Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[NH:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][CH3:16])[N:8]=1)([O-])=O.[C:22](O)(=O)[CH3:23]>C(OC(=O)C)(=O)C.[Fe]>[Cl:21][C:19]1[CH:18]=[CH:17][C:5]2[N:6]([C:7]3[N:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][CH3:16])[N:8]=3)[C:22]([CH3:23])=[N:1][C:4]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: COc1nc(Nc2ccc(Cl)cc2[N+](=O)[O-])nc(OC)n1
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(OC)nc(-n2c(C)nc3cc(Cl)ccc32)n1
Temperature: 25 °C

Procedure:
2-Nitro-4-chloro-N-(4,6-dimethoxy-[1,3,5]triazin-2-yl)aniline (0.5 g) and iron powder (0.3 g) were dissolved in acetic acid (10 ml) and acetic anhydride (5 ml), followed by reflux for 4 hours. The reaction mixture was cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, water was added to the residue, and the crystals were collected by filtration, washed with water and dried. Recrystallization from ethanol was carried out to obtain 0.39 g of the desired product as white feather-like crystals (m.p. 173-176° C.)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 1.84 g (5 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 0.56 g (6 mmol) of phenol, 0.83 g (6 mmol) of powdered potassium carbonate and 20 ml of dry dimethylformamide is stirred at room temperature for 26 hours, then poured into 100 ml of water and extracted three times with chloroform. The chloroform solution is washed twice with water and three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate. There is obtained phenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 211°-212°.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>CN1CCCC1=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:3]3[N:10]([CH2:11][CH3:12])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCn1ccc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Product: CCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Yield: 52.8 %

Procedure:
To a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in 1-methyl-2-pyrrolidone (0.94 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title compound (98 mg) was obtained as a pale-purple powder crystals by the reaction in the same manner as in Example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([O:22][CH2:38][C:37]1[C:36]([F:35])=[CH:43][CH:42]=[CH:41][C:40]=1[F:44])=[CH:15][CH:14]=3
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3c(F)cccc3F)ccc12
Temperature: 130 °C
Reaction time: 3 h

Procedure:
1 g 1-(2-Chloro-phenyl)-3,4-dimethyl-7-hydroxy-imidazo(1,5-a)quinoxaline, 2.24 g Caesium carbonate, 50 mL N,N-dimethylformamide, and 6 mL water were stirred for 10 min followed by addition of 0.83 g 2,6-difluorobenzylbromide. After 3 h stirring at 130° C. the reaction mixture was given into 150 mL water, filtered off, washed with water, dried under reduced pressure, and purified with silica gel, dichloromethane/methanol=95/5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Br)=[CH2:12].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1cccc2cc[nH]c12
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
1-bromo-2-nitrobenzene (6.000 g, 29.7 mmol) was added to tetrahydrofuran (65 mL) and cooled to −40° C. Vinylmagnesiumbromide (1M in tetrahydrofuran, 89 mL) was added quickly. The solution was stirred for 20 minutes and then poured into a saturated aqueous solution of ammonium chloride. The solution was extracted with diethyl ether and dried with brine and anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O>CO>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[N:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]=[CH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1
Reactant: O=Cc1ccccn1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CO
Product: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccn1)c1ccccn1
Temperature: 25 °C

Procedure:
15.0 g (0.13 mol) of trans-1,2-diaminocyclohexane are dissolved in 80 ml of methanol and, at room temperature, 28.1 g (0.26 mol) of pyridine-2-aldehyde are added a little at a time. The solution is refluxed for one hour and then cooled to room temperature. The precipitated solid is filtered off and dried in an oil pump vacuum. The product is obtained in the form of a light-yellow powder in a yield of 23 g (79 mmol, 60%). 1H-NMR (400 MHz, CDCl3): δ=8.55 (m, 2H, Py), 8.31 (s, 2H, ═C—H), 7.88, 7.63, 7.21 (3×m, 6H, Py), 3.52 (m, 2H, NC—H), 1.90–1.49 (m, 8H, (CH2)4) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)[CH:20]=[C:19]([C:38]([F:41])([F:40])[F:39])[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:18]=[C:19]([C:38]([F:39])([F:40])[F:41])[CH:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=18%). MS ISP (m/e): 550.4 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (d, 2H), 7.24 (d, 2H), 7.15 (d, 2H), 6.88 (s, 2H), 6.66 (s, 2H), 6.50 (s, 2H), 3.73 (s, 6H), 2.30 (, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH:16][CH2:17][CH2:18]Br)[C:6]=2[CH:20]=1.[O:21]=[C:22]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]2[NH:23]1.[ClH:36]>C(O)C>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH:16][CH2:17][CH2:18][N:33]3[CH2:32][CH2:31][C:30]4([N:25]5[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]5[NH:23][C:22]4=[O:21])[CH2:35][CH2:34]3)[C:6]=2[CH:20]=1
Reactant: O=C1NC2CCCCN2C12CCNCC2
Reactant: Clc1ccc2c(c1)C(=CCCBr)c1ccccc1CC2
Agent: Cl
Solvent: CCO
Product: O=C1NC2CCCCN2C12CCN(CCC=C1c3ccccc3CCc3ccc(Cl)cc31)CC2
Reaction time: 5 h

