Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][S:23][C:22]=1[C:30](Cl)=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][S:23][C:22]=1[C:30]([NH:19][CH2:18][C:12]1[CH2:13][C@@H:14]([N+:15]([O-:17])=[O:16])[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH:11]=1)=[O:31]
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 3-chloro-4-methanesulfonyl-thiophene-2-carbonyl chloride (43 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (48 mg, 84%). 1H NMR (300 MHz, CDCl3) δ ppm 8.39 (s, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 7.17-7.25 (m, 2H), 5.82 (m, 1H), 5.04-5.17 (m, 1H), 3.98-4.19 (m, 3H), 3.18-3.21 (m, 3H), 2.51-2.95 (m, 3H), 2.16-2.35 (m, 1H). MS (ESI) m/z 523 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CCO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4-Fluoro-3-nitrobenzyl alcohol (3.17 g, 18.5 mmol) was suspended in EtOH, and a slurry of palladium on carbon (10 wt %, 317 mg) in EtOH was added. The flask was sealed with a septum, evacuated, and a H2 filled balloon was introduced via syringe and the reaction was stirred at RT overnight. The reaction mixture was then filtered through a pad of Celite, washed with EtOH and the filtrates concentrated in vacuo to afford a oil which upon scratching crystallised to give the title compound (2.56 g, 98%). 1H NMR (300 MHz, CDCl3): 4.57 (2H, s), 6.63-6.71 (1H, m), 6.77-6.84 (1H, m), 6.90-7.00 (1H, dd, J=8.2, 11.0 Hz). No OH or NH signals observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[S:10][C:3]=12
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Reactant: C1CCNC1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1

Procedure:
This material was prepared from the coupling of 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid and pyrrolidine in a manner as previously described for example 9d. 1H NMR (300 MHz, CD3OD) δ 8.60 (1H, d, J=5.1 Hz), 7.84 (1H, s), 7.32 (1H, d, J=5.1 Hz), 3.82 (2H, t, J=6.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 267. found 267.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[OH:22][CH:21]([C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CC(=O)OCC=C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)C#CC(=O)OCC=C(C)C)cc(OC)c1OC
Reaction time: 0.17 h

Procedure:
A solution of 6.6 g (4g mmol) of 3-methyl-2-butenyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 30 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.4 g (48 mmol) of 3,4,5-trimethoxybenzaldehyde in 80 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 1 hour, then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The organic phases were washed in succession with saturated sodium chloride solution and with water dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of 2-chloro-4-nitrobenzoic acid (20 g), thionyl chloride (40 ml) and DMF (5 drops) was stirred and heated to reflux for 1 hour. The mixture was evaporated to give 2-chloro-4-nitrobenzoyl chloride which was used without further purification.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[CH3:2].[NH2:18]O.Cl.O>CCO>[CH3:2][C:1]1[O:3][N:18]=[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=12
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1onc2c1CNCC2
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxopiperidine-1-carboxylate (1.50 g) and NH2OH.HCl (0.50 g) in anhydrous EtOH was heated to reflux for 0.5 h. The reaction mixture was cooled to rt, and then poured into 20 mL of water. The resulted mixture was extracted with CH2Cl2 (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.45 g, 52.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 139.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31 (s, 3H), 2.86 (t, J=8.0 Hz, 2H), 3.15 (t, J=8.0 Hz, 2H), 3.92 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1ccc(OCC(O)CO)cc1
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce N2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.38 (s, 1H), 9.18 (s, 1H), 8.98 (s, 1H), 8.12 (d, 1H, J=3.5 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=2.3 Hz), 7.12 (dd, 2H, J=2.3 and 8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 6.45 (d, 1H, J=8.8 Hz), 4.91 (d, 1H, J=5.3 Hz), 4.65 (t, 1H, J=5.8 Hz), 3.92-3.89 (m, 1H), 3.79-3.74 (m, 2H), 3.44 (t, 2H, J=5.3 Hz); LCMS: ret. time: 12.79 min.; purity: 89%; MS (m/e): 387 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccncc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccncc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.9 %

Procedure:
A mixture of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (539 mg, 1.25 mmol/g, 0.66 mmol) in DMF (8 mL) is shaken at room temperature for 15 min, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (398 mg, 3.75 mmol/g, 1.49 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-4-yl-pyrimidine-5-carboxylic acid phenylamide (15 mg, 16%) as solid. MS: 277 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:26]O>>[CH3:26][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:8](=[O:9])[C:7]2[CH:19]=[CH:20][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94 %

