Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:27]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2o1

Procedure:
A solution of 2,2,2-trichloroethyl (2-methyl-1,3-benzoxazol-6-yl)carbamate (200 mg, 0.618 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.215 ml, 1.24 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 100 mg (38.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([Cl:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([Cl:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CSc1nn2c(Cl)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
0.1 g (1 mmol) of 1-methyl-piperazine in 3 ml of CH2Cl2 was added to a solution of 0.37 g (1 mmol) of 3-benzenesulphonyl-5,7-dichloro-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 20 ml of CH2Cl2 and stirred at RT for 1 hr. The mixture was poured on to ice-water, adjusted to pH8 with NaHCO3 solution and extracted three times with 30 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 4:1) yielded 0.38 g (86%) of 3-benzenesulphonyl-5-chloro-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]1[CH2:19][CH2:18][C@@:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]1)=[O:13].C1COCC1>C(N(CC)CC)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:28])[CH3:29])=[CH:26][CH:25]=1
Reactant: O=C=NC1CCCC1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)NC1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with cyclopentyl isocyanate (9 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (30 mg) and THF (2 mL). Triethylamine (11 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 511. MS found: (M+H)+=450.2.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:39][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)([CH3:39])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (51 mg, 0.102 mmol) in tetrahydrofuran (10.0 mL) at 0° C. was added methylmagnesium bromide (3 M in diethyl ether, 0.169 mL, 0.508 mmol). The mixture was stirred for 30 min. HPLC analysis indicated that there was still a significant amount of starting material remaining. Additional methylmagnesium bromide (0.10 mL) was added, and the reaction mixture was stirred for an additional 30 min. at 0° C. The reaction was slowly quenched with water and extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture ethyl acetate and hexane (50%-62%-75%-88%-100%) and reverse phase preparative HPLC afforded 7-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (24% yield) as an off-white solid and as a mixture of atropisomers. LC/MS M+1=518.2. 1H NMR (500 MHz, MeOD) δ 8.42-8.38 (m, 1H), 8.33 (dt, J=8.0, 1.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.83-7.77 (m, 2H), 7.70-7.59 (m, 3H), 7.53-7.44 (m, 1H), 7.25-7.15 (m, 1H), 7.06 (d, J=8.6 Hz, 0.6H), 6.81 (d, J=8.3 Hz, 0.4H), 2.51-2.46 (m, 3H), 1.81-1.78 (m, 3H), and 1.62-1.56 (m, 6H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH:18]([NH:22][C:23]4[C:32]5[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:19][CH2:20][OH:21])[CH:15]=[CH:16][CH:17]=3)=[O:10])[NH:7][N:8]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O.[OH-].[Na+]>CS(C)=O.ClCCl>[CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH:18]([NH:22][C:23]4[C:32]5[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:19][CH:20]=[O:21])[CH:15]=[CH:16][CH:17]=3)=[O:10])[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c(NC(CCO)c3cccc(NC(=O)c4cc(C5CC5)n[nH]4)c3)ncnc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NC(CC=O)c3cccc(NC(=O)c4cc(C5CC5)n[nH]4)c3)ncnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
227 mg (0.46 mmol) 4-(1-{3-[(5-Cyclopropyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-3-hydroxy-propylamino)-quinazoline-8-carboxylic acid amide were dissolved in 2.5 ml DMSO and 1.98 ml (0.59 mmol) 0.3 M Dess-Martin Periodane in dichloromethane wee added to the mixture. The mixture was stirred for 2 h at room temperature, 20 ml water and 2 ml 1N NaOH were added and the precipitate was filtered, washed with water and dried in vacuo. 245 mg, off-white solid.
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.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CCOc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxy-phenylboronic acid to give [1-(4-ethoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [C:1]12([PH:11](=O)[C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(P(Cl)(C34CC5CC(CC(C5)C3)C4)=O)CC3CC(CC(C3)C1)C2>>[C:1]12([PH:11][C:12]34[CH2:13][CH:14]5[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]5)[CH2:19]3)[CH2:21]4)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=[PH](C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: O=P(Cl)(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3

Procedure:
This example illustrates the formation of di-1-adamantylphosphine oxide from di-1-adamantylphosphinic chloride in two steps, the first step resulting in the formation of di-1-adamantylphosphine.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C([Li])CCC.[Br:17]Br>C1COCC1>[Br:17][C:5]1[N:1]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:2]=[N:3][CH:4]=1
Reactant: BrBr
Reactant: c1ccc(-n2ccnn2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cnnn1-c1ccccn1
Reaction time: 0.08 h

