Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:32]#[N:33]>>[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:32]([NH2:33])=[O:13]
Reactant: N#Cc1cnn(C2CCC(F)(F)CC2)c1N
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Product: NC(=O)c1cnn(C2CCC(F)(F)CC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.01 (s, 1H), 4.19 (m, 1H), 2.22-1.90 (m, 8H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=[C:32]2[NH2:42]>O1CCOCC1.O>[NH2:42][C:32]1[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc(N)c2cccc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(N)nc(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 49.6 %

Procedure:
Argon was bubbled into a slurry of potassium carbonate (Mallinkrodt; 0.140 g, 1.016 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (ii) (Aldrich; 0.018 g, 0.025 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.133 g, 0.51 mmol), 8-bromo-N2-(tert-butyl)quinazoline-2,4-diamine (484b; 0.075 g, 0.254 mmol) in 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and heated to 80° C. for 30 min. The reaction was adsorbed onto 1 g silica gel and dried in vacuo. The material was treated with purified by silica gel chromatography (12 g column) using 0-100% (90/10 (DCM/2.0 M NH3/MeOH) in DCM). The product-containing fractions were concentrated to afford (R)-2-(4-amino-2-(tert-butylamino)quinazolin-8-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.044 g, 0.126 mmol, 49% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (1H, s), 7.97 (1H, dd, J=7.6, 1.2 Hz), 7.83 (1H, d, J=8.0 Hz), 7.59 (1H, s), 7.32-7.47 (2H, m), 7.02 (1H, t, J=7.7 Hz), 6.76 (1H, d, J=1.2 Hz), 6.47 (1H, br. s.), 4.56 (1H, q, J=6.7 Hz), 1.49 (9H, s), 1.41 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 351.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(N(C(C)C)CC)(C)C.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 75 °C
Yield: 57.7 %

Procedure:
A stirred solution of 2-bromo-4-fluoro-5-nitrobenzotrifluoride (1.15 g, 4.0 mmol) in dimethylformamide (15 ml) at room temperature under argon was treated with diisopropylethylamine (1.8 ml, 10 mmol) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.90 g, 4.5 mmol), then heated at 75° C. for 3 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (30 ml) and extracted with ethyl acetate (2×40 ml). The combined extract was washed with brine (40 ml), then dried (Na2SO4) and concentrated under vacuum to leave an orange solid which was purified by chromatography on silica gel (20 g) eluting with dichloromethane to afford the title compound as a yellow solid (1.08 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1>O.O.CC1C=CC(S(O)(=O)=O)=CC=1>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][C:10]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:11]1
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: N#Cc1ccccc1NC1=CC(=O)CCC1
Yield: 92.8 %

Procedure:
A mixture of 2-aminobenzonitrile (120 g) and 1,3-cyclohexandione (120 g) in water (400 ml) was heated to 40° and 4-methylbenzenesulfonic acid monohydrate (6.2 g) was added, with stirring. The mixture was stirred at 40° for 1 hr. The mixture was filtered, and the filter cake was washed with water to provide 200 g (93%) of 2-(3-oxocyclohexen-1-yl)aminobenzonitrile, mp 191.4°.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:35]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cnc(Cl)cn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0507 g, 0.132 mmol) and 2,5-dichloropyrazine (0.0320 g, 0.215 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.67 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.7, 2H), 8.02 (d, J=2.5, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.6, 1H), 4.57 (s, 2H), 3.79-3.65 (m, 6H), 3.50 (d, J=4.3, 4H), 3.12 (dt, J=14.1, 7.1, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:15]=O)[CH2:2][CH3:3].[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:15][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:13]=[CH:14][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCCOc1ccc2ccccc2c1C=O
Product: CCCOc1ccc2ccccc2c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 2-propoxy-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 445.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:23])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[OH-].[Na+]>C(O)C.C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:20][CH2:21]2)[C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4scc(C(=O)O)c34)CC2)cc1
Temperature: 50 °C
Yield: 54.5 %