Procedure:
A solution of 4-(4-nitro-benzoyl)-benzoic acid (Dinsmore, Christopher J.; et al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345-1348) (4.00 g, 14.7 mmol) and sulfuric acid (1.2 mL) in MeOH (40 mL) was heated at reflux for 18 h. The mixture was filtered and after work-up gave 4-(4-nitro-benzoyl)-benzoic acid methyl ester as a yellow solid (3.97 g, 94%).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]([CH3:32])[C:19]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=2)=[CH:6][C:5]=1[O:33][CH3:34].[Li+].[OH-]>C1COCC1.CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[C:5]([O:33][CH3:34])[CH:6]=2)=[CH:12][C:13]=1[CH:18]([CH3:32])[C:19]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-methoxy-benzoic acid methyl ester (23 mg, obtained in Example 130, step 8) was dissolved in THF/methanol=5/1 (2.5 mL) followed by the addition of aqueous LiOH solution (1.0M, 0.074 mL). The mixture was stirred overnight at r.t. and then 1 hour at 50° C. The reaction mixture was cooled and evaporated. The residue was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The title compound was obtained as a colorless solid (14 mg, 63%) and was used without further purification. MS (neg. ion, m/e)=514.1 [(M−H)−].
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1([C:22]([F:25])([F:24])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1([C:22]([F:24])([F:25])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:36])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(C(F)(F)F)(C(F)(F)F)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C(F)(F)F)(C(F)(F)F)O2
Yield: 67.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 200 mg of 2,2-bistrifluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran and 210 mg of m-chloroperbenzoic acid (67%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 14 hours. Potassium carbonate solution was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 140 mg of 2-(2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 208°-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:18][C:19]([O:21]C)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:18][C:19]([OH:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cnc2c(OCc3ccccc3)ncnc21

Procedure:
Methyl (6-(Benzyloxy)purin-9-yl)acetate (2.10 g; 7.0 mmol) was dissolved in methanol (70 ml) and 0.1 M NaOH (85 ml) is added. After 15 min. the pH of the reaction mixture was lowered by addition of 0.1 M HCl (˜80 ml) to pH 3. The precipitate was separated from the mixture by filtration and washed with water and ether. Yield: 1.80 g (90.2%). 1H-NMR (DMSO-d6): 8.55 (1H, s); 8.37 (1H, s); 7.55-7.30 (5H, m); 5.64 (2H, s); 5.09 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCNC5)s4)c(Cl)cnc32)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCN(C)C5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ambient solution of 3-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)pyrrolidin-3-ol (Example 117D) (410 mg, 0.682 mmol) in tetrahydrofuran (10 mL) was added formaldehyde (0.254 mL, 3.41 mmol, 37 wt % in water) and acetic acid (0.195 mL, 3.41 mmol). The reaction was stirred at room temperature for 20 minutes, and sodium triacetoxyborohydride (0.723 g, 3.41 mmol) was added in a single portion. The reaction was stirred at room temperature for 1 hour and was quenched by the addition of water and chloroform. The layers were separated, and the aqueous layer was extracted with additional chloroform (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purifed by flash column chromatography on silica gel, wluting with a gradient of 0 to 8% methanol (containing 1% v/v ammonium hydroxide) in dichloromethane, to give the title compound. MS APCI(+) m/z 614.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:5])=[O:4].[C:13](Br)([Br:16])([F:15])[F:14]>CN1CCCC1=O>[Br:16][C:13]([F:15])([F:14])[O:12][C:11]1[C:6]([N+:3]([O-:5])=[O:4])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: FC(F)(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ncccc1OC(F)(F)Br
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To a stirred solution of sodium hydride (856 mg, 21.41 mmol) in N-methylpyrrolidinone (20 mL) was added a solution of 2-nitropyridin-3-ol (2 g, 14.28 mmol) in N-methylpyrrolidinone (10 mL). The reaction mixture was stirred at 20° C. for 30 min followed by heating at 50° C. for another 30 min before cooling to 20° C. CF2Br2 (4.49 g, 21.41 mmol) was added dropwise and the resulting mixture was stirred at 20° C. for 18 h. Then CF2Br2 (8.99 g, 42.83 mmol) was added dropwise and the mixture was stirred at 20° C. for another 18 h. The reaction mixture was slowly quenched into saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 15% ethyl acetate in petroleum ether) affording product (890 mg, 23%): 1H NMR (400 MHz, chloroform-d) δ 8.53-8.51 (m, 1H), 7.99-7.97 (m, 1H), 7.72-7.69 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2Cl)=[CH:4][CH:3]=1.[OH2:16].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=2[OH:16])=[CH:4][CH:3]=1
Reactant: O
Reactant: Fc1ccc(-c2nnc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Oc1cc(Cl)nnc1-c1ccc(F)cc1
Yield: 67.5 %

