Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=4)[CH2:21][CH2:22]OS(C)(=O)=O)=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[N:38]([CH2:22][CH2:21][C@H:20]([NH:19][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:18])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc([C@H](CCN=[N+]=[N-])NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 72 h

Procedure:
To a room temperature solution of methanesulfonic acid (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester (122 mg, 0.223 mmol) in DMF (2 mL) was added sodium azide (19 mg, 0.29 mmol). After 72 hours, the reaction was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The mixture was passed through a plug of silica gel eluting with a gradient of 0-5% methanol in dichloromethane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3-azido-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide which was used without further purification.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>N([O-])=O.[Na+].O>[Cl:7][C:6]1[C:1]([N+:16]([O-:18])=[O:17])=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 250-ml flask, place 17.0 g (0.1 m) of chlorzoxazone (1b; X=Cl), 50 ml of acetic acid, and 0.14 g of sodium nitrite. Warm and stir the slurry to 50° C. Add 11.3 g (0.125 m) of concentrated nitric acid (70%) and stir the mixture at 55°-63° C. for 5 hrs. Add 100 ml of hot water, cool to room temperature and let it stand overnight. Collect solid, wash with water, and dry in air to give 18.7 g (87%) of 5-chloro-6-nitro-benzoxazol-2-one (2b; X=Cl) as pale yellow solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH:7]=[C:6]([CH:13]=O)[C:5]2=[O:15].Cl.NO.C([NH2:21])=O.[Na]>C(O)=O>[C:13]([C:6]1[C:5](=[O:15])[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[O:8][CH:7]=1)#[N:21]
Reactant: O=Cc1coc2c(Cl)cc(Cl)cc2c1=O
Reactant: NC=O
Agent: Cl
Agent: NO
Agent: [Na]
Solvent: O=CO
Product: N#Cc1coc2c(Cl)cc(Cl)cc2c1=O
Reaction time: 18 h

Procedure:
15 g of 6,8-dichlorochromon-3-aldehyde, 5.43 g of hydroxylamine hydrochloride, 7.55 g of sodium formamide and 100 ml of formic acid are mixed at room temperature and refluxed for 4 hours. After a further 18 hours at room temperature, the precipitate is separated and the filtrate is poured into 1 l of water. The resulting precipitate is filtered off and washed twice with water and twice with ethanol to obtain the heading compound, m.p. 150°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15](OC)=[O:16])[CH:10]=1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: COC(=O)c1cc(OC)ccn1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1ccnc(CO)c1
Yield: 35.6 %

Procedure:
A solution of lithium aluminium hydride (1M in diethyl ether, 16 ml) was added dropwise to a stirred mixture of methyl 4-methoxypyridine-2-carboxylate (2.7 g) and diethyl ether (50 ml). The resultant mixture was heated to reflux for 1 hour. The mixture was treated with potassium sodium tartrate tetrahydrate and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent to give 4-methoxypyrid-2-ylmethanol (0.8 g);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[C:20]1(=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=[O:30])[CH2:22][O:21]1.N1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11](/[CH:14]=[C:22]3\[O:21][C:20](=[O:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]\3=[O:30])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1COC(=O)c2ccccc21
Reactant: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Solvent: C1COCCN1
Solvent: O
Solvent: CC(=O)O
Product: O=C1O/C(=C\[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the resulting stirred mixture from stage 1, at ambient temperature under argon, was added acetic acid (250 mL), 1H-2-benzopyran-1,4(3H)-dione (compound of formula (III)) (32.4 g, 200 mmol) and morpholine (17.5 mL, 200 mmol). The reaction mixture was heated to 40° C. for 4 hours then allowed to cool to ambient temperature and stir overnight. Water (250 mL) was added and the slurry stirred for 15 minutes at ambient temperature then filtered. The filter cake was washed twice with tert-butyl methyl ether (2×125 mL) and dried to give the title compound as a yellow solid (62.4 g). The material obtained was spectroscopically identical to that obtained in Stage 2, Example 3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1B(O)O)(=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:30])[CH3:29]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 50.9 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 224c (200 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), sodium acetate (74 mg, 0.90 mmol), K3PO4 (191 mg, 0.90 mmol), and acetonitrile/water (6:1, 3.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 224d (180 mg, 51%) as a brown solid. MS-ESI: [M+H]+ 708.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH:23]([CH3:25])[CH3:24])[C:11](=[O:26])[C:10]=2[C:27]([OH:29])=O)=[CH:5][CH:4]=1.Cl.[CH3:31][NH2:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH:23]([CH3:25])[CH3:24])[C:11](=[O:26])[C:10]=2[C:27](=[O:29])[NH:32][CH3:31])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(C(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(C(C)C)c1=O
Yield: 92.3 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isopropyl-2H-pyridazin-3-one and methylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 92.3%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O[C:27]1[CH:31]=[CH:30][O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][C:27]5[CH:31]=[CH:30][O:29][N:28]=5)[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (3.52 g, 10 mmol), 3-hydroxyisoxazole (893 mg, 10.05 mmol), and triphenylphosphine (3.03 g, 12 mmol) were dissolved by stirring in dry tetrahydrofuran (75 ml) under nitrogen. The mixture was cooled in an ice-bath, and diisopropylazodicarboxylate (2.33 g, 12 mmol) added dropwise over 10 minutes. The solution was stirred 18 hours, allowing the temperature to rise to ambient. The mixture was diluted with EtOAc (750 ml). the organic layer washed with water (3×500 ml), dried (magnesium sulfate) and evaporated. The residue was purified by MPLC on silica, eluting with a gradient between 0.25% and 1% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give product (3.58 g).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1>C(O)C>[OH:10][CH2:11][CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:2](=[S:3])[NH:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C=Nc1cccnc1
Reactant: OCCC1Cc2ccccc2CN1
Solvent: CCO
Product: OCCC1Cc2ccccc2CN1C(=S)Nc1cccnc1
Reaction time: 5 h
Yield: 80.5 %

