Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.45 g, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.16 g, 0.9 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 195 mg, 35%). MS (H+), 628.
Reaction SMILES: Cl[C:2]([C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:38]([C:41]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([SH:52])=[N:50][N:49]=[N:48]2)=[CH:43][CH:42]=1)([OH:40])=[O:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([C:2]([S:52][C:51]2[N:47]([C:44]3[CH:43]=[CH:42][C:41]([C:38]([OH:40])=[O:39])=[CH:46][CH:45]=3)[N:48]=[N:49][N:50]=2)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(-n2nnnc2S)cc1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nnnn1-c1ccc(C(=O)O)cc1)C(=O)c1ccc(OC)cc1)c1ccccc1
Yield: 93.3 %

Procedure:
33 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide and 16 g of 1-(4-carboxyphenyl)-5-mercaptotetrazole were dispersed in 200 ml of chloroform to which was added dropwise 10 ml of triethylamine at room temperature over a period of about 30 minutes. After stirring for 3 hours the chloroform solution was washed with water and concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 41.2 g of α-(4-methoxybenzoyl)-α-[1-(4-carboxyphenyl)-5-tetrazolylthio]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 93%. Melting Point: 172° to 174° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH:19]=[O:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)C[C@@H]2O1
Solvent: ClCCl
Product: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 102 %

Procedure:
A solution of compound 2 (1.4 g, 3.6 mmol) in DCM (25 mL) was treated with DMP (3.1 g, 7.3 mmol) for 3 h at room temperature. The reaction mixture was quenched with saturated aqueous Na2S2O3 (10 mL) and extracted with DCM (4×20 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (20 mL) and brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude aldehyde 3 (1.4 g, yellow oil), which was used in the next step without further purification. (ES, m/z): [M+H]+ 382.0; 1H NMR (300 MHz, CDCl3), δ: 9.74 (s, 1H), 7.28-7.46 (m, 10H), 4.54-4.85 (m, 5H), 3.85-3.90 (m, 1H), 3.69-3.74 (m, 1H), 3.60-3.65 (m, 1H), 2.94-2.96 (m, 1H), 2.19-2.27 (m, 1H), 1.94-2.00 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N+:11]([O-])=O)([O-:3])=[O:2].[CH:14]1([CH2:20]N)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:11][CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NCC1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of 8.1 g of 1,2-dinitro-4-chlorobenzene in 20 ml of 95% ethanol is added dropwise a solution of 13.6 g of cyclohexylmethylamine in 10 ml of 95% ethanol. The temperature rises to 50° C. The reaction medium is kept stirring for 2 hours and the solvent is then evaporated off under vacuum. The residue is taken up in DCM, washed with water, then with 2N hydrochloric acid and next with water, dried over Na2SO4 and the solvent is then evaporated off under vacuum. The residue is chromatographed on silica, eluting with isopropyl ether. After recrystallization from heptane, 4.21 g of the expected product are obtained, mp=73° C.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:21]>C(OCC)C>[CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][Br:21])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NOCc1ccccc1)c1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(=NOCc1ccccc1)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 194.2 %

Procedure:
To a solution of 2.55 g (10 mmol) of 3-(1-(benzyloxyimino)ethyl)benzylalcohol in 20 ml of dry diethyl ether was added dropwise 1.35 g (4.5 mmol) of phosphorous tribromide with ice-cooling. The mixture was removed from an ice bath and stirred at room temperature for 6 hours. To the reaction mixture were added ice water and diethyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated to obtain 2.78 g (8.74 mmol) of 3-(1-(benzyloxyimino)ethyl)benzylbromide.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[O:18][N:17]=3)=[C:10]2[CH:9]=[CH:8]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].CO>[OH-].[NH4+]>[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[O:18][N:17]=3)=[C:10]2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3noc(-c4cccc(C#N)c4)n3)ccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1cccc(-c2nc(-c3ccnc4[nH]ccc34)no2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
The crude 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxa-diazol-5-yl]benzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under nitrogen and then heated to 60° C. After heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The resulting residue was taken up in methanol and concentrated to remove as much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and ammonium hydroxide (1 mL). This mixture was stirred at rt for 2 h and the reaction was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by prep HPLC on a C-18 column eluting with a ACN:water gradient with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H)+ 288. 1H NMR (DMSO-d6) δ 12.1 (bs, 1H), 8.65(s, 1H), 8.48(d, 1H, J=6.4), 8.39(d, 1H, J=4.8), 8.16(d, 1H, J=6.4), 7.84(t, 1H, J=6.4), 7.75(d, 1H, J=4.8), 7.68(m, 1H), 6.99 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C1CCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a 250 mL of flask was added 3-(4-bromo-phenyl)-propionic acid 38a (20.6 g, 90 mmol, ABCR) and dried in vacuo for 20 minutes followed by addition of 110 mL of anhydrous dichloromethane under nitrogen atmosphere, and then thionyl chloride (20 mL, 276 mmol) was added. The reaction mixture was heated to reflux overnight. The mixture was concentrated under reduced pressure to remove most solvent followed by addition of 100 mL of dichloromethane, and then aluminium trichloride (24.5 g, 25.8 mmol) was added. The generated gas was released. The mixture was warmed up to reflux and stirred overnight. The mixture was poured into 200 g of ice to form a copious amount of precipitates and filtered through silica gel. The filtrate was separated and the aqueous layer was extracted with 30 mL of dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound 6-bromo-indan-1-one 38b (18.34 g, yield 96.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:13]=[C:12](I)[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[CH3:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH2:28].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:13]=[C:12]([NH:28][C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:21])[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(I)c2C1
Reactant: Cc1cnccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CC(C)(C)C2
Temperature: 85 °C

