Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.C[O-].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[SH:29]>CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCCCCSc3cc(Cl)ccc3Cl)ccc2N1
Temperature: 25 °C

Procedure:
8.94 gm (0.03 mol) of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) were added to a solution of 2.21 gm (0.0315 mol) of potassium methylate and 5.76 gm (0.0315mol) of 98% 2,5-dichloro-thiophenol in 54 ml of methanol. The mixture was refluxed, whereupon at first a clear solution was obtained. After 5 minutes so much crystalline reaction product was separated out that the reaction mixture solidified into a barely stirrable crystal slurry. After one hour the mixture was cooled to room temperature, suction-filtered and the filter cake was recrystallized from ethanol. Colorless crystals with a melting point of 133°-134° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:6]
Reactant: Cc1ccccc1N
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1NC(=O)c1c(N)cccc1Cl
Yield: 55.3 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (1.0 g, 5.83 mmol) and SOCl2 (1.1 mL, 14.6 mmol) in benzene (30 mL), followed by o-toluidine (1.4 mL, 12.8 mmol) and CHCl3 (30 mL). The product was chromatographed in CH2Cl2 to provide 840 mg of an oily yellow solid (55%). NMR (CDCl3) δ: 7.96 (d, J=7.9 Hz, 1H); 7.60 (br s, 1H); 7.23-7.30 (m, 2H); 7.14 (t, J=7.5 Hz, 1H); 7.11 (t, J=8.3 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 6.64 (d, J=8.2 Hz, 1H); 4.73 (br s, 2H); 2.35 (s, 3H). MS (ES): m/z 261.0 (M+).
Reaction SMILES: C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4C[CH2:22][O:23]C=4C=3)C2=O)C=CC=CC=1.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:64])=[C:39]([CH:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:42]2=[O:63])[CH:40]=1>>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:64])=[C:39]([C:41]2([CH2:22][OH:23])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([CH:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:42]2=[O:63])[CH:40]=1
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 26C, and making non-critical variations to replace 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 500.4 (M+1), 502.4 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(O)ccc1N
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)C(C)C)cnc12
Yield: 55.4 %

Procedure:
A solution of 3-isobutyryl-4-chloro-8-methoxyquinoline (1.32 g, 5 mmol) and 4-amino-3-methylphenol (0.62 g, 5 mmol) in dioxan (50 ml) was heated at reflux for 1 hour, then cooled and the solid filtered off. This was taken up in a hot mixture of ethanol and tributylamine, cooled, and the solid filtered off. Recrystallisation from ethanol gave 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (0.97 g, 55%), m.p. 243°-5°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:31][CH:30]=1)[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:34]4[CH:35]=[C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])[CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 9) (107.0 mg, 0.207 mmol) and 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (64 mg, 0.207 mmol) in THF (2.3 mL) was added aqueous potassium carbonate (1.6 mL of a 1M solution, 1.6 mmol). The mixture was degassed with nitrogen. While stirring the reaction vigorously at room temperature, 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (6.7 mg, 0.01 mmol) was added. The reaction was stirred vigorously at room temperature for 15 min, and then diluted with EtOAc (50 mL). The organics were washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) afforded impure product, which was repurified with 1:1:1 CH2Cl2:hexanes:Et2O on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (40% EtOAc/hexanes). LCMS=616.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 6.94-7.85 (m, 8H), 5.40-5.55 (m, 1H), 4.81-5.08 (m, 1H), 3.54-4.36 (m, 7H), 1.95-2.59 (m, 1H), 1.30-1.34 (m, 6H), 0.62-0.74 (m, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 5 was prepared from diphenylacetyl chloride and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.35–7.23 (m, 12H), 7.20 (s, 1H), 6.95 (d, 2H, J=7.6 Hz), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.48 (m, 1H), 2.40 (t, 2H, J=6.4 Hz), 2.34 (t, 2H, J=7.2 Hz), 1.98 (t, 2H, J=11.2 Hz), 1.82–1.60 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][N:21]=2)[CH2:11][CH2:10]1.CCOC(C)=O>C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][N:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2cnc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCc2cnc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Yield: 93.3 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.417 g, 0.937 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 2 hours. The reaction was filtered and concentrated to give a white solid. EtOAc was added and the product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.391 g, 93%). MS: APCI: M+1: 447.2 (Exact Mass: 446.16).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:19][C:20]([F:29])([F:30])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])=[CH:10][C:2]=2[Cl:1])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl

