Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:35][C@H:34]([CH3:36])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:37][OH:38]
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Reaction time: 3.5 h
Yield: 61.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k) and commercially available L-threoninol (0.57 g, 5.38 mmol) were dissolved in methanol (25 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (1.70 g, 5.38 mmol) was added at room temperature, followed by stirring for 3.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate (100 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-6%) to afford the desired compound (883 mg, 62%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:17]([C:18]([OH:20])=O)=[C:5]2[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:4]2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH2:51])([CH3:45])([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH:51][C:18]([C:17]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:8][C:7]([CH3:16])=[CH:6][C:5]=12)=[O:20])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1cc(OCCC(C)C)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 45 mg (0.163 mmol) of 2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 8A in 3 ml of tetrahydrofuran was admixed with 30 mg (0.177 mmol) of 1-hydroxybenzotriazole and 30 mg (0.177 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The resulting solution was stirred at room temperature for 15 min, and then 45.7 mg (0.212 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.85 ml (0.212 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for a further 18 h. The solvent was drawn off under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was removed and washed with water and aqueous sodium chloride solution, dried with a phase separation cartridge and dried further under reduced pressure, which gave 80 mg (61% of theory, 54% pure) of the target compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([NH:10][NH2:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1)[CH3:2].[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH2:1]([S:3][C:4]1[N:9]2[C:18]([CH3:19])=[N:11][N:10]=[C:8]2[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(NN)cc(-c2ccccc2)n1
Reactant: CCOC(C)(OCC)OCC
Product: CCSc1nc(-c2ccccc2)cc2nnc(C)n12

Procedure:
Using the method of Example 19, 2-ethylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethyl orthoacetate to provide 5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine which was recrystallized from a 50/50 mixture of ethyl acetate/cyclohexanes to provide white crystals of 5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 219.5°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(Cl)cnn1C
Yield: 1 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Fluorophenyl isocyanate in a similar manner to as described in Example 1.53, providing 0.5 mg (1%) of Compound 36: LCMS m/z (%)=377 (M+H37Cl, 40), 375 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.23 (s, 1H), 7.45 (dt, J1=12, J2=4, J3=2 Hz, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 7.17 (d, J=24 Hz, 1H), 7.15 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.03 (dd, J1=8 Hz, J2=4 Hz, 1H), 6.77 (d, J=2 Hz, 1H), 6.63 (td, J1=8 Hz, J2=4 Hz, 1H), 3.68 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O-:14])=[O:13])[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1CC(=O)[O-]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNc1ccccc1CC(=O)OC(C)C(=O)OCC

Procedure:
To a warm mixture of 7 g. sodium 2-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 2-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCCC1>[Cl:13][C:6]1[N:5]=[C:4]([NH:3][C:14](=[O:16])[CH3:15])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a suspension of sodium hydride (120 mg, 5 mmole) in tetrahydrofuran(10 ml), a solution of 2-amino-3-nitro-6-chloropyridine (870 mg, 5 mmole) in 20 ml of tetrahydrofuran (20 ml) was added. The reaction mixture was stirred at room temperature for 30 min. A solution of acetic anhydride (377 μl, 6 mmole) in tetrahydrofuran (10 ml) was added and stirred at room temperature overnight. The reaction mixture was quenched with water and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and washed with brine. The organic layer was dried with sodium sulfate and then concentrated under vacuo. The crude was purified by flash chromatography, eluting 78% hexane:22% ethyl acetate to give a yellow product (88 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[K].[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][S:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Yield: 66.8 %

Procedure:
0.98 g (0.006 mol) of 2-amino-4,6-dichloropyrimidine and 3.03 g (0.012 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the remaining ethyl acetate dissolved in the aqueous was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under section and washed with water. After drying there were obtained 1.37 g (67%) of N-[4-(2-amino-6-chloro-pyrimidin-4-yisulfamoyl)-phenyl]-acetamide as beige crystals; m.p.: 272-273° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][O:21][C:22](=[O:29])[C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)[CH:3]=1)([CH3:25])[C:22]([O:21][CH3:20])=[O:29]
Reactant: COC(=O)C(C)(C)N=C=O
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a solution of 4-(3-amino-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (4) (50 mg, 0.195 mmol) in dry DCM (10 ml) was added 2-isocyanato-2-methyl-propionic acid methyl ester (60 mg, 0.428 mmol). The resulting solution was stirred for 2 days, washed with water (3×10 ml), dried over sodium sulphate and concentrated in vacuo to yield a semi-crystalline solid (44 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:39][CH:36]3[CH2:38][CH2:37]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 90 °C
Yield: 54.7 %

Procedure:
To a solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (2173.mg, 4.61 mmol) in ethanol (36 mL) was added cyclopropanecarbaldehyde (0.53 mL, 6.91 mmol) and piperidine (0.23 mL, 2.3 mmol). The reaction was heated to 90° C. for 75 minutes, then cooled and concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with water and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (100 g column, 1%-7% MeOH/DCM) to provided 1.32 g (55% yield) of the title compound. LCMS m/z 524 (M+H)+.
Reaction SMILES: CO[C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[F:5].[C-:30]#[N:31].[Na+]>CN>[C:23]1([S:20]([C:4]([CH:6]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=4)[NH:9][C:8]=3[CH2:7]2)([F:5])[C:3]([NH:31][CH3:30])=[O:29])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: [C-]#N
Agent: CN
Agent: [Na+]
Product: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 289.5 %

