosphere of nitrogen. Then a 2.0 M solution isopropylmagnesium chloride in THF (30.5 mL, 61.0 mmol) was added dropwise over 5 minutes. The reaction mixture was permitted to stir at −78° C. under an atmosphere of nitrogen for 10 minutes. Then a 2.0 M solution of benzylmagnesium chloride in THF (116 mL, 232 mmol) was added dropwise over 10 minutes. The reaction mixture was permitted to warm to 0° C. After 2 hours the reaction mixture was quenched at 0° C. by addition of a saturated solution of ammonium chloride. The reaction was permitted to warm to room temperature, suspended in ethyl acetate, washed with a saturated solution of ammonium chloride, a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (1-40% EtOAc/5% DCM/Hexane) to give tert-butyl{1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (1-3) as a waxy off-white solid. HRMS (M+Na)+: observed=388.1892, calculated=388.1883.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([OH:37])[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].O>O1CCCC1.C(OCC)C>[CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
3-Dodecyloxy-1-triphenylmethoxy-2-propanol (13.5 g, 0.027 mol) was added dropwise to an ice-cooled suspension of sodium hydride (80%, 1.6 g, 0.054 mol) in 150 mL of tetrahydrofuran under nitrogen. After stirring for 2 h at room temperature, heat was applied (55° C.). 1-Bromodecane (6 g, 0.027 mol) was added dropwise, and heating continued for 6 h. After cooling for 3 h, water was added slowly. Diethyl ether (2×100 mL) was added, and the solution washed with 15% sodium thiosulfite, water, and brine. After drying over sodium sulfate, the ether was removed, and the residue chromatographed with a gradient of hexanes:ethyl acetate (100:0 to 20:1) to give 9 g (52%) of a clear liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1.[CH3:17][NH:18][CH3:19]>>[ClH:1].[ClH:1].[CH3:17][N:18]([CH3:19])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[S:5]1
Reactant: CNC
Reactant: CN1CC(CCCl)Sc2ncccc2C1=O
Product: CN(C)CCC1CN(C)C(=O)c2cccnc2S1
Product: Cl

Procedure:
A solution of 1.5 g (0.0058 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-thiazepin-5(4H)-one in 20 ml of dimethylamine was stirred at 25° C. in a sealed container for 72 hr. The excess dimethylamine was allowed to evaporate and the residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was concentrated and the residue, the free base of the title compound, was dissolved in isopropyl alcohol and reacted with hydrogen chloride. The resulting hydrochloride salt weighted 1.5 g (77%), m.p.>250° C.
Reaction SMILES: C([O:3][P:4]([C:9]([F:25])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:8])[O:5]CC)C.C(Cl)Cl>>[F:25][C:9]([P:4](=[O:3])([OH:5])[OH:8])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCC(F)(F)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(F)(F)P(=O)(O)O
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of vacuum dried 10 (225 mg, 0.585 mmol) in methylene chloride (5 mL) bromotrimethyl silane (895 mg, 5.85 mmol) was added and the mixture was stirred at room temperature. TLC showed completion of the reaction after 6 h. Solvents were removed under reduced pressure, and the residue was stirred in 95% methanol (3 mL) for 1 h. The mixture was concentrated under reduced pressure, dried under vacuum to give 150 mg (78%) of 11 as light yellow solid. mp 66-69° C.; 1H NMR (CD3OD): δ2.03 (m, 2H), 1.59 (m, 2H), 1.24 (br s, 22H), 0.90 (t, J=6.6 Hz, 3H); MS: [M-H]— at m/z 327.3. Anal. (C15H3]F2O3P.0.2H2O)C, H.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=CC(=O)[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].NC1C=C([C@@H](O)CBr)C=CC=1OCC1C=CC=CC=1>>[NH2:19][C:20]1[CH:15]=[C:14]([C@@H:5]([OH:6])[CH2:4][N:1]=[N+:2]=[N-:3])[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 14 in place of (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsily)oxy]ethyl]quinolin-2(1H)-one. ES/MS calcd. for C15H17N4O2+ 285.1. Found m/z=285 (M+H)+.
Reaction SMILES: ICC.C([O-])([O-])=O.[K+].[K+].[C:10]([O:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([OH:21])[C:15]=1[Cl:22])(=O)[CH3:11]>CN(C=O)C.C(OCC)C>[Cl:22][C:15]1[C:14]([O:13][CH2:10][CH3:11])=[CH:19][C:18]([I:20])=[CH:17][C:16]=1[OH:21]
Reactant: CC(=O)Oc1cc(I)cc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(I)cc(O)c1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Iodoethane (0.78 mL, 9.6 mmol) and K2CO3 (1.3 g, 9.6 mmol) were added to a solution of 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (2.0 g, 6.4 mmol) in DMF (5 mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to RT, diluted with diethyl ether (100 mL) and washed with brine (3×100 mL). The solvent was removed in vacuo and the residue was dissolved in MeOH (20 mL). K2CO3 (1.0 g, 7.2 mmol) was added and the mixture was stirred at RT for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (100 mL) and evaporated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-30% EtOAc in isohexane) to afford 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 58% yield) as a colourless solid: m/z 297 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (1H, s), 6.89 (2H, d), 4.04 (2H, br s), 1.32 (3H, br s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[N:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=3)[N:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: FC(F)(F)c1ccc2nc(CCl)ccc2c1
Solvent: CCO
Product: FC(F)(F)c1ccc2nc(CN3CCCC3)ccc2c1

