Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.O.[CH3:35][N:36](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([C:35]#[N:36])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:14])=[CH:5]2
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ((S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (1.5 g, 3.1 mmol, 1.0 eq) and tetrakis(triphenylphosphine)palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at RT, dicyanozine (476 mg, 4.06 mmol, 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonitrile 29.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[CH3:13][C:9]1([CH3:12])[CH2:8][O:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[C:2][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-(4-iodo-phenyl)-ethanone. MS (ESI) 320.2 (M•)+.
Reaction SMILES: [C:1]([CH:3]1[C:12]2[CH2:11][CH2:10][C:9]3=[N:13][N:14]([CH2:16][C:17]4[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=4)[N:15]=[C:7]([C:8]=23)[C:6]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:5][S:4]1)#[N:2].Cl.C(N(CC)CC)C.[N-:50]=[N+:51]=[N-:52].[Na+]>CN(C)C=O>[CH3:25][O:24][C:21]1[C:20]([CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][N:14]2[N:13]=[C:9]3[CH2:10][CH2:11][C:12]4[CH:3]([C:1]5[NH:2][N:52]=[N:51][N:50]=5)[S:4][N:5]=[C:6]([NH2:27])[C:7]([C:8]=43)=[N:15]2)[C:22]=1[CH3:23]
Reactant: COc1c(C)cnc(CN2N=C3CCC4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4C#N)c1C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(CN2N=C3CCC4=C3C(=N2)C(N)=NSC4c2nnn[nH]2)c1C
Temperature: 105 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
A mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Step 4) of Example 23 (53 mg), N,N-dimethylformamide (1 mL), triethylamine hydrochloride (14.5 m) and sodium azide (6.8 mg) was sealed in a tube and heated with stirring at a bath temperature of 105° C. for 15 hours. After cooling to room temperature, the reaction solution was separated with ethyl acetate and a 0.1 N sodium hydroxide solution. The aqueous layer was made acidic with a 0.1 N hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol-lower layer of water) to obtain the title compound (5.6 mg, 19%) as a solid.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH:6]([C:9]1[CH:25]=[C:24]2[N:12]([CH2:13][C:14]3[C:15]2=[N:16][C:17]2[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:26])[C:10]=1[CH3:27])[CH2:7][CH3:8])=[O:4].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.[ClH:33]>O>[ClH:33].[N:28]1([CH2:2][C:3]([O:5][CH:6]([C:9]2[CH:25]=[C:24]3[N:12]([CH2:13][C:14]4[C:15]3=[N:16][C:17]3[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:26])[C:10]=2[CH3:27])[CH2:7][CH3:8])=[O:4])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCC(OC(=O)CI)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: O
Product: CCC(OC(=O)Cn1ccnc1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and imidazole. 1H NMR (CDCl3 /MeOH-d4) d 9.17 (s, 1H), 8.60 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.95 (m, 1H), 7.75 (m, 1H), 7.61 (s, 1H), 7.51 (br s, 1H), 7.41 (br s, 1H), 5.95 (m, 1H), 5.65 (d, 1H), 5.42 (d, 1H), 5.33 (s, 2H), 2.36 (s, 3H), 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C24H22N4O3.2 HCl.11/4 H2O: C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:17]3[C:18]4[C@H:19]([CH2:29][C:30](OCC)=[O:31])[CH2:20][CH2:21][CH2:22][C:23]=4[S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:31][CH2:30][CH2:29][C@H:19]1[C:18]2[C:17]3[C:16]([O:15][CH:12]4[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of ethyl 2-[(13S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate (800 mg, 1.63 mmol, 1.00 equiv) in THF (30 mL) in an ice/water bath under nitrogen was added LiAlH4 (121.2 mg, 3.20 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature and quenched with water, extracted with ethyl acetate (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give 490 mg (67%) of tert-butyl N-(4-[[(13S)-13-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O>[O:22]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCc2cccnc2)cc1

