Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=[O:3])[CH3:2].[Cl:46][C:47]1[N:55]=[C:54]2[C:50]([N:51]=[CH:52][N:53]2[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)=[C:49](Cl)[N:48]=1.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:49]2[N:48]=[C:47]([Cl:46])[N:55]=[C:54]3[C:50]=2[N:51]=[CH:52][N:53]3[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](NC(=O)OC(C)(C)C)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7C6CCCCO6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)-2-(2-Chloro-6-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 1) (5.2 mmol) was treated with 1:1 trifluoroacetic acid/dichloromethane (20 ml) for ca. 2 h. This was concentrated in vacuo and the residue was purified by SPE (SCX, 50 g), eluting sequentially with dichloromethane, methanol, 40% (2M ammonia in methanol): dichloromethane and 2M ammonia in methanol. The appropriate fraction was concentrated in vacuo and suspended in propan-2-ol (60 ml). To this was added N,N-diisopropylethylamine (4 m. eq.) and 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (prepared according to the method disclosed in WO2003080604A1) (1 m. eq.) and this was heated at 60° C. overnight. After cooling to room temperature, further 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.5 m. eq.) and N,N-diisopropylethylamine (4 ml) were added and this was heated at 60° C. for a further ca. 5 h. After cooling to room temperature, the reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane (ca. 60 ml) and water (ca. 60 ml). The organics were washed with water (ca. 60 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as an off-white crystalline solid, 4 g.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:53]=[CH:52][C:29]3[N:30]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:32][C:28]=3[CH:27]=2)=[CH:22][C:21]=1[CH:54]=O.[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][C@@H:64]1[CH2:68][NH:69][CH2:70][C:71]1[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClC(Cl)C.ClCCl>[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][C@@H:64]1[CH2:68][N:69]([CH2:70][C:71]1[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=1)[CH2:54][C:21]1[CH:22]=[C:23]([C:26]2[CH:53]=[CH:52][C:29]3[N:30]([C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:32][C:28]=3[CH:27]=2)[CH:24]=[CH:25][C:20]=1[F:19])=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNCc1ccc(F)cc1
Reactant: O=Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN(Cc1ccc(F)cc1)Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Sodium triacetoxyborohydride (159 mg, 0.75 mmol) and acetic acid (36 mg, 0.6 mmol) were added to a mixture of 5-(4-fluoro-3-formylphenyl)-1-trityl-1H-benzotriazole (145 mg, 0.3 mmol) and (R)-2-[(4-fluoro-benzylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (111 mg, 0.36 mmol) and 4 angstrom molecular sieves in 5 mL of dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with ethyl acetate/cyclohexane) provided 119 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1cccc(F)c1

Procedure:
The title compound, white solid, m.p. 96° C. and MS: m/e=305 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-fluoro-phenyl)-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[N:10]1([C:16]2[CH:25]=[C:24]3[C:19]([C:20](=O)[NH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:20]1[C:19]2[C:24](=[CH:25][C:16]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(N3CCOCC3)ccc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
1.3 ml (7.57 mmol) of N-ethyldiisopropylamine were slowly added dropwise to a suspension of 3.5 g (15.11 mmol) of 7-morpholin-4-yl-3H-quinazolin-4-one in 20 ml of phosphoryl chloride. The reaction mixture was subsequently stirred at 115° C. for 2 h. Conventional work-up gave 3.75 g of 4-chloro-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=250 as solid.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[S:11](Cl)([Cl:13])=[O:12]>>[Cl:13][S:11]([O:8][CH:3]([CH2:4][C:5]([CH3:7])=[CH2:6])[C:2]([Cl:10])([Cl:9])[Cl:1])=[O:12]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: C=C(C)CC(OS(=O)Cl)C(Cl)(Cl)Cl