Procedure:
To 400 mg (0.92 mmol) of (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester (from example 12) in a sealed tube were added 20 mL of methylamine (33% wt. solution in EtOH) and 13 mg (0.27 mmol, 0.3 eq) of sodium cyanide. The reaction mixture was stirred at 90° C. for 2 hours, and the solvent was evaporated. Column chromatography on silica gel with EtOAc yielded 340 mg (86%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS: 435 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1ccnc(S)n1
Product: Cc1ccnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)n1
Yield: 70 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-4-methylpyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 70% yield.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:37])([F:36])[C:12]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:33]([N:32]([CH2:31][C:12]([OH:30])([CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([F:37])([F:36])[F:10])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:34][CH3:35]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[O:23][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 8.55 (0.0515 moles) of 2,3,5,6-tetrafluorophenol, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 300 ml of absolute ethanol to give 11.36 g (73% yield) of purified 2-(2,3,5,6-tetrafluorophenoxy)-5-nitrobenzonitrile, mp 152.5°-154.5° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:14][C:15]1[C:24](F)=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>CN(C=O)C>[Cl:14][C:15]1[C:24]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Fc1ccc2cnccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(OC2CCC3(CC2)OCCO3)ccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
887 mg (5.61 mmol) 1,4-Dioxa-spiro[4.5]decan-8-ol were dissolved in 50 ml DMF and 224 mg (5.61 mmol) sodium hydride (60%) were added. After stirring for 30 minutes at room temperature, a solution of 815 mg (4.49 mmol) 5-chloro-6-fluoro-isoquinoline (8) in 10 ml DMF was added and the mixture was heated to 100° C. After 4 h one additional equivalent of 1,4-dioxa-spiro[4.5]decan-8-ol and sodium hydride were added and stirring was continued at 100° C. After 1.5 h complete conversion could be detected. For working up, the solvent was removed under reduced pressure, the residue was taken up in H2O and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The obtained orange oil (2.17 g) was stirred in diisopropyl ether and the insoluble white precipitate was filtered off. After drying of the precipitate, 549 mg of the title compound could be isolated. Rt=1.15 min (Method #1). Detected mass: 320.1/322.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[C@H:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][C@H:10]1[C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[C:16]([F:24])[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(F)c(F)c2ccoc12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCC[C@H]1c1cc(F)c(F)c2ccoc12

Procedure:
The title compound was prepared by treating trans-1-(tert-butoxycarbonyl)-3-methyl-4-(4,5-difluorobenzofur-7-yl)piperidine with 4N hydrochloric acid in dioxane essentially as described for the cis-isomer.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[O:15]1[C:19]2[C:20]([CH2:24]O)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1>>[O:15]1[C:19]2[C:20]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc2c1OCC2
Product: N#Cc1ccnc(-n2nccc2OCc2cccc3c2OCC3)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 2,3-dihydro-1-benzofuran-7-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.27 (2H, q, J=8.8 Hz), 4.68 (2H, q, J=8.8 Hz), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.86 (1H, q, J=7.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.22 (1H, d, J=7.2 Hz), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O2, 319. Found, 319.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[CH:12]=[C:11]([OH:17])[N:10]=1)[CH3:7].O.[OH-].[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[C:12]([Cl:4])=[C:11]([OH:17])[N:10]=1)[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1nc(O)cc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(O)c(Cl)c(CCl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.8 ml (0.035 mol) of sulphuryl chloride are added dropwise to a solution of 6 g (0.032 mol) of 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine in 90 ml of methylene chloride and the mixture is subsequently stirred at room temperature for 4 hours. The mixture is then treated with 100 ml of water and adjusted to pH 7 with 30% sodium hydroxide solution. The organic phase is separated and the combined organic phases are extracted with water, dried over anhydrous sodium sulphate and evaporated. There is obtained crystalline 2-ethoxy-5-chloro-4-chloromethyl-6-hydroxy-pyrimidine, 1H-NMR (CDCl3): 1.45 (t, OCH2CH3), 4.54 (q, OCH2CH3), 4.54 (s, CH2Cl), 9.80 (broad signal, OH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[CH3:23][C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1>CCO>[CH3:22][N:7]1[C:6]2=[C:5]3[CH:29]([C:27]4[O:28][C:24]([CH3:23])=[CH:25][CH:26]=4)[NH:1][CH2:2][CH2:3][N:4]3[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]2[C:10](=[O:19])[N:9]([CH3:20])[C:8]1=[O:21]
Reactant: Cc1ccc(C=O)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: CCO
Product: Cc1ccc(C2NCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
6-(2-Amino-ethyl)-1,3-dimethyl-5-phenyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (Intermediate A) (519 mg, 1.740 mmol) in EtOH (3 mL) was treated with 5-methylfuran-2-carbaldehyde (commercial) (0.173 mL, 1.740 mmol) and heated at 100° C. for 30 min using microwave irradiation. A further portion of 5-methylfuran-2-carbaldehyde (0.173 mL, 1.740 mmol) was added and heating continued at 100° C. for 10 min. The solvent was removed under reduced pressure and purification by chromatography on silica eluting with 40-80% EtOAc in iso-hexanes afforded the title compound as a yellow solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[N:6]#[C:7]Br.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:13]([NH:15][NH2:16])=[O:14].CCOC(C)=O>C(O)C>[NH2:9][C:10]1[CH:11]=[C:12]([C:13]2[O:14][C:7]([NH2:6])=[N:16][N:15]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cc(N)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(-c2nnc(N)o2)cc(C(F)(F)F)c1
Yield: 71.7 %

Procedure:
Add sodium bicarbonate (270 mg, 3.21 mmol) and cyanogen bromide (187 mg, 1.76 mmol) to the solution of 3-amino-5-(trifluoromethyl)benzohydrazide (400 mg, 1.6 mmol) in ethanol (5 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate the mixture, partition the residue between EtOAc and water, collect the organic layer, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to afford the crude product. Recrystallization in ethyl acetate yields the pure product (280 mg, 63%).