Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C[Sn](C)C.C[Sn](C)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:4]1[S:5][C:6]([C:6]2[S:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Br)s1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C(C)=O)s2)s1
Temperature: -5 °C

Procedure:
To a slurry of 1 g tetrakis(triphenyl phosphine) Palladium (0) in 30 ml of dry toluene was added a solution of 6.26 g (30.5 mmol) of 2-acetyl-5-bromo thiophene in 30 ml of dry toluene under argon. The reaction was heated to reflux and to this solution was added dropwise a solution of 5 g (15.26 mmol) of hexamethylditin (99%) in 50 ml toluene (dry) over a period of 1.5 h. The reaction mixture was refluxed for another 6 h and then cooled down to -5° C. Light yellow crystals of the product were isolated by suction filtration and were washed with hexane. The product was then continuously extracted through Whatman filter paper #42 with dioxane using a soxhlet apparatus until all of the product was dissolved and collected in the boiling flask. Slow cooling of the dioxane solution resulted in needle shaped light yellow crystals of the monomer which were separated by suction filtration and dried in vacuum. A Yield of 2.56 g (67%) having the following characteristics was obtained: mp 235° C. (lit. mp 233.5°-234° C.); UV/vis λmax (CHCl3): 367 (log ε=4.19), 262 (3.57); FT-IR (KBr,cm-1): 3070, 1797 1656, 1611, 1511, 1433, 1361, 1302, 1270, 1089, 1036, 1020, 937, 897, 881, 792, 745, 673, 611, 593, 555, 463, 442; 1H NMR (CDCl3 300 MHz, TMS) δ 2.58 (s,6H), 7.30 (d,2H), 7.62 (d,2H). Anal. calcd. for C12H10S2 : C, 57.58; H, 4.03; N, 0.0. Found: C, 57.48; H, 3.87; N, 0.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@H:11]1[C:20]([O-:22])=[O:21].CO.[OH-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C([O-])[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of trans 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decane-7-carboxylate from Step E (1.82 g, 5.5 mmol) dissolved in tetrahydrofuran (11 mL) and methanol (22 mL) was treated with aqueous lithium hydroxide solution (1.OM, 18.5 mL) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with hydrochloric acid (1N) to pH 1 and extracted with ethyl acetate. The organic phase was washed by saturated brine solution, dried over anhydrous sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.NCCN(CCN)CCN>ClCCl>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:23])=[CH:20][CH:19]=1
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: NCCN(CCN)CCN
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(OCCN1CCOCC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 8 mL vial was charged with 2-morpholinoethanol (200 μL, 1.63 mmol), dichloromethane (5 mL), polystyrene-linked diisopropylamine (4.90 mmol), and 4-iodobenzoyl chloride (479 mg, 1.80 mmol), and the reaction mixture was shaken at room temperature. After 16 hours, the reaction mixture was charged with polystyrene-linked tris(2-aminoethyl)-amine (1.63 mmol), and shaken at room temperature for 2 hours. The reaction was filtered, and the resin was washed with dichloromethane (3×10 mL), tetrahydrofuran (2×10 mL), and diethyl ether (2×10 mL). The combined filtrates were concentrated in vacuo to give 2-morpholinoethyl 4-iodobenzoate (434 mg, 1.19 mmol) as a white solid.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14](Cl)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Cl)n1)C(N)=O
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Oc2ccc(F)cc2)n1)C(N)=O
Temperature: 120 °C
Yield: 37.9 %

Procedure:
5-Bromo-6-chloro-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (50 mg, 143 μmol) was dissolved in DMF (0.5 mL) to give a colorless solution. 4-Fluorophenol (19.3 mg, 172 μmol) and sodium carbonate (45.6 mg, 430 μmol) were added successively to give a yellow solution. The reaction mixture was stirred at 120° C. over the weekend, cooled to ambient temperature and poured into 40 mL water. The mixture was extracted with isopropyl acetate (2×40 mL), organic phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 2.0 mm, isopropyl acetate) to give the title compound (23 mg, 38%) as colorless oil, MS (ESI): m/e=421.9 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[O:13]COC.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[OH:13]
Reactant: COCOc1c(Br)cccc1/C=C/[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])/C=C/c1cccc(Br)c1O
Reaction time: 4 h

