Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.C([SiH](CC)CC)C.C([O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][N:29]=[C:30]2[C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:25][N:24]=1)C1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:38][N:36]1[CH:37]=[C:33]([C:30]2[N:29]=[CH:28][CH:27]=[C:26]3[C:31]=2[CH:32]=[C:23]([OH:22])[N:24]=[CH:25]3)[CH:34]=[N:35]1
Reactant: Cn1cc(-c2nccc3cnc(OCc4ccccc4)cc23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nccc3cnc(O)cc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.2 %

Procedure:
A solution of Pd(OAc)2 (4 mg, 0.019 mmol), Et3N (7.5 uL, 0.053 mmol), triethylsilane (0.085 mL, 0.531 mmol) in DCM (8 mL) was stirred at room temperature for 10 minutes. A solution of 7-(benzyloxy)-1-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridine (Preparation 88, 120 mg, 0.379 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with aqueous saturated ammonium chloride (20 mL) and extracted with ether (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound (13 mg, 15%).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:10]1[CH:14]=[C:13]([B:15]2[O:23][C:20]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[O:16]2)[CH:12]=[N:11]1>C(#N)C>[N:5]1([C:3](=[O:4])[CH2:2][N:11]2[CH:12]=[C:13]([B:15]3[O:16][C:17]([CH3:19])([CH3:18])[C:20]([CH3:22])([CH3:21])[O:23]3)[CH:14]=[N:10]2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)N1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC(=O)N3CCCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A solution of 1-(bromoacetyl)pyrrolidine (Chemical Diversity Labs; 3.0 g, 15.6 mmol, 1.2 eq.) in acetonitrile (15 mL) was slowly added over a suspension of pyrazole-4-boronic acid pinacol ester (2.5 g, 12.9 mmol, 1 eq.) in acetonitrile and stirred overnight at RT. The reaction mixture was filtered and the filtrate was diluted with DCM and washed with water then brine. Separated organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (2.72 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].Cl>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)N2CCCCc3ccccc32)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of methyl 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzoate (450 mg) in a mixture of methanol (15 ml) and 1 N aqueous sodium hydroxide (3 ml) was stirred at 60° C. for 2 hours and the solution was cooled to room temperature. The solution was adjusted to pH 2-3 with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with ether to give 2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzoic acid (410 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>O>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1c(C(F)(F)F)nn(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1N
Temperature: 60 °C
Reaction time: 10 h
Yield: 85.1 %

Procedure:
To 10 ml of water, 2.37 g (10 mmol) of ethyl 5-amino-1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 0.44 g (11 mmol) of sodium hydroxide were added and stirred at 60° C. for 10 hours. After cooling to room temperature, the reaction mixture was washed with toluene. The resulting aqueous solution was made pH 1 by adding concentrated hydrochloric acid. Precipitate was filtered and dried to obtain 1.78 g of desired 5-amino-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid as white solid. The yield was 85% Following results were obtained by NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=O)=[CH:9][S:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:21])=[CH:9][S:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)csc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCO
Product: C#Cc1csc(NC(=O)OC(C)(C)C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.1 %

Procedure:
2-t-Butoxycarbonylamino-4-formyl-thiophene-3-carboxylic acid ethyl ester (6.35 g, 21.31 mmol) from example 240d was dissolved in absolute EtOH (325 mL). This was treated with potassium carbonate (%.89 g, 42.62 mmol) followed by (1-diazo-2-oxopropyl)-phosphonic acid dimethyl ester (4.91 g, 25.57 mmol). The reaction was stirred at room temperature for 14 hr. The reaction was concentrated to 12 volume then poured into sat. NaHCO3 (250 mL) and then extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (2×250 mL). They were dried (Na2SO4), filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 1 EtOAc/9 hexanes) to afford the title compound (5.86 g, 93%). MS m/e (CI) 296.0 (M+H), 313.1 (M+NH4); 1H NMR (300 MHz, CDCl3): δ ppm 1.41 (t, 3H), 1.53 (s, 9H), 3.11 (s, 1H), 4.37 (q, 2H), 6.98 (s, 1H), 10.30 (s, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Cc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Fluoropyridin-3-yl)methanol (215 mg, 1.69 mmol) in CH2Cl2 (10 mL) containing triethylamine (354 μL, 2.54 mmol) was treated with methanesulfonyl chloride (291 mg, 2.54 mmol) dropwise at 0° C., stirred at 0° C. for 30 min, diluted with water, and extracted with CH2Cl2 (2×10 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated to afford a crude oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1>[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CN1CCCN(C2CCNCC2)CC1

