Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(NC(NC3CCN(C4C=CC=CN=4)CC3)=O)CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:119]([O:121][C:122]([C:124]1[CH:125]=[CH:126][C:127]([N:130]2[CH2:135][CH2:134][CH:133]([NH:136][C:137](N3C=CN=C3)=[O:138])[CH2:132][CH2:131]2)=[N:128][CH:129]=1)=[O:123])[CH3:120]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:119]([O:121][C:122]([C:124]1[CH:125]=[CH:126][C:127]([N:130]2[CH2:135][CH2:134][CH:133]([NH:136][C:137]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:14]4[N:22]=[C:21]5[C:17]([N:18]=[CH:19][N:20]5[C@@H:23]5[CH2:27][C@H:26]([N:28]6[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]6)[C@@H:25]([OH:35])[C@H:24]5[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:15]=4)[CH2:10]3)=[O:138])[CH2:132][CH2:131]2)=[N:128][CH:129]=1)=[O:123])[CH3:120]
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)n3ccnc3)CC2)nc1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)N[C@@H]3CCN(c4nc(NCC(c5ccccc5)c5ccccc5)c5ncn([C@@H]6C[C@H](n7cc(CO)cn7)[C@@H](O)[C@H]6O)c5n4)C3)CC2)nc1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 76) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with 4-[(imidazole-1-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid ethyl ester. MS (ES+) m/e 436 (MH+/2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[Cl-:11].[C:1]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2cnccc2c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nccc2ccccc12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isoquinoline (5.50 g, 42.5 mmol) was dissolved into 50 mL of anhydrous THF and ethyl chloroformate (4.47 mL, 46.8 mmol) was added slowly. The resulting pale yellow mixture was stirred at RT for 30 min. Then, the resulting precipitate was collected via filtration through a cintered glass funnel and dried under vacuum for 2 days to yield the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCN
Reactant: COc1cccc(C(=O)O)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0 mmol) in methylene chloride (250 mL) were added heptylamine (2.78 g, 27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over MgSO4. Concentration in vacuo afforded 6.81 g (98%) of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:20])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: -25 °C

Procedure:
100 g of 4-hydroxy-3-methoxycinnamic acid were dissolved in 1 l of methanol and treated with 14.4 ml of concentrated sulphuric acid. The solution was heated under reflux for 2.5 hrs. Subsequently, the majority of the methanol (about 750 ml) was distilled off and the residue remaining was poured into 1 l of water. Then, the mixture was extracted three times with 500 ml of ethyl acetate each time and the organic phases were combined, washed twice with 250 ml of 10% sodium bicarbonate solution each time, dried over sodium sulphate, filtered and evaporated. The residue was dissolved in 800 ml of methanol, filtered and, for crystallization, cooled to -25° C. The crystals were thereupon filtered off under suction, washed with 100 ml of cold methanol and dried in a high vacuum at room temperature. This gave 54.7 g of yellowish colored crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:10][C:11](=[S:12])[O:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Oc1cc(F)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1cc(F)c2oc(=S)oc2c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3,5-Difluorobenzene-1,2-diol (670 mg, 4.6 mmol) was stirred in dry chloroform (8 mL), treated with thiophosgene (580 mg, 5.0 mmol), cooled to 5-10° C., and treated dropwise with 10% NaOH solution (4.2 g, 11 mmol) over 45 min. After 30 min, the volatiles were removed by rotary evaporation and the residual solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (30 mL), washed with water (2×20 mL), washed with saturated NaCl (1×10 mL), dried (Na2SO4), and evaporated. The residue was purified by chromatography on silica with a 0-20% ethyl acetate-hexane gradient to give the title compound (710 mg, 82%): 1H NMR (400 MHz, CDCl3) δ 6.95 (ddd, J=6.8, 2.3, 1.4 Hz, 1H), 6.89 (td, J=9.5, 2.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −109.99 (s), −127.93 (s); EIMS m/z 188.
