Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:29]=O.O.[OH-].[Na+]>C(O)=O>[CH3:29][N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:4][CH2:5]1
Reactant: C=O
Reactant: OC1(C(CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 1-{2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (590 mg, 1.59 mmol) (see Example 23), in formic acid (3.1 mL) at 50° C., was treated with an aqueous solution of formaldehyde (37% in water, 1.3 mL, 1.94 mmol). The reaction was heated at 70° C. for 1.5 h, after which time the reaction was poured into water (50 mL) and basified to pH=10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3×20 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 442 mg (72%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H29F3N2O2.2.00 HCl, 458.1715; found (ESI), 387.2263.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH:16]=2)[CH:12]=[N:13][CH:14]=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=2)[CH:10]=1
Reactant: CN1CCC[C@H]1COc1cncc(-c2cc(CCCO)no2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cncc(-c2cc(CCCOc3ccccc3)no2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154 %

Procedure:
To a solution of 3-[5-[5-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-3-pyridyl]-3-isoxazolyl]-1-propanol (10 mg, 33 μmol), phenol (5 mg, 50 μmol, 1.5 equiv.) and PPh3 (13 mg, 50 μmol, 1.5 equiv.) in anhydrous THF (0.2 mL) was added diethyl azodicarboxylate (DEAD; 8 μL, 50 μmol, 1.5 equiv.) at 0° C. The mixture was stirred for 1 h at 0° C. and then warmed to room temperature. Stirring was continued for 11 h, then the mixture was concentrated in vacuo. The residue was purified by CC on SiO2 with CH2Cl2/MeOH 9:1 to give 3-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-[3-(3-phenoxypropyl)-5-isoxazolyl]pyridine (20 mg, 51%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C(O[C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH3:10])C>O>[NH2:13][C:12]1[O:3][N:2]=[C:9]([CH3:10])[C:11]=1[C:14]#[N:15]
Reactant: NO
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1noc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (27.8 g, 0.4 mol) and sodium hydroxide (16.0 g, 0.4 mol) in water (1000 mL) was treated with 2-(1-ethoxy-ethylidene)-malononitrile (54.42 g, 0.4 mol) over 1 h. After the addition, the reaction mixture was stirred at room temperature for 18 h. The resulting suspension was collected, washed with cold EtOAc (1000 mL) and air dried to afford the desired product as a white solid (35.8 g, 72%); 1H NMR (DMSO-d6) δ 8.32 (s, 2 H), 2.1 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Reactant: COC(OC)N(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (65) (84.5 g, 190.2 mmol) in N,N-dimethylformamide dimethyl acetal (250 mL) was heated to reflux for 5 h. At this time, the reaction was cooled to room temperature. The solids that resulted were collected by filtration, washed with a 1:1 mixture of methyl tert-butyl ether:heptane (70 mL) followed by heptane (70 mL) and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (66) (63.57 g, 73%) as an off-white solid; ES(+)-LRMS for C22H17Cl2N3O4 (M+H)+ at m/z=458. Exact Mass=457.0596; Molecular Weight=458.30.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC.C(Cl)Cl>[C:24]1([C:22]#[C:23][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(C#CC2=CCCCC2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (80 mg, 63%); 1H NMR δ (CDCl3): 6.63 (s, 1H), 6.27-6.29 (m, 1H), 3.96 (s, 3H), 2.14-2.22 (m, 4H), 1.73-1.58 (m, 4H); LCMS m/z: 254.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.[CH3:21][C:22]1([CH3:45])[CH:31]([CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23]1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:33][CH2:32][CH:31]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]2([CH3:21])[CH3:45])[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CCC2Cc3ccccc3OC2(C)C)C1
Reaction time: 15 h
Yield: 67 %

Procedure:
First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropyl-amine are added to a solution of 9 g (25 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100 ml of N,N-dimethylformamide. The solution is stirred for 15 hours at 60° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution (30%) while cooling and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 5.52 g (67% of theoretical yield) of 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester in the form of a light-yellow oil. 1-[2-(2,2 -dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from methanol/diethyl ether and melts at 196°-197°.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[N:22]1[C:26](=[O:27])[C:25](Br)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1.O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[C:15]=1[N:22]1[C:26](=[O:27])[C:25]([N:10]2[C:11](=[S:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9]2)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3-n3nnn(-c4ccccc4)c3=S)c2)c(C(C)(C)CC)c1