Procedure:
3-(4'-Fluorophenyl)-4,6-dichloropyridazine (145.84 g, 0.600 mol) was dissolved in dioxane (800 ml) at 60° C., water (300 ml) was added, and the solution was refluxed. Sodium hydroxide solution (48 g of solid NaOH, dissolved in 300 ml of water) was then added dropwise in the course of half an hour, and the mixture was kept under reflux for a further 5 hours. The mixture was then evaporated to dryness in vacuo, the residue was dissolved in hot water (5 l), insoluble particles were filtered off, and the solution was brought to pH 1 using concentrated hydrochloric acid. The solid obtained was isolated, washed with water and dissolved in dilute ammonia (8 l of water, pH 9-10) for further purification. Small amounts of 3-(4'-fluorophenyl)-4-chloro-6-pyridazinone were then selectively precipitated by carefully adding hydrochloric acid and then removed (by filtration), and the main bulk was then precipitated out (up to pH 1). The solid product obtained was isolated, washed with water and dried to constant weight. 91.0 g (0.4051 mol) of 3-(4'-fluorophenyl)-4-hydroxy-6-chloropyridazine of m.p.=254°-260° C. (point of decomposition) were obtained, which corresponds to a yield of 67.5% of theory.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>C1COCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:12])([F:11])[F:3])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2.45 g (61.2 mmol) of sodium hydride was introduced to 15 ml of THF and cooled to 5° C., and then 10.6 g of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise thereto. The resulting solution was stirred at 5° C. for 30 minutes, and then 5.0 g of 2-chloro-5-nitropyridine dissolved in 10 ml of THF was added dropwise thereto and stirred at room temperature for 3 hours. The reaction solution was allowed to stand at room temperature for 3 days, the water was added thereto, and the mixture was extracted with ethyl acetate and then washed with saturated salt water. The resultant was dried over anhydrous magnesium sulfate, and then the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane AcOEt=10:1) to obtain 8.4 g of the desired product (Yield: 92%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=O)([O:39]C1C=CC([N+]([O-])=O)=CC=1)[O:9][C@@H:10]1[CH2:14][C@H:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24]([S:27]([C:30]5[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[C@H:12]([CH2:37][CH3:38])[CH2:11]1>CN(C1C=CN=CC=1)C.O1CCOCC1>[C:2]1([NH:1][C:8](=[O:39])[O:9][C@@H:10]2[CH2:14][C@H:13]([C:15]3[N:19]4[C:20]5[CH:26]=[CH:25][N:24]([S:27]([C:30]6[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=6)(=[O:29])=[O:28])[C:21]=5[N:22]=[CH:23][C:18]4=[N:17][N:16]=3)[C@H:12]([CH2:37][CH3:38])[CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H]1C[C@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](OC(=O)Nc2ccccc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To aniline (0.063 g, 0.677 mmol) and DMAP (0.033 g, 0.271 mmol) in 1,4-dioxane (1 mL) at about 40° C. was added a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.080 g, 0.135 mmol, prepared from Example #42 Step N) in 1,4-dioxane (1 mL). After about 2 h, the solvent was removed and the residue was purified by silica gel chromatography (12 g) eluting with 0-40% EtOAc in DCM to give (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl phenylcarbamate (0.0468 g, 63%): LC/MS (Table 1, Method b) Rt=2.58 min; MS m/z: 545 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][C:14](=[O:16])[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12.[CH3:17][Mg]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:13][C:14]([CH3:17])([OH:16])[CH2:15]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[C:6]=12
Reactant: C[Mg]Cl
Reactant: O=C1CC(c2nc(Br)c3c(Cl)nccn23)C1
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (51.988 g, 0.17 mol) in anhydrous THF (550 g, 620 mL) under nitrogen at −78° C. was treated with a 3.0 M solution of methyl magnesium chloride in THF (130 mL, 0.38 mol) over 30 min. The mixture was stirred at −78° C. for 30 min and then the cooling bath was removed and the mixture quenched with 14% NH4Cl (132 g). EtOAc was added to the aqueous phase and the pH was adjusted to ˜5 with 20% HCl and the layers separated. The combined organic phases were concentrated in vacuo to a slurry and 0.5 L of toluene was added and the mixture concentrated in vacuo until the EtOAc was removed. The slurry was heated at reflux until homogeneous then allowed to cool to provide desired product, which was isolated by filtration and dried in vacuo. 1H NMR (DMSO-d6, 400 MHz): δ 1.37 (s, 3H), 2.35-2.49 (m, 4H), 3.52 (dddd, 1H, J=9.6, 9.6, 9.6, 9.6 Hz), 5.18 (bs, 1H), 7.37 (d, 1H, J=5.2 Hz) and 8.26 (d, 1H, J=5.2 Hz).