Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1
Reactant: ClCc1ccccn1
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccn2)c1
Yield: 96.6 %

Procedure:
3-Bromophenol (1.00 g, 5.8 mmol), 2-picolyl chloride hydrochloride (950 mg, 5.8 mmol) and potassium carbonate (3.20 g, 23 mmol) were stirred together in DMF (10 mL) at room temperature overnight. The solvent was removed in vacuo, azeotroping with xylene to remove the last traces of DMF. The residual material was partitioned between ethyl acetate (70 mL) and water (70 mL), then the organic phase was washed with saturated sodium chloride solution (1×50 mL), was dried over magnesium sulfate, and was concentrated in vacuo to afford 2-(3-bromophenoxymethyl)pyridine (1.48 g, 97%). m/z (ES+) 265 [MH]+.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=O)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[CH2:2])=[CH:9][CH:8]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCc2ccc(Br)cc21
Reaction time: 1 h
Yield: 62 %

Procedure:
A 2.5 M solution of n-BuLi in hexanes (23.6 mL, 59 mmol) was added dropwise to a 0° C. slurry of methyltriphenylphosphonium bromide (16.8 g, 47.0 mmol) in THF (200 mL). After 1 h, a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.0 mmol) in THF (50 mL) was added to the resulting solution and the reaction cold bath was removed. Upon completion, the reaction was quenched with water (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford 6-bromo-1-methylene-2,3-dihydro-1H-indene (6.06 g, 62% yield) as a clear oil after purification by flash chromatography over silica gel (hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.0, 1.8 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.45 (t, J=2.5 Hz, 1H), 5.08 (t, J=2.1 Hz, 1H), 2.88-2.98 (m, 2H), 2.78-2.86 (m, 2H); MS (EI) m/z=210.1 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn1Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 493 mg of potassium tert-butoxide in 5 mL of dimethylformamide (anhydrous) is added dropwise a solution of 556 mg of ethyl pyrrole-2-carboxylate (prepared as described in Organic Synthesis, Vol. 51, p. 100) in 5 mL of anhydrous dimethylformamide. On completion of the addition the mixture is allowed to stir at room temperature for 1 hour. To this mixture is added a solution of 1 g of 4-chloro-2-nitrobenzyl bromide in 5 mL of dimethylformamide. The reaction mixture is then heated to 75° and maintained at this temperature for 18 hours, then allowed to cool to room temperature. The reaction mixture is poured into 20 mL of ice-water and extracted with 2×30 mL of ether. The combined ethereal extracts are washed with 2×30 mL of water followed by 30 mL of saturated sodium bicarbonate solution. The ethereal extracts are dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield ethyl 1-(4-chloro-2-nitrobenzyl)-pyrrole-2-carboxylate melting at 104°-106°.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:16][CH:17]1[CH2:19][CH2:18]1.Cl[C:39]1[N:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][N:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:17]1([CH2:16][N:15]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:14]2[N:13]=[C:12]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:11]3=[CH:10][C:9]=2[CH2:8][N:7]([CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=2)[C:39]2[N:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][N:40]=2)[CH2:18][CH2:19]1
Reactant: CC(=O)c1cnc(Cl)nc1
Reactant: Cc1nn(C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3c(C)nn(C)c3nc2N(CC2CC2)CC2CC2)nc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-N,N-bis(cyclopropylmethyl)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-amine (0.761 mmol, 0.400 g) in DMF was treated with 1-(2-chloropyrimidin-5-yl)ethanone (0.761 mmol, 0.119 g) and K2CO3 (2.283 mmol, 0.315 g). The reaction mixture was stirred at 60-70° C. for 12-16 h. The reaction mixture was then extracted with EtOAc. The combined organic layer was washed with water and brine solution, dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography using silica gel and 50% EtOAc in petroleum ether as eluent to get the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][C:11]=2[CH3:13])[O:6][CH2:5]1.[CH:14]1(B(O)O)C[CH2:15]1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][C:11]=2[CH:13]2[CH2:15][CH2:14]2)[O:6][CH2:5]1
Reactant: OB(O)C1CC1
Reactant: CON=C1COc2cncc(C)c21
Product: CON=C1COc2cncc(C3CC3)c21

