Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:54])([F:53])[C:46]1[CH:47]=[C:48]([NH2:52])[CH:49]=[N:50][CH:51]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:48]3[CH:49]=[N:50][CH:51]=[C:46]([C:45]([F:54])([F:44])[F:53])[CH:47]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cncc(C(F)(F)F)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-trifluoromethyl-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=424.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[N:7](S(C)(=O)=O)[C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:5]2.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:13])([F:14])[F:12])[NH:7][C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:5]2
Reactant: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure as describe in General Procedures Example B, reacting 2-(5-fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol (0.59 g, 1.26 mmol) and using 4N sodium hydroxide as base (1 mL, 4.0 mmol) to yield the title cmpound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH:22][C:8](=[O:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1cccc(-c2nnco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Yield: 80.6 %

Procedure:
A solution of 4-bromopyridine-2-carboxylic acid (3.76 g, 18.6 mmol), 3-[1,3,4]oxadiazol-2-yl-phenylamine (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (7.1 g, 18.7 mmol), and diisopropylethylamine (15 mL) in N,N-dimethylformamide was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was stirred with acetonitrile (40 mL) and water (40 mL). The solid thus obtained was isolated by filtration, washed with water (20 mL), acetonitrile (20 mL) and diethyl ether (40 mL), and dried under reduced ressure to give N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide as a white powder (5.2 g, 15.0 mmol, 81% yield).
Reaction SMILES: O[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:12](=[O:25])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:12](=[O:25])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc(-n2c(=O)c3c(O)[nH]c4ccccc4n-3c2=O)cc1
Product: CCOc1ccc(-n2c(=O)c3c(Cl)[nH]c4ccccc4n-3c2=O)cc1

Procedure:
A solution of 4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]-quinoxaline-1,3(2H,5H)-dione (3.2 g) in phosphorous oxychloride (40 mL) was refluxed for 16 h. The solvent was removed in vacuo and water (15 mL) was added. The pH was adjusted to 7.0 using ammonium hydroxide and this resulting solid was filtered and dried to yield 4-Chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 36).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]#[N:14])[CH:12]=1)[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:6]1[C:5]2[C:10](=[C:11]([C:13]#[N:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2ccc3cc(OC)cc(C#N)c3c2=O)cc1
Product: COc1ccc(-n2cc(Br)c3cc(OC)cc(C#N)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Compound 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carbonitrile (0.22 g, 0.72 mmol) and N-bromosuccinimide (0.15 g, 0.86 mmol) were placed in a dry, argon flushed 150 mL single-necked flask fitted with a stirring bar and sealed with a rubber stopper. Acetonitrile (10 mL) was added via a syringe at room temperature under argon atmosphere. After the mixture was stirred at room temperature for 4 hours, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica-gel, hexanes/EtOAc=2/3 v/v) to give a white solid product, 0.23 g, 83.3% yield. M.p. ° C. (decomposed). MS: m/z 387.1 [M+H]+. 1H NMR (DMSO-d6, 300 MHz), δ 8.01 (s, 1H), 7.81 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=2.4 Hz), 7.42 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.7 Hz), 4.02 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:19][CH3:17])=[O:16]
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2cccc(Cl)c2)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.8 %