Procedure:
To a solution of 2-(5-Chloro-2-fluoro-phenyl)-4-iodo-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine (100 mg, 0.25 mmol), 3-Methyl-pyridin-4-ylamine (30 mg, 0.27 mmol), Pd(OAc)2 (3 mg, 12.42 μmol) and Rac-BINAP (12 mg, 18.63 μmol) in dry dioxane (3 mL) was added Cs2CO3 (121 mg, 0.37 mmol). The mixture was heated for 48 h at 85° C., cooled and evaporated. HPLC purification gave, after lyophilization, the desired product 60 as the TFA salt, a white solid (6.4 mg).
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C@@H:21]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:20][CH2:19][C@H:18]2[O:32]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]/[CH:24]=[CH:23]\[CH2:22][C@H:21]1[CH2:20][CH2:19][C@@H:18]([OH:32])[C@@H:17]1[C:14]1[CH:13]=[CH:12][C:11]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=1
Reactant: CCCCCC(OC(C)=O)c1ccc([C@@H]2[C@@H](C/C=C\CCCC(=O)OC)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(OC(C)=O)c1ccc([C@@H]2[C@@H](C/C=C\CCCC(=O)OC)CC[C@H]2O)cc1
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A mixture of 27 (53 mg, 0.09 mmol) and K2CO3 (7 mg, 0.05 mmol) in CH3OH (2.6 mL) was stirred for 1 h. Saturated NH4Cl solution (20 mL) was added and the resulting mixture was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (40% ethyl acetate/hexanes) to give compound 28 (27 mg, 67%) along with the deacetylated side product (9 mg, 26%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[C:17]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:17]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH:9]=[CH:10][N:11]=[CH:12]4)[CH2:2]2)[CH:30]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(OCCOC(=O)c2ccccc2)c1
Reactant: c1cc(N[C@@H]2CCNC2)c2ccncc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCCOc1cccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)c1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a 100 mL round-bottomed flask with a magnetic stir bar were added (R)-N-(pyrrolidin-3-yl)isoquinolin-5-amine scuccinic acid salt (2.00 g, 6.04 mmol, from Example 5), tetrahydrofuran (30 mL), and 2-(3-formylphenoxy)ethyl benzoate (1.63 g, 6.04 mmol). The mixture was stirred at 20 to 25° C. for 15 minutes. To the mixture was added sodium triacetoxyborohydride (1.92 g, 9.05 mmol). The mixture was stirred at 20 to 25° C. for 20 hours. The reaction was quenched with 20 mL of 15% Na2CO3 (final pH ˜10). Tetrahydrofuran was removed by distillation under vacuum. The residue was extracted with 30 mL of methyl tert-butyl ether. The organic layer was washed with 30 mL of water (twice) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-12% methanol/dichloromethane) to give (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethyl benzoate as a oil (2.57 g, 91% yield).
Reaction SMILES: I[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[CH3:11][S:12]([C:15]([S:34]([CH3:37])(=[O:36])=[O:35])=[N:16][CH2:17][C:18]([N:20]1[CH:24]2[CH2:25][CH:26]3[C:29]([CH3:31])([CH3:30])[C:23]2([CH2:28][CH2:27]3)[CH2:22][S:21]1(=[O:33])=[O:32])=[O:19])(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]([S:34]([CH3:37])(=[O:36])=[O:35])=[N:16][CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])[C:18]([N:20]1[CH:24]2[CH2:25][CH:26]3[C:29]([CH3:31])([CH3:30])[C:23]2([CH2:28][CH2:27]3)[CH2:22][S:21]1(=[O:32])=[O:33])=[O:19])(=[O:14])=[O:13]
Reactant: CC1(C)C2CCC13CS(=O)(=O)N(C(=O)CN=C(S(C)(=O)=O)S(C)(=O)=O)C3C2
Reactant: C=Cc1ccccc1CI
Product: C=Cc1ccccc1CC(N=C(S(C)(=O)=O)S(C)(=O)=O)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C