Procedure:
A mixture of 3.0 g of 3-chloro-5-(3-bromopropylidene)-10,11-dihydro-5H-dibenz[a,d]cycloheptene and 3.0 g of 1,2,3,5,6,7,8,8a-octahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine in 20 ml of ethanol is boiled under reflux with stirring for 5 hours. The ethanol is then distilled off under reduced pressure, and the residue is dissolved in 30 ml of toluene. The toluene solution is washed with water and extracted with 30 ml of 5% hydrochloric acid. The aqueous layer is treated with activated charcoal and made alkaline. The separated oil is allowed to stand. The crystals thus obtained is dissolved in ethanol, and ethanolic hydrochloric acid is added to give 2.8 g of 1'-[3-(3-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-1,2,3,5,6,7,8,8a-octahydro-2-oxo-imidazo[1,2-a]-pyridine-3-spiro-4'-piperidine dihydrochloride as white crystals, m.p. 262° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10](OCC)=[O:11].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][C:24]([F:35])([F:34])[F:23])=[CH:27][CH:28]=2)[C:10](=[O:11])[CH:9]([CH3:15])[CH2:8]1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: CC1CC(c2ccccc2-c2ccccc2)N(Cc2ccc(OC(F)(F)F)cc2)C1=O

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.03 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17](O)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[CH:27][C:21]=3[CH3:20])=[O:18])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1cc(C(F)(F)F)ccc1N
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (150 mg) and 2-methyl-4-trifluoromethylaniline (2152 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(2-methyl-4-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (92.5 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH3:23])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][CH2:17][C:16]=3[CH2:15]2)=[CH:12][CH:13]=1)=[O:7].FC(F)(F)C([O-])=O.[Br:31][C:32]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=1[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:1][CH:2]([CH2:22][CH3:23])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:21][C:20]3[CH2:19][N:18]([C:34](=[O:35])[C:33]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:32]=4[Br:31])[CH2:17][C:16]=3[CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CCC(O)CCNC(=O)c1ccc(N2CC3=C(CNC3)C2)nn1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: CCC(O)CCNC(=O)c1ccc(N2CC3=C(CN(C(=O)c4cc(OC)ccc4Br)C3)C2)nn1

Procedure:
N-(3-Hydroxypentyl)-6-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)pyridazine-3-carboxamide, trifluoroacetate (466 mg, 0.464 mmol) were reacted with 2-bromo-5-methoxybenzoic acid after activation with HATU analogously to example 3f. M+H+: 530.02.
Reaction SMILES: [Si](OCC[C:21]1[NH:22][C:23]2[C:28]([C:29]=1C(=O)C(OCC)=O)=[CH:27][C:26](Cl)=[CH:25][CH:24]=2)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:38](Br)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH:38]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:21]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate (Step 4, 1 eq), Ph2CHBr (1.5 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.1M). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was chromatographed with CH2Cl2 as eluent to give the N-benzhydryl indole as an orange gum in 45% yield. m/z (M+H)+ 701.3
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:45]=[CH:44][C:33]([C:34]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:35])=[CH:32][CH:31]=2)=[N:22][CH:21]=1.CC([O-])(C)C.[Na+]>CN(C=O)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>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:20]2[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[C:23]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:36][CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[O:35])=[CH:44][CH:45]=3)=[N:22][CH:21]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2cnc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3nccn23)ccn1
Temperature: 85 °C

