Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[O:9])[CH:2]=1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]2[O:18][C:16]([CH:13]3[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:9])[CH2:15][CH2:14]3)=[N:27][N:26]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Oc1cccnc1)N1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (300 mg), 4-fluorobenzohydrazide (222 mg), HOBt (170 mg), and DCM (6 mL) was added WSC hydrochloride (299 mg), followed by stirring at room temperature overnight. The reaction liquid was purified directly by silica gel column chromatography (chloroform/methanol=99/1 to 90/10). The residue was dissolved in THF (6 mL), and toluenesulfonyl chloride (686 mg) and triethylamine (1.0 mL) were added thereto, followed by stirring at 50° C. for 8 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100). To the purified product were added isopropanol/water, and the resulting solid was collected by filtration and dried to obtain pyridin-3-yl 4-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (224 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.8) (0.385 g, 0.9 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.19 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.4 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH:24]=[O:25])=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([NH:4][C:5]1[C:6]([CH:24]=[O:25])=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(COc2cccc(NC(C)=O)c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cccc(OCc2ccc(C(=O)O)cc2)c1C=O

Procedure:
Ethyl 4-(3-acetylamino-2-formylphenoxymethyl)benzoate (0.45 g, 0.00132 N) was suspended in 95% ethanol (10 ml) with stirring and treated with 1N sodium hydroxide solution (1.32 ml) over 1 hour. The mixture was then diluted with water (3 ml) and stirred at room temperature overnight. A further 15 ml of water was added and the mixture stirred at room temperature (4 hr). The mixture was then extracted with ethyl acetate and the aqueous phase acidified with concentrated hydrochloric acid with cooling. The precipitated solid was filtered off, washed well with water, and recrystallised from ethanol to give 4-(3-acetylamino-2-formylphenoxymethyl)benzoic acid, m.p. 242°-244° C. (dec.) (Found: C, 65.27; H, 4.93; M, 4.23%. C17H15NO5 requires C, 65.17; H, 4.83; N, 4.47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[CH:55]=[N:56][C:57]2[C:62]([CH:63]=1)=[CH:61][CH:60]=[CH:59][CH:58]=2>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[NH:53][C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21