Procedure:
Prepared analogously to Example A3f) from hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine by hydrogenolysis but using Pearlman's catalyst instead of palladium/charcoal, in a quantitative yield. Colourless viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.C1([C@H](N[C:17]2[C:18](=[O:42])[N:19]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]4[CH2:31][CH2:30]4)[CH:23]=3)[CH:21]=2)C)C=CC=CC=1.C1(OC2C=C([C@@H]3N(C4C=CC(C(F)(F)F)=CC=4)C(=O)C(=O)C3)C=CC=2)CC1.[CH3:70][C:71]([NH2:83])([C:73]1[CH:74]=[N:75][C:76]([C:79]([F:82])([F:81])[F:80])=[CH:77][CH:78]=1)[CH3:72].C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:72][C:71]([NH:83][C:17]1[C:18](=[O:42])[N:19]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)[C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:31][CH2:30]3)[CH:23]=2)[CH:21]=1)([C:73]1[CH:74]=[N:75][C:76]([C:79]([F:81])([F:82])[F:80])=[CH:77][CH:78]=1)[CH3:70]
Reactant: CC(C)(N)c1ccc(C(F)(F)F)nc1
Reactant: C[C@@H](NC1=C[C@H](c2cccc(OC3CC3)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccccc1
Agent: O=C1C[C@H](c2cccc(OC3CC3)c2)N(c2ccc(C(F)(F)F)cc2)C1=O
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC1=C[C@H](c2cccc(OC3CC3)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add trifluoroacetic acid (1.5 mL, 20 mmol) to a mixture of (R)-3-((R)-1-phenyl-ethylamino)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.92 g, 4.01 mmol) in toluene (10 mL) and water (4 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. LCMS, Ret. time=4.14 min., Method 3, MS (m/z): 376.0 (M+), 374.0 (M−1). Add a solution of 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (1.2 g, 5.9 mmol) in toluene (10 mL) to the reaction solution. Then add acetic acid (1.9 mL, 33 mmol). Heat at 50° C. for 14 hours. Concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-10% ethyl acetate-hexane) to obtain (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one as a tan foam. LCMS, Ret. time=5.40 min., Method 3, MS (m/z): 562.0 (M+), 560.0 (M−1). Dissolve (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.09 g, 1.94 mmol) in acetic acid (20 mL) and add sodium cyanoborohydride (240 mg. 3.8 mmol). Stir 1 hour at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in dichloromethane and wash with saturated sodium bicarbonate solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-15% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (645 mg, 59%) as a white foam. LCMS, Ret. time=5.04 min, Method 3 MS (m/z): 564.0 (M+1).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C)CCN)(OC(C)(C)C)=O.[CH:25](=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>CO>[C:1]([NH:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCCCCCCCCC=O
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: CN(CCN)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCN(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a stirred solution of N—BOC—N′-methylethylenediamine and N—BOC—N-methylethylenediamine (1:1, 1.73 g, 4.96 mmol each) in MeOH (50 mL) were added decanal (9.31 g, 59.6 mmol) followed by sodium cyanoborohydride (585 mg, 9.31 mmol) at room temperature. The reaction was stirred overnight at room temperature. The reaction was concentrated on a rotevaporator and the concentrate was diluted with water (50 mL). The pH was lowered to ˜2 with 6 N HCl and the acidic solution was extracted with ethylacetate (3×100 mL). The amine products were extracted into the organic phase. The ethylacetate portion was washed with 0.1 N NaOH (1×100 mL) and brine (2×100 mL) and the solvent was removed. The resulting liquid was dried overnight in vacuo at room temperature. The product was isolated by column chromatography on silica gel column (4×15 cm). Side products were eluted from the column with land 2% MeOH in CH2Cl2 then the product was eluted with 5 and 10% MeOH in CH2Cl2. The solvent was removed from the product fractions and the residue was dried in vacuo at rt to yield N—BOC—N′-decyl-N′-methylethylenediamine as a pale yellow solid (470 mg, 21%): TLC (silica gel, 1 MeOH:9 CH2Cl2) Rf=0.6; 1H NMR (DMSO-d6) δ 0.82 (t, 3H), 1.23 (s, 16H), 1.35 (s, 9H), 2.10 (s, 3H), 2.25 (m, 4H), 2.95 (m, 2H), 6.80 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=2)[N:17]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3nccs3)n2)cc1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: O=C(O)c1ccc(Nc2nccc(-c3nccs3)n2)cc1

Procedure:
4-(4-thiazol-2-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 9 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>ClCCCl.C(O)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:23]([NH:22][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)ccc1NC1CCCCC1
Temperature: 25 °C