Procedure:
According to the method disclosed in Pharmazle, 29 (2) page 90, a mercuric salt of 1-phenyl-5-mercaptotetrazole and 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone were reacted in dimethylformamide. The reaction mixture was poured into water, was extracted with ethyl acetate and washed. After evaporating off the ethyl acetate under reduced pressure, the remaining substance was recrystallized from ethanol to provide 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-(4-phenyl-5-thioxotetrazolin-1-yl)-5-pyrazolone having a melting point of 169° to 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 1 Step (b) (10 g) was dissolved in DMF (50 ml) and triethylamine (14.8 ml) was added. tert-Butyl 3-bromopropylcarbamate (10 g) was then added and the solution stirred at room temperature for 24 hrs. The solvent was evaporated and the resulting solid dissolved in ethyl acetate and water were added, the organic phase separated, dried, filtered and evaporated to a solid (17.51 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([CH:15]1[NH:20][CH2:19][C:18]2[S:21][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([S:32]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[C:40]([Cl:45])[CH:41]=5)[CH:36]=4)(=[O:34])=[O:33])[CH2:28][CH:27]3[C:46](=[O:48])[NH2:47])=[O:25])=[N:23][C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([CH:27]1[CH2:28][N:29]([S:32]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([Cl:45])[CH:41]=3)[CH:36]=2)(=[O:34])=[O:33])[CH2:30][CH2:31][N:26]1[C:24]([C:22]1[S:21][C:18]2[CH2:19][NH:20][CH2:15][CH2:16][C:17]=2[N:23]=1)=[O:25])(=[O:48])[NH2:47]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(N)=O)sc2CN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNCC2

Procedure:
To trifluoroacetic acid (1 ml), a solution of 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (303 mg) dissolved in dichloromethane (1 ml) was added, followed by concentration under reduced pressure. The resulting precipitate was collected by filtration and washed with diethyl ether, whereby the title compound (263 mg, 83%) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:21][N:20]=1>C1(C)C=CC=CC=1>[C:25]1([C:23]2[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][N:20]=[C:19]([NH:7][CH2:8][CH:9]3[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NCC1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=C(O)C1CCC(CNc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a suspension of 133 mg (0.84 mmol) of 4-aminomethylcyclohexanecarboxylic acid in 5 ml of toluene, and the mixture was stirred at room temperature. After 30 minutes, 150 mg (0.56 mmol) of 2-chloro-4,5-diphenyl-pyrimidine were added, and the mixture was stirred at 120° C. for 31 hours. The solvent was removed in vacuo and the residue was mixed with dichloromethane and water. The resulting precipitate was filtered off with suction. 135 mg (62%) of the desired product were obtained.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCCN1CCNC1=O
Product: COc1cc(NCCN2CCNC2=O)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 78 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-aminoethyl)imidazolidin-2-one instead of thiomorpholine to the title compound (203 mg, 78%) which was obtained as an off-white solid. MS: m/e 479.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][Cl:10]
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)[C@@H](N)C(C)C
Product: COC(=O)[C@@H](NC(=O)CCCCCl)C(C)C

Procedure:
Using the method of Example 1, Step A, valine methyl ester and 5-chloropentanoyl chloride were coupled to provide N-(5-chloropentanoyl)valine methyl ester.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH:15](=O)[CH2:16][CH3:17].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:15][CH2:16][CH3:17]
Reactant: CCC=O
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNc1cc(F)ccc1C(=O)N(C)OC
Reaction time: 1.5 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.27 g, 1.36 mmol), propionaldehyde (0.15 mL, 2.08 mmol), and AcOH (0.12 mL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (576 mg, 2.72 mmol) at 5° C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide quantitatively.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccccc21)C(F)(F)F
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-trifluoro-1-(indolin-1-yl)ethanone (5 g, 16 mmol) was added to neat chlorosulfonic acid at 0° C. and then the solution was allowed to warm to rt and stirred for an additional 2 hrs. Reaction mixture was slowly added to ice chips and stirred for 10 min then filtered off 4.2 g of the title compound as a dark red colored solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13](=O)[C:3]1=2.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CCO.O>[OH:17][N:16]=[C:13]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:11][CH2:12]1
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3ccccc31)CCC2=NO
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (3.0 g) in 30 ml of 95% EtOH was added hydroxylamine hydrochloride (2.25 g) in 9 ml water followed by sodium acetate (4.4 g) in 9 ml water. The mixture was heated at reflux for 4 hours and thereafter an additional 1.1 gram of hydroxylamine hydrochloride in 5 ml water and 2.2 grams of sodium acetate in 5 ml water were added.. After an additional 2 hours of reflux, the mixture was allowed to stand at room temperature overnight. The material which precipitated was collected and recrystallized from 95% EtOH to give 1.9 grams of analytically pure material.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([OH:28])[C@H:19]([NH:22][C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:20][F:21])=[CH:14][CH:13]=1)=[N+:10]=[N-:11]>>[Cl:25][CH:24]([Cl:26])[C:23]([NH:22][C@H:19]([CH2:20][F:21])[C@H:18]([OH:28])[C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH:3]=[C:2]([CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[N:11]=[N:10]2)=[CH:17][CH:16]=1)=[O:27]
Reactant: C#CCNS(C)(=O)=O
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CS(=O)(=O)NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1