Procedure:
To 20.35 g of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene was added 23.8 g of thionyl chloride. The resulting solution was heated at 80°-90° for one hour. After cooling, the excess thionyl chloride was removed under reduced pressure. The residue was fractionally distilled. A fraction weighing 5.9 g; bp, 100°/2.8 mm, was analyzed by vapor phase chromatography and mass spectrometry. The major component of the fraction was identified as 1,1,1-trichloro-4-methyl-4-penten-2-yl chlorosulfinate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([N:14]=[C:15]=[S:16])(=[O:13])[CH3:12].O>CC(C)=O>[C:11]([NH:14][C:15]([NH:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])=[S:16])(=[O:13])[CH3:12]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC(=O)N=C=S
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NC(=S)Nc1c(F)cc(Br)cc1F
Temperature: 72 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
4-bromo-2,6-difluorobenzenamine (2.514 g, 12.1 mmol) was dissolved in acetone (75 ml) and ethanoyl isothiocyanate (1.30 ml, 14.8 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (70-74° C.) and the reaction was stirred under nitrogen for 90 minutes. The reaction was then cooled to room temperature and poured into water (200 ml), and the resultant suspension was filtered. The solid was washed with water, collected, and dried under high vacuum in water bath (60° C.) to afford 1-acetyl-3-(4-bromo-2,6-difluorophenyl)thiourea (3.435 g, 93% purity, 85% yield). MS (ESI pos. ion) m/z: 309 (MH+, 79Br), 311 (MH+, 81Br). Calculated exact mass for C9H7BrF2N2OS 308 (79Br), 310 (81Br).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:25])[CH2:19][C:20](OCC)=[O:21])[NH:14][N:13]=1.O>CO.O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][CH2:9][CH2:10][CH2:11][C:5]2=[N:4][C:3]=1[C:12]1[CH:16]=[C:15]2[N:17]=[C:18]([OH:25])[CH:19]=[C:20]([OH:21])[N:14]2[N:13]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2nc3c(nc2C)OCCC3)n[nH]1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(nc1-c1cc3nc(O)cc(O)n3n1)CCCO2
Temperature: 25 °C

Procedure:
A suspension of ethyl 3-{[3-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate (293 mg, 0.848 mmol) and N,N-dimethylaminopyridine (518 mg, 4.24 mmol) in methanol (3 mL), tetrahydrofuran (3 mL), and water (3 mL) was heated for 8 h. After being cooled to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was triturated with ethyl acetate to give 2-(3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol. MS (APCI): m/z 300 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH2:5][OH:6].CI.[CH3:21]COC(C)=O.CCCCCCC>CN(C)C=O.COC(C)(C)C>[CH:13]([Si:9]([CH:10]([CH3:11])[CH3:12])([CH:16]([CH3:18])[CH3:17])[O:8][CH2:7][C@@H:4]([CH3:3])[CH2:5][O:6][CH3:21])([CH3:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(C)[Si](OC[C@@H](C)CO)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CI
Product: COC[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 60 h

Procedure:
3.09 g of sodium hydride (60% dispersion in oil) are added to a solution of 9.55 g of (S)-2-methyl-3-triisopropylsilanyloxypropan-1-ol [256643-28-4] and 7.3 ml of methyl iodide in 70 ml of N,N-dimethylformamide at 0° C. After 60 hours at room temperature, the reaction mixture is diluted with tert-butyl methyl ether and washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title as a yellow oil. Rf=0.51 (EtOAc-heptane 1:10).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1>O1CCOCC1>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: Clc1nc(Cl)nc(N2CCCCC2)n1
Reactant: N
Solvent: C1COCCO1
Product: Nc1nc(Cl)nc(N2CCCCC2)n1
Temperature: 70 °C
Yield: 98 %

Procedure:
Ammonia was bubbled for 5 min in a solution of 2,4-dichloro-6-piperidin-1-yl-[1,3,5]triazine (500 mg, 2.15 mmol) in dry 1,4-dioxane (20 mL). The solution was heated at 70° C. for 16 h in a sealed tube. The reaction mixture was allowed to cool to room temperature, and partitioned between AcOEt and a solution of sat. NH4Cl. After separation, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH]=214.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>Cl.C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[N:20]([CH2:19][C:18]([F:22])([F:21])[F:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Temperature: 100 °C
Yield: 84.3 %

