Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[NH:15][C@@H:16]1[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[CH2:17]1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28](C(O)=O)=[C:27]2[NH:37][C@H:38]1[CH2:42][CH2:41][C@H:40]([O:43][CH3:44])[CH2:39]1.IC.[OH-:47].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:37]([CH3:27])[C:38](=[O:47])[N:15]([C@@H:16]4[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[CH2:17]4)[C:5]=3[C:4]=2[CH:3]=1.[Br:23][C:24]1[CH:33]=[CH:32][C:31]2[N:30]=[CH:29][C:28]3[N:15]([CH3:5])[C:16](=[O:47])[N:37]([C@H:38]4[CH2:42][CH2:41][C@H:40]([O:43][CH3:44])[CH2:39]4)[C:27]=3[C:26]=2[CH:25]=1
Reactant: CO[C@H]1CC[C@H](Nc2c(C(=O)O)cnc3ccc(Br)cc23)C1
Reactant: [OH-]
Reactant: CO[C@@H]1CC[C@@H](Nc2c(C(=O)O)cnc3ccc(Br)cc23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CO[C@@H]1CC[C@@H](n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)C1
Product: CO[C@H]1CC[C@H](n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid: 6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic acid (1:1 mixture) (13 g, 35.8 mmol), tetrabutylammonium bromide (1.16 g, 3.60 mmol), iodomethane (7.645 g, 53.86 mmol) and sodium hydroxide (2.15 g, 53.75 mmol) in DCM (600 mL) and water (380 mL) was stirred at ambient temperature overnight. The resulting solution was concentrated under vacuum to remove the organics and the solids collected by filtration, washed with water (5×10 mL) and dried in a vacuum oven to afford the desired material (racemic mixture) (9.8 g, 73%) as a off-white solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.81-1.87 (1H, m), 2.33-2.51 (4H, m), 2.45-2.51 (1H, m), 3.28 (3H, s), 3.49 (3H, s), 4.02-4.21 (1H, m), 5.40 (1H, p), 7.73 (1H, dd), 7.98 (1H, d), 8.35 (1H, d), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=375.9.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a suspension of 2-chloro-4-hydroxybenzaldehyde (0.50 g) and potassium carbonate (1.1 g) in N,N-dimethylformamide (5 mL) was added methyl iodide (0.40 mL) at room temperature, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-chloro-4-methoxybenzaldehyde (0.54 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutyl-benzaldehyde.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.O.S(=O)(=O)(O)O>CC(O)C>[CH2:11]1[C:10]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH:7][C:9]=2[CH2:13][CH2:12]1
Reactant: O=C1CCCC1
Reactant: NNc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCC3
Temperature: 20 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of phenylhydrazine (32.44 g, 300 mmol) in 2-propanol (300 mL) was treated with cyclopentanone (27 mL, 25.7 g, 305 mmol). The solution was stirred at 20° C. for 1 h and poured onto mixture of ice (900 g) and water (300 mL). The chilled mixture was stirred until the ice had melted then filtered. The filter-cake was washed with water (2×300 mL) an the resultant damp solid (85 g) was added to water (540 mL). The stirred suspension was treated with concentrated sulfuric acid (33 mL, 61 g, 600 mmol) then heated under reflux for 30 min, cooled to 0° C. and stirred for 15 min. The dark red solid was filtered off, washed with water (2×60 mL) and air-dried for 18 h. The crude product was added to dichloromethane (300 mL), stirred for 30 min then filtered, washing with dichloromethane (100 mL). The filtrate was treated with silica (48 g), stirred for 1 h, filtered and washed with dichloromethane (400 mL). The filtrate was concentrated to give a solid, which was triturated with hexane to give 1,2,3,4-tetrahydrocyclopent[b]indole (30 g, 65%) as a pink solid. Analytical data for 1,2,3,4-tetrahydrocyclopent[b]indole are included in Table 3 below.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1.[CH2:35]([Cl:37])Cl>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[C:10]([Cl:34])=[C:35]1[Cl:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Reactant: OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Product: OC(c1ccc2c(c1)c(Cl)c(Cl)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 21 %

Procedure:
A solution of 400 mg (1.07 mmol) of 2-(1-benzyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 16) in 2 mL CH2Cl2 was treated portionwise with 286 mg (2.14 mmol) of NCS and stirred at RT for 10 hrs. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 3:1 to 1:1 yielded 100 mg (21%) of 2-(1-benzyl-2,3-dichloro-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown oil, MS: 441 (M−H)−, 2Cl.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7](S(C)(=O)=O)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CC(O)C>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1nc(S(C)(=O)=O)c2c(-c3ccccc3)coc2n1
Reactant: NCc1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CS(=O)(=O)c1nc(NCc2ccccn2)c2c(-c3ccccc3)coc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.2 %