Procedure:
Cyclohexanone and sodium triacetoxyborohydride were added to a 1,2-dichloroethane-acetic acid solution of methyl 2-amino-5-chlorobenzoate, followed by stirring at room temperature. By post-treating the reaction liquid, methyl 5-chloro-2-(cyclohexylamino)benzoate was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH2:23][CH:24]([OH:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].O>CN(C)C=O.O1CCOCC1>[OH:34][CH:24]([CH2:23][NH:22][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Under a nitrogen atmosphere, triethylamine (72 g, 710 mmol) was added to a solution of 4-chloro-3-nitroquinoline (98.9 g, 474 mmol) in N,N-dimethylformamide (DMF) (1 L). A solution of tert-butyl 3-amino-2-hydroxypropylcarbamate (108.19 g, 569 mmol) in dioxane (800 mL) was slowly added, and the reaction was stirred overnight at ambient temperature and then poured into water (3 L) with continuous stirring. A precipitate formed and was isolated by filtration, washed with water, and dried for three days in a vacuum oven at 65° C. to provide 167.54 g of tert-butyl 2-hydroxy-3-[(3-nitroquinolin-4-yl)amino]propylcarbamate as a bright yellow powder.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of valeryl chloride (13.3 mL, 112 mmol) in dichloromethane (35 mL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (100 mL), and the reaction was stirred overnight at room temperature and then stirred for one hour with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to provide 11.1 g of N-(4-chloroquinolin-3-yl)pentanamide as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]3([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][O:21][CH2:20]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.ClCCl.C(=O)(O)[O-].[Na+]>[C:26]([SiH2:25][O:24][C:23]([CH3:31])([CH3:30])[C:19]1([N:12]2[C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:32])[F:45])=[CH:39][CH:38]=4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11]2)[CH2:20][O:21][CH2:22]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(n2cc(C(=O)c3cncc(N)c3)c3cncnc32)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)C1(n2cc(C(=O)c3cncc(NC(=O)Cc4ccc(C(F)(F)F)cc4)c3)c3cncnc32)COC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
(5-Amino-pyridin-3-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (Preparation 216, 30 mg, 0.068 mmol) was dissolved in dry pyridine (2 mL) under nitrogen and to this was added (4-trifluoromethyl-phenyl)-acetic acid (21 mg, 0.102 mmol), followed by HATU (39 mg, 0.102 mmol). The reaction mixture was heated to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with dichloromethane (5 mL) and saturated aqueous sodium bicarbonate was added (5 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (3×5 mL). The combined organics were concentrated to dryness to afford N-(5-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-trifluoromethyl-phenyl)-acetamide as a pale yellow solid 39 mg, 92% yield.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH:12]=[CH:11]2
Reactant: Brc1nccs1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccn2-c2nccs2)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
2-Bromo thiazole (0.837 g, 5.10 mmol) was added to a solution of 5-bromo indole (1 g, 5.10 mmol) in DMF (15 mL) followed by cesium carbonate (3.32 g, 10.20 mmol), and the mixture was stirred at 90° C. for 12 h. Insoluble solids were filtered off, the filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography using 5% ethyl acetate in pet ether to afford title compound (0.75 g, 52.7%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J=8.8 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.62 (dd, J1=3.2 Hz, J2=10.4 Hz, 2H), 7.45 (dd, J1=2.0 Hz, J2=8.8 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 6.66 (d, J=4.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:18])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Cc1ccccc1O
Product: Cc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-phenol to give (1H-pyrazol-3-yl)-(1-o-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a 30 mL vial containing 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (100 mg, 0.23 mmol) in DCM (1 mL) was added BBr3 (1 M in hexanes, 0.680 mL, 0.68 mmol) and the reaction mixture was stirred for 1 h at room temperature. Upon completion the reaction was quenched with 4 mL MeOH and stirred for 10 min. The mixture was the concentrated in vacuo onto silica gel and the crude material was purified by column chromatography (SiO2, 1-100% EtOAc/Heptane) to afford 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (72 mg, 0.17 mmol, 77% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.47-7.57 (m, 2 H), 7.35-7.45 (m, 2 H), 7.20 (d, J=2.02 Hz, 1 H), 7.16 (d, J=8.59 Hz, 1 H), 6.73-6.90 (m, 5 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)(=[O:16])=[O:15])(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.00 g (12.9 mmol) of [5-(3-nitro-benzenesulfonylamino)-pentyl]-carbamic acid-tert-butyl ester is mixed with 15 ml of trifluoroacetic acid and stirred for 90 minutes at room temperature. The reaction mixture is concentrated by evaporation, and the residue is made basic with saturated NaHCO3 solution. Then, it is extracted with ethyl acetate (2×). The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. 3.4 g (11.8 mmol, corresponding to 91% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: OC(c1ccccc1)c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Product: Clc1cccc(C(Cl)c2ccccc2)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of (3-chlorophenyl)(phenyl)methanol (500 mg, 2.3 mmol) in thionyl chloride (3 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column (eluting with petroleum ether/ethyl acetate=100/1) to give the desired product (200 mg, 37%) as yellow oil.