Procedure:
5-(Benzyloxy)-2-methyl-4H-pyran-4-one (4.32 g, 20.0 mmol) was mixed with trifluoroethylamine (6.92 g, 70.0 mmol) in 6N HCl (11.7 mL) and ethanol (5.8 mL). The reaction mixture was heated in a sealed flask at 100° C. for 20 hours. The mixture was then concentrated in vacuo and the residue was diluted with water. The solid was filtered, washed with water and ether to give 5-(benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (5.01 g) as white solid. Yield=84%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.99 (s, 1H), 7.14-7.65 (m, 5H), 6.80 (s, 1H), 4.91-5.25 (m, 4H), 2.53 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[N:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:13])[N:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Brc1ccc2nc(Br)ccc2n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 3-necked roundbottom flask was charged with a solution of 2,6-dibromo-1,5-naphthyridine (39 g, 135.42 mmol) in methanol (150 ml). The mixture was cooled to 0° C. and a solution of sodium methoxide (8.77 g, 162.41 mmol) in methanol (50 ml) was added dropwise. The resulting solution was allowed to react, with stirring, for three hours at 0° C. The reaction mixture was cooled to <0° C. and a solid precipitated. The mixture was filtered and the filtrated was quenched by the addition of 500 ml of ice water. The solids that formed were collected by filtration and them dissolved in ethyl acetate and dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 1:10 ethyl acetate:petroleum ether as eluant to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>COCCOCCOC>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[CH:7][CH:6]=2)=[O:9])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: COCCOCCOC
Product: CCCCc1ccc(C(=O)c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 180 °C
Yield: 31.7 %

Procedure:
Under argon, 4-n-butylphenyl 4-hydroxyphenyl ketone (727 mg) obtained in Example 148 and 4-chloro-6,7-dimethoxyquinoline (639 mg) were dissolved in diethylene glycol dimethyl ether (10 ml), and the solution was then refluxed with heat at 180° C. for 10 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by chromatography on silica gel eluting with hexane/acetone to obtain 400 mg of the title compound (yield: 32%).
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+].[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.CO>COCCOC>[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:11]#[N:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ccnc1CC#N
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Under inert atmosphere, 0.91 g (4.6 mmol) of TOSMIC in solution in anhydrous DME (4 ml) is added to 0.96 g (8.6 mmol) of potassium tert-butylate in suspension in 4 ml of anhydrous DME at −35° C. The reaction mixture is cooled to −50° C. then 1 g (4.4 mmol) of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (Whitten J P, JOC 1986, 51 (10) 1891-1894) in solution in 4 ml of anhydrous DME is added dropwise, keeping the temperature below −45° C. The reaction mixture is stirred at this temperature for 30 min, then 11 ml of methanol is added, and the mixture is heated at 80° C. for 15 minutes. The solvents are concentrated under reduced pressure, and the residue is taken up in a water/acetic acid mixture (13 ml/0.5 ml), the aqueous phase is extracted with dichloromethane (3×100 ml), the organic phases are then washed with a saturated solution of NaHCO3, then dried over Na2SO4. After filtration, the filtrate is concentrated under reduced pressure and the residue is purified by filtration on basic alumina (eluent: A/B=DCM/AcEt 0 to 50% of B), 0.71 g of compound is thus obtained in the form of a yellowish orange oil. Yield=67%. MH+: 238 (Tr: 6.9 min, condition 1).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].Cl.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1>CCO>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][C:3]([CH3:4])=[C:2]2[CH3:1]
Reactant: NNc1ccc(Br)cc1
Reactant: CCC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(Br)cc2c1C
Yield: 67 %

