Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1.[CH3:31][O-:32].[Na+]>CO>[OH:1][CH:2]([CH2:22][O:23][C:24]1[C:29]([O:32][CH3:31])=[N:28][CH:27]=[CH:26][N:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[CH2:6][CH2:5]1
Reactant: C[O-]
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1OCC(O)CN1CCC(N2CCN(c3ccccc3)C2=O)CC1

Procedure:
With stirring, 10.1 g of 1-{1-[2-hydroxy-3-(3-chloropyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one (see Example 6) and 1.41 g of sodium methylate in 110 ml of methanol are refluxed for 10 hours. The reaction mixture is concentrated in a water jet vacuum. The residue is dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried over sodium sulphate and concentrated in a water jet vacuum. The residue crystallises from methylene chloride-ether to yield 1-{1-[2-hydroxy-3-(3-methoxy-pyrazin-2-yloxy)-propyl]-4-piperidinyl} -3-phenyl-imidazolidin-2-one with a melting point of 128°-129° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1.Cl.N([O-])=[O:15].[Na+]>O>[OH:15][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1
Reactant: COCc1nc(N)nc(O)c1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COCc1nc(O)nc(O)c1C
Temperature: 70 °C
Yield: 55.1 %

Procedure:
2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine (2.7 g, 16 mmol) was added to 20% aqueous hydrochloric acid solution (7 ml), and heated to 70° C. A solution of sodium nitrite (2.3 g, 33.3 mmol) in water was added dropwise to a reaction mixture while maintaining the reaction temperature under 70° C. The reaction mixture was cooled to a room temperature. The resulting solid was filtered and dried to give 1.5 g of the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[CH:26]2[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]12.[Na]>CN(C)C=O>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[CH:26]3[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[CH:26]2[CH:30]=[CH:31][CH2:32][CH2:33][CH:25]12
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: O=C1NC(=O)C2CCC=CC12
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1C2C=CCCC2C(=O)N1CCOC(OCCN1C(=O)C2C=CCCC2C1=O)(C(=O)c1ccccc1)c1ccccc1
Yield: 87.6 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 11.42 g of sodium 1,2,5,6-tetrahydrophthalimide were dissolved in 100 ml of N,N-dimethylformamide, and reacted and worked up in the same way as in Example 4. There was obtained 15.3 g (yield 85.9%) of benzil-di-(β-1,2,5,6-tetrahydrophthalimidoethyl)ketal.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[Li+].[OH-:32].Cl>O1CCOCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:29])([F:30])[F:28])(=[O:32])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (15.0 mg, 0.036 mmol) in dioxane (1 mL) was added 1 M LiOH (aq) (3.0 mL). The reaction was stirred at 50° C. for 48 h. 1 M HCl (aq) was added until pH=3. The mixture was extracted with EtOAc. The organic extract was dried over MgSO4 and purified by preparative HPLC/MS to give the title compound as a solid (3.1 mg). LCMS m/z=433.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14-2.27 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz, 1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.63 (m, 1H), 3.90-4.00 (m, 1H), 4.04-4.15 (m, 1H), 5.21 (s, 2H), 6.01 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.49-7.60 (m, 2H), 7.75 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 12.28 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3B1OC(C)(C)C(C)(C)O1.I[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1.[OH-].[Ba+2].[OH-]>C(#N)C.O.Cl>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1
Reactant: Cc1csc(I)n1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,3-dimethyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (step 5) (295 mg, 0.66 mmol), 2-iodo-4-methylthiazole (Intermediate O) (135 mg, 0.60 mmol), Pd-118 (19.6 mg, 0.03 mmol) and barium hydroxide (206 mg, 1.20 mmol) in acetonitrile/water (1:1, 3 mL) was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with 1M HCl (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were filtered through a hydrophobic frit and the solvent was removed under vacuum. The residue was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to give the title compound.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH3:21][O:22][CH2:23][CH2:16][CH2:15][S:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCSC1CCN(C(=O)O)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[O:7])=[C:4](F)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[O:7])=[C:4]([O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=2[O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(F)ccc1O
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2Oc2ccc(F)cc2OC)cn1
Temperature: 70 °C

Procedure:
Methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (50 mg, 0.14 mmol), 4-fluoro-2-methoxy-phenol (18.27 μL, 0.16 mmol) and K2CO3 (60.41 mg, 0.44 mmol) were combined in DMF (0.5 mL) and heated at 70° C. for 1.5 hours to form methyl 5-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxylate. Aqueous NaOH (145.7 μL of 3 M, 0.44 mmol) was then added and heating continued for 30 min. HPLC purification (1-99% CH3CN/5 mM HCl) provided 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) (35.28 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.75 (s, 3H) ppm. ESI-MS m/z calc. 450.02, found 451.1 (M+1)+; Retention time: 1.61 minutes (3 minutes run).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: FC(F)(F)c1cncc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C#CC=C2CCN(c3cncc(C(F)(F)F)c3)CC2)n1
Temperature: 160 °C
Yield: 1.3 %

