Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@@H:17]([OH:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:54](O)=[O:55].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@H:17]([O:33][CH:54]=[O:55])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=CO
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H](O)CC[C@]3(C)[C@H]21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](OC=O)CC[C@]3(C)[C@H]21

Procedure:
11β-N,N-Dipropylaminoacetoxy-3β-hydroxy-5α-pregnan-20-one (110 mg) was stirred with triphenylphosphine (364 mg) and formic acid (0.1 ml) in tetrahydrofuran (5 ml.) and diethylazodicarboxylate (240 mg) added. Further reagent (5 drops) was added until a good yellow colour persisted. After 16 hours the mixture was concentrated and filtered through silica gel (20 g) in ethyl acetate: petroleum ether (1:1). Evaporation of the eluate gave a residue which was purified by preparative TLC (ethyl acetate: petroleum ether (1:1)) to give 11β-N,N-dipropylaminoacetoxy-3α-formyloxy-5α-pregnan-20-one (30 mg), [α]D +73°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O.[C:29](OC)(=[O:33])[C:30]([CH3:32])=[CH2:31]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:29]([O:20][CH:18]([CH2:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)[CH3:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)OC(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A one-liter flask was charged with a mixture of 69.5 grams (0.25 mole) of 4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-ol, 350 milliliters of methyl methacrylate, 0.5 gram of hydroquinone and 5 grams of tetraisopropyl titanate as the catalyst. The mixture was heated to reflux and a methanolmethylmethacrylate azeotrope slowly distilled off over a 3.5 hour period. The reaction flask was cooled slightly and 25 milliliters of water was added dropwise to hydrolyze the catalyst. The reaction mixture was allowed to cool to room temperature. The mixture was stirred 15 minutes longer and then filtered through diatomaceous earth. One hundred milliliters of hexane was added to the filtrate which separated into organic and inorganic phases. The organic phase containing the product in hexane was separated and dried over magnesium sulfate. The hexane was evaporated to obtain 82 grams (95 percent) of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-2-butyl methacrylate. The boiling point of this compound was 150° C. to 155° C. at .15 milliliters of mercury pressure.
Reaction SMILES: [F:1][B-](F)(F)F.[Cl:6][CH2:7][CH2:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+]#N)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]>CCCCCCC>[Cl:6][CH2:7][CH2:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:1])[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: F[B-](F)(F)F
Reactant: N#[N+]c1ccc2c(c1)N(C(=O)CCCl)CC2
Solvent: CCCCCCC
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
1.23 g (3.8 mmol) of 1-(3-chloropropionyl)indoline-6-diazonium tetrafluoroborate [prepared as described in step (1) above] were suspended in 20 ml of heptane, and the suspension was heated under reflux for 1 hour. At the end of this time, the mixture was cooled to room temperature, and the reaction product was poured into ice. The mixture was then extracted with 50 ml of ethyl acetate, and the organic extract was washed with 50 ml of water, after which it was dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 810 mg (3.6 mmol) of the title compound (yield: 95%).
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1N[C:18]([C:21]2[CH:26]=CC(C#C)=[CH:23][CH:22]=2)=[CH:19]N=1)=O)C(C)C.[CH3:30][O:31][C:32](=[O:57])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=2)=[CH:48][N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36]>>[CH3:30][O:31][C:32](=[O:57])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53]3[C:52](=[CH:19][CH:18]=[C:21]([C:22]#[CH:23])[CH:26]=3)[CH:51]=2)=[CH:48][N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Product: C#Cc1ccc2cc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)ccc2c1

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example AY), substituting (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[O:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH2:25]>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:25][C:24]3[CH:23]=[CH:22][S:21][C:20]=3[C:16]3[O:15][CH:19]=[CH:18][N:17]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccsc1-c1ncco1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1ncco1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (48 mg, 0.246 mmol) and 2-(oxazol-2-yl)thiophen-3-amine (41 mg, 0.246 mmol) according to protocol A. Retention time (min)=2.206, method [7], MS(ESI) 336.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.79 (s, 1H), 9.71 (s, 1H), 8.59 (d, J=6.5 Hz, 1H), 8.36 (d, J=6.5 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.07-8.13 (m, 2H), 7.95 (dd, J=8.3, 7.3 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=5.3 Hz, 1H), 6.95 (s, 1H), 4.36 (s, 2H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:12]I.[H-].[Na+]>>[CH3:12][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1N=CC=Cc2ccccc21

