Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1Br)=[O:5])[CH3:2].[C:17]([Cu])#[N:18].C(Cl)Cl>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[C:17]#[N:18])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1c(Br)c(C(C)(C)C)nn1C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C#N)c(C(C)(C)C)nn1C
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.46 mmol) and CuCN (372 mg, 4.15 mmol) in NMP (10 mL) was stirred at 200° C. under microwave irradiation for 1 h. After cooling to room temperature, the mixture was treated with DCM (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (0:100-10:90 EtOAc-hexanes) to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.45 (q, J=7.2 Hz, 2H), 4.14 (s, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C12H17N3O2: 236.1 (M+H), Measured: 236.1.
Reaction SMILES: [C:1]1([NH:7][C:8](=[NH:10])[SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH3:12].C(OC(=O)C)C>C(O)C>[CH2:11]([S:9][C:8](=[NH:10])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCBr
Reactant: N=C(S)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCSC(=N)Nc1ccccc1

Procedure:
4 gram N-phenylisothiourea (33 mmol) and 5 ml ethyl bromide were refluxed for 10 hours in ethanol. Again 5 ml ethyl bromide was added. The reaction course was followed by thin layer chromatography (ethylacetate/petroleumether 3:7). Subsequently the solvent was evaporated and the residue crystallised from ethanol/ethylacetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.4 g, 8.1 mmol), 1-(2-methoxy-ethyl)-piperazine (2.0 g, 14.0 mmol) and anhydrous potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120-130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (15 ml) and stirred vigorously. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford 5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-2-nitro-phenylamine (1.7 g, 75%) as a yellow brown powder.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[C@@H:10]1[F:34])C1C=CC=CC=1.[Si](C(F)(F)F)(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[F:34][C@H:10]1[C@H:11]2[N:12]=[C:13]([NH:25][CH3:26])[S:14][C@H:15]2[O:16][C@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@H:9]1[OH:8]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: C[Si](C)(C)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (major isomer from the TMSCF3 addition step) (0.18 g, 0.35 mmol) and PMB (0.15 g, 1.0 mmol) in dry DCM (5 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜4 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:13), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.086 g, 77%). 1H NMR (600 MHz, CD3OD) δ 6.37 (d, J=6.7 Hz, 1H), 4.83 (ddd, J=3.5, 4.6, 46.7 Hz, 1H), 4.61-4.57 (m, 1H), 4.33-4.30 (m, 1H), 3.90 (d, J=6.9 Hz), 2.88 (s, 3H), 1.34 (s, 3H); 13C NMR (150.9 MHz, CD3OD) δ 165.55, 127.29 (q, J=286.0 Hz), 90.86 (d, J=8.4 Hz), 89.66 (d, J=186.5 Hz), 76.23 (d, J=4.0 Hz), 75.41 (q, J=27.4 Hz), 72.65 (d, J=16.6 Hz), 67.79 (d, J=16.6 Hz), 30.84, 17.28; MS, (ES, m/z) [M+H]+ 319.1.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([N:12]1[CH:15]([S:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH:14]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]1=[O:39])[C:9]([CH3:11])=[CH2:10])=[O:7])[CH2:2][CH2:3][CH3:4].[Br:40]N1C(C)(C)C(=O)N(Br)C1=O.C1OC1C>[Hg].ClCCCl>[CH2:1]([O:5][C:6]([CH:8]([N:12]1[CH:15]([S:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH:14]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:13]1=[O:39])[C:9]([CH2:11][Br:40])=[CH2:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C=C(C)C(C(=O)OCCCC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Agent: CC1CO1
Agent: [Hg]
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OCCCC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 10 %