Procedure:
A mixture of 2,4-bis-methylsulfonyl-5-phenyl-furo[2,3-d]pyrimidine (54 mg, 0.153 mmol), triethylamine (17 mg, 0.168 mmol) and 2-(aminomethyl)pyridine (18 mg, 0.168 mmol) in propan-2-ol (5 ml) was warmed to obtain a solution and stirred at ambient temperature for 2.5 hr. Water (50 ml) was then added and the mixture was extracted with dichloromethane (3×30 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude (2-methanesulfonyl-5-phenyl-furo[2,3d]pyrimidin-4-yl)-pyridin-2-ylmethylamine which was purified by flash chromatography (silica) eluting with 40′-60° C. petroleum ether followed by ethyl acetate to give a white solid (17 mg), m.pt. 171-173° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:14][O:13][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=1)[C:3]([OH:2])=[O:15]
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Product: COC(Cc1cccc(OCCCOc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C25H26O6 [M+NH4]+: 440.2, [M+Na]+: 445.2. 1H-NMR (CDCl3, 200.15 MHz): 7.33–7.17 (m, 3H), 7.07–6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[Cl:12][CH2:13][C:14](Cl)=[O:15].Cl>C(OCC)(=O)C>[Cl:12][CH2:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:15]
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCNC(=O)CCl
Reaction time: 0.5 h

Procedure:
20 g (153 mMol) 6-Amino-hexanoic acid was mixed with 80 ml of 2N Sodium Hydroxide (NaOH). 18 ml (221 mMol) of Chloro-acetylchloride and 6N NaOH were added to the mixture at Room Temperature (RT). The pH of the reaction mixture was maintained between 10 and 11 during the addition of Chloro-acetylchloride and 6N NaOH by using a burette to control the addition. The mixture was stirred for 30 mins at this constant pH. Ethyl acetate (EtOAc) was then added to the reaction mixture and the pH was adjusted to 2 with 2N Hydrochloric Acid (HCl). To work up the product, the EtOAc-layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were dried and the solvent was evaporated. The residue was then re-crystallized from diisopropylether/EtOAc (1:1, v:v).
Reaction SMILES: [NH2:1][C@@:2]1([CH2:18][OH:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:8]3[C:3](=[CH:4][C:5]([I:17])=[CH:6][CH:7]=3)[C@:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH2:18][OH:19])[C:15]=2[CH:14]=1
Reactant: N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
The (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol) was dissolved in THF (200 mL). The solution was cooled to 0° C., and TEA (1.425 mL, 10.22 mmol) and 2-chloroacetyl chloride (0.707 mL, 9.07 mmol) were added. The reaction was allowed to warm naturally to RT. After 14 h, the reaction was concentrated. The residue was taken up in aqueous 1 M Na2CO3 (50 mL) and the aqueous phase was extracted with 7.5% MeOH-DCM (3×133 mL). The organics were combined, washed with aqueous 1 M Na2CO3 (30 mL), dried over sodium sulfate and concentrated. The residue was dissolved in THF (100 mL) and aqueous 1 M Na2CO3 (15 mL) was added. The reaction was concentrated. The residue was taken up in 5% MeOH-dcm (400 mL) and the organic phase was washed with dilute brine (40 mL), dried over sodium sulfate and concentrated to afford crude (S)—N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroacetamide, which was used in the next step without further purification.
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:13][NH:12][C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:30][CH2:31]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCc1cc(CNC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccc(Br)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 46.7 %

Procedure:
4-bromobenzene-1,2-diamine (1.43 g, 7.64 mmol) and piperidine-4-carboxylic acid (0.99 g, 7.64 mmol) were dissolved in polyphosphoric acid (20 g). This mixture was heated at 190° C. for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 14. Solid was filtered, washed with methanol and dried to obtain the title compound (1 g) as a dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.Cl.[C:26]([NH:29][CH2:30][C:31](=N)OCC)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:26]([NH:29][CH2:30][C:31]1[N:17]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=4[N:7]=3)=[CH:16][C:14]=2[N:15]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=N)CNC(C)=O
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)NCc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1C1CCOCC1
Yield: 21.1 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in ethanol (5 mL) was added ethyl 2-acetylaminoacetimidate hydrochloride (263 mg, 1.45 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (65.2 mg, 21% yield) as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1[CH:25]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1/[CH:25]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylmethyl-benzenesulfonamide (Ex-53A, 617 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (20 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (25 mL) and water (50 mL) gave the title compound as a red solid (626 mg, 58%), mp 112–116° C. 1H-NMR (300 MHz, DMSO-d6) 8.40 (m, 3H), 8.19 (d, 2H, J=9.0 Hz), 8.05 (d, 1H, J=15.9 Hz), 7.89 (d, 2H, J=9.0 Hz), 7.62 (m, 2H), 7.25 (dd, 1H, J=4.5, 5.7 Hz), 7.17 (s, 1H), 6.67 (s, 1H), 4.05 (d, 2H, J=5.7 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C27H29N3O5S: 508.1906 [(M+H)+]; Found: 508.1902.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[NH2:10])=[N:7][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])=[N:7][CH:8]=1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Reactant: CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=NN(C)c1ccc(C(F)(F)F)cn1)C(C)C