Procedure:
This compound was prepared using a method analogous to that of 4-methylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime (A.2.11.4), cyclopropylboronic acid replacing trimethylboroxine. Purification by CC using Hept/EtOAc (9/1 to 8/2) gives the desired product as white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(OCCBr)c(Cl)c1
Temperature: 85 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-4-methylphenol (500 mg, 3.62 mmol) in acetonitrile (20 mL) was added 1,2-dibromoethane (3.29 g, 17.53 mmol) followed by cesium carbonate (2.28 g, 7.01 mmol). The resulting mixture was heated at 85° C. for 48 h, then cooled to rt. The solution was filtered through a Celite® pad. The Celite® was washed with acetone and the combined eluents were concentrated under reduced pressure to give the title compound as a white solid (697 mg, 76%). GC/MS (EI) m/z 248 (M)+, RT 7.33 min.
Reaction SMILES: [Cl:1][C:2]1[C:18]([OH:19])=[CH:17][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Cl:20].[N+]([O-])(O)=[O:22]>C(O)(=O)C>[C:9]([C:6]1[C:5]2[C:17](=[O:22])[C:18](=[O:19])[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=2[O:8][CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccc1)c1coc2c(Cl)c(Cl)c(O)cc12
Solvent: CC(=O)O
Product: O=C1C(=O)c2c(C(=O)c3ccccc3)coc2C(Cl)=C1Cl
Temperature: 60 °C

Procedure:
To a solution of compound 4 (100 mg, 0.32 mmol) in glacial acetic acid (2 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 3 h, allowed to cool to room temperature, and poured over crushed ice. The resulting precipitate was filtered, dried, and recrystallized (CH2Cl2-pet. ether) to afford compound SKC-BF-09 (40 mg, 40%) as brick red solid. TLC Rf=0.5 (petroleum ether-EtOAc, 7:3); 1H NMR (CDCl3) δ 7.93 (s, 1H), 7.86 (d, J=6.9 Hz, 2H), 7.64 (app t, 1H), 7.50 (d, J=7.6 Hz, 2H); MS (ES) m/z 321 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:26][CH:25]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)c(F)c1