Reaction SMILES: CC1C=CC=CC=1C=[S:5].Cl[CH2:11][C:12]([OH:14])=[O:13].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[S:5]1[C:11]([C:12]([OH:14])=[O:13])=[CH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: Cc1ccccc1C=S
Reactant: Cc1ccccc1
Reactant: O=C(O)CCl
Product: O=C(O)c1cc2ccccc2s1
Temperature: 110 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
A four-necked flask (300 ml capacity) equipped with a stirrer, thermometer and condenser was charged with 30.4 g (0.20 mol) of 2-methylthiobenzaldehyde and 28.4 g (0.30 mol) of monochloroacetic acid and the reaction was conducted with stirring at 110° C. for about 10 hours. After completion of the reaction, 150 g of toluene was added to dissolve the reaction mixture and the solution was cooled for precipitation. The precipitate was collected by filtration and dried to give 28.5 g (yield 80%) of 2-benzo[b]thiophenecarboxylic acid as light yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:33]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:8][CH:9]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.08 mmol) in DCM (2 mL) was added triethylamine (25 uL) followed by benzoyl chloride (11 uL) and the resulting mixture stirred at room temperature for 2 hours The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-(benzamidomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0128 g, 0.03 mmol, 36%). 1H NMR (DMSO) δ 4.54 (2H, d), 7.40 (2H, t), 7.49 (4H, m), 7.55 (1H, m), 7.74 (3H, m), 7.92 (2H, m), 8.18 (2H, d), 9.15 (1H, t). LCMS (2) Rt: 2.82 min; m/z (ES+) 434.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH2:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2ccc(C)cc2C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccc(CBr)cc2C(=O)OC)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 4-methyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (2.26 g, 7.9 mmol) in CCl4 (50 mL) were added benzoyl peroxide (0.010 g, 0.04 mmol) and NBS (1.42 g, 8.0 mmol), and the mixture was refluxed for 3 days. The reaction mixture was allowed to cool to rt, filtered, and concentrated. The residue was purified by column chromatography (95:5 to 90:10 hexanes/EtOAc) to afford 4-bromomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.71 g, 60%): 1H NMR (DMSO-d6) δ 3.61(s, 3H), 3.88 (s, 3H), 4.84 (s, 2H), 7.48–7.50 (d, J=8.0 Hz, 1H), 7.59–7.60 (m, 2H), 7.72–7.75 (m, 1H), 7.85 (s, 1H), 7.90 (m, 1H), 7.97–7.99 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C.Cl>O.CN1CCCC1=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]2[NH:16][N:15]=[N:14][N:11]=2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C2OCCO2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: c1cc(C2OCCO2)ccc1-c1nnn[nH]1
Temperature: 150 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
A mixture of 4-(1,3-dioxolan-2-yl)benzonitrile (1.0 g), sodium azide (1.48 g), triethylamine hydrochloride (1.18 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred at 150° C. for 3 hrs. After cooling, 1 M hydrochloric acid and water were added to the reaction mixture to adjust to pH=3 to 4. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 5-[4-(1,3-dioxolan-2-yl)phenyl]-1H-tetrazole (0.300 g, yield 24%) as brown prism crystals. melting point: 197–199° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[S:12][CH:13]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2csc(Cl)n2)cc1
Yield: 64.1 %

Procedure:
A mixture of 28.05 g (114.4 mmole) of 4-(4-trifluoromethyl-phenyl)-3H-thiazol-2-one and 85 mL (0.92 mole) of phosphorus oxychloride was heated at reflux for 5 hours. The mixture was cooled and the excess phosphorus oxychloride was removed under reduced pressure. The residue was diluted with ethyl acetate and the slurry was poured onto ice. The mixture was made basic by the addition of saturated aqueous sodium carbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 10:90-20:80) to give 19.34 g of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole as a light brown solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:7]2[CH2:6][CH:5]3[CH:4]([CH2:3][N:2]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([O:14][C:15]5[S:16][C:17]6[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=6[N:19]=5)=[CH:24][CH:25]=4)[CH2:1]3)[CH2:8]2)=[CH:31][CH:30]=1