Procedure:
A solution of 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (5.9 g; 0.031 mol), 3-methyl-2-butanone (5.6 g; 0.065 mol) and p-toluenesulphonic acid (0.1 g) in xylene (30 ml) was heated under reflux, with water removal (azeotrope), for 7 h. The solution was concentrated to yield an oil which was purified by distillation (70° C./72 mbar) to yield 3-methyl-2-butanone 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as a yellow oil (5.8 g; 72%). ##STR15##
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.OCC[NH:19][NH2:20].[CH2:21]([OH:23])[CH3:22]>>[OH:23][CH2:21][CH2:22][C:14]1[S:13][C:4]2[S:5][CH2:6][CH2:7][CH:8]3[CH2:9][C:10](=[O:12])[NH:20][N:19]=[C:2]3[C:3]=2[CH:15]=1
Reactant: NNCCO
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Reactant: CCO
Product: O=C1CC2CCSc3sc(CCO)cc3C2=NN1

Procedure:
A mixture of 1.4 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 1.5 g of 2-hydroxyethylhydrazine in 50 ml of ethanol is refluxed under heating for 10 hours. After the mixture is concentrated, to the residue is added water and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated. To the residue is added isopropyl ether and the solution is allowed to stand. The precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol to give 1.7 g of 9-(2-hydroxyethyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as pale yellow crystals, melting at 165°-167° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]2[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:11][CH:12]=1)(=O)=O.[CH3:23][NH:24][CH:25]([CH3:27])[CH3:26]>>[Cl:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:24]([CH:25]([CH3:27])[CH3:26])[CH3:23])=[CH:8][N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[N:17]=1
Reactant: CNC(C)C
Reactant: Cn1nc(Cl)cc(Nc2ccc(COS(C)(=O)=O)cn2)c1=O
Product: CC(C)N(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1

Procedure:
Following Example 186c, 180c and methylisopropylamine were reacted to give 180d.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.N1C=CC=CC=1.[Cl-].[OH:29][C@H:30]1[CH2:34][NH2+:33][C@@H:32]([C:35](=[O:50])[NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]3=[O:49])=[CH:39][CH:38]=2)[CH2:31]1.C(N(C(C)C)C(C)C)C>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]([N:33]2[CH2:34][C@H:30]([OH:29])[CH2:31][C@@H:32]2[C:35]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]3=[O:49])=[CH:41][CH:42]=2)=[O:50])=[O:3])=[N:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1)[C@H]1C[C@@H](O)C[NH2+]1
Reactant: Nc1ccc(Cl)cn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
894 mg (4.43 mmol) of 4-nitrophenyl chloroformate are added to a solution of 570 mg (4.43 mmol) of 2-amino-5-chloropyridine and 0.73 ml (9.0 mmol) of pyridine in 50 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. 1.49 g (4.43 mmol) of (2R,4R)-4-hydroxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride and 1.5 ml (9.0 mmol) of N-ethyldiisopropylamine are added to the resultant suspension, and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent, giving 1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A6”) as a colourless solid, ESI 454.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:17][S:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[C:3]([OH:18])=[O:2])(=[O:16])=[O:15]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid methyl ester (1.0 g, 3.54 mmol) in dioxane (15 mL) was added water (15 mL) and lithium hydroxide monohydrate (186 mg, 4.43 mmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 100 ml 1M aqueous hydrochloric acid and 100 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 100 mL ethyl acetate. The organic layers were washed with 100 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Colorless solid (930 mg, 98%). MS (ESI−): m/z=266.995 ([M−H]−).
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)C(O)=O)#[N:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CO>[CH3:11][S:10][C:7]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:3][C:1]#[N:2]
Reactant: CSC(SC)=C(C#N)C(=O)O
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=CC#N)N1CCOCC1
Temperature: 20 °C

Procedure:
2-Cyano-3,3-bis-methylsulfanyl-acrylic acid (the compound of formula (F), 35 g, 0.18 mol) was dissolved in 250 mL of methanol. Morpholine (the compound of formula (O), 28 mL, 0.32 mol) and triethylamine (25 mL, 0.18 mol) were added to the solution while the temperature was maintained at approximately 20° C. The reaction was warmed slightly to a temperature of between 25-27° C. and this temperature was maintained overnight. The solvents were then removed under reduced pressure taking care not to heat the reaction mixture. The resulting crude material was filtered through a short silica gel column eluting with MeOH:CH2Cl2=1:5 to afford the 3-methylsulfanyl-3-morpholin-4-yl-acrylonitrile of formula (P).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=1.[C:44]([O-:47])([O-])=[O:45].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:44]([OH:47])=[O:45].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=4)=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)o3)cc2)nc(N)n1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in 2.5 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.703 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 6-chloro-2,4-diamino-pyrimidine (81.3 mg, 0.562 mmol) was added, followed by anhydrous K2CO3 (19.5 mg, 0.141 mmol). Then the vial was capped and microwaved at 200° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (75.8 mg of beige solid).