Procedure:
A vial was filled with a mixture of the compound of Example 3 (84.9 mg, 0.4 mmol), 3-bromo-5-(trifluoromethyl)pyridine (93 mg, 0.4 mmol), DIPEA (140 μL, 0.8 mmol), 1 mL of anhydrous N-methylpyrrolidone and sealed. The vial was heated in a microwave oven at 160° C. (200 W) for 2 h. The reaction mixture was then cooled to r.t., diluted with EtOAc, washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude black oily residue was purified by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording 1.8 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH:24]1([NH:30][C:22]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:21]=2)=[N:6][C:7]2[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(NC4CCCCC4)c(F)cc3cc2c1=O

Procedure:
Ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 4, but from 3 g of ethyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate and 2.2 cm3 of cyclohexylamine in 30 cm3 of dimethyl sulphoxide. After filtering 2 times with 15 cm3 of ethanol, 3.3 g of ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15]OCC2)=[C:6]([NH:8][C:9]#[N:10])[CH:7]=1.[CH3:17][NH:18][CH3:19].[CH2:20]([OH:22])[CH3:21]>>[CH3:17][N:18]([CH3:19])[C:9]([NH2:10])=[N:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH2:15][O:22][CH2:20][CH2:21]1
Reactant: CCO
Reactant: CNC
Reactant: N#CNc1cc(Cl)ccc1N1CCOCC1
Product: CN(C)C(N)=Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 272, N-(5-chloro-2-morpholinophenyl)cyanamide (2.3 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) were heated under reflux for 4 hours to give 1,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine (m.p. 135°-138° C.) which was recrystallised from hexane and then was converted into its monofumarate salt (m.p. 223°-225° C.) which was recrystallised from methanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pt](=O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C/C=C/C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: N#CCCC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A mixture of (E)-3-(1-benzylpiperidin-4-yl)-2-propenenitrile (5.5 g) and platinum(IV) oxide (0.5 g) in methanol (70 ml) was hydrogenated at atmospheric pressure for 8 hours. After platinum(IV) oxide was removed by filtration, the filtrate was evaporated in vacuo to give 3-(1-benzylpiperidin-4-yl)propanenitrile (2.7 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(C)(O)C1CCNCC1
Solvent: CO
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(C)(C)O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A solution of N-(7-chloro-pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 2-(piperidin-4-yl)propan-2-ol (130 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (105 mg, 41%). 1H NMR (METHANOL-d4) δ: 8.00 (d, J=2.3 Hz, 1H), 7.95 (d, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.39 (s, 1H), 6.33 (d, J=1.5 Hz, 1H), 4.59 (d, J=11.6 Hz, 2H), 2.97 (t, 2H), 1.95 (d, J=9.1 Hz, 2H), 1.61-1.69 (m, 3H), 1.56 (s, 6H), 1.21 (s, 6H). ESI-MS: m/z 438.0 (M+H)+.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21](Cl)([CH3:23])[CH3:22].O>CCOCC>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21]([CH:4]1[CH:3]=[CH:2][CH:1]=[CH:5]1)([CH3:23])[CH3:22]
Reactant: C1=CCC=C1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C=CC=C1
Temperature: 0 °C