Procedure:
To a solution of Example 21 (900 mg, 1.97 mmol) in ethanol/THF (1:1, 10 mL) was added aqueous NaOH solution (2M, 10 mL). The reaction mixture was heated to 50° C. for 12 hours. On completion, the reaction mixture was concentrated in vacuo and then re-dissolved in warm water. The pH was adjusted to pH 5-6 with 2M HCl, and the precipitate was filtered and dried on a sinter to give the title compound (460 mg) as a white solid. δH (DMSO-d6, 300 MHz) 8.43 (1H, s), 7.68 (1H, s), 7.35 (2H, d, J 8.8 Hz), 6.82 (2H, d, J 8.8 Hz), 6.44 (2H, br s), 3.70 (3H, s), 3.49-3.34 (8H, br m+H2O). LCMS (pH 10) MH+ 429, RT 0.79 minutes. LCMS (pH 3) MH+ 429, RT 1.15 minutes.
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:5]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]2[S:8][CH:9]=[CH:10][C:6]=12)[CH3:2].C([Li])CCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36].O>O1CCCC1>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][C:11]1[C:7]2[S:8][C:9]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:10][C:6]=2[C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:13]2[S:14][C:15]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:16][C:12]=12)[CH3:24]
Reactant: CCCCC(CC)Cc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1c2cc([Sn](C)(C)C)sc2c(CC(CC)CCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4,8-bis(2-ethylhexyl)benzo[1,2-b:4,5-b′]dithiophene (237 mg, 0.57 mmol) in dry tetrahydrofuran (11 mL) was added n-butyllithium (2.5 M in hexane, 0.5 mL, 1.25 mmol) at −78° C. After 1 hour, trimethyltin chloride (264 mg, 1.32 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water (20 mL) and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (437 mg, yield 100%). Upon standing in a freezer for 2 days, pale yellow crystals emerged and were collected (326 mg, yield 77%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.07-3.23 (m, 4H), 1.96-2.07 (m, 2H), 1.21-1.50 (m, 16H), 0.94 (t, J=7.0 Hz, 6H), 0.89 (t, J=7.0 Hz, 6H), 0.46 (s, 18H).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:1]([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=3)[C:6]#[N:7])[N:2]=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)cc2)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylisonicotinonitrile (PREPARATION 2) and (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one according to the procedure for the preparation of Example 26, part B. 1H NMR (500 MHz, CDCl3) δ 8.36 (d, 1H, J=4.8 Hz), 8.0 (s, 1H), 7.7 (s, 1H), 7.37 (d, 1H, J=3.8 Hz), 7.25 (d, 2H, J=5.8), 7.0 (t, 2H, J=8.7 Hz, 1H), 6.45 (s, 1H). [M+H] Calc'd for C15H9FN4, 265. Found, 265.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([CH:8]=1)[NH2:7].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([NH:7][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCCc1ccccn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCCc1ccccn1)c1cc2ccccc2o1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline (439 mg, 1.663 mmol) and benzofuran-2-sulfonyl chloride (2×359 mg, 2×1.663 mmol) in pyridine (5 ml).
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[C:10]2[N:12]([CH2:16][CH3:17])[C:13]([NH2:15])=[N:14][C:9]2=[CH:8][CH:7]=1>C(O)C.[Pd]>[CH2:16]([N:12]1[C:10]2=[N:11][CH:6]=[CH:7][CH:8]=[C:9]2[N:14]=[C:13]1[NH2:15])[CH3:17]
Reactant: CCn1c(N)nc2ccc(Cl)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCn1c(N)nc2cccnc21
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Ammonium formate (1.55 g, 24.6 mmol) is added to a solution of 5-chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-2-amine (410 mg, 2.09 mmol) in ethanol (10 mL) containing 10% palladium on carbon (40 mg). The mixture is stirred for 16 h, filtered, and concentrated. The residue is purified via flash column chromatography using a gradient of 0-10% methanol in CH2Cl2 to afford the title compound (192 mg, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:26](O)([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C>[C:26]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
To a mixture of the compound (6.9 g) obtained in Example 63 and methylene chloride (70 ml) were added t-butanol (20 ml), N,N-dimethylaminopyridine (2.63 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.9 g) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 7.64 g of the titled compound (yield, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[C:14]([CH3:20])[C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:33][CH3:34]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:20])[CH:15]=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2c(C)c[nH]c(=O)c21
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.22 g (5.44 mmol) of the compound from Example 28A are suspended in 100 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 10 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: initially dichloromethane then isohexane/ethyl acetate 1:1). The product fractions are combined, the solvent is removed, and the residue is crystallized from ethyl acetate/diethyl ether. The precipitate is filtered off and dried under high vacuum. 1.80 g (77% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:15]([O:17]CC)=[O:16])=[C:7]([C:10]([O:12]CC)=[O:11])[CH:8]=2)[CH2:3][CH2:2]1.Cl>C(O)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:15]([OH:17])=[O:16])=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2c(cc1C(=O)OCC)CCC2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(cc1C(=O)O)CCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of the product of above-mentioned (a) (0.36 g, 1.4 mmol) in acetic acid (0.8 ml) was added concentrated hydrochloric acid (0.4 ml) and stirred at 80° C. overnight. To the reaction solution was added ice-cold water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.28 g of 5,6-indandicarboxylic acid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C@H:16]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:26])[N:13]=[C:12]3[S:27][C:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[C:11]=23)=[CH:6][CH:5]=1>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:15]([C@H:16]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:17]([OH:19])=[O:18])=[C:14]([CH3:26])[N:13]=[C:12]3[S:27][C:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[C:11]=23)=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Br)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2sc3c(c2c(-c2ccc(Br)cc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 34.5 %