Procedure:
3-Isothiocyanatopyridine (2.6 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (3.3 g) in ethanol (40 cc). A white precipitate forms after 5 hours; stirring is continued for 12 hours at a temperature of about 20° C. The crystals which have appeared are filtered off and washed with diethyl ether (2×5 cc). (RS)-3-(2-Hydroxyethyl)-N-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (4.7 g), melting at 174° C., is thus obtained.
Reaction SMILES: B(Br)(Br)Br.ClC1N(C)N=C(C)C=1S([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2([C:33]3[CH:38]=[C:37]([Cl:39])[N:36]=[C:35]([Cl:40])[CH:34]=3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:32])=[N:24]2)[CH:18]=1)(=O)=O>ClCCl>[NH2:32][C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:19]2[CH:18]=[C:17]([OH:16])[CH:22]=[CH:21][CH:20]=2)([C:33]2[CH:34]=[C:35]([Cl:40])[N:36]=[C:37]([Cl:39])[CH:38]=2)[N:24]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Oc1cccc(C2(c3cc(Cl)nc(Cl)c3)N=C(N)c3ccccc32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=NC(c2cccc(O)c2)(c2cc(Cl)nc(Cl)c2)c2ccccc21
Reaction time: 6 h
Yield: 50.7 %

Procedure:
Boron tribromide (0.229 mL, 2.42 mmol) was added to a solution of 1-(2,6-dichloropyridin-4-yl)-1-(3-methoxyphenyl)-1H-isoindol-3-amine (Scheme #19, C, 0.62 g, 1.61 mmol) in dry dichloromethane (40 mL) at 0° C. The reaction was aloud to reach room temperature and stirred for 6 h. The reaction was quenched by addition of saturated aqueous sodiumhydrogen carbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. Purification by flash chromatography using ethyl acetate afforded 0.302 g (51% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.86-7.77 (m, 2 H), 7.53-7.46 (m, 2 H), 7.37 (s, 2 H), 7.07 (t, J=7.83 Hz, 1 H), 6.96 (br s, 2 H), 6.72-6.58 (m, 3 H); MS (API) m/z 370 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])([CH3:8])[C:3](OCC)=[O:4].[Cl-].[OH:30][NH3+:31].[OH-].[K+]>CO>[CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])([CH3:8])[C:3]([NH:31][OH:30])=[O:4]
Reactant: [NH3+]O
Reactant: CCOC(=O)C(C)(C)OCCCCCCc1nc(-c2ccc(C)cc2)oc1C
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C(=O)NO)c(C)o2)cc1
Yield: 104.8 %

Procedure:
To 20 ml of a solution of 4.84 g of ethyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate in methanol, 3.47 g of hydroxylammonium chloride was added, and then 12.5 ml of solution of 5 M potassium hydroxide in methanol was added dropwise slowly under ice-cooling with stirring. The ice-bath was removed and the mixture was stirred for 36 hours at room temperature. The reaction solution was concentrated. The residue was acidified with 50% aqueous acetic acid solution, water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine serially, dried over anhydrous magnesium sulfate and concentrated. The residue was concentrated after addition of toluene, and again concentrated after addition of ethanol to provide 4.90 g of the objective compound as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14])(=[O:32])[CH3:31]
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)c2nc(C)nc3ccc(NC(C)=O)cc23)cc1

Procedure:
The title compound was prepared from (6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (30 mg, 0.102 mmol), triethylamine (0.021 ml, 0.153 mmol), acetyl chloride (0.011 ml, 0.153 mmol) and DMAP (1 mg) in 5 ml of dichloromethane similar to example 28 to give 3 mg (9%) of paint brown solids. 1H NMR (CDCl3): 7.71 (s, 2H), 7.19 (s, 1H), 7.12-7.09 (m, 2H), 6.93-6.91 (m, 3H), 3.84 (s, 3H), 3.56 (s, 3H), 2.71 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]#[N:13].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>O>[CH3:11][N:10]1[C:6]([C:2]2[O:1][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=2)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]1
Reactant: O=[N+]([O-])O
Reactant: Cn1ncc(C#N)c1-c1ccco1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1ncc(C#N)c1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Yield: 80 %