Procedure:
Following the general procedure of Example 66, Step 3 and making non-critical variations but using the product of step 1, Example 67 with the product of Example 66, Step 2 the title compound is obtained (45 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 2.95 (s, 3H), 4.25-4.26 (m, 1H), 4.30 (s, 2H), 4.33-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.95 (t, 1H, J=3.3 Hz), 6.08 (d, 1H, J=3.92 Hz), 6.49 (s, 1H), 7.55 (d, 2H, J=8.56 Hz), 7.84 (d, 2H, J=8.6 Hz), 8.64 (d, 1H, J=9.04 Hz), 8.70 (s, 1H). LC-MS (m/z): [M+H]=453.9.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])OC(C(F)(F)F)=[C:3]1[C:19]([O:21][CH3:22])=[O:20].[C:23]([C:27]#[N:28])([Cl:26])([Cl:25])[F:24].C1CCN2C(=NCCC2)CC1.Cl>COCCOC>[Cl:25][C:23]([Cl:26])([F:24])[C:27]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([OH:1])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])[N:28]=1
Reactant: N#CC(F)(Cl)Cl
Reactant: COC(=O)c1c(C(C)C)oc(C(F)(F)F)c(C(=O)OC)c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COC(=O)c1c(C(C)C)nc(C(F)(Cl)Cl)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 17.80 g (0.073 mol) of dimethyl 2-(isobutyryl)-3-oxo-1,5-pentendioate (Step B of Example 208) in 300 mL of DME at -78° C. was added 18 g (0.4 mol) of CFCl2CN followed by 11.1 g (11 ml, 0.073 mol) of DBU. The reaction was warmed up to 25° C., poured into 3.7% HCl, and extracted twice with EtOAc. The EtOAc extract was washed again with 3.7% HCl, saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 25.88 g of a dark brown solid. The crude was purified by HPLC using 2% HOAc/16% EtOAc/82% cyclohexane as eluting solvent, affording 21 g (81%) of product as a beige solid. For elemental analysis a portion of this solid was washed with hexane affording the product as a white solid: mp 75°-76° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][NH:8][CH3:9])([CH3:3])[CH3:2].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][N:8]([CH3:9])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1)([CH3:3])[CH3:2]
Reactant: CNCc1cccc(OC)c1OC(C)C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c1OC(C)C
Yield: 47 %

Procedure:
According to the procedure of Example 1, except substituting 2-isopropoxy-3-methoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 47%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.41-10.21 (m, 1H), 10.13 (br s, 1H), 8.41-8.31 (m, 1H), 8.01-7.93 (m, 1H), 7.51-7.43 (m, 1H), 7.31-7.11 (m, 1H), 7.01-6.91 (m, 2H), 6.70-6.59 (m, 1H), 4.76-4.52 (m, 5H), 4.11-3.85 (m, 7H), 3.84-3.60 (m, 3H), 3.59-3.51 (m, 21), 3.40-3.31 (m, 2H), 3.07-2.86 (m, 4H), 1.23 (m, 6H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:16][CH:17]3[O:21][CH2:20][CH2:19][O:18]3)[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1>CN1CCCC1=O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:16][CH:17]3[O:21][CH2:20][CH2:19][O:18]3)[CH2:14][N:13]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=3)[C:12](=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC[C@](CC2OCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Reactant: Cc1cccc(Br)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(N2C[C@@](CC3OCCO3)(c3ccc(Cl)c(Cl)c3)CCC2=O)n1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
A mixture of (5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone (WO 9807722) (6.5 g, 19.7 mmol), potassium carbonate (3.05 g, 21.7 mmol), copper (I) iodide (400 mg, 2.1 mmol) and 2-bromo-6-methylpyridine (10.2 g, 60 mmol) in 1-methyl-2-pyrrolidinone (200 ml) was stirred at 140° C. for 24 hours. The cooled mixture was partitioned between ethyl acetate and 10% aqueous ammonia, and the layers separated. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with water, then brine (3×), dried (MgSO4) and evaporated under reduced pressure to give a gum. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to afford the title compound as a brown solid, 3.02 g.