Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]=O)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[C:27]1([CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)/[N:19]=[CH:17]/[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Solvent: CCOC(C)=O
Product: C(=N/C(c1ccccc1)c1ccccc1)\c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 0.03 h

Procedure:
2-Phenylquinoline-7-carbaldehyde (85.00 g, 0.364 mol) and EtOAc (255 mL) were added to a rbf and heated in a 70° C. oil bath. Half of aminodiphenylmethane (70.11 g, 0.38261 mol) was added quickly. After 2 min, a light brown solid precipitated. The reaction was exothermic and the reaction temperature increased to 73° C. The remaining aminodiphenylmethane was then added within 3 min. The reaction temperature decreased to 67° C. slowly. After 30 min, heating was discontinued and the reaction was cooled in an ice bath to about 15° C. The yellow solid was collected by vacuum filtration and dried in vacuo at 45° C. overnight. The title compound was isolated as a yellow solid (115.77 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.69 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.38 (m, 4H), 7.43-7.50 (m, 5H), 7.50-7.57 (m, 2H), 7.84 (d, J=8.59 Hz, 1H), 7.90 (d, J=8.59 Hz, 1H), 8.13-8.19 (m, 2H), 8.22 (d, J=8.08 Hz, 1H), 8.26 (dd, J=8.46, 1.64 Hz, 1H), 8.37 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)(OC(C)(C)C)=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(OC2CNC2)c1
Yield: 8 %

Procedure:
The title compound (D53) (100 mg) was prepared according to the experimental procedure described in Description 52 starting from 1-Boc-3-hydroxyazetidine (1 g, 5.77 mmol) and 3-(Trifluoromethyl)phenol (0.69 ml, 5.77 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.F[C:31](F)(F)[C:32](O)=[O:33].C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:15][CH2:16]1)(=[O:33])[CH3:31]
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 40.0 mg (0.0546 mmol) of 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide tris(trifluoroacetic acid salt) (as prepared in Example 16) suspended in 2 mL of anh THF was added 6.2 μL (0.0655 mmol) of acetic anhydride followed by 47.6 μL (0.716 mmol) of DIEA. After stirring for 20 min at RT, the mixture was poured into satd aq NaHCO3 (20 mL) and extracted with EtOAc (20 mL). The extract was dried (Na2SO4) and concentrated in vacuo and the resulting solid was chromatographed on a 2-g silica SPE column with 25-40% EtOAc-dichloromethane to afford 22.0 mg (92%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.59 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H, J=8.9, 2.6 Hz), 3.77-3.80 (m, 2H), 3.62-3.64 (m, 2H), 3.11-3.17 (m, 4H), 2.98-3.01 (m, 2H), 2.73-2.76 (m, 2H), 2.15 (s, 3H), 1.83-1.86 (m, 2H), 1.52-1.62 (m, 1H), 1.46-1.56 (m, 2H) and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C24H29N5O3, 436.2 (M+H), found 436.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)/[CH:17]=[CH:18]/[CH3:19]>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]=[CH:18][CH3:19])([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: C/C=C/C=O
Product: CC=CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 83 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with crotonaldehyde as described in Example 11 to give 1-nitro-5-propenyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 115°-117° C. Yield: 83%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:18][NH:19][O:20][CH3:21]>>[NH2:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([O:20][CH3:21])[CH3:18])=[O:5]
Reactant: Nc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc(S(F)(F)(F)(F)F)cc1N

Procedure:
2-Amino-4-(pentafluorosulfanyl)benzoic acid (2.0 g) was reacted with N,O-dimethylhydroxylamine hydrochloride analogously to example 15a). 2.3 g of the desired product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][C:3]=1[O:22][CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:34][C:35]1[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:21][Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([O:22][CH3:23])[CH:4]=2)[N:8]([C:40]([C:38]2[S:39][C:35]([Cl:34])=[CH:36][CH:37]=2)=[O:41])[C:7]=1[CH3:11]
Reactant: COc1cc2c(CC(=O)OCC[Si](C)(C)C)c(C)[nH]c2cc1F
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc2c(CC(=O)OCC[Si](C)(C)C)c(C)n(C(=O)c3ccc(Cl)s3)c2cc1F
Reaction time: 0.5 h