Procedure:
A solution of 5.7 g of 5-chloro-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid and 5.4 g of carbonyldiimidazole in 150 ml DMF was stirred at room temperature for 20 minutes. Next, 3.0 g of methylamine hydrochloride and 4.4 g of triethylamine were added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and the precipitated solid was collected by filtration and dried. The solid was recrystallized from toluene to provide 3.1 g of 5-chloro-1-(3-chlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. Yield 50%. mp=163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[CH:21]1([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][N:9]=[CH:10][C:2]=4[F:1])[CH:20]=3)[C:16]([CH3:27])([CH3:28])[C:17]2=[O:26])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccncc1F
Reactant: CC1(C)C(=O)N(C2CCCC2)c2cc(N)ccc21
Product: CC1(C)C(=O)N(C2CCCC2)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopentyl-3,3-dimethyl-1,3-dihydro-indol-2-one. The title compound was obtained as yellow foam.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][C:25](=[O:28])[C:24]12[C:32]2=[CH:33][C:34]3[O:38][CH2:37][O:36][C:35]=3[CH:39]=[C:31]2[O:30][CH2:29]1>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]([F:40])([F:17])[F:41])[C:24]3([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]3)[C:25]2=[O:28])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(Cl)s2)c2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 165-166° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.24 (dd, J=7.8, 7.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.80 (d, J=3.8 Hz, 1H), 6.70 (s, 1H), 6.22 (s, 1H), 5.91 (d, J=4.4 Hz, 2H), 5.09 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.9, 156.2, 149.2, 142.4, 139.9 (2C), 138.7, 135.4, 129.1, 127.4, 127.2, 126.9, 125.9, 123.9, 119.4, 111.5, 103.5, 102.0, 93.9, 80.7, 56.5, 42.3; MS (ES+) m/z 481.2 (M+1), 479.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21][CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:46])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Example 112 (2.7 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid (70%, 1.2 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and then water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain tert-butyl (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno(2,3-b]pyridin-4-yl}phenoxy)-acetate from the fraction eluted with ethyl acetate. It was recrystallized from ethyl acetate-hexane (2.2 g, 79%). Colorless prisms. Melting point 175-176° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.40 g (93% yield) of tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[S:8]1[C:4]2[CH:3]=[C:2]([N:1]=[C:11]=[O:12])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc2ncsc2c1

Procedure:
A mixture of 6-aminobenzothiazole (600 mg; 4 mmol) in toluene (40 ml) and phosgene (20 ml 20% in toluene; 40 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 6-benzothiazolylisocyanate. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (500 mg; 2.0 mmol) in toluene (20 ml) and refluxed for 16 h. The precipitate was isolated and recrystallized from methanol/ether to give 440 mg of the title compound. M.p. 210°-213° C. MS (70 eV): m/z 430 (13%, M+), 254 (32), 209 (77), 176 (100), 121 (38), 70 (83).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1.[CH:29](N1CCOCC1)=[O:30].Cl>C1COCC1.O>[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][C:26]([CH:29]=[O:30])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: O=CN1CCOCC1
Reactant: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc(-c3ccc(C=O)[se]3)cc2)c(F)c1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5.5 ml (32.3 mmol) of TMP are initially introduced at −20° C. in 50 ml of THF, and 20.0 ml (31.8 mmol, 15% soln. in hexane) of n-BuLi are metered in. The mixture is warmed to 5° C., and a solution of 10.0 g (26.5 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene in 100 ml of THF is metered in. The batch is warmed to RT and stirred for 30 min. The mixture is cooled to −70° C., and 3.5 ml (35.0 mmol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 1 h. 2 N hydrochloric acid is added, and the batch is added to 1 l of water. The solid forming is filtered off and crystallised from toluene, giving 5-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene-2-carbaldehyde as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11]COC.Cl[C:16]1[CH:17]=[C:18]([B:22]2C3C=CC(F)=CC=3CO2)[CH:19]=[CH:20][CH:21]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:22]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:16][CH:17]=3)[O:11][CH2:10][CH2:9][C:3]=2[CH:4]=1
Reactant: Fc1ccc2c(c1)COB2c1cccc(Cl)c1
Reactant: COCOCCc1cc(F)ccc1Br
Product: Fc1ccc2c(c1)CCOB2c1ccccc1