Procedure:
The bromide 20 (Bogatskii A V, et al., (1977) Pharm Chem J (Engl Transl) 11:1520-1525; Vejdelek Z, Protiva M (1983) Collect Czech Chem Commun 48:1477-1482) was reacted with trimethylsilyacetylene in the presence of a palladium catalyst to provide trimethylsilyl analog 52. This product was methylated with methyl iodide/sodium hydride to give the N-methyl benzodiazepine 54 (XLi 351). This was subjected to fluoride-mediated desilylation to furnish 53 (XLi 350) from 53 and 55 (XLi 352) from 54.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[OH:9])=[C:4]([CH2:23]O)[CH:3]=1.P(=O)(O)(O)O>>[CH3:15][N:13]([CH2:12][CH2:11][CH2:10][C:8]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:9][CH2:23][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]1=2)[CH3:14]
Reactant: CN(C)CCCC(O)(c1ccc(F)cc1)c1ccc(Br)cc1CO
Agent: O=P(O)(O)O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(Br)ccc21
Yield: 85.1 %

Procedure:
The (4-bromo-2-(hydroxymethyl)phenyl)-(4′fluorophenyl)-(3-dimethylamino-propyl)methanol residue (160 g) was heated with 50% aqueous phosphoric acid (1.99 kg) with vigorous stirring. The reaction mass was purified by extraction and neutralized with aqueous ammonia at a temperature below 30° C. The reaction mass was extracted with toluene and the solvent distilled under reduced pressure to give 1-(4′fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane (130 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1>>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: COc1ccnc(Cl)c1
Agent: [Na+]
Product: COc1ccnc(OC)c1
Yield: 59.4 %

Procedure:
According to Scheme 23 Step 1: To a solution of sodium methoxide (30% in MeOH, 2 eq, 35 mmol) was added 2-chloro-4-methoxypyridine (1 eq, 17.0 mmol, 2.50 g). The reaction was refluxed overnight. The reaction was allowed to cool, poured onto water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2,4-dimethoxypyridine (10.1 mmol, 1.40 g, 58%) as a colorless oil. The crude product was reacted on.
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1C(=O)CCC1>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][CH:24]=4)[N:21]=[CH:20][CH:19]=[CH:18]5)=[N:11][C:10]=3[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(Nc4ccc5ncccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 45.7 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-(quinolin-6-ylamino)thiazole-4-carboxamide (90 mg, 0.22 mmol) and 1-methyl-piperazine (110 mg, 1.10 mmol) in NMP (3 mL) was heated at 150° C. for 1.5 h. The reaction mixture was diluted with ice-water (5 mL), and the resulting solids were collected by filtration and washed successively with water, ether and dried to give 0.049 g (45% yield) of the titled compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:8]([O:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=2)=[C:9]([CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 3.1 %

Procedure:
Cs2CO3 (146.6 mg, 0.45 mmol) was added to a solution of 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (37.5 mg, 0.15 mmol) and 4-trifluoro methoxyphenol (80.1 mg, 0.45 mmol) in DMF (0.9 mL) and the reaction was stirred at 100° C. for 8 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (101) (1.9 mg, 3%). ESI-MS m/z calc. 408.07. found 409.3 (M+1)+; Retention time: 1.68 minutes (3 minutes run).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[F:20][CH2:19][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:26][CH3:27])=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: CCO
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 41.7 of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid, 20 ml of sulfuric acid and 300 ml of ethyl alcohol was heated under refluxing for 6 hours. The reaction mixture was poured into ice-water, and the precipitated crystals were separated by filtration to obtain 42.7 g of ethyl 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylate having a melting point of 96°-98° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]([C:3]#[C:2][CH2:1][OH:4])=[CH:7][CH:8]=1
Reactant: C#CCO
Reactant: Brc1ccc(-c2ccccc2)cc1
Product: OCC#Cc1ccc(-c2ccccc2)cc1

Procedure:
In a manner described in Example 1 above, propargyl alcohol was reacted with 4-bromobiphenyl to give the title compound as white crystals: NMR (CDCl3) δ 4.53 (d, J=4.74, 2H ), 7.38 (d, J=7.17, 1H ), 7.42-7.60 ( m, 8H ). MS m/z 208 ( M+calcd. for C15H12O 208 ).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[Na+].O>CO>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: CC(C)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNc1ccc(C(C)C)cc1