Procedure:
In a dry flask 2-trimethylsilylethyl (6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl)acetate (4, R1=H=B, R2=CH3, R3=F, R4=CH2CH2Si(CH3)3), (1.0 g, 2.96 mmol) was dissolved in tetrahydrofuran (THF) (10 mL) and hexamethylphosphoramide (HMPA) (1 mL) and cooled to −78° C. Potassium bis(trimethylsilyl)amide 0.5M in toluene (6.52 mL) was added and the reaction was stirred for 30 minutes. 5-Chlorothiophene-2-carbonyl chloride (562 mg, 3.1 mmol) in 3 mL of THF was added and the reaction was stirred for 0.5 hours at −78° C. and 0.5 hours at 0° C., and then treated with saturated ammonium chloride (20 mL) and the reaction extracted with ethyl acetate (3×30 mL), dried over MgSO4 and concentrated to give a thick oil which was purified by chromatography to afford 2-trimethylsilylethyl-{1-[(5chlorothien-2-yl)carbonyl]-6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl}acetate (5, R1=H=B, R2=CH3, R3=F, R4=CH2CH2Si(CH3)3, A=5-chlorothiophene). (600 mg, 1.24 mmol, 42%, >99% pure) as light yellow oil; 1H-NMR (CDCl3/300 MHz) consistent with the assigned structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:44].[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64](Br)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:44].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52]1)[C@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[CH:8]=4)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2
Reactant: O=S(=O)(Oc1cccc(N2CCOCC2)c1)C(F)(F)F
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(N4CCOCC4)c3)c2s1

Procedure:
143.3 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl trifluoromethanesulphonate (Example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150 mg (0.37 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 ml of DMF are reacted by general method D. Drying under high vacuum results in 67 mg (37.1% of theory) of the title compound.
Reaction SMILES: O[C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CC1CCc2sc3ncnc(O)c3c2C1
Product: CCOC(=O)CC1CCc2sc3ncnc(Cl)c3c2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (10.10 g, 34.55 mmol, 1.00 equiv) in POCl3 (80 g, 521.75 mmol, 15.00 equiv) was stirred for 1 h at 90° C. in an oil bath under nitrogen. The resulting mixture was concentrated under vacuum. The residue was added dropwise to a cooled saturated aqueous sodium bicarbonate and extracted with 3×200 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (6.67 g, 62%) as a yellow solid. MS: m/z 311, 313 (M+H)+.
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.[Cl:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[Cl:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[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])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:66][CH:65]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

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 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with 4-chloroaniline (Fluka) (0.054 g, 0.43 mmol) to give 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 (4-chloro-phenyl)-amide as a off white solid (Yield 95 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[C:3]=1[NH:20][C:21](=O)[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=1.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:4](=[O:19])[C:3]3[NH:20][C:21]([CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=4)=[N:1][C:2]=3[N:7]([CH3:8])[C:6]2=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(Cn2c(=O)c(NC(=O)CCCOc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3[nH]c(CCCOc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(3-(trifluoromethoxy)phenoxy)butanamide (150 mg, 0.287 mmol) in ethanol (7 mL) was added 2N NaOH (1 mL). The mixture was stirred at 80° C. for 3 h. The reaction was neutralized with saturated ammonium chloride and the product precipitated. The solids were collected and washed with water. The solids were dissolved in ethyl acetate, dried over sodium sulfate and concentrated to give 1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (130 mg, 89.7%) as a light yellow solid. LCMS retention time 1.635 min; LCMS MH+ 505.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[CH:4]1)[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[CH2:21]([C:23]1[C:28]([NH2:29])=[CH:27][N:26]=[CH:25][N:24]=1)[CH3:22]>C1COCC1>[CH2:21]([C:23]1[C:28]([NH:29][C:8]([C:6]2[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])=[CH:27][N:26]=[CH:25][N:24]=1)[CH3:22]
Reactant: CCc1ncncc1N
Reactant: CCn1cnc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1ncncc1NC(=O)c1cn(CC)cn1

Procedure:
A solution of 1-ethyl-1H-imidazole-4-carboxylic acid (2.5 g, 17.8 mmol) and thionyl chloride (65 mL) is refluxed for 1.5 h. The thionyl chloride is removed in vacuo using toluene to azeotrope thionyl chloride. To a suspension of the residue is added THF (60 mL) and pyridine (3.2 mL, 39.2 mmol), followed by 4-ethyl-5-pyrimidineamine (2.2 g, 17.8 mmol). The reaction mixture is refluxed for 17 h, and concentrated in vacuo. The residue is taken up in water (100 mL), and the pH of the solution is adjusted to 8.0 by the addition of solid potassium carbonate. The aqueous layer is extracted with methylene chloride (3×100 mL). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (300 g) using 3% MeOH in CH2Cl2 as eluent. The product fractions are combined and the solvent removed. The resultant material is triturated with ether+MeOH (19+1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:5]2[OH:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:5]2[OH:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCOC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCOC2)C1=O
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-5′,6′-dihydro-spiro[naphthalene-1,3′-pyran]-3-yl)carbonyl)glycinate (106 mg, 252 μmol) was mixed with TFA (6300 μL, 252 μmol) and stirred for 30 minutes. The product was co-evaporated with DCM (5×) to give the title compound. MS m/e=366.0 (M+H)+. Calculated for C17H16ClNO6 365.07.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CCOC(=O)C1CCC(c2ccccc2)N1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 29.2 %