Procedure:
In step c, the appropriate 1-iodomethyl-2-vinyl-benzene derivative of structure (3) is subjected to an addition, elimination reaction with 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-ethanone (4) to give the corresponding 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one derivative of structure (5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.3 g, 0.858 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.355 g, 1.029 mmol) according to the general procedure VI. Obtained as a white solid (0.220 g, 48%). MS (ISP) 533.2 [(M+H)+]; mp 242° C. (dec.).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[C:40]([C:39]1[CH:42]=[C:35]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:36]=[N:37][CH:38]=1)#[N:41]
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow wax. UPLC-MS (Condition 3) tR=1.02 min, m/z=458.3 [M+H]+, m/z=456.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.47 (t, J=5.38 Hz, 2H) 3.56 (t, J=6.11 Hz, 2H) 4.34-4.84 (m, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.79-7.90 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.00 (dd, J=7.21, 2.08 Hz, 2H) 10.21 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH:3]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)Cc1cccc(OCC2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cc1cccc(OCC2CCCCC2)c1
Temperature: 23 °C

Procedure:
A solution of aqueous sodium hydroxide (1N, 14 mL, 14.0 mmol, 10 equiv) was added to a solution of ethyl 3-cyclohexylmethyloxy-phenylacetate 29-3 (384 mg, 1.39 mmol, 1 equiv) in a mixture of t-butanol (8 mL) and water (4 mL) at 23° C. The reaction mixture was heated at reflux for 2 h. The solution was cooled to 23° C. and was diluted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 10% potassium hydrogen sulfate solution (2×25 mL), then was dried over magnesium sulfate and was concentrated to afford the product 29-4 as a white solid, which was used without further purification.
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.O.C(=O)([O-])[O-:20].[Na+].[Na+]>CS(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1ccncc1)c1cccc(F)c1
Agent: Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(C(=O)c1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Hydrobromic acid (7.9 mL, 48% in H2O, 69.7 mmol) was added with caution to a stirred solution of 1-(3-fluorophenyl)-2-pyridin-4-ylethanone (5.0 g, 23.2 mmol) in DMSO (40 mL) at 55° C. The reaction was stirred for 2 h and then allowed to cool to room temperature. Water was added and the aqueous phase was neutralized with solid sodium carbonate and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to provide the title compound as a yellow solid (2.85 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-(4-fluorobenzoyl)benzoic acid (5 g; 20.47 mmol) is suspended in ethanol (100 ml). Hydrazine (3 M in ethanol; 60 mmol) is added, and the mixture is stirred at room temperature for 4 days. A white solid precipitates, is filtered off and is washed with ethanol (20 ml). Yield: 3.20 g of 4-fluorophenylphthalazine-1-one.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][OH:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=1
Reactant: COc1cc(C(F)(F)F)c(CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)c(C=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a cooled (−78° C.) solution of DMSO (0.15 mL, 2.13 mmol) in dichloromethane (2 mL) was added oxalyl chloride (0.14 mL, 1.60 mmol), and the mixture was stirred for 10 minutes. 6-Methoxy-4-trifluoromethyl-3-pyridinemethanol (220 mg, 1.06 mmol) in dichloromethane (4 mL) was added to the reaction mixture. After stirring at −40° C. for 50 minutes, the mixture was treated with triethylamine (0.44 mL, 3.16 mmol), stirred for 90 minutes while warming to room temperature, and quenched with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (162 mg, 74.4%) as a solid. The crude product was used directly in the following Swern oxidation.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1.[Sn](Cl)Cl>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([NH2:19])=[CH:4][N:3]=1
Reactant: N#Cc1ccc2cnn(C3NC(N)=NC=C3[N+](=O)[O-])c2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1ccc2cnn(-c3nc(N)ncc3N)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A mixture of 1-(2-amino-5-nitro-3,4-dihydropyrimidin-4-yl)-1H-indazole-6-carbonitrile (40% purity, 400 mg, 0.64 mmol) and tin (II) chloride (577 mg, 2.56 mmol) in ethanol (15 mL) was heated at 60° C. for 2 hr then at 70° C. for 3 hr. LC-MS (Method B) showed 11% desired product and 74% degradation. The reaction mixture was concentrated in vacuo. The residue was vigorously stirred with a mixture of saturated aqueous Rochelle salt (potassium sodium tartrate (20 mL), saturated aqueous NaHCO3 (20 mL) and EtOAc (30 mL) for 30 min. The EtOAc layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (Biotage) (100% EtOAc) to give the title compound as a pale yellow solid: 1H NMR (250 MHz, DMSO) δ 5.40 (2H, br. s.), 6.30 (2H, s), 7.69 (1H, dd, J=8.38, 1.22 Hz), 8.01-8.25 (2H, m), 8.62 (1H, d, J=0.76 Hz), 9.31 (1H, s); LC-MS: m/z=+252.0 (M+H)+.