Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([OH:7])[N:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)C>C(O)(=O)C>[C:13]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([OH:7])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)c1sc(N)nc1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1sc(NC(C)=O)nc1O
Yield: 82.2 %

Procedure:
Ethyl 2-amino-4-hydroxy-1,3-thiazole-5-carboxylate (6.00 g, 31.9 mmol) was dissolved in 100 mL of acetic acid with stirring. Acetic anhydride (15.0 mL, 159 mmol) was added via syringe. The reaction was stirred for 16 hours and 100 mL of diethyl ether was added. The reaction was filtered and the pale yellow solid was washed with diethyl ether, dried, and collected to afford 6.04 g (82%) of ethyl 2-(acetylamino)-4-hydroxy-1,3-thiazole-5-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 11.32 (s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.16 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31]>C(O)C>[CH3:29][O:28][C:25]1[CH:24]=[C:23]([O:30][CH3:31])[C:22]([O:21][CH3:20])=[CH:27][C:26]=1/[N:15]=[N:14]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(OC)c(OC)c1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1/N=N/c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.1 h
Yield: 72.5 %

Procedure:
Diazonium salt 1 (14.1 mg, 0.0443 mmol) and 1,2,4-trimethoxybenzene (15.6 mg, 0.0928 mmol) were dissolved in 0.148 g of 95% aqueous ethanol. After 0.1 h, a red solid precipitated. After filtration the red solid was purified by SiO2 column chromatography (7:3 hexane/ethyl acetate) to give 27c as a red oil (12.8 mg, 72%): IR (ATR): {tilde over (v)}=2941, 1607, 1598, 1505, 1472, 1436, 1269, 1209, 1126, 1093, 1030, 839, 824 cm−1. MS (GC, EI): m/z=398 [M+], 140, 110. 1H NMR (500 MHz, CDCl3): δ=7.91 (d, J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 2H), 7.44 (s, 1H), 6.64 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.93 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.74 (C), 154.70 (C), 154.3 (C), 154.0 (C), 144.1 (C), 135.1 (C), 126.9 (2CH), 122.4 (2CH), 98.8 (CH), 97.5 (CH), 57.6 (CH3), 56.22 (CH3), 56.17 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.3 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.[OH-].[K+].Cl[CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19]>>[CH:18]([NH:17][CH2:16][CH:15]([OH:21])[CH2:14][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2)([CH3:20])[CH3:19]
Reactant: Oc1cccc2c1C=CC2
Reactant: CC(C)NCC(O)CCl
Agent: [K+]
Agent: [OH-]
Product: CC(C)NCC(O)COc1cccc2c1C=CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.44 g. of 4-hydroxyindene in 4 ml. of an aqueous 10% potassium hydroxide solution there was added 0.65 g. of 1-chloro-2-hydroxy-3-isopropylaminopropane. After stirring the resulting mixture at room temperature for 15 hours, the reaction mixture was extracted with ether, the ether extract was dried with anhydrous sodium carbonate and the ether was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using acetone as eluent, and 0.23 g. of white crystals of 4-(3-isopropylamino-2-hydroxypropoxy)indene was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Agent: O=S(=O)(O)O
Product: COc1ccc(C(=O)CCC(=O)O)cc1NC(C)=O

Procedure:
A mixture of 3-(3-amino-4-methoxybenzoyl) propionic acid (15.61 g.) with acetic anhydride (7.14 g.) was treated with concentrated sulphuric acid (2 drops) and heated on the steam bath for 3 hours. It was then cooled and decomposed by the addition of ice. The resultant solid was collected and crystallised from methanol to yield the product, (10.5 g.), m.p. 184°-185°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:17]=2)[CH:7]=1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>C1COCC1>[CH3:44][O:43][C:41](=[O:42])[CH2:40][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:31][CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:17]=1
Reactant: COc1ccc(F)cc1-c1ccncc1NC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.5 %

Procedure:
To a solution of N-[4-(5-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-5-trifluoromethyl-benzamide (50 mg, 0.11 mmol) in THF (5 mL) were added potassium tert-butoxide (24 mg, 0.21 mmol) and methyl bromoacetate (22 mg, 0.14 mmol) at 0° C. and the reaction mixture was stirred for 12 hours at 25° C. The reaction mixture was quenched with water (5 mL) and extracted by EtOAc (2×20 mL). The combined EtOAc layers were dried over Na2SO4 and evaporated. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to get the desired compound as an off-white solid (8 mg, 14%). MS (ESI): m/z=541.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19](OCC)=[O:20]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:7])[NH:8][C:19](=[O:20])[O:11][C:4]=2[CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 22L, five neck, round bottom flask was equipped with an overhead stirrer, reflux condenser, addition funnel, thermocouple temperature read out, and a heating mantle. The reactor was purged with nitrogen. Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782 g, 10.4 mol) were charged to the reaction flask and the stirring was started. Pyridine (1133 mL, 14.0 mol) was charged to the reactor. The resulting reaction slurry was cooled to less than 10° C. with an ice bath. Ethyl chloroformate (1091 mL, 1237 g, 11.4 mol) was placed in the addition funnel and charged slowly to the stirred reaction mixture such that the temperature of the reaction mixture did not exceed 15° C. during the addition. The temperature of the reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours. Liquid chromatographic analysis of the reaction mixture indicated that the reaction was only 80% complete. Approximately half of the solvent was removed by atmospheric distillation. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Additional pyridine (215 mL, 2.65 mol) was added to the reaction mixture. Ethyl chloroformate (235 g, 2.17 mol) was added slowly via an addition funnel to the cold reaction mixture. The reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours, after which time liquid chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Water (1600 mL) was added slowly via an addition funnel and the resulting slurry held at <10° C. for 90 minutes. The solid product was collected by vacuum filtration through a large sintered glass funnel. The product filter cake was washed with deionized water and vacuum dried at 50° C. for 18 hours to give 1914 g of 7-chloro-2H-1,3-benzoxazine-2,4(3H)-dione as a tan solid. The yield was 83%.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH2:26]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:54])C(=O)C1>C(Cl)Cl>[Br:54][CH2:26][C:8]1[N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[C:10]2[C:15]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 2 h
Yield: 28.8 %