Procedure:
The sub-title compound is prepared in analogy to 1b from 2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid (2.00 g, 7.1 mmol), 4-trifluoromethoxyaniline (0.96 mL, 7.1 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (1.13 mL, 8.5 mmol), DIPEA (2.85 mL, 16 mmol) and DCM (40 mL).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12].C(N(CC)CC)C>C(O)C.C1COCC1>[CH3:10][N:11]([CH3:12])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc(C#N)cn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
In a 25 ml sealed tube, 1.0 g (7.2 mmol) of 6-chloro-nicotino-nitrile and 1.9 ml (10.8 mmol, 5.6 M, 1.5 eq.) of a solution of dimethyl-amine in ethanol are dissolved in 10 ml of THF. Then, 1.5 ml (10.8 mmol, 1.5 eq.) of triethyl-amine are added and the reaction mixture heated to 75° C. After 4 h, the mixture was cooled to rt and concentrated. The residue was taken up in dichloro-methane and aqueous NaHCO3 (5%), the phases separated and the aqueous phases extracted two times with dichloro-methane. The combined organic phases were dried (Na2SO4) and concentrated. The title compound was obtained as a beige solid and used for the next step without further purification. Mass spectrum: m/z (M+H)+: 148.0
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:17][C@H:18]1[C@H:24]([CH3:25])[O:23][C:22]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:21]=2[NH:20][C:19]1=[O:34].[C:35]([O:39][C:40]([N:42]([CH3:48])[C@@H:43]([CH3:47])[C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[O:41])[N:42]([CH3:48])[C@H:43]([C:44](=[O:45])[NH:17][C@@H:18]1[C:19](=[O:34])[NH:20][C:21]2[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:22]=2[O:23][C@H:24]1[CH3:25])[CH3:47])([CH3:36])([CH3:38])[CH3:37]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
In a similar manner to that described for Example 36 Step 1 except 4 equivalents of DIEA were used, (2S,3S)-3-amino-2-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (58 mg, 0.155 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (31.5 mg, 155 μmol) were converted to a material which was purified by silica gel chromatography to afford methyl-[(S)-1-((6S,7S)-6-methyl-8-oxo-2-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (52 mg, 75%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.Cl>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C:20]=1[CH3:22])=[O:16])[CH3:19]
Reactant: NNc1ccc(Br)cn1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Yield: 73.3 %

Procedure:
Next, 5-bromopyridin-2-ylhydrazine (25.3 g) and ethyl 2-ethoxymethyleneacetoacetate (25.1 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added to a mixed solvent of 1N hydrochloric acid aqueous solution (320 ml) and ethanol (370 ml), stirred at reflux temperature for 4.5 hours and the solvent was evaporated in vacuo. Water was added to the residue, the precipitated solid was washed with water and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (30.6 g) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19](O)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:47][CH:48]1[CH2:51][NH:50][CH2:49]1.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[F:47][CH:48]1[CH2:51][N:50]([C:19]([C:16]2[N:8]3[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[C:7]3=[N:18][CH:17]=2)=[O:20])[CH2:49]1
Reactant: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1CC(F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
A mixture of 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (100 mg), HATU (154 mg), 3-fluoroazetidine hydrochloride (45.0 mg), N,N-diisopropylethylamine (0.147 mL) and DMF (2 mL) was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (110 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([C:14]#[CH:15])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1sc(NC(=O)OC(C)(C)C)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1sc(NC(=O)OC(C)(C)C)nc1C
Yield: 92.8 %