Procedure:
1 M Aqueous sodium hydroxide solution (1.6 mL, 1.6 mmol) was added to a solution of (S)-methyl 2-(4-(4-bromophenyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)-2-(tert-butoxy)acetate (83 mg, 0.16 mmol) in 1:1 tetrahydrofuran/industrial methylated spirit (4 mL) at room temperature. The resulting mixture was heated to 60° C. and stirred at 60° C. 2 hours. The resulting solution was concentrated in vacuo and the residue was dissolved in water (10 mL). The aqueous solution was adjusted to pH 5 by the addition of 2 M aqueous hydrochloric acid solution and the resulting suspension was extracted with dichloromethane (20 mL). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product as a pale yellow solid. This was purified by trituration with industrial methylated spirit (5 mL). The resulting solid was collected by filtration to give the title compound (27 mg, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ=1.02 (s, 9H), 2.00-1.40 (m, 6H), 2.69 (s, 3H), 2.83-2.70 (m, 2H), 5.11 (s, 1H), 7.25-7.06 (m, 1H), 7:63-7.42 (m, 3H). LCMS (run time=5 minutes, basic): Rt=3.19 minutes; m/z 490.00 [M+H+].
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)Cl
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc2cc3ccccc3cc2c1
Yield: 27.5 %

Procedure:
Anthracene (0.156 g), acryloyl chloride (0.11 g), and aluminium chloride (0.15 g) were treated in the same manner as described in Example 1 to obtain the title compound (56 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1>CO>[CH:19]1([CH2:22][NH:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([O:5][C:4]3[CH:15]=[CH:16][C:17]([F:18])=[C:2]([F:1])[CH:3]=3)[CH2:11][CH2:10]2)[CH2:21][CH2:20]1
Reactant: O=CC1CC1
Reactant: NCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Solvent: CO
Product: Fc1ccc(OC2CCN(CCNCC3CC3)CC2)cc1F
Reaction time: 4 h