Procedure:
A mixture of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid methyl ester (4:1) molar hydrate (1.1 g) in hot methanol (10 mL) was treated with 1N sodium hydroxide (5 mL) and diluted with water. The organic solvent was removed under vacuum and the residue in water was washed with diethyl ether. The aqueous layer was concentrated to about 25 mL and chilled in ice. Cold 2N hydrochloric acid (2.5 mL) was added dropwise and the product was allowed to crystallize and was filtered and air dried. Recrystallization from acetone provided 0.64 g of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid as a colorless solid, mp 163°-165° C.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3](=O)[NH:2]1.B.CO>C1COCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[CH2:3][NH:2]1
Reactant: O=C1NC(=O)C2(CC2)c2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)CNCC21CC1
Temperature: 0 °C

Procedure:
0.5 g (2.7 mmol) 1′H-spiro[cyclopropane-1,4′-isoquinoline]-1′,3′(2′H)-dione in 50 mL THF were heated to the reflux temperature of the solvent. 11 mL (11 mmol) of a 1M borane in THF solution were added dropwise and the mixture was refluxed for 3 h. The reaction mixture was cooled to 0° C. and mixed with 50 mL methanol. The reaction mixture was evaporated down, the residue was combined with 15 mL of a 4M hydrochloric acid solution and refluxed for 30 min. After neutralisation with 15 mL of an aqueous 4M sodium hydroxide solution the mixture was extracted twice with ethyl acetate. The combined organic phases were dried and evaporated down. The product was purified by HPLC. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:18])[CH:12]3[CH:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:18])[CH:12]3[CH:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:43])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Solvent: ClCCl
Product: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S(=O)c3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.6 %

Procedure:
To a solution of 200 mg of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 15 mL of methylene chloride at -50° under nitrogen was added 90 mg of m-chloroperbenzoic acid in 3 mL of methylene chloride. The solution was stirred at -40° for 45 min and then warmed to room temperature over a 45 min period. The mixture was partitioned between methylene chloride and aqueous sodium sulfite. The organic layer was washed twice with bicarbonate, then brine, then dried over sodium sulfate and evaporated to dryness. The crude reaction product was purified by preparative thin layer chromatography two 20×20×0.2 cm silica gel plates, eluting with 5% methanol in methylene chloride, to afford 144 mg (69.6%) of 3-phenylsulfinyl-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]-hept-2-en-2-carboxylic acid, diphenylmethyl ester, a diastereomeric mixture, as a colorless glass. IR (Nujol mull): 1780, 1710, 1600, 3400 cm-1 ; NMR (220 MHz; CDCl3 indicative of a 3:1 mixture of diastereoisomers at sulfur): δ 1.15 (3H, d, J=6.5, major isomer), 1.30 (3H, d, J=6.5, minor isomer), 2.3-3.0 (3H, m), 3.3-3.6(1H, m), 3.93 (1H, m, major isomer), 4.02 (1H, m, minor isomer), 4.52 (1H, m, minor isomer), 4.68 (1H, m, major isomer), 6.95 (1H, s), and 7.2-7.7 (15H, m). ##STR25##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1>O>[CH3:5][C:4]1[N:1]([C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[C:10]([CH3:9])=[CH:2][CH:3]=1
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(CC#N)cc1
Yield: 34 %