Procedure:
A mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (85 mg, 0.34 mmol), 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl benzamide (150 mg, 0.35 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) and NaOtBu (109 mg, 1.1 mmol) in DMF:water (3:1, 9 mL) is heated at 85° C. for 18 hours. After this time the reaction mixture is cooled to room temperature and the solvents removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title ethoxypyridine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:15]([Si:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)ccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-fluoro-3-methylphenol (15 g, 0.12 mol) and imidazole (18 g, 0.26 mol) in N,N-dimethylformamide (100 mL) was added tert-butyl(chloro)dimethylsilane (20 g, 0.13 mol) at 0° C. The reaction mixture was stirred at room temperature for 20 h, and quenched by the addition of water. The aqueous layer was extracted with diethyl ether (400 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to afford 30 g (quant.) of the title compound as a yellow oil:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67-11.81 (bs, 1H), 8.38-8.41 (m, 1H), 7.85-7.98 (m, 2H), 7.25-7.32 (m, 1H), 7.20-7.24 (m, 2H), 7.09-7.19 (m, 4H), 3.75 (s, 2H), 2.37 (s, 3H), 2.05 (s, 3H); MS (APCI+) M/Z 420 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([C:19](OCC)=[O:20])=[C:12]([OH:24])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH2:19][OH:20])=[C:12]([OH:24])[C:11]=3[CH:10]=[CH:9]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cnc2c(=O)n(Cc3ccc(OC)cc3)ccc2c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc3c(O)c(CO)cnc3c2=O)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
Ethyl 7-(4-methoxybenzyl)-4-hydroxy-8-oxo-7,8-dihydro-1,7-naphthyridine-3-carboxylate (4.00 g, 11 mmol) was suspended in anhydrous THF (60 ml) and the mixture was cooled down to −10° C. Lithium aluminum hydride 2M in THF (11 ml, 23 mmol) was added dropwise to the mixture. The cold bath was then removed and the reaction was stirred for two hours at room temperature. Sodium sulfate decahydrate (10 g) was added portionwise to the reaction. The mixture was stirred for 3 hours and then filtered. The cake collected in the filter funnel was extracted for 12 hours in a soxhlet apparatus in a 2:1 mixture of chloroform and methanol. The filtrate was directly loaded unto silica gel and purified by column chromatography on silica gel using a gradient of 0 to 10% methanol in DCM to give 7-(4-methoxybenzyl)-4-hydroxy-3-(hydroxymethyl)-1,7-naphthyridin-8(7H)-one (1.3 g, 37% yield) as light yellow solid. MS (M+H)+ 313.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.O[CH:15]([C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]>ClCCl>[F:11][CH:15]([C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)COc1ccc(C(O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(F)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
To a solution of bis-(2-methoxyethyl)aminosulfur trifluoride (0.031 g) in anhydrous dichloromethane (0.05 ml) at −78° C. under nitrogen was added a solution of ethyl [4-(1-hydroxy-2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]acetate (intermediate 16, 0.061 g) in anhydrous dichloromethane (1 ml). After two hours at −78° C. the reaction was quenched with saturated sodium bicarbonate solution (2.5 ml) and the product extracted into dichloromethane. The organic extract was separated by hydrophobic frit and evaporated to yield a yellow oil. Purification by flash column chromatography using neat cyclohexane and ethyl acetate:cyclohexane (1:9) as eluents to give the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])O.[Na+].[CH:23]1([C:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:36]=3)[NH:31][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>COCCOC.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>[CH:23]1([C:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:36]=3)[NH:31][C:30]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Brc1ccccc1SCCOC1CCCCO1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
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: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCOC3CCCCO3)[nH]c2c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a suspension of 2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (1.00 g, 3.2 mmol), sodium hydrogen carbonate (1.10 g, 13.2 mmol) and tetrakis(triphenylphosphine)palladium (363 mg, 0.310 mmol) in 1,2-dimethoxyethane (10 ml) and water (5 ml) was added methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (1.45 g, 3.78 mmol) with heating under reflux and the mixture was heated under reflux for 2.5 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-3:1) to give methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-indole-6-carboxylate (1.38 g, yield 74.5%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([OH:18])=O.[NH2:24][C:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:13][C:14]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([NH:24][C:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:18]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: NC1(CO)CCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1(CO)CCCC1)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
Carbonyldiimidazole (254 mg, 1.57 mmol) was added to a suspension of 2-chloro-5-fluoro-nicotinic acid (250 mg, 1.42 mmol) in dichloromethane (10 ml) under nitrogen at room temperature. The resulting solution was stirred for 15 min after which a solution of (1-amino-cyclopentyl)-methanol (197 mg, 1.71 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (5 ml) was added. The reaction was stirred at room temperature for 18 h then diluted with dichloromethane (20 mls) and washed with sat. ammonium chloride solution (20 ml). The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with dichloromethane (5 ml) to give 2-Chloro-5-fluoro-N-(1-hydroxymethyl-cyclopentyl)-nicotinamide (100 mg) as white solid.