Procedure:
The title compound, light green solid (71 mg, 53%), MS (ISP) m/z=408.2 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][O-:16].[Na+].O.Cl>CO>[CH3:15][O:16][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (2 g, 8.9 mmol) and sodium methoxide (1.9 g, 36 mmol) in methanol (20 mL) was heated at reflux for 48 hours. The mixture was allowed to cool to room temperature then poured into water (50 mL). This was cooled in an ice-bath and acidified with hydrochloric acid (2 N, aq). The resulting precipitate was filtered and dried to give 2-methoxy-6-(trifluoromethyl)nicotinic acid as a white solid (1.1 g): 1H NMR (400 MHz, CDCl3): δ 8.61 (1H, d, J 7.7), 7.48 (1H, d, J 7.7), 4.25 (3H, s).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:31][N:14]3[C:15](=[O:30])[CH2:16][CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=4)[CH2:19][C@@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:10][C@@H:11]1[CH2:31][N:14]2[C:15](=[O:30])[CH2:16][CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][N:21]=3)[CH2:19][C@@H:13]2[CH2:12]1
Reactant: O=C(O[C@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To (8S,9aS)-5-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-8-yl 4-nitrobenzoate (135 mg, 0.291 mmol, Part C) in methanol (2.5 mL) was added potassium carbonate (24 mg, 0.174 mmol). The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 78 mg (85% yield) of the titled compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.28 (m, 1 H), 2.45 (m, 1H), 2.63 (m, 1 H), 3.35 (m, 3 H), 3.44 (m, 1 H), 3.92 (m, 1H), 4.17 (m, 1H), 4.42 (m, 2H), 5.09 (br s, 1H), 7.00 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 8.43 (s, 1 H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [CH2:1]([Si:5]([CH:18]1[S:23][CH2:22][CH2:21][CH2:20][S:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([Li])CCC.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH2:1]([Si:5]([C:18]1([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19][CH2:20][CH2:21][CH2:22][S:23]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Reactant: CC(C)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 32 (4.68 g, 13.1 mmol) in THF (100 mL) at -78° C. was added dropwise over 10 min n-butyllithium (1.6M in hexanes, 18.4 mmol). After 3 h of stirring under argon, 1-bromo-2-methylpropane (2.14 mL, 19.7 mmol) was added dropwise over 5 min, and the mixture was stirred for 2 h at -78° C. and overnight at rt. The reaction mixture was quenched with water (10 mL) and the excess organic solvent was removed under reduced pressure. The crude mixture was extracted with three 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 26 as a colorless solid (5.0 g, 92%): R.function. =0.75 (1/9 EtOAc:hexane); mp 67°-69° C. 1H NMR (300 MHz, CDCl3) δ7.83 (d, J=6.0 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=10.1, 1.7 Hz, 1H), 3.04 (m, 2H), 2.49 (t, J=4.3 Hz 1H), 2.44 (t, J=4.1 Hz, 1H), 2.08 (d, J=5.1 Hz, 2H), 1.98 (m, 4H), 1.79 (m, 1H), 1.54 (m, 2H), 0.82 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ141.5, 136.7, 132.9, 129.9, 127.7, 113.0, 45.7, 39.9, 28.3, 27.2, 24.6, 24.3, 24.2, 11.0; IR (film) 3068 (m), 3043 (m), 2951 (s), 2912 (s), 2863 (m), 1432 (s), 1274 (w), 1113 (s), 997 (m), 913 (m), 738 (s), 705 (s) cm-1 ; MS (EI) m/e (rel. intensity) 289 (M+ -123, 3), 237 (8), 183 (72), 175 (100), 159 (32), 143 (17), 119 (16), 105 (35); HRMS (FAB) calcd for C24H32S2Si: 412.1715 (MH+ -1), found: 412.1727. Anal. Calcd for C24H32S2 Si: C, 69.84; H, 7.82. Found: C, 70.08; H, 8.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:44])(=[O:45])[NH2:43])=[CH:37][C:33]=1[C:34]([N:21]1[CH2:20][CH2:19][N:18]([C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22]1)=[O:35]
Reactant: COc1ccc(-c2cc(N3CCNCC3)nc(C)n2)cc1OC
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(N3CCN(C(=O)c4cc(S(N)(=O)=O)c(Cl)cc4Cl)CC3)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(1-piperazinyl)pyrimidine (0.8 g) in chloroform (10 ml) were added triethylamine (0.39 ml) and 2,4-dichloro-5-sulfamoylbenzoyl chloride (0.74 g), and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated. The obtained mixture was chromatographed on silica gel eluting with chloroform-methanol mixture (49:1 v/v), to give 4-[4-(2,4-dichloro-5-sulfamoylbenzoyl)piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (1.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([C:10]([NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To a stirred solution of 1 kg of 2,5-dichloroaniline in 2500 ml of pyridine is added 840 ml of pivaloyl chloride and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured into water. The solid is filtered, washed with water and air dried to yield N-tert-butylcarbonyl-2,5-dichloroaniline, melting at 74°-76°.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)[CH3:11].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.O>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl)-acetic Acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0° C. and NaBH4 (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1:1 mixture of saturated aqueous NaHCO3:H2O was added. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (231 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25 (t, 3H); MS 298 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[ClH:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:10])[O:14][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Product: CCOC(=N)Cc1ccc(F)cc1