Procedure:
In a 100 ml 3 necked round bottom flask, 2-(1H-1,2,3-triazol-1-yl)pyridine (2 g) was taken in dry THF (2 ml) under nitrogen. n-Butyl lithium (2.3 ml) was added at −78° C. and stirred for 5 minutes, then bromine (1.86 ml was added dropwise to the above reaction mixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with sodium bisulphate, brine, dried and concentrated. The crude product was purified by column chromatography using pet ether & ethyl acetate as eluent to give compound 2-(5-bromo-1H-1,2,3-triazol-1-yl)pyridine as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[NH:21][C:20](=S)[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:26]>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[N:21]=[C:20]([NH2:26])[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Temperature: 110 °C
Yield: 21.5 %

Procedure:
6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 124 Step 2, 40 mg, 0.09 mmol) was dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) in a microwave vial. The vial was capped, and heated to 110° C. for 30 min in a microwave reactor. The solution was concentrated, and the residue dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) and heated to 110° C. in a microwave reactor. This cycle (concentration, addition of ammonia and heating) was repeated until all starting materiel was converted to product (6 times). The reaction mixture was cooled to r.t., concentrated in vacuo and purified by preparative chromatography to give the title compound (8 mg, 21% yield):
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]2[O:17][C:18]3[C:23]([C:24](=O)[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1>C1COCC1>[O:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:25]=[C:16]1[C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:28][CH:27]=1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Oc1ccc(C2=CCc3ccccc3O2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
A suspension of aluminum chloride (680 mg, 5.1 mmol) in dry THF (50 mL) was cooled to 0° C. under nitrogen. LAH (580 mg, 15.5 mmol) was added to the above solution and the resulting mixture was stirred for 20 min at 0° C., and then at rt for additional 20 min, and cooled down to −50° C. 4′-Hydroxyflavone (400 mg, 1.7 mmol) dissolved in 60 mL of THF was added slowly. The reaction mixture was stirred at −50° C. for 2 h and then for 2 h at rt. The reaction was quenched by careful addition of water (traces, to decompose LiAlH4) and the solvent was removed under reduced pressure. The crude product was initially purified by crystallization from MeOH, and then further purified by column chromatography (silica gel, 5-20% EtOAc/hexane) and repeated crystallization from MeOH to afford 109 mg of 4-(4H-chromen-2-yl)-phenol (29%). MS (ES) m/z: 225.10 (M+1), 149.04.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])C.C(=O)([O-])O.[Na+]>C(O)=O>[CH2:1]([N:8]([CH:23]=[O:25])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=CN(Cc1ccccc1)C1CCCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of N-benzyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (2.8 g), formic acid (8 ml) and acetic anhydride (16 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo to give N-benzyl-N-formyl-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (2.71 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH:7]([F:9])[F:8])=[CH:4][CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.C([Li])CCC.Cl>O1CCCC1>[F:8][CH:7]([F:9])[O:6][C:5]1[CH:10]=[CH:11][C:2]([B:12]([OH:17])[OH:13])=[CH:3][CH:4]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropyl borate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 3.42 ml). The mixture was stirred at room temperature overnight. Added thereto was 6N aqueous hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with cold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:26][C:27]1[C:35]([Br:36])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=1)[N:6]2[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.Cl>C(OCC)(=O)C>[Br:36][C:35]1[C:27]([S:26][C:5]2[N:6]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:7]3[C:3]([N:4]=2)=[C:2]([NH2:1])[N:10]=[CH:9][N:8]=3)=[CH:28][C:29]2[O:33][CH2:32][O:31][C:30]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCC1CCCNC1
Reaction time: 8.5 h