Procedure:
A mixture of 2.7 g (5 mmoles) of 1-(1-n-butyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 200 ml of 1,2-dichloroethane, 1,4 g (5 mmoles ) of 1,3-dibromo-5,5-dimethylhydantoin and 3 ml of propylene oxide was irradiated under nitrogen for 3 hours at 14° C with a Hanovia TQ 150 mercury high pressure lamp using a Pyrex filter. After concentrating the reaction mixture, the residue was chromatographed over silica gel [toluene -ethyl acetate 5:1 (v/v)] to obtain 300 mg (0.5 mmole) of 1-(1-n-butyloxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [O:1]1CCCC1.B.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:16])=[CH2:15])=[CH:10][N:9]=1.[OH-].[Na+].OO>C1COCC1>[F:7][C:8]1[N:9]=[CH:10][C:11]([CH:14]([CH3:16])[CH2:15][OH:1])=[CH:12][CH:13]=1
Reactant: C=C(C)c1ccc(F)nc1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: CC(CO)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
Borane tetrahydrofuran complex (1.0M in THF) (Aldrich, St. Louis, Mo.; 15.75 mL, 15.75 mmol) was added to a solution of 2-fluoro-5-(prop-1-en-2-yl)pyridine (1.44 g, 10.50 mmol) in THF (70 mL) at 0° C. and the resulting mixture was stirred under argon at 25° C. for 1.5 h. The resulting mixture was then cooled to 0° C., and sodium hydroxide (2.5N, aqueous; 5.25 mL, 13.12 mmol) and hydrogen peroxide (30%, aq.) (Columbus Chemical Industries, Columbus, Wis.; 1.877 mL, 18.37 mmol) were sequentially added (gas evolution), and the resulting light-yellow solution was stirred at 60° C. for 1.25 h. The reaction mixture was then partially concentrated in vacuo (to remove THF) and partitioned between EtOAc (300 mL) and half-saturated aqueous NaHCO3 (100 mL). The organic layer separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished 2-(6-fluoropyridin-3-yl)propan-1-ol (0.951 g, 6.13 mmol, 58.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.0 Hz, 1H), 7.68 (td, J=8.0, 2.5 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.67-3.79 (m, 2H), 3.00 (sxt, J=6.8 Hz, 1H), 1.31 (d, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ ppm −71.31 (br. s., 1 F). m/z (ESI, +ve) 156.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=[CH:16][CH:17]=2)[N:4]([CH3:30])[N:3]=1.O.NN>C(O)C>[CH3:30][N:4]1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=2)=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN)c1
Yield: 71.7 %

Procedure:
A solution of 2-[[3-[3-[(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)amino]propoxy]phenyl]methyl]-1H-isoindole-1,3-(2H)-dione (1.62 g) and hydrazine hydrate (0.22 g) in ethanol (10 ml) was heated at reflux for 1.5 h. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was basified with sodium carbonate, evaporated to dryness and extracted with hot isopropanol to give an oil which was purified by column chromatography using methanol/0.88 ammonia 79:1 as eluant to give the title compound as a crystalline solid (0.79 g) TLC silica, methanol/0.88 ammonia 79:1 Rf 0.5 NMR (d4MeOH) 2.77 t (1H); 3.0-3.3 m (3H); 5.95 t (2H); 6.30 s (2H); 6.57 q (2H); 6.65 s (3H); 7.95 m (2H).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=[O:23]>C1COCC1>[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[CH:22]([C:18]1[S:17][CH:21]=[CH:20][N:19]=1)[OH:23]
Reactant: O=Cc1nccs1
Reactant: COCOc1cccc(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cc(C)ccc1C(O)c1nccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of t-BuLi (1.7 M in pentane, 5.0 mL, 8.5 mmol), 1-(methoxymethoxy)-3-methylbenzene (see example 33, step 1) was added dropwise (1.18 g, 7.73 mmol), maintaining the internal temperature below 16° C. The suspension was stirred at 0° C. for 1 h, cooled to −78° C., and THF (15 mL) was added. A solution of 1,3-thiazole-2-carboxaldehyde (0.962 g, 8.5 mmol) was added and the cooling bath was removed. The reaction mixture was allowed to warm to 0° C., extracted twice with EtOAc from NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (30-50% EtOAc in hexanes) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.77 (d, 1H), 7.48 (s, 1H), 7.33 (d, 1H), 6.95 (s, 1H), 6.83 (d, 1H), 6.36 (d, 1H), 5.32 (d, 1H), 5.21 (s, 2H), 3.38 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([C:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=1)([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:30]([F:47])=[C:31](/[CH:35]=[C:36](/[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[F:46])\[C:37]#[N:38])[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[C:30]=2[F:47])[C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[F:46])([C:37]#[N:38])[CH:9]([CH2:10][C:11]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH:15]=2)([CH3:13])[CH3:12])[NH:8]1)=[O:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCN(Cc3ccccc3)CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 73.5 %

Procedure:
In a manner similar to the method described in Example 100b, [3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 127a (2.4 g, 6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.8 g, 6.4 mmol) prepared in Example 52a, AgF (1.3 g, 10 mmol), and triethylamine (2 mL, 14.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3.2 g, 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:4][C:3]=1[F:34].[CH3:35]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=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:34][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)[CH:6]=[N:7][C:2]=1[CH3:35]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnc(Cl)c(F)c2)c1
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1F
Temperature: 110 °C