Procedure:
To a suspension of Example 383B in methanol (15 mL) was added 4 N HCl in dioxane (1 mL). The mixture was stirred for 4 hours, concentrated, and diluted with water. The precipitates were collected to afford the titled compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:33][C:34]#[N:35].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:34](=[O:33])[N:35]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc(NCc2cccc([N+](=O)[O-])c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A red solution of 34 g (79.4 mmol) of the benzophenone prepared in step A in 200 ml acetic acid is treated with 6.2 g (95 mmol) sodium cyanate under vigorous stirring which is continued overnight. The mixture is diluted with water and extracted with ethyl acetate. Concentration after washing with bicarbonate solution yields several crops of product. While the initial batches are yellow and pure, the subsequent ones are orange and have to be purified by flash chromatography. Combined yield: 25.9 g (72%). m.p. 167-168° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1.CN1CCOCC1>C(#N)C>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OC2CCNCC2)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (24 uL, 0.00033 mol) in 0.5 ml of ACN was added to a solution of 1-tert-butyl 2-methyl (1S,2S,4R)-4-(piperidin-4-yloxy)cyclohexane-1,2-dicarboxylate hydrochloride made above (50 mg, 0.0001 mol) and 4-methylmorpholine (44 uL, 0.00040 mol) in acetonitrile (1.5 mL, 0.029 mol) at 22 Celsius. It was stirred at rt for 30 min, then quenched with Water, extracted with EA, and concentrated to give 1-tert-butyl 2-methyl (1S,2S,4R)-4-[(1-acetylpiperidin-4-yl)oxy]cyclohexane-1,2-dicarboxylate.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:23])[F:22])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH:4]=[C:3]1[CH3:11].Cl.[CH3:26][O:27][NH2:28].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:22])[F:23])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[N:28][O:27][CH3:26])[CH:4]=[C:3]1[CH3:11]
Reactant: CON
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=NOC)CC1(C)C)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Ethyl (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (60 mg, 0.17 mmol), O-methylhydroxylamine hydrochloride (17 mg, 0.21 mmol) and sodium acetate (30 mg, 0.37 mmol) were dissolved in a 1:1 mixture of ethanol and water (4 ml) and then stirred at a temperature of 60° C. for 4 h. After cooling to room temperature, ethanol was removed under reduced pressure and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-[1-hydroxy-4-(methoxyimino)-2,6,6-trimethylcyclohex-2-en-1-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (40 mg, 58% of theory) was obtained in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.65/6.63 (s, 1H), 6.00/5.94 (s, 1H), 4.27 (q, 2H), 3.89/3.86 (s, 3H), 2.62/2.56 (br. s, 1H, OH), 2.46 (d, 1H), 2.39 (m, 1H), 2.08/2.05 (s, 3H), 1.31 (t, 3H), 1.18 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [CH:1](/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3].[C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[F:28])#[N:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1](/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[C:22]([F:28])[CH:23]=3)=[O:15])=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)=[CH:2]\[CH3:3]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C/C=C/[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(C#N)c(F)c3)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 2.68 g of 4-[trans-4-(1E-propenyl)cyclohexyl]benzoic acid, 1.8 g of 4-cyano-3-fluorophenol and 187 mg of 4-(dimethylamino)pyridine in 25 ml of methylene chloride was cooled to 0° C. and treated while stirring with 3.17 g of N,N'-dicyclohexylcarbodiimide. After stirring at 0° C. for 5 minutes and at room temperature for 3 hours the suspension was filtered and the filtrate was concentrated. Chromatographic purification of the residue on 50 g of basic aluminium oxide with methylene chloride and subsequent crystallization from hexane/ethyl acetate gave 2.67 g of 4-cyano-3-fluorophenyl 4-[trans-4-(1E-propenyl)cyclohexyl]benzoate as colourless crystals; m.p. (C-N) 117.5° C., cl.p. (N--I) 233.1° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added m-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (196 mg, 94% yield) as colorless crystals.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:26])=O>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 51 %