Procedure:
Add 1.0 g of 5-(2-furyl)-1-methylpyrazole-4-carbonitrile to 4.1 ml of concentrated sulfuric acid at from -10° C to -12° C and, at the same temperature, slowly add a nitrating mixture (0.91 ml of concentrated sulfuric acid and 0.45 ml of fuming nitric acid) dropwise to the resulting reaction mixture for 1 hour at this temperature, and then pour the prepared solution onto 20 g of ice and water. Crystallize the thus-prepared precipitate in an ice-bath to obtain an 80% yield of 1-methyl-5-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 149.5° to 151.5° C].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14](OCC)=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[BH4-].[Na+].O.C(Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 20 °C
Reaction time: 10 h
Yield: 35.4 %

Procedure:
To a solution of ethyl 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetate (2 g, 4.45 mmol) in ethanol (20 mL) was added sodium borohydride (1.683 g, 44.5 mmol). The reaction mixture was stirred at 20° C. for 10 hr. To the reaction mixture was added 50 mL of H2O and 50 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure. The crude product was added to a prep HPLC column eluting with MeCN/TFA 0.1% to provide 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)ethanol (500 mg, 25.5%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:17][CH:16]=1
Reactant: Nc1nccs1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccccc2F)nc1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.25 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 29.9 mg (0.3 mmol) of 2-aminothiazole. Yield: 16 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([O:22]C)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>Br>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([OH:22])[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(O)c3O2)cc1

Procedure:
Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (22.1 g, 0.06 mol) with hydrogen bromide (30 wt. % in acetic acid, 400 mL) followed by potassium carbonate (4.15 g, 0.03 mol) provided (±)-(5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a brown oil. Treatment of the phenyl with sodium hydride (3.2 g, 0.053 mol) and allyl bromide (6.4 g, 0.053 mol) generally according to the procedure described for Intermediate 37 afforded (±)-[7-(allyloxy)-5-chloro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the allyl ether in refluxing mesitylene (250 mL) generally according to the procedure described for Intermediate 1 afforded 4.5 g (19%) of (±)-(6-allyl-5-chloro-7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid. mp 128-131° C.; Anal. calcd. for C19H19ClO5S: C, 57.79; H, 4.85. Found: C, 58.28; H, 4.68.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:29][C:13]2=[CH:14][C:15]3[C:16](=[O:28])[N:17]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][C@@H:42]([NH2:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)CCC>[O:8]=[C:4]1[C:3]([C:10]2[NH:11][C:12]3=[CH:20][C:19]4[C:18](=[O:21])[N:17]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)[C:16](=[O:28])[C:15]=4[CH:14]=[C:13]3[N:29]=2)=[C:2]([NH:44][C@@H:42]([CH3:43])[CH2:41][C:33]2[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=2[F:31])[CH:7]=[CH:6][NH:5]1
Reactant: C[C@H](N)Cc1c(F)c(F)cc(F)c1F
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1cccnc1)C3=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: C1COCCO1
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1cccnc1)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
2-(4-Chloro-2-methoxypyridin-3-yl)-6-(pyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.60 g, 1.48 mmol) was dissolved in 10 mL of 1,4-dioxane and 5 mL of concentrated HCl at rt. The reaction mixture was stirred at rt overnight. Then, the volatile was removed to give a yellow-brown solid. This solid was mixed with (S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.46 g, 2.22 mmol), N,N-diisopropylethylamine (1.32 mL, 7.40 mmol) and n-butanol (30 mL) in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Then, volatiles were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow-brown solid product, 0.65 g, 78.3% yield. MS: 560.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.48 (s, 1H), 11.35 (d, 1H, J=4.5 Hz), 10.91 (d, 1H, J=8.0 Hz), 8.73-8.72 (m, 1H), 8.63-8.61 (m, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.95 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz), 7.77-7.70 (m, 1H), 7.62-7.58 (m, 1H), 7.41 (t, 1H, J=4.5 Hz), 6.18 (d, 1H, J=7.5 Hz), 4.25 (m, 1H), 3.18-3.10 (m, 2H), 1.93 (d, 3H, J=6.0 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: O=C/C=C/c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-imidazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:11]#[N:12])=[C:6]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(Oc2ccccc2)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1Oc1ccccc1
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a stirred suspension of 270 mg (0.98 mmol) 2-amino-4-methanesulfinyl-6-phenoxy-pyrimidine-5-carbonitrile in 10 ml DME were added 0.33 ml (3.45 mmol) 2-(hydroxymethyl) pyridine and 0.22 ml (1.48 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 40 mg (13%) 2-amino-4-phenoxy-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 320 (M+H+, 100).