Reactant: c1ccc2sc(Oc3ccc(CN4CC5CNCC5C4)cc3)nc2c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CC3CN(Cc4ccc(Oc5nc6ccccc6s5)cc4)CC3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a solution of 2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazole (200 mg, 0.56 mmol) in CH2Cl2 (22 mL) was added 4-formyl-benzoic acid methyl ester (103 mg, 0.62 mmol) followed by the addition of acetic acid (28 μL, 0.48 mmol) then sodium triacetoxyborohydride (144 mg, 0.68 mmol). The reaction stirred at rt for 16 h. The reaction was then washed with satd. aq. NaHCO3 (2×20 mL). The organic layer was dried, filtered and concentrated. The resulting oil was purified by column chromatography (20% to 60% EtOAc in Hexanes) to afford the title compound (55 mg, 19%). MS (ESI): mass calcd. for C29H29N3O3S, 499.64; m/z found, 500.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.47-7.38 (m, 1H), 7.35-7.26 (m, 4H), 7.68 (d, J=7.9 Hz, 4H), 3.92 (s, 4H), 3.65 (d, J=12.2 Hz, 4H), 2.71-2.60 (m, 3H), 2.38 (d, J=7.2 Hz, 4H), 1.27 (s, 2H).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.[CH:11]1[CH:12]=[CH:13][C:14]2[N:19](O)N=[N:17][C:15]=2[CH:16]=1.NCC1C=CC=CN=1>C1COCC1>[N:17]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH2:14][NH:19][C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCC(=O)NCc1ccccn1
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of butyric acid (4.5 mL, 48.7 mmol) in THF (50 mL) was added EDC (11.2 g, 58.4 mmol) and HOBt (7.88 g, 58.4 mmol). The mixture was stirred for 10 min. then 2-(aminomethyl)pyridine (4.7 mL, 46.3 mmol) was added. The solution was allowed to stir for 3 h then quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield N-pyridin-2-ylmethyl-butyramide (5.82 g, 67%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:32])([F:31])[F:30])[C:18]([CH2:33]N)=[CH:17]2.C([N:38](CC)C(C)C)(C)C.C(O)C>>[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:30])([F:31])[F:32])[C:18]([CH2:33][C:9]1[N:8]=[C:7]3[C:3]([N:4]=[CH:5][NH:6]3)=[C:2]([NH2:38])[N:10]=1)=[CH:17]2
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Product: Nc1nc(Cc2cc3cccc(Cl)c3nc2-c2ccccc2OC(F)(F)F)nc2[nH]cnc12
Temperature: 75 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloropurine (0.1109 g, 0.7175 mmol), (8-chloro-2-(2-(trifluoro-methoxy)phenyl)quinolin-3-yl)methanamine (0.2531 g, 0.7175 mmol), and N,N-diisopropylethylamine (0.2500 mL, 1.435 mmol) in ethanol (4.221 mL, 0.7175 mmol) was stirred at 75° C. After 36 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give N-(((8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (1 H, s), 8.38 (1 H, s), 8.03-8.32 (3 H, m), 7.96-8.02 (1 H, m), 7.93 (1 H, dd, J=7.5, 0.9 Hz), 7.51-7.75 (5 H, m), 4.69 (2 H, br. s.); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:15]=3[C:21]([F:24])([F:23])[F:22])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([NH2:41])[N:27]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:41][C:28]1[N:27]=[C:26]([CH3:25])[C:31]([C:18]2[CH:17]=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[C:14]([S:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:13])=[O:12])[CH:19]=2)=[CH:30][N:29]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1ccc2c(c1)OCO2)c1cc(Cl)ccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(C(F)(F)F)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1

Procedure:
N-Benzo[1,3]dioxol-5-yl-5-chloro-2-trifluoromethyl-benzenesulfonamide (0.088 g, 0.23 mmol), 4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate G, prepared according to WO 2007/084786, p. 92) (0.082 g, 0.34 mmol) and PdCl2(dppf).DCM (0.0185 g, 0.023 mmol) are placed in a microwave vial containing degassed DME (2 ml) and 2M Na2CO3 (0.23 ml). The resulting mixture is heated using microwave radiation at 120° C. for 60 minutes. After evaporation of the solvent, the reaction mixture is purified by flash chromatography on silica eluting with cyclohexane/EtOAc (1:2) to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:36]=[CH:35][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:37][CH2:38][C:39]1[C:40]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=2)=[N:41][CH:42]=[CH:43][CH:44]=1>>[ClH:37].[ClH:37].[ClH:37].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:38][C:39]2[C:40]([C:45]3[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH3:54])=[C:47]([O:55][CH3:56])[CH:46]=3)=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: CCCCc1ccc(N(Cc2cccnc2-c2cc(OC)c(OC)c(OC)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl ]methyl]piperidine (147 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].O.BrC1C=CC=C2C=1N=C(NC(C)(C)C)C(Cl)=N2>CS(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[N:7]2
Reactant: CC(C)(C)N
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Agent: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc2cccc(Br)c2nc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-2,3-dichloroquinoxaline (LeadGen Labs, LLC, Orange, Conn.) (305 mg, 1.10 mmol) and 2-methylpropan-2-amine (Aldrich) (0.12 mL, 1.10 mmol) in DMSO (5.0 mL) was stirred under argon at 65° C. for 17 h (water-cooled reflux condenser attached to flask). Additional 2-methylpropan-2-amine (0.06 mL, 0.57 mmol) was added, and the resulting solution was stirred at 100° C. for 5 h. The reaction mixture was subsequently cooled to 25° C. and diluted with half-saturated aq. NaHCO3 (80 mL). The resulting mixture was extracted with DCM (2×80 mL), and the combined extracts were sequentially washed with water (2×50 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished a ˜2.5:1 mixture of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine and 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (224 mg, 0.71 mmol, 65% yield) as an off-white solid: 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, dd, J=7.6, 1.0 Hz), 7.72 (1H, dd, J=8.2, 1.0 Hz), 7.21 (1H, t, J=7.9 Hz), 5.63 (1H, br. s.), 1.63 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+. 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (1H, d, J=3.7 Hz), 7.63 (1H, d, J=3.3 Hz), 7.39 (1H, t, J=8.0 Hz), 5.60 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[C:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α,α-Diphenyl-2-biphenylmethanol was prepared by the following procedure (Reaction Scheme 1). To a solution of 2-bromobiphenyl (5.00 g, 21.45 mmol) in freshly distilled THF (50 mL) at −78° C. was added n-BuLi (1.37 g, 21.45 mmol, 8.6 mL of 2.5 M solution in hexanes) dropwise via syringe. Approximately 5 minutes after complete addition, benzophenone (4.10 g, 22.52 mmol) was added in a single portion, after which time the ice bath was removed and the solution allowed to warm to room temperature. After 2 h, the reaction was quenched with the addition of NH4Cl and H2O (100 mL), and extracted with Et2O (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to dryness. Chromatography gave the product as a white solid (6.27 g, 87% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:5])[CH3:2].[C:20]([OH:23])(=[S:22])[CH3:21]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:19])[CH:16]([CH3:18])[CH2:17][S:22][C:20](=[O:23])[CH3:21])=[O:5])[CH3:2]
Reactant: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC
Reactant: CC(O)=S
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The mixture of 3.0 g of 1-methacryloylindoline-2-carboxylic acid ethyl ester and 0.97 g of thioacetic acid is stirred under nitrogen at room temperature for 4 days. Traces of thioacetic acid are removed by distillation, to give the 1-(3-acetylthio-2-methylpropanoyl)-indoline-2-carboxylic acid ethyl ester, showing peaks in the NMR-spectrum at 9.45, 2.33 and 1.25 ppm. Said compound can also be prepared analogous to the method illustrated by Example 1.