Procedure:
To a suspension of tert-Butyl 3-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carboxylate (0.03 g) in ethyl acetate (10 mL) was added 6N HCl (5 mL) at room temperature and stirring was continued at rt for 1-16 h. The solvent and the excess hydrochloric acid was evaporated to dryness. The oily residue was co-evaporated with toluene (3×5 mL) to afford title product as hydrochloride salt. 1H NMR (CD3OD) δ 8.38 (s, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 6.10 (s, 2H), 4.43-4.41 (m, 2H), 3.49-3.46 (m, 1H), 2.95-2.92 (m, 1H), 2.80-2.65 (m, 2H), 1.92-1.76 (m, 4H), 1.39-1.23 (m, 4H); TOF LC-MS [M+H]+] 477.1
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([OH:11])[CH2:9][CH2:8][N:7]([CH2:27][CH2:28][CH:29]=[C:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=3[CH2:34][O:33][C:32]3[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]2=3)[CH2:6]1)=[O:4]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)C1(C)CNCCC1(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.9 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-hydroxy-3-methyl-piperidine-3-carboxylic acid methyl ester (0.71 g, 2.5 mmol) in acetonitrile/water (8:2) (25 mL) was added K2CO3 (1.40 g, 10.0 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.937 g, 2.5 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound (0.835 g, 58%). 1H-NMR (CDCl3): 1.30 (s, 3H), 1.57 (s, 6H), 1.76 (d, 1H), 2.24–2.53 (m, 7H), 2.65 (d, 1H), 2.86 (d, 2H), 3.44 (s, 3H), 5.30 (bs, 2H), 6.16 (d, 1H), 6.82 (d, 1H), 7.26 (m, 4H), 7.45 (s, 1H), 7.53 (d, 1H), 7.58 (d, 1H), 8.49 (d, 1H). ESI-MS m/z: 577 (M+1), retention time 1.50.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25]O)=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=[N:21]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=1[N:20]1[C:24]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=[N:21]1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: CC(=O)c1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a 0° C. suspension of 4′-hydroxy-2′-methylacetophenone (969 mg, 6.45 mmol), [3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (1.85 g, 6.45 mmol), tri-n-butylphosphine (2.42 ml, 9.73 mmol) in toluene (20 mL) is added ADDP (2.46 g, 9.73 mmol). The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is chromatographed eluting with 0% to 30% EtOAc/Hex to yield the title compound (1.71 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, 1H, J=8.5, 2.1 Hz), 7.72 (d, 1H, J=1.3 Hz), 7.49 (d, 1H, J=2.2 Hz), 7.47 (s, 1H), 7.41 (dd, 1H, J=9.2, 6.6 Hz), 6.78 (d, 1H, J=8.4 Hz), 4.99 (s, 2H), 3.22 (sept, 1H, J=7.0 Hz), 2.52 (s, 3H), 2.06 (s, 3H), 1.46 (d, 6H, J=7.0 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[N+:17]([O-])=O)[CH2:3][CH2:2]1>CO.O=[Pt]=O>[NH2:17][C:7]1[CH:8]=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: COC(=O)Cc1ccc(OCC2CC2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)Cc1ccc(OCC2CC2)c(N)c1
Reaction time: 0.25 h
Yield: 107.6 %

Procedure:
To a solution of crude methyl 2-(4-(cyclopropylmethoxy)-3-nitrophenyl)acetate (theoric 4.74 mmol) in MeOH (50 ml), a catalytic amount of PtO2 was added and the mixture was hydrogenated in a Parr apparatus at 30 psi for 15 minutes. The catalyst was filtered off, and the solvent was removed to give crude methyl 2-(3-amino-4-(cyclopropylmethoxy)phenyl)acetate (1.2 g, yield considered to be quantitative, MS/ESI+ 236.0 [MH]+). This crude was used without any additional purification.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].C(O)(C)C>[Cl-].[Na+].O.[Cu]I>[C:7]1([CH:5]([OH:6])[CH2:4][NH:3][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1ccccc1
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccccc1NCC(O)c1ccccc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (83.0 mg, 2.08 mmol), and rac-2-amino-1-phenylethanol (143 mg, 1.04 mmol). 2-Iodotoluene (159 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with 0.1 M NaOH (2×10 mL), washed with brine (1×15 mL), dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using methylene chloride. The product was obtained as a pale yellow, viscous oil in 92% yield (217.4 mg).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([N:18]([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[O:42]([CH:44]([CH3:46])[CH3:45])[Na].C[O-].[Na+]>CC(O)C.CO>[CH3:19][N:18]([CH3:20])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:42][CH:44]([CH3:46])[CH3:45])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CN(C)c1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Reactant: CC(C)O[Na]
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(C)O
Product: CC(C)Oc1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(N(C)C)c1-c1ccccc1

Procedure:
The title compound was prepared using (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol (Example 47) and NaOiPr in iPrOH in place of (3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol and NaOMe in MeOH, respectively, according to the procedure described in Example 79. 1H NMR (400 MHz, MeOH-d4) δ 9.08 (s, 1H), 8.84 (d, J=6.11 Hz, 2H), 8.11 (s, 1H), 8.05 (d, J=6.11 Hz, 2H), 7.87 (d, J=8.80 Hz, 1H), 7.64 (d, J=8.80 Hz, 1H), 7.33-7.50 (m, 3H), 7.16-7.27 (m, 3H), 5.32-5.50 (m, 1H), 3.72 (s, 3H), 2.59 (s, 6H), 1.23 (d, J=6.11 Hz, 6H); MS m/e 494.2 [M+H]+.