Procedure:
The product of Step d (0.4 g) dissolved in MeOH (6 ml) was added to cyclopropanecarbaldehyde (0.116 ml) and the resulting mixture was stirred for 4 hours. The solvent was evaporated, the residue re-dissolved in methanol (6 ml) and NaBH4 (0.095 g) added and the mixture left for 30 minutes. Aqueous sodium hydroxide (1N) was added and the aqueous extracted with diethyl ether. The organic extracts were dried with Na2SO4, filtered and concentrated to give the sub-title product as an oil (0.493 g).
Reaction SMILES: O[C:2]([C:10]1([CH3:13])[CH2:12][CH2:11]1)=[CH:3][C:4](=[O:9])[CH:5]=[CH:6][O:7]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:13][C:10]1([C:2]2[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=2)[CH2:11][CH2:12]1
Reactant: COC=CC(=O)C=C(O)C1(C)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cc(=O)cco2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.9 %

Procedure:
A mixture of 1-hydroxy-5-methoxy-1-(1-methyl-cyclopropyl)-penta-1,4-dien-3-one (Step 40.7) (1.07 g, 5.9 mmol) and TFA (0.9 mL, 11.7 mmol, 2 eq) in toluene (50 mL) is stirred for 14 h at rt and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:0→3:7) provides 442 mg of the title compound as a red solid: ESI-MS: 151.1 [M+H]+; tR=2.89 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 1:1).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]2[CH2:22][CH:21](CS([O-])(=O)=O)[CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:18]([N:19]1[CH2:22][CH:21]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:20]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=S(=O)([O-])CC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
A mixture of 2-tert-butylaniline (0.50 g, 3.35 mmol) and 1-(diphenylmethyl)-3-azetidinylmethanesulfonate (1.60 g, 5.03 mmol) was heated at 100° C. for 15 min. After this toluene (5.0 ml) was added to the resulting yellow solid, the reaction mixture was cooled to room temperature, partitioned between THF and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90:10 to 80:20 heptane/ethyl acetate) to provide 1-benzhydryl-N-(2-tert-butylphenyl)azetidin-3-amine (0.73 g, 59%) as a yellow gum-like substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].Cl.[C:17]([O:21][NH2:22])([CH3:20])([CH3:19])[CH3:18].Cl>O>[C:17]([O:21][N:22]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)ON
Reactant: O=C(O)C(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)ON=C(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A solution of thien-2-ylglyoxylic acid (6.2g.) and sodium bicarbonate (3.36g.) in water (100 ml.) was added dropwise to a stirred solution of t-butoxyamine hydrochloride (5.65 g.) and sodium bicarbonate (3.78g.) in water (100 ml.) at 0°-5° and the mixture was stirred at room temperature for 18 hr. The mixture was acidified with 2N hydrochloric acid to pH 2.0 and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to give a solid (9.75 g.). Recrystallisation from petroleum (b.p. 60°-80°) gave the title compound (4.0 g., 44%), m.p. 106°-107°, λmax. (EtOH) 290 nm (ε11,600), τ (CDCl3) values include 2.46, 2.66, 2.98 (d doublets, thienyl protons), 8.60 (C(CH3)3).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([F:18])=[C:16]([F:19])[C:7]([CH2:8][O:9]C2CCCCO2)=[C:6]([F:20])[C:5]=1[F:21])[C:2]#[CH:3].Cl>CO>[CH2:1]([C:4]1[C:5]([F:21])=[C:6]([F:20])[C:7]([CH2:8][OH:9])=[C:16]([F:19])[C:17]=1[F:18])[C:2]#[CH:3]
Reactant: C#CCc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Agent: Cl
Solvent: CO
Product: C#CCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 2-[4-(prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (0.8 g), dilute hydrochloric acid (2N, 5 cm3) and methanol (30 cm3) was stirred together at the ambient temperature for 2 hours, after which the more volatile portion was removed by evaporation under reduced pressure. The residue was extracted with diethyl ether, the extracts combined, washed with water, and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded an oil which crystallised on standing to give 4-(prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.5 g), m.p. 51°-52° C., after recrystallisation from petroleum ether (boiling range 60°-80° C.).