Procedure:
Following a published procedure (Gundersen, E. G. U.S. Patent App. Publ. US 2005/070592) 2-Butanone (0.11 mL, 1.278 mmol) was added to a solution of 4-bromophenylhydrazine hydrochloride (0.300 g, 1.342 mmol in EtOH (3.8 mL). The mixture was heated to reflux for 22 h, concentrated in vacuo, and partitioned between EtOAc and 1N HCl. The organic layer was washed with H2O and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by chromatography (SiO2, 0-20% EtOAc/Hexane) to afford the desired indole as a pink powder (200 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:15][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1)=[O:31]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(4-nitrophenoxy)pyridin-2-amine [US Pat Appl 2008319188, Production Example 53] (0.60 g, 2.60 mmol) and DIPEA (0.680 μL, 3.89 mmol) in DCM (15.0 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (225 μL, 3.89 mmol) dropwise over 5 min. The reaction was maintained at RT for 16 hr and was quenched by the addition of a 1% solution of NH3 in MeOH (10 mL). The mixture was evaporated in vacuo and the residue was taken up into DCM (50 mL) and was washed with water (25 mL) and brine (25 mL), and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in DCM, 0-30%, gradient elution) to afford 2-methoxy-N-(4-(4-nitrophenoxy)pyridin-2-yl)acetamide as a white solid (0.73 g, 92%); Rt 1.88 min (Method 2); m/z 304 (M+H)+ (ES+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:20])=[O:19]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCSc1ccccc1

Procedure:
Using the general method of Example 37 Part D, N-(5-chloropentyl)-3-nitroquinolin-4-amine (10 g, 34 mmol) was reacted with benzenethiol (1.1 eq) to provide 12.6 g of 3-nitro-N-[5-(phenylthio)pentyl]quinolin-4-amine as a solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C.O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:16]=1[C:17]#[N:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 106.9 %

Procedure:
To a 20 mL vial containing a magnetic stir bar was added sodium hydride (103.7 mg, 4.32 mmol, 60% in mineral oil) followed by anhydrous DMF (2 mL) resulting in gas evolution. To this stirring reaction mixture was added 2-naphthol (623 mg, 4.32 mmol) as a solid in small portions over 5 min. The mixture was stirred at room temperature for 3 min and then 2,6-difluorobenzonitrile (601 mg, 4.32 mmol) in anhydrous DMF (4 mL) was added in one portion. The reaction mixture was heated in an oil bath at 100 ° C. for a total of 2 h and allowed to cool to room temperature. The reaction mixture was diluted with water (15 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (3×20 mL), dried (Na2SO4), filtered and concentrated to give K-1 as brown solid (1.216 g) of sufficient purity (contained 2-naphthol) to be used in the subsequent step. 1H NMR.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:8]([OH:11])[CH:9]=[CH2:10])[CH:7]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:8]([OH:11])[CH:9]=[CH2:10])[CH:7]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
1-(5'-Hydroxy-2'-nitrophenyl)-2-propen-1-ol (2.0 g) is dissolved in dry dimethylformamide (100 ml) and thereto are added sodium iodide (1 equivalent) and potassium carbonate and 3-t-butoxycarbonylaminopropyl tosylate (1.5 equivalent). The mixture is stirred at 50° C. for 6 hours, and thereto is added ethyl acetate. The mixture is washed with an aqueous saturated saline solution, dried over sodium sulfate. After distilling off the solvent, the residue is purified with a silica gel column chromatography to give 1-[5'-(3"-t-butoxycarbonylaminopropyloxy)-2'-nitrophenyl]-2-propen-1-ol (3.53 g) as pale brown caramel.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:7]=2[C:8]([O:10]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:19][NH:20][O:21][CH3:22].[Li]CCCC>>[CH:1]1([C:4]#[C:5][C:6]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:7]=2[C:8]([N:20]([CH3:19])[O:21][CH3:22])=[O:10])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(OC)cc1C#CC1CC1
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(C(=O)N(C)OC)c(C#CC2CC2)c1
Yield: 86 %

Procedure:
Treatment of methyl 2-(cyclopropylethynyl)-4-(methyloxy)benzoate (149) (0.49 g, 2.13 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.47 g (86%) of the title compound (150) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.70-0.90 (m, 4H), 1.40-1.50 (m, 1H), 3.28 (br s, 3H), 3.63 (br s, 3H), 3.80 (s, 3H), 6.83 (dd, J1=8.5 Hz, J2=2.6 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 260 (M+H)+.