Procedure:
To a solution of [3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]methanol (1.31 g, 3.47 mmol) and triphenylphosphine (1.09 g, 4.16 mmol) in DCM (30 mL) at RT under a nitrogen atmosphere was added NBS (240 mg, 4.16 mmol) and stirring was continued for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 2-Bromomethyl-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole as a gum (440 mg, 29%). 1H NMR (CDCl3, 400 MHz): δ 8.16 (1H, dt, J=8.48, 0.84 Hz), 7.92-7.88 (2H, m), 7.60-7.49 (4H, m), 7.48-7.37 (3H, m), 7.28-7.22 (3H, m), 5.05 (2H, s), 2.38 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: BrCCCCBr
Product: N#Cc1cccc(OCCCCBr)c1

Procedure:
The procedure is as for Example 53, Step A, using as substrate 3-hydroxybenzonitrile and 1,4-dibromobutane.
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:13]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(Br)cc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)cc1Br
Temperature: 0 °C
Yield: 66.2 %

Procedure:
3,5-Dibromo-2-methoxy-pyridine (427) (1.5 g, 5.62 mmol) was dissolved in anhydrous DMF (14 mL) and chilled to 0° C. While stirring, POCl3 (2.1 mL, 22.48 mmol) was added drop wise over a period of 5 minutes. The mixture was stirred at 0° C. for 1 h. The mixture was then heated to 100° C. under N2, for 16 h. TLC indicated complete reaction at this point. Ice-chips (10 g) were added to the cooled solution and the mixture was stirred for 20 minutes. The mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (2×50 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by column chromatography gave the desired product (428) as an off white solid upon concentration (1.01 g, 3.722 mmol, 66.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 1H, J=2 Hz), 8.38 (d, 1H, J=1.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccc(Cl)cc2)c[nH]1
Product: Clc1ccc(-c2ccc(Cl)nc2)cc1