Procedure:
A solution of 2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester (1.5 g, 5.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.37 g, 6.27 mmol), N,N-diisopropylethylamine (2.41 mL, 13.8 mmol) and 3-aminoquinoline (0.904 g, 6.27 mmol) in acetonitrile was heated to reflux for 20 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was separated, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexane to give the product, 1.43 g (64%). MS: m/z 390 (MH+). 1H NMR (DMSO-d6): δ 1.54 (s, 9 H), 3.16 (t, 2 H), 4.00 (t, 2 H), 7.57-7.83 (m, 3 H), 7.88-8.00 (m, 4 H), 8.84 (d, 1 H), 9.15 (d, 1 H) and 10.53 (s, 1 H).
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])/[CH:8]=[CH:7]/[C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C#CC(=O)OC
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Ethyl aluminum dichloride (104.5 mL, 192 mmol, 1.8 M in toluene) was added to a solution of methyl propiolate (13.58 mL, 153 mmol) in DCM (100 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (22 g, 64.3 mmol) was added. After stirring for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, and the mixture was poured into cold (0° C.) water (200 mL). The phases were separated and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined and washed sequentially with water (200 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by slurring in methanol (280 mL) to provide compound 1.7a (17.5 g 68%) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[C@@H:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[NH2:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:25][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1ccc(N2CCC(=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(N[C@@H]3CCCC[C@H]3N)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a round bottom flask under argon was added the ethyl 4-(3-oxopyrrolidin-1-yl)benzoate (1.23 g, 5.27 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.602 g, 5.27 mmol), CH2Cl2 (30 ml), solid anhydrous Na2SO4 (2.5 gm) and HOAc (1 ml). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (2.012 g, 9.49 mmol) was added to the reaction which was then stirred at rt overnight. The reaction was filtered and water (10 ml) was added to the reaction. The reaction mixture was then diluted with CH2Cl2 (100 ml). The resulting solution was washed with saturated aqueous NaHCO3 (100 ml), water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated to give the product ethyl 4-(3-((1R,2R)-2-aminocyclohexylamino)pyrrolidin-1-yl)benzoate (1 g, 3.02 mmol, 57.2% yield) as brown solid. Anal. Calcd. for C19H29N3O2 m/z 331.4, found: 332.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]([CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][N:11]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-[3-(2-pyridin-2-ylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (46.7 mg, 0.0918 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.18 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (43.8 mg, 0.413 mmol), water (2 mL) and butyl chloroformate (16.3 μL, 0.0129 mmol) and the reaction mixture was stirred for 23 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound as a white solid in 63% yield, over two steps, (32 mg, 0.058 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Br-].[Zn+2].[Br-].[Zn]>[CH3:9][C:8]1[C:2]([CH3:1])=[C:3]2[C:5]([CH2:32][CH2:31][C:29]([CH2:28][CH2:27][CH2:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33]2)=[C:6]([CH3:11])[C:7]=1[OH:10]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a mixture consisting of 69.9 g (0.460 mol) of 2,3,5-trimethylhydroquinone, 69.7 g (0.31 mol) of zinc bromide, 7.5 g of concentrated hydrochloric acid and 1.2 g of zinc dust, was added dropwise, under stirring at 50° C. over 1 hour, 138.8 g (0.460 mol) of isophytol (purity: 98.1%). Further, the resulting mixture was stirred at the same temperature for 1 hour. The reaction liquid was washed with water, followed by concentrating, whereby 199.4 g of the title compound was obtained as a brown oil (yield: 98.6%, GLC purity: 97.8%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10](Cl)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=[NH:83])(C1C=CC=CC=1)C1C=CC=CC=1.NO>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH2:83])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Cl)cc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: NO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cnc(N)cc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
An oven dried flask under N2 was charged with 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-chloro-5-methyl-pyridine (9-5, 0.600 g, 2.21 mmol), NaOtBu (0.297 g, 3.09 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.040 g, 0.040 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.083 g, 0.13 mmol) and anhydrous toluene (10 mL). Benzophenone imine (0.444 mL, 2.65 mmol) was added and the reaction was heated to 80° C. After 3 hours the reaction was allowed to cool to room temperature and was diluted with 50 mL of diethyl ether. The resulting mixture was filtered through celite, washing with ether. The filtrate was concentrated, redissolved in 10 mL MeOH and hydroxylamine (50% aqueous, 0.405 mL, 6.62 mmol) was added. After stirring overnight, an additional 0.680 mL of hydroxylamine solution was added. After 8 hours the solution was concentrated in vacuo. The residue was purified by flash column chromatography (sample was loaded in DCM and eluted with a 1:1 Hex/EA to EA, ethylacetate, gradient) to afford the titled product, 9-6. 1H NMR indicates that product is contaminated with BINAP dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#[CH:11])[C:3]=1[N+:12]([O-])=O.O.O.[Sn](Cl)Cl>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#[CH:11])[C:3]=1[NH2:12]
Reactant: C#CCOc1cccc(F)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCOc1cccc(F)c1N
Yield: 38.5 %

Procedure:
To a solution of 1-fluoro-2-nitro-3-prop-2-ynyloxy-benzene (460 mg) in EtOAc (50 mL), was added tin(II) chloride dihydrate with stirring. After 6 hours the mixture was diluted with EtOAc and washed 3 times with brine. The organic layer was dried with sodium sulfate, concentrated and the residue purified by silica gel chromatography to afford 150 mg of 2-fluoro-6-prop-2-ynyloxy-phenylamine: 1H NMR (300 MHz, CDCl3) δ 6.9-6.7 (m, 3H), 4.8 (s, 2H), 4.0 (bs, 2H), 2.6 (s, 1H).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:5][N:6]=1.C(ON=O)CC(C)C>C1COCC1>[S:3]1[C:4]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:5][N:6]=[CH:2]1
Reactant: Nc1ncc(CN2CCCC2=O)s1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1cncs1
Yield: 32.7 %