Procedure:
2-(Pyrrolidin-1-ylmethyl)-6-trifluoro-methylquinoline may be prepared by carrying out the procedure as in Example 29, but starting with 3 g of -2-chloromethyl-6-trifluoromethylquinoline and 2.6 g of pyrrolidine in 30 ml of ethanol. The crude product obtained is chromatographed on a silica gel column, eluting with a mixture of dichloromethane and methanol (99-1 by volume). 2.5 g of 2-(pyrrolidin-1-ylmethyl)-6-trifluoromethylquinoline are thus obtained in the form of an orange-coloured oil [1H NMR spectrum in CDCl31 T=300K, δ in ppm (300 MHz) : 2.15 (4H, m, 2 CH2), 3.30 (4H, m, 2 NCH2), 4.50 (2H, s, NCH2), 7.90 (1H, d, J=8 Hz, arom. CH), 8.15 (2H, m, 2 arom. CH), 8.25 (1H, d, J=8 Hz, arom. CH), 8.35 (1H, d, J=8 Hz, arom. CH)].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[N:29]([CH3:31])[CH3:30].[C:32](OC(=O)C)(=[O:34])[CH3:33].[O:39]1CCO[CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:32]([N:1]([C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[N:29]([CH3:31])[CH3:30])[C:40](=[O:39])[CH3:41])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: C1COCCO1
Reactant: CN(C)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(C(C)=O)c1c(N(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 105 °C

Procedure:
To the product of EXAMPLE 72 (48.8 mg) in 1,4-dioxane (1 mL) was added acetic anhydride (2 mL) and DMAP (20 mg). The reaction was heated to 105° C. After about 1 hour the reaction was cooled to room temperature and diluted with EtOAc. The solution washed with saturated aqueous NaHCO3/1 M aqueous NaOH solution (1:1). The organic layer was dried (Na2SO4). The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. HPLC/MS: 557.1 (M+1), 559.1 (M+3); Rt=4.40 min.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([O:3][CH2:4][CH3:5])=[O:2].[C:14]1(=[O:21])[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]1.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](=[NH:29])[NH2:28])[CH3:23]>C(O)C>[CH2:22]([O:24][C:25]([C:26]1[CH:9]([C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[C:15]2[C:14](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]=2[NH:28][C:27]=1[NH2:29])=[O:30])[CH3:23]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1cccc(C=O)c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc(C(=O)OCC)c1
Yield: 54 %

Procedure:
Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-4-(3-carbethoxyphenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 234°C (ethanol) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (284 mg).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (100 mg, 0.31 mmol), 4-formylphenylboronic acid (56 mg, 0.37 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 1M Na2CO3 aqueous solution (1.2 mL, 1.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 100 mL of water. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as orange/red solid. Yield: 100 mg, 93%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:47])[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)nc1

Procedure:
1-[4-(5-Nitro-pyridin-2-ylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (20 mg; 0.038 mmol, prepared in accordance with Example 95) is reacted with Lawesson's reagent (8 mg; 0.019 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (8 mg; 0.015 mmol). The structure was confirmed using Protocol I-B. Calculated mass=537; observed mass=537; HPLC retention time=4.39 min.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4](O)=[O:5])[CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:26].Cl.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(N(CC)CC)C>CN(C=O)C.C(OC(=O)C)C>[ClH:26].[NH2:1][C@@H:2]([CH3:3])[C:4]([NH:32][CH2:31][C:30]([F:34])([F:33])[F:29])=[O:5]
Reactant: ClCCCl
Reactant: NCC(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Boc-Ala-OH (14.24 g, 75.3 mmol), HOBT (1.35 g, 10 mmol), EDC (17.3 g, 90.4 mmol) and 2,2,2-trifluoroethylamine hydrochloride (10.2 g, 75.3 mmol) were dissolved in DMF (100 mL) using a water bath to maintain temperature. After the solids dissolved, triethylamine (20 mL, 150 mmol) was added and the resulting heterogeneous mixture stirred at room temperature overnight. The mixture was poured into ethylacetate (350 mL), washed with 1N HCl and brine then dried over Na2SO4. The solvent was removed under reduced pressure and the resulting oil dissolved in methanol (50 mL) and 2M HCl in ether (95 mL) then heated at 50° C. for 0.5 hours. The solvent was removed and the residue dried at 45° C. under vacuum to afford 12.2 g (78% yield) of the title compound (FF) as a white solid. FIA for C5H9F3N2O: 170.9 ES+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[N:6][CH:7]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=3[CH3:17])=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(=O)(=O)c3ccc(C#N)cc3)cn2)s1

Procedure:
Using an analogous procedure to that described in Example 83, N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was reacted with 4-cyanophenylsulfonyl chloride to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.48 (s, 3H), 7.57 (m, 2H), 7.94 (d, 2H), 8.07 (d, 2H), 8.26 (m, 1H), 10.86 (br s, 1H), 12.06 (s, 1H); Mass Spectrum: M+H+ 414.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[N:10][CH:11]=2.[C:14]1([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]=[C:5]1[C:6]2[C:7](=[N:8][CH:9]=[N:10][CH:11]=2)[N:12]=[C:3]([CH2:2][NH:1][S:22]([CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:24])=[O:23])[NH:4]1
Reactant: NCc1nc2ncncc2c(=O)[nH]1
Reactant: O=S(=O)(Cl)CCc1ccccc1
Product: O=c1[nH]c(CNS(=O)(=O)CCc2ccccc2)nc2ncncc12

Procedure:
In analogy to the procedure described in example 20.4, 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (example 20.3) was treated with 2-phenyl-ethanesulfonyl chloride [4025-71-2] to obtain 2-phenyl-ethanesulfonic acid (4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-amide as light brown solid. MS: m/e=346.3 [M+H+].