Procedure:
(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 53, 139 mg, 0.28 mmol) and trimethyl-boroxine (34.4 mg, 0.274 mmol) were dissolved in dioxane (1.5 mL). K2CO3 (104 mg, 0.756 mmol) was added, the RM was flushed with argon and Pd(PPh3)4 (32.4 mg, 0.028 mmol) was added. The RM was heated overnight at 110° C. After cooling to RT, the RM was dissolved in EtOAc treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH). Further purification by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10 to 41% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH and evaporated under reduced pressure to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 7) m/z=477.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.42-2.56 (m, 3H) 2.87 (d, J=11.73 Hz, 1H) 3.14-3.28 (m, 2H) 3.33-3.43 (m, 1H) 4.18 (br. s, 1H) 4.84 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.71 (dd, J=10.17, 1.56 Hz, 1H) 7.79-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.34 (s, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([F:29])=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19](F)[C:20]=3[Cl:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[CH:11]=1>CN(C)C=O>[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([F:29])=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([NH:4][CH:1]4[CH2:3][CH2:2]4)[C:20]=3[Cl:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[CH:11]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4CC4)c(Cl)c32)c(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Cyclopropylamine (50 mg) and 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) were, added to N,N-dimethylformamide (2 ml), and the mixtures was stirred at 60° C. for 2 hours. After the reaction mixture was cooled back to room temperature, the solvent was, distilled off under reduced pressure. Ethanol was added to the residue, and solids deposited were collected by filtration to obtain the title compound (80 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:11]=1[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.CCCCCC.[C:31](=[O:33])=[O:32].Cl>C1COCC1>[CH2:1]([O:9][C:10]1[C:11]([F:19])=[C:12]([F:18])[C:13]([C:31]([OH:33])=[O:32])=[C:14]([F:17])[C:15]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=O
Reactant: CCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
33.4 g of the compound (8) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 90 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 21.4 g (66 mmol) of 4-octyloxy-2,3,5,6-tetrafluorobenzoic acid (9).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=N[C:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([NH:34][CH2:33][C:32]2[CH:5]=[CH:4][C:3]3[C:30](=[CH:29][CH:6]=[CH:7][CH:2]=3)[CH:31]=2)=[O:19])=[CH:12][N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(COCc2ccccc2)nc1O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2ccccc2c1)c1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of compound 2-e (5 g, 19.2 mmol) in DMF (50 mL) was added HATU (8.04 g, 21.1 mmol) and EIPEA (2.73 g, 21.1 mmol). The reaction mixture was stirred at ambient temperature until all dissolved. To this stirred solution was added compound 2-22-a (3.17 g, 20.2 mmol) in DMF (20 mL) via syringe. The solution was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with DCM and then concentrated to give a residue. The residue was purified by column chromatography with the eluent DCM:MeOH=60:1 to afford product, 2-22-b, (5.2 g, 68%). 1H NMR (300 MHz, CDCl3): δ 9.38 (s, 1H), 8.90 (s, 1H), 7.81-7.75 (m, 4H), 7.43-7.34 (m, 8H), 4.77 (d, J=6.0 Hz, 2H), 4.67 (s, 2H), 4.56 (s, 2H). LC-MS: (M+H)+ 400.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]2[S:9][C:10]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:11]=3[N:12]=2)[CH2:2]1.[C:20](=O)([O-])[O-].[K+].[K+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(O)=O.C=O.O.C(Cl)(Cl)Cl.C(#N)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:20][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]2[S:9][C:10]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:11]=3[N:12]=2)[CH2:2]1
Reactant: c1ccc2c(c1)Cc1sc(CC3CCCNC3)nc1-2
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: O=CO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN1CCCC(Cc2nc3c(s2)Cc2ccccc2-3)C1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
In 0.13 ml of formic acid and 0.3 ml of a 35% aqueous formaldehyde solution, 94 mg of 2-(3-piperidylmethyl)-8H-indeno[1,2-d]thiazole was dissolved, followed by heating at 90° C. for 14 hours. The reaction mixture was diluted with water and chloroform, followed by the addition of potassium carbonate to adjust the pH of the aqueous layer to about 8. An organic layer was separated, and the resulting aqueous layer was extracted twice with chloroform. The organic layers were combined and washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol), whereby 99 mg of a brawn oily substance was obtained. The substance was dissolved in 1 ml of acetonitrile, and 40 mg of fumaric acid was added thereto. The resulting mixture was stirred at room temperature for 30 minutes and the crystals formed were collected by filtration, whereby 90 mg of 2-[(1-methyl-3-piperidyl)methyl]-8H-indeno[1,2-d]thiazole fumarate was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25](F)=[C:24](C(F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:61][N:62]4[CH2:65][CH2:64][CH2:63]4)C=C(C4CCCCC4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:61][N:62]4[CH2:65][CH2:64][CH2:63]4)[CH:19]=[C:20]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(C3CCCCC3)cn2CCN2CCC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(C3CCCCC3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=453, obsd.=453).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C=O)C>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: O=c1cc(COC2CCCCO2)occ1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCBr
Temperature: 92.5 °C
Yield: 91 %

Procedure:
The compound was prepared according to example 11 using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (3.5 g, 15.5 mmol) in 20 mL of DMF, Cs2CO3 (5.04 g, 15.5 mmol) and 1,5-dibromopentane (8.8 g, 36.7 mmol). The sealed tube was heated at 90-95° C. for 1 h 40. A white solid 1 was obtained (5.30 g, 91% yield).