Procedure:
By proceeding in a fashion similar to that described in Example 1 but starting from 2.2 g of ethyl (2RS,5SR)-5-phenylprolinate, 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 50 cm3 of anhydrous 1,2-dichloroethane and 0.72 cm3 of sulphinyl chloride, 1.2 g of ethyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate, melting at 115° C., are obtained after recrystallization in acetonitrile.
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:36])[C@@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Reaction time: 18 h

Procedure:
The product from Example 150B (0.242 g, 0.41 mmol) was dissolved in a mixture of ethyl acetate (2.0 mL) and methanol (2.0 mL) and 20% Pd(OH)2 on carbon (0.10 g) and a solution of HCl in dioxane (0.10 mL, 4 N) were added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 18 hours. The mixture was filtered through celite and the solvent was evaporated to give the title compound as the hydrochloride salt (0.273 g, which was used without further purification.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[BH4-].[Na+]>CO.Cl>[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[OH:12])[CH2:3]1)[CH2:9]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 5-hydroxy-2-adamantanone (5.14 g, 30.9 mmol) in MeOH (100 mL) was cooled in an ice bath and three 1-g NaBH4 caplets (3 g, 78 mmol) were added. The mixture was allowed to warm to rt and stirred overnight. The mixture was diluted with 5% aq HCl (20 mL) and concentrated to dryness. The residue was taken up in EtOAc (200 mL), washed with water (25 mL) and brine (25 mL), and dried over Na2SO4. Removakl of the solvent left the title compound as a white solid (4.88 g, 94%) as a 1:1 mixture of cis and trans isomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:35])([C:30]([O:32]CC)=O)[C:28](=[O:36])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[NH2:37][NH2:38]>CO>[NH2:1][C:2]1[C:3]2[C:29]([CH3:35])([C:30]([NH:37][NH2:38])=[O:32])[C:28](=[O:36])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])[N:9]=2)[N:7]=1
Reactant: NN
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Solvent: CO
Product: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 50 °C

Procedure:
A methanol (9.5 mL) solution of ethyl 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as described in Example 157, (1.02 g, 1.91 mmol) and hydrazine (3.13 g, 96 mmol) was heated at 50° C. After 1.5 hours the solution was concentrated in vacuo. The crude reaction mixture was dissolved in methanol and concentrated in vacuo again. The remaining material was lyophilized from water and acetonitrile to give the title compound as a yellow solid which was used without further purification. m/z=519.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][C:19]([O:32][CH3:33])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:38])([CH2:35][CH2:36][CH3:37])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:34])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])=[CH:20][C:19]([O:32][CH3:33])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 118 mg (0.157 mmol, 73% purity) of rac-{1-[({7-[(2,6-difluorobenzyl)oxy]-5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 164A) in 12 ml of dichloromethane was admixed with 1.5 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative HPLC chromatography (Method 21), which gave 37 mg (53% yield) of product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Under an argon gas atmosphere, 70.0 g (407 mmol) of 2-naphthalene boronic acid, 115.1 g (407 mmol) of 4-bromoiodobenzene, 9.40 g (8.14 mmol) of tetrakis(triphenylphosphine) palladium(0), 1.2 L of toluene and 600 mL of 2M sodium carbonate solution were mixed, and stirred for 20 hours at 90 degrees C. After the reaction in the mixture was over, toluene was distilled away therefrom, and the mixture was added with methanol, such that precipitated solid was separated by filtration. By recrystallizing the obtained solid by acetic ether and methanol and subsequently drying the solid, 77.2 g of 2(4-bromophenyl)naphthalene was obtained with an yield of 67%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2].[I:16][C:17]1[CH:18]=[C:19]([C:23]2[O:28]C(C)(C)[O:26][C:25](=O)[CH:24]=2)[CH:20]=[CH:21][CH:22]=1>>[I:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[CH2:24][C:25]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:26])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)C=C(c2cccc(I)c2)O1
Product: O=C(CC(=O)c1cccc(I)c1)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-4-pyrrol-1-yl-phenylamine (Example E1) (610 mg, 3 mmol) and 6-(3-iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L4) (1.49 g, 4.5 mmol) according to the general procedure M. Obtained as a brown solid (876 mg).