Procedure:
20 g (0.15 mol) of p-aminobenzyl cyanide, 19 ml (0.17 mol) of 2,5-dicetohexane and 2.88 g (0.015 mol) of hydrated p-toluene sulphonic acid are dissolved in a 500 ml flask. This mixture is heated to reflux, the water formed is trapped using a Dean Stark apparatus. At the end of the reaction, the solvent is evaporated off under vacuum and the residue is taken up in 300 ml of AcOEt. The organic solution is washed successively with twice 200 ml of water, 200 ml of a saturated solution of Na2CO3, 200 ml of water, 200 ml of a saturated solution of KHSO4 and finally 200 ml of water and 200 ml of brine. After drying over sodium sulphate, filtration and concentration under vacuum, the residue is purified rapidly on a silica column. A light beige solid is obtained with a yield of 34%. Melting point: 112-113° C.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH:15]([C:18]1[NH:19][C:20]([CH:41]([CH3:43])[CH3:42])=[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:17])[CH3:16]>C(Cl)Cl>[CH:41]([C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH:15]([CH3:17])[CH3:16])[N:19]=1)([CH3:43])[CH3:42]
Reactant: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OCC)C1c1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are added to a solution of 6.6 g (16.4 mmol) of the compound from Example II in 200 ml of methylene chloride p.A. and the mixture is stirred at room temperature for 1 hour. It is then filtered through kieselguhr with suction, and the methylene chloride phase is extracted 3 times with 100 ml of water each time and dried over magnesium sulphate. After concentrating in vacuo, the residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ 3.5 cm, using ethyl acetate/ petroleum ether 1:9)
Reaction SMILES: C1(CN2CCC(C[CH2:15][C:16]3[C:20]4[CH:21]=[CH:22][C:23]5[NH:27][C:26](=[O:28])[CH2:25][C:24]=5[C:19]=4[O:18][N:17]=3)CC2)C=CC=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:15][C:16]1[C:20]2[CH:21]=[CH:22][C:23]3[NH:27][C:26](=[O:28])[CH2:25][C:24]=3[C:19]=2[O:18][N:17]=1
Reactant: O=C1Cc2c(ccc3c(CCC4CCN(Cc5ccccc5)CC4)noc23)N1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc2c3c(ccc12)NC(=O)C3
Yield: 33.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (0.334 g, 1.35 mmol) and pyridine (0.55 mL, 6.75 mmol) in DMF (25 mL). After work-up, the residue was purified by silica gel flash chromatography (50→75% EtOAc-hexanes) to give the title compound (0.086 g, 34%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([F:21])([CH3:20])[CH3:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:31]#[C:30][C@:28]([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:10]=3)[C:6]([C:18]([F:21])([CH3:20])[CH3:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CC(C)(F)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(C)(C)F)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C

Procedure:
To a solution of 4-[6-bromo-3-(2-fluoropropan-2-yl)-1H-indazol-1-yl]pyrimidin-2-amine (95 mg, 0.26 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (79 mg, 0.52 mmol). The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Biotage, eluent:DCM containing a 1-10% MeOH gradient). Further purification by reverse phase preparative HPLC furnished the title compound as an orange solid: 1H NMR (500 MHz, DMSO) delta 1.76-2.00 (9H, m), 2.62 (3H, s), 6.82 (1H, s), 6.95-7.15 (3H, m), 7.39 (1H, d, J=9.93 Hz), 7.95 (1H, d, J=9.93 Hz), 8.33 (1H, br. s.), 8.94 (1H, s); LC-MS: m/z=+422.05 (M+H)+.
Reaction SMILES: [H-].[Na+].C1COCC1.[N:8]1([CH2:14][CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27](F)=[CH:26][C:24]=2[N:25]=1)[CH3:19]>O>[CH2:18]([C:20]1[N:21]=[N+:22]([O-:31])[C:23]2[CH:29]=[CH:28][C:27]([O:17][CH2:16][CH2:15][CH2:14][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:26][C:24]=2[N:25]=1)[CH3:19]
Reactant: CCc1nc2cc(F)ccc2[n+]([O-])n1
Reactant: OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(OCCCN3CCOCC3)ccc2[n+]([O-])n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
NaH (60% dispersion in oil, 310 mg, 7.75 mmol) was added to dry THF (10 mL) and stirred at 20° C. for 20 min prior to the addition of 3-(4-morpholinyl)propanol (676 mg, 4.66 mmol). The mixture was stirred for 30 min, fluoride 28 (300 mg, 1.55 mmol) added and the resulting solution stirred at 20° C. for 2.5 h under N2. Water was added and the solution extracted with DCM (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-5%) MeOH/DCM to give 1-oxide 31 (257 mg, 52%) as a pale yellow solid, mp 108-111° C.; 1H NMR δ 8.33 (d, J=9.3 Hz, 1 H, H-8), 7.21-7.26 (m, 2 H, H-7 and H-5), 4.22 (t, J=6.4 Hz, 2 H, CH2), 3.73 (t, J=4.6 Hz, 4 H, 2×CH2O), 3.00 (q, J=7.6 Hz, 2 H, CH2), 2.55 (t, J=7.0 Hz, 2 H, CH2), 2.48 (t, J=4.6 Hz, 4 H, 2×CH2N), 2.06 (m, 2 H, CH2), 1.43 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 168.7, 164.6, 150.3, 128.4, 123.1, 121.6, 106.3, 67.3 (2), 66.9, 55.1, 53.7 (2), 30.7, 26.0, 12.2. Anal. Calcd for C16H22N4O3: C, 60.4; H, 7.0; N, 17.6. Found: C, 60.4; H, 7.0; N, 17.4%.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1F)([O-:21])=[O:20]>O.C(O)C>[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:13]=2)[NH:6][CH:7]=1)([O-:21])=[O:20]
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2[nH]cc(CCNc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1 mMole of 5-metyltryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 85% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.8) which is well resolved from the starting materials under the same conditions.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16](=[O:22])[CH2:17][C:18](=O)[CH2:19][CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:19]([C:18]1[NH:8][CH:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]=1[C:16](=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:20]
Reactant: C1=C(c2ccccc2)N1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: CCc1[nH]cc(-c2ccccc2)c1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
The preparation is carried out in accordance with the general procedure in Example 1. The reactants are 2-phenylazirine and 1-phenylpentane-1,3-dione. The reaction product is dissolved in 150 ml of hot ethanol and the solution is allowed to stand overnight at room temperature. The precipitated crystals are filtered with suction.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@@:5]3([N:21]=[C:20]([NH:22]C(=O)OC(C)(C)C)[CH2:19][O:18][CH2:17]3)[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@@:5]3([N:21]=[C:20]([NH2:22])[CH2:19][O:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(I)cc12
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reaction time: 2 h
Yield: 12.4 %