Procedure:
In a 250 ml, three-necked flask fitted with a magnetic stirrer and reflux condenser under inert atmosphere, 1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one 248 (1.04 g, 6.8 mmol) is dissolved in THF 20 ml). Isoamylnitrite (1.59 g, 13.6 mmol) is added and the mixture is heated at reflux for 3 h. The solvent is evaporated and the residue is purified by chromatography on silicagel (CH2Cl2/MeOH: 95/5 (v/v)) to give 405 mg of 1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one 249.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CS(C)=O>[CH2:25]([O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH:24]=[CH2:23]
Reactant: Oc1cccc(F)c1-c1ccc(Cl)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1Cl
Yield: 92.3 %

Procedure:
Treatment of 2′,4′-dichloro-6-fluorobiphenyl-2-ol (1.6 g, 6.2 mmol) with potassium carbonate (1.3 g, 9.3 mmol) and allyl bromide (0.79 mL, 9.3 mmol) in DMSO (50 mL) according to the procedure described for Example 69, Step 3 provided 1.7 g (92%) of 2′-allyloxy-2,4-dichloro-6′-fluorobiphenyl as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(N)C(C)(C)O
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 140 °C

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chloro-phenyl)-amide, 27, (0.11 g, 0.25 mmol) in N-methyl-pyrrolidinone (3 mL) is added diisopropylethylamine (0.22 mL, 1.28 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.11 g, 0.77 mmol). The mixture is heated to 140° C. for 4 hours and the resulting solution purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (s, 1H), 7.45-7.40 (m, 3H), 7.32-7.22 (m, 3H), 7.13 (t, J=8.1 Hz, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 468.0.0 (100, M++H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Yield: 37.6 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (100 mg, 0.46 mmol) in benzene (5 mL) were added 3,5-bis(trifluoromethyl)phenylboronic acid (141 mg, 0.55 mmol), 2M Na2CO3 (6860, 1.37 mmol), and catalytic amounts of Pd(PPh3)4 (106 mg, 0.09 mmol). The reaction mixture was refluxed for 6 hrs, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (61 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=[O:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:32][CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(Cl)cc1COc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 525.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].O>ClCCl>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=2)[CH2:3]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC1CNCC(C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C(=O)N2CC(C)CC(C)C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3,5-Dimethylpiperidine (0.73 g) and triethylamine (2.25 ml) were dissolved in dichloromethane (20 ml). A solution of 3-methylbenzoylchloride (1.00 g) in dichloromethane (10 ml) was added dropwise at the freezing point. After stirring for 30 minutes at 0° C., the reaction solution was poured into water (100 ml) and extracted with chloroform (50 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent: n-hexane/ethyl acetate=4:1) to obtain the subject compound (NCR-1 cis form:trans form=9:1) (0.95 g, yield 63%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz, δ; ppm) 0.76-1.86 (10H, m), 2.15-2.23 (0.9H, m), 2.36 (3H, s), 2.44-2.49 (0.9H, m), 3.08 (0.1H, m), 3.20 (0.1H, m), 3.32-3.34 (0.1H, m), 3.63-3.65 (0.9H, m), 7.14 (1H, d, J=7.3 Hz), 7.19 (1H, d, J=7.3 Hz), 7.20 (1H, s), 7.26 (1H, t, J=7.6 Hz); MS (EI) m/z: 231 (M+).
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:5]1[CH2:6][CH2:7][N:2]([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:3][CH2:4]1)(=[O:40])=[O:39]
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added DIEA (158 μL, 0.91 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with MsCl (26 μL, 0.33 mmol) and the resulting solution was stirred (rt, 2 h). The reaction mixture was partitioned with EtOAc and brine (20 mL each) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a white solid (42 mg, 31%). MS (ESI): mass calcd. for C20H20N4O4S2, 444.54; m/z found, 445.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.74 (d, J=8.5, 1H), 7.62-7.56 (m, 2H), 7.30 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.69 (d, J=0.5, 2H), 3.32-3.21 (m, 4H), 2.79 (s, 3H), 2.67-2.54 (m, 4H).