Procedure:
This compound was synthesized from 22a and 7a in a similar manner to compound 9f: colorless oil; 1H NMR (300 MHz, CDCl3) δ (ppm) 3.02 (t, J=6.1 Hz, 2H), 4.34 (t, J=6.1 Hz, 2H), 6.9-7.1 (m, 2H), 7.4-7.6 (m, 3H), 7.8-7.9 (m, 3H); ESI-MS m/z 227 (M+H)+; HPLC purity 95.3%; Anal (C14H12BFO 0.1H2O)C, H.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[Cl:14][C:4]1[CH:5]=[CH:6][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:2][CH:3]=1
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 4′-chloroacetophenone and 2.53 mL of EtOAc to yield 1.7 grams of Intermediate 28: TLC analysis: Rf=0.73 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 6.13 (s, 1H), 2.2 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[CH:25][N:24]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][O:21][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:25][N:24]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Fc1ccc(-n2ccnn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4ccnn4)cn3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (720 mg; 60 wt %; 432 mg NaH contained; 17.99 mmol) in DMF (9 mL) at 0° C. was treated with a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g; 13.84 mmol) in DMF (9 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was treated with a solution of 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (2.499 g; 15.22 mmol) in DMF (10 mL). The reaction was stirred at 0° C. for 45 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried over sodium sulfate, filtered and evaporated to a residue. The residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane). The fractions containing the desired product were combined and evaporated to a white solid. Crystalline solid was also recovered from the chromatography fractions. The solid isolated from chromatography was recrystallized from EtOH/heptane. The solid (4 g) was suspended in EtOH (150 ml), then heated until completely dissolved, allowed to cool to RT and heptane (100 ml) was added. The mixture was aged at RT overnight, cooled to 0° C. for 5 minutes and filtered to provide the title compound). LCMS: calc. 425.17 obs: 426.09 (M+1). 1H NMR (CDCl3): δ 8.48 (d, 1H), 8.20 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDCl3), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2O), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), −0.08 (q, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](O)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH2:28]([NH2:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](=[O:20])(=[O:21])[NH:30][CH2:28][CH3:29])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCN
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(C)ccc1Cl
Product: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OCC)cnc12
Yield: 87.4 %

Procedure:
Using 7-(2-chloro-5-methylphenylamino)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.72 g, 1.75 mmol) obtained in Example 12 step 2 and ethylamine (2.0 mol/L THF solution; 3.5 mL, 7.01 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.67 g, 87%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OC)cc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-5-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.65 (br, —CO2H); 7.11 (m, 1 arom.H); 7.00 (m, 2 arom.H); 5.95 (m, —CH═CH2); 5.39, 5.17 (2 d-like, CH═CH2); 4.49 (d-like, CH2—CH═CH2); 3.68 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 167.06 (C═O); 152.69; 150.99; 133.70; 122.54; 118.27; 116.84; 115.76; 115.08; 69.50; 55.49.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][CH3:34])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1O)OCO3
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1OC)OCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Compound 33 (95 mg, 0.21 mmol) was dissolved in a mixture of MeOH (3 mL) and THF (6 mL). (Trimethylsilyl)diazomethane (2 M in hexanes, 0.6 mL, 1.2 mmol) was added to the solution. The mixture was stirred for 12 h at room temperature, and then concentrated in vacuo. The crude material was purified by column chromatography on silica gel using CH2Cl2 to afford 35 (97 mg, 99%) as a yellow oil. 1H NMR (CDCl3) δ 7.86 (d, 1H, H5, J=8.7 Hz), 7.26 (d, 1H, H6, J=8.7 Hz), 6.75-6.82 (m, 3H, H2′+H5′+H6′), 6.00 (AB, 2H, 3′,4′-OCH2O—, Δδ=11.7 Hz, J=1.2 Hz), 5.87 (AB, 2H, 7,8-OCH2O—, Δδ=9.0 Hz, J=1.2 Hz), 4.39 (q, 2H, OCH2CH3, J=7.2 Hz), 4.06 (s, 3H, 4-OCH3), 4.03 (q, 2H, OCH2CH3, J=7.2 Hz), 1.38, 1.04 (each t, 2×3H, 2×OCH2CH3, J=7.2 Hz); MS (EI) m/z 466 [M]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([C@@H:21]([CH3:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:20][S:11]([N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:15])(=[O:13])=[O:12]
Reactant: COC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1
Reactant: CN(CCc1ccccn1)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)N(C)CCc1ccccn1)[C@@H](C)OCc1ccccc1

Procedure:
To the resulting compound from Example 87 (1 mmol) and (O-benzyl)threonine methyl ester (1 mmol) in CH2Cl2 was added triethylamine (2.0 mmol). After 1 h the product was isolated as described in Example 80.