Procedure:
A solution of 4-isopropylaniline (5.05 g, 37.3 mmol), methyl bromoacetate (5.99 g, 39.2 mmol) and anhydrous sodium acetate (3.21 g) in absolute methanol (30 mL) was heated to reflux for 2 h. The solution was cooled and poured into 300 mL water. The resulting solid was collected by filtration and recrystallized from ethanol/water to afford pure product, methyl-2-(4-isopropylanilino)acetate, m.p. 35-36° C. (4.53 g, 55%). 1H NMR (CDCl3, 300 MHz): δ7.06 (2H, d, J=8.2 Hz), 6.57 (2H, d, J=8.2 Hz), 4.18 (1H, v br), 3.90 (2H, s), 3.78 (3H, s), 2.81 (1H, m, J=7.0 Hz), 1.20 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 209 (3), 208 (31), 148 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=1)[O:35][CH2:36][C:37]([OH:39])=[O:38])=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=3)[O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Product: O=C(O)COc1cccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (3-formyl-phenoxy)-acetic acid according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([Mg]Cl)(C)C.CON(C)[C:19]([C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)(=[O:30])=[O:29])=[CH:25][C:24]([Cl:42])=[CH:23][N:22]=1)=[O:20]>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C:26]2[C:21]([C:19]([C:2]3[C:3]4[CH:4]=[N:5][NH:6][C:7]=4[N:8]=[CH:9][CH:10]=3)=[O:20])=[N:22][CH:23]=[C:24]([Cl:42])[CH:25]=2)(=[O:30])=[O:29])=[CH:32][C:33]=1[C:38]([F:39])([F:41])[F:40]
Reactant: Ic1ccnc2[nH]ncc12
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ncc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-7-azaindazole (Potashman et. al., WO2005070891) (123 mg) in THF (2 mL) at 0° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.5 mL). The mixture was stirred at 0° C. for 30 min and 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (114 mg) was added. The reaction mixture was warmed to room temperature, stirred for 2 h and quench by saturated aqueous NH4Cl solution (2 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 515.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCn1cc(Br)cn1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1cc(Br)cn1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (for a preparation see Intermediate 29) (120 mg, 0.573 mmol) was mixed with potassium phthalimide (159 mg, 0.859 mmol), dissolved in N,N-Dimethylformamide (DMF) (4 mL) and stirred under nitrogen at 120° C. for 20 hours. The reaction was left to cool to room temperature and the product was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine, 30 mL), dried (MgSO4), filtered and evaporated to dryness to give a white solid. The product was purified on a 25+S Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 7:3). Product-containing fractions were evaporated to dryness to give a white solid (85 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)c(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Yield: 55.8 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3-chloro-4-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.1 g, 9.84 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 0.59 g, 14.76 mmol), iodomethane (1.22 mL, 19.68 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (1.81 g, 56%). MS m/z (rel. intensity, 70 eV) 273 (19), 228 (13), 187 (17), 133 (12), 57 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][N:3]=1.[Cl-:12].[Al+3].[Cl-:14].[Cl-:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:15])([Cl:14])[Cl:12])=[CH:4][N:3]=1
Reactant: [Cl-]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Al+3]
Product: Clc1ccc(C(Cl)(Cl)Cl)cn1
Temperature: 0 °C

Procedure:
To 18.2 g of 2-chloro-5-trifluoromethyl pyridine, 20 g of aluminum chloride was added in 2 hours, and they were reacted under the predetermined reaction conditions as shown in Table 1. After the completion of the reaction, the reaction product was cooled and then introduced into ice water, and the oil layer was separated by liquid separation. The solvent was removed by distillation to obtain 2-chloro-5-trichloromethyl pyridine.
Reaction SMILES: C([NH:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=O.[OH-].[K+]>C(O)C.O>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[CH2:18][N:9]1[C:8]2[CH:7]=[N:6][C:5]([CH2:4][NH2:3])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=CNCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C

Procedure:
This formamide (2.90 g, 7.5 mmol) was treated with potassium hydroxide (5.40 g, 9.4 mmol) in ethanol/water (5:1, 48 mL) at reflux for 6 hours. The resulting suspension was cooled to room temperature, concentrated, and diluted with CH2Cl2 (50 mL). The organic phase was washed with water (2×25 mL), dried (Na2SO4), filtered and concentrated to give [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine as a yellow solid. The crude material was recrystallized from ethyl acetate/hexane to give 1.48 grams (55%) of a pale-yellow solid. 1H NMR (CDCl3) δ8.70 (s, 1H), 8.18 (d,J=7.9 Hz, 1H), 8.03 (s, 1H), 7.58 (td,J=7.2, 1.1 Hz, 1H) 7.32-7.42 (6-line m, 3H), 7.20 (dd, J=9.6, 2.6 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 5.60 (s, 2H), 4.28 (d, 1H), 1.96 (br s, 2H); MS monoisotopic mass (calculated) 355.1, MH+ (observed) 356.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]=2[N:14]=1
Reactant: CC(C)Br
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 122 mg, 0.540 mmol) in DMF (5 mL) was added NaH (110 mg, 2.75 mmol) and the reaction was stirred for 10 min. 2-Bromopropane (111 μL; 0.688 mmol) was added and the mixture was stirred at RT for another 2.5 h. The reaction was quenched with water (50 mL), poured into a separatory funnel containing EtOAc (150 mL), the mixture was shaken and the layers were separated. The organic layer washed with brine (100 mL), dried, filtered and concentrated. The crude product was purified by silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 2-amino-9-isopropyl-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (13, 30 mg, 21%). NH4OAc standard conditions. DAD Retention time =6.95 min. M+H=269. 1H NMR (300 MHz, DMSO-d6): Δ8.72 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (br s, 2H), 7.29 (ddd, J=8.4, 8.4, 1.2 Hz, 1H), 7.17 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 5.23 (septet, J=6.9 Hz, 1H), 1.60 (d, J=6.9 Hz, 6H).