Procedure:
A mixture of 22.27 g. of 5-(4-chlorophenyl)-2(1H)-pyridinone and 100 ml. of phosphorus oxychloride is refluxed for 16 hours, chilled and poured onto cracked ice. The solid formed is collected by filtration and then is dissolved in chloroform. The chloroform solution is washed with water and with saturated sodium bicarbonate and then is dried over magnesium sulfate. The solvent is evaporated at reduced pressure to yield 21.1 g. of the product of the Example as a gray solid, m.p. 113°-115° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH2:36][CH3:37]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:35][CH2:36][CH3:37])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 48.4 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (657 mg), potassium carbonate (242 mg) and propyl iodide (427 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (352 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11]O)[C:6]=2[CH:13]=1.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([CH2:11][Cl:22])[C:6]=2[CH:13]=1
Reactant: OCC1=CCOc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: ClCC1=CCOc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2.86 g of 6-chloro-4-hydroxymethyl-2H-1-benzopyrane in 50 ml of ether is reacted with 2 ml of pyridine. To the resulting mixture are then slowly added dropwise, with cooling by ice/water, 1.71 g of thionylchloride in 10 ml of diethylether. Reaction is continued for 5 hours at room temperature, the mixture poured onto ice/water and the ether phase separated. This is then washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and concentrated by evaporation. The product is used directly for further reaction.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc[n+]([O-])cc1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cc[n+]([O-])cc2OCCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a solution of the compound (0.60 g) obtained in step 3 in THF (15 mL) was added sodium hydride (60% in oil, 0.34 g), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the resultant product was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 80% ethyl acetate/hexane→5% ammonia/ethyl acetate) to give 4-benzyl-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one 8-oxide (0.27 g, 48%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]#[N:12])[N:4]=1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([CH2:11][NH2:12])[N:4]=1
Reactant: COc1ccc(C#N)nc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN)nc1OC
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dimethoxy-6-cyanopyridine (4-5, 5.1 g, 31.1 mmol) in MeOH (260 mL) was added Pearlman's Catalyst (2.18 g, 3.11 mmol, 20 wt %) and concentrated HCl (20.0 mL, 249 mmol, 12M). The system was then stirred under an atmosphere of hydrogen via a balloon for 1.5 h. The reaction contents were filtered through a pad of celite and methanol was removed in vacuo. The crude mixture was then basified using saturated Na2CO3 and then extracted using 4:1 Chloroform:Ethanol. The organic phase was washed with brine, dried over Na2SO4, filtered and purified by gradient elution on silica gel (0 to 12% MeOH (10% NH4OH) in DCM) to yield the desired product (4-6) as a bone semi-solid. ESI+MS [M+H]+ C8H12N2O2: M-16 (—NH2), 152.06 found, 168.2 required.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)OC(C)(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
4-(t-Butyloxycarbonyl)-1 -methoxycarbonyl-2-methoxybenzene (770 mg, 2.9 mmol) from Step 3 was dissolved in 1:1 THF:H2O (10 mL) and to the solution was added 1N NaOH (4 mL, 4 mmol). After being stirred at ambient temperature for 24 h, the solution was acidified to pH 2 with 1N HCl and the solvents were removed under reduced pressure. The residue was dissolved in CHCl3 and washed with water. The CHCl3 layer was dried (MgSO4), filtered, and evaporated under reduced pressure to give 4-(t-butyloxycarbonyl)-2-methoxybenzene 1-carboxylic acid as a white solid (86% yield).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[F:40])[CH2:27][CH2:26]2)[CH2:43][CH2:44]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (46.8 mg, 0.076 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 0.036 mmol) in THF (760 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (39.6 mg, 99%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 0.52-0.59 (m, 2H), 0.75-0.83 (m, 2H), 1.84-1.97 (m, 2H), 2.02-2.12 (m, 2H), 2.64-2.71 (m, 1H), 2.93-3.16 (m, 4H), 3.35 (s, 2H), 3.52-3.63 (m, 2H), 3.75 (s, 3H), 4.20-4.31 (m, 2H), 4.32-4.40 (m, 1H), 6.63-6.69 (m, 1H), 6.73 (dd, J=12.9, 3.0 Hz, 1H), 7.03-7.10 (m, 1H); ESI-MS m/z [M+H]+ 414.3.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>CS(C)=O.CO>[O:19]1[C:20]2[C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([CH2:6][NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[CH:29]=[N:28][N:27]4[C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)([OH:5])[C:7]([F:10])([F:8])[F:9])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: Nc1cccc2c1cnn2-c1ccncc1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccncc1)C(F)(F)F)c1cccc2c1OCC2
Temperature: 150 °C
Yield: 8.5 %

Procedure:
A mixture of racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163, 27 mg, 0.095 mmol) and 1-(4-pyridinyl)-1H-indazol-4-amine (Intermediate 5) (20 mg, 0.095 mmol) was heated by microwave (200 W) at 150° C. for 20 minutes. The crude product was cooled, dissolved in DMSO/MeOH and purified by mass-directed autopreparation. The appropriate fractions were evaporated to give the title compound (4 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12]
Reactant: Oc1ncnc2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ncnc2ccc(-c3ccccn3)cc12
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Preparation D12, Step 2: A mixture of 6-bromoquinazolin-4-ol (173 mg, 0.77 mmol) and 2-tributylstannylpyridine (850 mg, 2.30 mmol) in toluene (10 mL), plus a few drops of DMF to improve solubility, was degassed under vacuum/argon, then a catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added, the mixture was degassed again, and then heated at reflux for 4 h. The reaction was cooled to room temperature, and some solids were removed by filtration. Analysis by LC/MS indicated that the desired product was present in both the solids and the filtrate. The solids were slurried in 8:2 methylene chloride/methanol, the mixture was filtered, the filtrate was combined with the original filtrate, and this mixture was concentrated in-vacuo. The residue was purified over silica gel, eluting with 50% EtOAc/hexanes, 75% EtOAc/hexanes, 100% EtOAc, 5% MeOH/EtOAc, to yield 106 mg of 6-(pyridin-2-yl)quinazolin-4-ol as a colorless solid. MS (ES+)=224 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[N:14]1([C:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18 g (57.7 mmol) of methyl 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoate is placed under a nitrogen atmosphere together with 6.66 g (5.77 mmol) of tetrakis-triphenylphosphinepalladium(0) and 0.439 g (2.31 mmol) of copper(1) iodide in 150 mL of N,N-diisopropylamine, the mixture is heated to 80° C. and 16.6 mL (115 mmol) trimethylsilylethyne is added. The reaction mixture is stirred for 8 hours at 80° C. and then for 16 hours at ambient temperature. Then volatile constituents are eliminated in vacuo, the residue is taken up in ethyl acetate, insoluble matter is filtered off, and the solvent is eliminated in vacuo. The residue is purified by chromatography on silica gel (gradient: dichloromethane/ethanol 100:0□95:5). Yield: 7.7 g (41%); Rf value: 0.44 (silica gel; dichloromethane/ethanol=95:5); C18H23NO3Si (329.48); mass spectrum: (M+H)+=330.