Procedure:
A solution of 4-fluorophenylacetonitrile (50 g, 0.37 mol) in absolute ethanol (300 ml) was treated with dry HCl gas with ice cooling for 1 hour. The solvent was evaporated in vacuo, and the residual oil triturated with ether. The solid was filtered off, washed with ether and dried (67 g, 83%), then used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:15]([N+:16]([O-])=O)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:19]([O-])=O)=[CH:6][C:5]([CH3:22])=[CH:4][N:3]=1.O>CC(O)=O.[Fe]>[NH2:19][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([NH2:16])[C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[C:5]([CH3:22])[CH:6]=1)[C:12]#[N:13]
Reactant: Cc1cnc(F)c(-c2c([N+](=O)[O-])cc(C#N)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc(F)c(-c2c(N)cc(C#N)cc2N)c1
Temperature: 76 °C
Yield: 156.6 %

Procedure:
Compound 122 (119 mg, 0.39 mmol) was stirred in HOAc (3 mL) with H2O (0.5 mL) and stirred at 76° C. Iron powder (˜325 mesh, 88 mg, 1.56 mmol) was added, and the reaction stirred for 4 h. The solution was concentrated in vacuo, diluted with EtOAc (30 mL), and made basic with sat. NaHCO3. The material was then filtered through Celite, and the organics were separated, dried (MgSO4), and concentrated in vacuo to give 148 mg (66%) of the title compound as a brown oil. MS (ES) [m+H] calc'd for C13H11FN4, 243; found 243.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:16][C:14]([F:15])([F:17])[C:11]1([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc3c(c2)NC(=O)CS3)(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSc2ccc(CNC3(C(F)(F)F)CCNCC3)cc2N1

Procedure:
A solution of 6-[{1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidin-4-ylamino}methyl]-4H-benzo[1,4]thiazin-3-one (3f) in 1:1 TFA/CH2Cl2 is stirred at room temperature until the starting material is consumed, then is concentrated to dryness in vacuo. The residue is partitioned between dilute NaOH and CH2Cl2, and the layers are separated. The aqueous layer is extracted with CH2Cl2, and the combined organic extracts are dried (Na2SO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)=CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)C=C(C)C
Reaction time: 0.5 h

Procedure:
A solution of 12.5 ml of 3-methylbut-2-enoyl chloride in 110 ml of toluene is added dropwise at room temperature to a solution of 13.4 ml of methyl 2-aminobenzoate and 21.8 ml of triethylamine in 110 ml of toluene. After 30 minutes, the reaction mixture is diluted with toluene, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:10 EtOAc-heptane); Rt=4.78.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[CH2:29]([CH2:33][C:34](=O)[CH3:35])[C:30]([CH3:32])=O.O.[OH-].[Li+]>C1(C)C=CC=CC=1>[CH3:35][C:34]1[N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:7]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:6]3[C:4]([OH:3])=[O:5])=[CH:27][CH:26]=2)[C:30]([CH3:32])=[CH:29][CH:33]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc(N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A mixture of 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester (0.20 g, 0.54 mmol), acetonylacetone (0.16 mL, 1.35 mmol), and toluene (15 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 6 h. The reaction was cooled and concentrated. The residue was re-dissolved in 10 mL of 2:1:1 THF/MeOH/water. Lithium hydroxide monohydrate (0.09 g, 2.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by HPLC to afford the title compound (0.027 g, 6%) as a brown solid: 1H NMR (DMSO-d6) δ 1.91 (s, 6H), 5.75 (s, 2H), 7.01-7.30 (m, 6H), 7.32-7.38 (m, 2H), 7.40-7.50 (m, 6H), 7.68 (d, J=8.54 Hz, 1H), 12.80 (br s, 1H); MS (ESI) m/z 421 (MH+); MS (ESI) m/z 419 ([M−H]−); HRMS calcd for C28H26N2O2: 421.1905; found (ESI+): 421.1915.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:11]([C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)cc[nH]1
Yield: 31 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. The cooled mixture was then treated with water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone, as a yellow solid (32% yield), mp: 250-251° C.; 1H NMR (DMSO-d6): δ 11.74 (s, 1H), 8.45 (d, J=5.0 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 (d, J=5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2.0.2H2O: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.