Procedure:
To a solution of 1.32 g (20.0 mmol) of freshly distilled cyclopentadiene in 120 ml of ether, 8.00 ml of 2.5 M (20.0 mmol) nBuLi in hexanes was added dropwise, while vigorously stirring, at 0° C. This mixture was stirred for 2 h at room temperature, and then 6.03 g (20.0 mmol) of (4-bromo-2-methyl-1H-inden-1-yl)(chloro)dimethylsilane was added dropwise over 30 min at −80° C. The resulting mixture was stirred for 1 h at this temperature, for 12 h at room temperature, and then 100 ml of water was added. The organic layer was separated. The aqueous layer was extracted with 2×100 ml of dichlorodimethylsilane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. The product was isolated using flash-chromatography on Silica Gel 60 (40-63 um, d 30 mm, 1 300 mm, eluent: hexanes). Yield 5.50 g (83%) of colorless oil of a mixture of isomers I, II, and III.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:25][C:26]1[C:31]([F:32])=[C:30](F)[CH:29]=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35]>C(OCC)(=O)C>[F:32][C:31]1[C:26]([F:25])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=[CH:29][C:30]=1[O:11][C:8]1[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(F)c2F)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
112 mg of 6-methanesulfonyl-pyridin-3-ol and 100 mg of potassium carbonate were added to an N-methylpyrrolidinone (3 ml) solution of 135 mg of 2,3,4-trifluoro-nitrobenzene, and the reaction liquid was stirred at 50° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15]O)[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[N:48]1C(=O)CC[C:49]1=O.C([Na])#N>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:14][CH2:13][C@H:12]([CH2:15][C:49]#[N:48])[NH:11][C:10]3[N:17]([CH3:26])[N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:9]2=3)=[C:4]([CH3:27])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1[C@H]1SC[C@H](CO)Nc2c1c(-c1ccccn1)nn2C
Agent: N#C[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H]1SC[C@H](CC#N)Nc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a solution of rac-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)methanol (0.070 g, 0.16 mmol, Example #K.10) and triphenylphosphine (0.041 g, 0.16 mmol) in DCM (5 ml)/DMF (0.5 ml) at 0° C. was added 1-bromopyrrolidine-2,5-dione (0.028 g, 0.16 mmol). The reaction was stirred at 0° C. for about 2 h. The reaction was partitioned between DCM (25 mL) and saturated solution of NaHCO3 (40 mL). The organic layer was dried with Na2SO4, filtered and was concentrated in vacuo. The resulting residue was dissolved in DMF (1.5 ml) and cyanosodium (0.077 g, 1.57 mmol) was added. The reaction was heated at about 100° C. for about 1 h. The reaction was partitioned between EtOAc (25 mL) and brine (25 mL). The organic layer was washed with brine (25 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to give rac-2-((4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-yl)acetonitrile (0.005 g, 0.005 mmol, 3%) as a white solid: LC-MS (Table 1, Method g): LC-MS (Table 1, Method g) Rt=2.57 min, m/z 454/456 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.48-8.45 (m, 1H), 7.83-7.80 (m, 1H), 7.75-7.70 (m, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.74 (s, 1H), 6.19 (d, J=5.7 Hz, 1H), 4.03-3.92 (m, 1H), 3.77 (s, 3H), 2.95-2.85 (m, 2H), 2.79-2.74 (m, 1H), 2.71-2.63 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.FC1CNC1.C([N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:36]2[CH2:37][CH2:39][CH2:42][CH2:40]2)=[O:27])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: FC1CNC1
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 88.6 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), 3-fluoroazetidine hydrochloride (202 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue (772 mg) is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording 1-methyl-N-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (152 mg, 88.7%) as a white solid. mp.: 210-2° C. MS: m/z=429.4 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](Cl)=[O:24]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:21][C:19]1[CH:20]=[CH:15][C:16]([CH:22]2[C:23](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8]2)=[CH:17][CH:18]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2OC1c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
To a solution of 2-aminophenol (13.5 g) in ethyl acetate (150 ml) is added a solution of sodium hydrogen carbonate (15 g) in water (300 ml), and to the mixture is added dropwise a solution of o-bromo-4-chlorophenylacetyl chloride (32.2 g) in toluene with vigorous stirring under ice cooling. After the mixture is stirred at room temperature for one hour, the solvent in the organic layer is distilled off and the residue is dissolved in acetone. To the solution is added potassium carbonate (20 g), and the mixture is stirred at room temperature overnight. The solvent is distilled off and to the residue is added water. The mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(4-chlorophenyl)-3-oxo-3,4-dihyro-2H-1,4-benzoxazine (24.0 g) as crystals. M.p. 180.5°-181.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[S:15]([OH:18])(=O)=[O:16].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl-:21].[Cl:21][S:15]([C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[NH:6][CH:3]=[N+:2]([CH3:5])[CH3:1])(=[O:18])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CN(C)C=O
Reactant: COc1ccc(N)c(S(=O)(=O)O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(NC=[N+](C)C)c(S(=O)(=O)Cl)c1
Product: [Cl-]
Temperature: 70 °C

Procedure:
Dimethylformamide (0.152 mol) is added dropwise to a suspension of 2-amino-5-methoxybenzenesulphonic acid (0.152 mol) in thionyl chloride (0.763 mol). The reaction mixture is heated very gradually to 70° C. and is maintained at that temperature for 1.5 hours. After cooling, the stirred reaction solution is treated by the addition of 20 ml of toluene. A precipitate is formed which is rapidly filtered off, rinsed with toluene and then dried at 40° C. in vacuo in the presence of KOH pellets, to yield the title product.