Procedure:
DMF (0.5 ml) was added to a mixture of 6-methoxy-7-(2-methoxyethoxy)3,4-dihydroquinazolin-4-one (5.1 g, 20 mmol) in thionyl chloride (50 ml). The mixture was stirred and heated at reflux for 3 hours, allowed to cool and the excess thionyl chloride removed by evaporation. The residue was suspended in methylene chloride and washed with aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with methylene chloride and the combined extracts dried (MgSO4). The crude product was recrystallised from methylene chloride/hexane to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.8 g, 51%) as a fine white solid.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:3])=[O:2].[CH2:21]1[CH2:31][CH2:30]N2C(=NCCC2)C[CH2:22]1.C1(C=O)CC1>CN(C=O)C.O>[CH:21]1(/[CH:22]=[C:4](/[C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)\[N+:1]([O-:3])=[O:2])[CH2:30][CH2:31]1
Reactant: O=[N+]([O-])Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: O=CC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])/C(=C\C1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a room temperature solution of 4-(nitromethyl)-4′-(trifluoromethyl)biphenyl (200 mg, 0.711 mmol) and DBU (54.4 mg, 0.355 mmol) in DMF (3 ml) was added cyclopropanecarbaldehyde (99.7 mg, 1.42 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (110 mg) as a colorless solid. To a solution of the impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (55 mg, 0.16 mmol) in THF (3 mL) was added Raney nickel. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (40 psi) overnight. The reaction mixture was purified by preparative TLC to give 2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethanamine (20 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.04-4.08 (m, 1H), 1.70-1.56 (m, 1H), 1.54-1.49 (m, 1H), 0.65-0.50 (m, 1H), 0.45-0.30 (m, 2H), 0.15-0.00 (m, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccn3)c12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (271 mg, 1.14 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). LCMS (Method C): RT=2.81 min, [M+H]+=473. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue triturated with diethyl ether to give 288 as a white solid (174 mg, 51%) 1H NMR 400 MHz δ (DMSO-d6 80° C.): 8.55-8.49 (1H, m), 8.01 (1H, s), 7.89 (1H, td, J=7.7, 1.9 Hz), 7.65 (1H, d, J=7.6 Hz), 7.49 (1H, dd, J=8.7, 4.7 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 0.9 Hz), 7.17 (1H, br s), 7.02 (1H, dd, J=10.6, 9.0 Hz), 5.57 (1H, br s), 1.66 (3H, s), 1.55 (3H, d, J=6.8 Hz). LCMS (Method K): RT=3.01 min, [M+H]+=389
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CC=CC=1>CN(C)C=O>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
19-Hydroxy-4-androstene-3,17-dione, t-butyldimethylsilylchloride and pyridine are mixed in dry dimethylformamide and heated on a steam bath overnight. The reaction mixture is poured onto water and stirred well for 15 minutes. The resulting solid is filtered and dissolved in methylenechloride, dried over magnesium sulfate and the solvent removed. The residue is crystallized from an acetone-hexane solution to yield 19-t-butyldimethylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 134.0 grams (1.0 mole) of p-isopropenylphenol and 186.0 grams (2.0 moles) of aniline was stirred and heated to 150° C. To the mixture was added 5.0 grams of a solution obtained by adding 1.28 grams of 10% hydrochloric acid to 93 grams of aniline and stirring the mixture well. The reaction was carried out for 3.0 hours (10,800 s) at the 150° C. reaction temperature. The reaction product was cooled to 120° C. then 350 milliliters of toluene was added. The product was then cooled to 25° C. and the solid precipitated product was recovered by filtration. The crude product was slurried into 350 milliliters of methanol and heated to a reflux then maintained for 15 minutes (900 s). After cooling, the product was recovered by filtration and dried under vacuum to yield 4-(1-(4-aminophenyl)-1-methylethyl)phenol as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([OH:18])[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:30])[CH3:29].Cl.[OH-].[Na+]>ClCCl>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C@H:5]2[CH2:6][CH2:7][CH2:8][C@:3]([CH2:2][NH:1][C:28](=[O:30])[CH3:29])([OH:18])[CH2:4]2)[C:15]([F:16])=[CH:14][N:13]=1
Reactant: NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reaction time: 0.08 h

Procedure:
(1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol, 46b, (0.19 g, 0.69 mmol) was dissolved in dichloromethane (15 mL) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted into 1N HCl (30 mL), and the aqueous layer was brought to a basic pH by addition of 1N NaOH. The resulting suspension was extracted with dichloromethane (50 mL). The organic layer was dried on Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg of N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclo-hexyl]methyl}acetamide as a white foamy solid. LCMS RT=2.82 (M+1) 317.33.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:39]1[C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[C:44]([F:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)(C(C)(C)C)(C)C>>[F:48][C:44]1[C:43]([C:2]2[N:3]=[C:4]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:42]2[C:47](=[CH:46][CH:45]=1)[NH:39][CH:40]=[CH:41]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate (0.2 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A and purified via reverse phase hplc to produce 57.5 mg of 137. MS (Q1) 547.3 (M)+