Procedure:
In a 150-mL resealable vessel, the (S)-tert-butyl 2′-bromo-7′-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate (1.475 g, 2.58 mmol) was dissolved in dcm (10 mL), and 2,2,2-trifluoroacetic acid (1.989 mL, 25.8 mmol) was added. The vessel was sealed and placed in a 50° C. oil bath. After 2 h, the reaction was concentrated and the mixture was neutralized with 0.5 M aqueous Na2CO3 (15 mL) and the aqueous phase was extracted with 5% MeOH-dcm (3×33 mL). The organics were combined, washed with dilute brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (5.5% MeOH/DCM) to afford (S)-2′-bromo-7′-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (151 mg, 0.321 mmol). MS (m/z) 471/473 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)([CH3:7])[C:3]([O:5]C)=O.F[C:19]1[C:28]([N+:29]([O-])=O)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:32](F)(F)F)[CH:20]=1>>[CH3:7][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:3](=[O:5])[NH:29][C:28]2[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]([CH3:32])=[CH:20][C:19]=2[O:1]1
Reactant: COC(=O)C(C)(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Product: COC(=O)c1cc2c(cc1C)OC(C)(c1cccc(C(F)(F)F)c1)C(=O)N2

Procedure:
Using methyl 2-hydroxy-2-[3-(trifluoromethyl)phenyl]propanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C@H:7]1[O:12][C@@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][C@H:11]1[O:12][C@@H:7]([CH3:6])[CH2:8][N:9]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulfuryl dichloride (0.363 ml, 4.47 mmol) was added at room temperature to a solution of cis-2,6-dimethylmorpholine (0.500 ml, 4.06 mmol) and 4-dimethylaminopyridine (496 mg, 4.06 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 24 hours. The reaction mixture was quenched with H2O (10 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo to give cis-2,6-dimethylmorpholine-4-sulfonyl chloride.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCCN
Product: CCCCNc1ccccc1C
Yield: 67 %

Procedure:
General procedure B using 55.1 mg (0.229 mmol) of o-tolyltriflate and 34.0 μl (0.344 mmol) of n-butylamine gave 67% yield of N-butyl-2-methylaniline after silica gel chromatograph using 5% ethyl acetate in hexanes.