Procedure:
The above prepared (5-ethynyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.420 g, 1.76 mmol) was dissolved in 12 mL of ethyl acetate and hydrogenated over 0.200 g of Pd on charcoal (10%) at atmospheric pressure and ambient temperature over night. Filtration over a pad of Celite and evaporation off all solvents yielded 0.396 g of the title product as light brown viscous oil, sufficiently pure for the next step.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].CCN(CC)CC.C1COCC1.[SH2:27]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[S:27])[NH2:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ncc2cc(C#N)ccc21
Reactant: S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)n1ncc2cc(C(N)=S)ccc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1-acetyl-1H-indazole-5-carbonitrile (1.1 g, 6 mmol), Et3N (2.5 mL, 17.8 mmol) and THF (20 mL) was bubbled in H2S gas over 10 min. Stirred at 0° C. for 24 h. Concentrated in vacuo to give a yellow solid which was triturated with CH2Cl2 and filtered insoluble solid to give 1-acetyl-1H-indazole-5-carbothioic acid amide as a yellow solid. MS m/z: 220.0 (M+H). Calc'd for CloH9N3OS 219.26.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:20]=2)[O:17][CH:18]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Reactant: CC(C)CBr
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1OCC(C)C

Procedure:
Using the compound obtained in Example 272 and isobutyl bromide, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]-propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Reactant: COc1cccc(OC)c1B(O)O
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: CC#N
Solvent: O
Product: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (40 mg, 0.068 mmol), 2,6-dimethoxyphenylboronic acid (18.6 mg, 0.102 mmol), tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, 0.204 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone, which was used in step 2 without further purification.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[C:8]([C:25](=[O:26])[CH2:24][CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)N1CCC(CCC(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)N1CCC(CCC(=O)c2ccc3[nH]c4ccccc4c3c2)CC1
Temperature: 70 °C
Reaction time: 11 h
Yield: 25 %

Procedure:
To a 90 ml solution of 5.0 g of carbazole and 7.2 g of 3-(1-acetylpiperidin-4-yl)propionyl chloride in nitromethane, 9.3 g of aluminum chloride was added little by little, followed by stirring at 70° C. for 11 hours. The reaction mixture was poured over 100 ml of ice water, and the organic layer was separated and then washed by sequential additions of a 50 ml saturated aqueous sodium hydrogen carbonate solution and 50 ml of distilled water. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to yield an oily residue. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-methanol=20:1 (v/v)) to yield 2.6 g of the title compound as a light yellow powder.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[O:21])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)Nc2ccc(F)cc2)CC1
Reaction time: 3 h

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (536 mg) in dichloromethane (5 ml) were added 4-fluorophenyl isocyanate (375 μl) and diisopropylethylamine (575 μl ) at ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with dichloromethane. An organic phase was separated and an aqueous phase was extracted with dichloromethane. A combined organic phase was dried over magnesium sulfate and the solvents were removed under reduced pressure. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (448 mg) was obtained.
Reaction SMILES: [CH:1](I)=[CH2:2].C([Li])(C)(C)C.[F:9][C:10]([F:20])([F:19])[C:11]([C:13]1[S:17][C:16]([SH:18])=[N:15][CH:14]=1)=[O:12]>CCOCC>[F:20][C:10]([F:9])([F:19])[C:11]([C:13]1[S:17][C:16]([SH:18])=[N:15][CH:14]=1)([OH:12])[CH:1]=[CH2:2]
Reactant: C=CI
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C=CC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of vinyl iodide (1.88 g, 12.2 mmol) in Et2O at −78° C. was added t-butyl lithium (14.3 ml, 1.7 M/pentane, 24.3 mmol). The mixture was stirred at −78° C. for 1 h and warmed up to −30° C. for 5 min. The mixture was cooled back to −78° C. and 2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanone (1.18 g, 5.53 mmol) in Et2O was added. The reaction mixture stirred 30 min at −78° C., brought to 0° C. and partitioned between aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (toluene/acetone; 90:10) to give the title compound.