Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1N=[C:12]2[C:8]([N:9]=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)C(O)C2O)=[C:7](NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O.NC1CC[CH:47]([NH:50][C:51]([C:53]2[N:61]=[C:60]3[C:56]([N:57]=[CH:58][N:59]3[C@@H:62]3[CH2:66][C@H:65]([N:67]4[CH:71]=[C:70]([CH2:72][OH:73])[CH:69]=[N:68]4)[C@@H:64]([OH:74])[C@H:63]3[OH:75])=[C:55]([NH:76][CH2:77][CH:78]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[N:54]=2)=[O:52])CC1.NCC(N)(C)C>>[NH2:9][C:8]([CH3:12])([CH3:7])[CH2:47][NH:50][C:51]([C:53]1[N:61]=[C:60]2[C:56]([N:57]=[CH:58][N:59]2[C@@H:62]2[CH2:66][C@H:65]([N:67]3[CH:71]=[C:70]([CH2:72][OH:73])[CH:69]=[N:68]3)[C@@H:64]([OH:74])[C@H:63]2[OH:75])=[C:55]([NH:76][CH2:77][CH:78]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[N:54]=1)=[O:52]
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)C(O)C3O)c2n1
Agent: CC(C)(N)CN
Product: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
This compound is prepared from 9-[(1R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Example 62) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide (Example 83, first step a) replacing trans-1,4-diaminocyclohexane with 1,2-diamino-2-methylpropane.
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].Br[C:10]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[C:14]([F:22])[C:11]=1[C:12]#[N:13].O>C1COCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:14]1[C:11]([C:12]#[N:13])=[C:10]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: [Zn+]c1ccccn1
Reactant: COc1cc(F)c(C#N)c(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C#N)c(-c2ccccn2)c1OC
Temperature: 98 °C
Yield: 94.5 %

Procedure:
A mixture of pyridyl zinc chloride (max 31.5 mmol, prepared from 2-bromopyridine by bromine to magnesium to zinc exchange) in THF (30 ml) and 2-bromo-6-fluoro-3,4-dimethoxybenzonitrile (prepared according to step (d), 3.30 g, 12.7 mmol) in DMF (75 ml) was charged with tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol), warmed to 98° C. and maintained at this temperature for 15 hours. After this time, the reaction mixture was cooled to room temperature and water (300 ml) added. The resulting mixture was extracted with ethyl acetate (3×150 ml), and the combined organics dried over MgSO4 before being concentrated in vacuo. The crude product was purified on silica gel (eluting with hexane/ethyl acetate [7/3 followed by 1/1] to give 3.1 g of the title product (93%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]Cl)[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:12]2[C@H:8]([C:7]([CH3:15])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]2=[O:13])[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1
Reactant: ClCc1cncc(Br)c1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as colorless oil. MS: 399.2, 401.2 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:12]([N:18]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CCCO1

Procedure:
19.8 g (134 mmol) of phthalic anhydride were dissolved in 500 ml of chloroform. To the resultant solution, 10 g (99 mmol) of tetrahydrofurfurylamine were added with stirring. The resultant mixture was subjected to a reflux overnight while the reactant water yielded was distilled off. The thus obtained reaction mixture was allowed to cool and then was poured into 300 ml of aqueous solution of saturated sodium hydrogencarbonate. Thereafter, an organic solvent layer was separated from the reaction mixture. The residual water layer was subjected to an extraction twice with chloroform and the extract thus obtained was combined with the organic solvent layer which was previously separated.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH3:13][C:14]([CH3:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14](=[O:15])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To the solution of 4-chlorobenzaldehyde (8.43 g, 60 mmol) in acetone(60 ml) and ethanol (6 ml) was added under stirring 10% NaOH aqueous solution(48 ml) and water(240 ml), the reaction solution was stirred at 25° C. for 8 hr. The precipitated solid was collected by filtration and washed with water, dried to give the title compound 10.5 g as a white solid, mp 56-57° C., yield: 96.9%.
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([I:7])[N:6]=1.[H-].[Na+].I[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.I>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[N:3]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([I:8])=[C:5]([I:7])[N:6]=1
Reactant: Ic1nc(I)c(I)[nH]1
Reactant: ICCN1CCCC1
Agent: I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1nc(I)n(CCN2CCCC2)c1I
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 2,4,5-triiodo-1H-imidazole (165) (4.08 g, 9.1 mmol) in DMF (28 mL) at 0° C., was added NaH (1.46 g, 36.4 mmol) portionwise over 30 mins. Then 1-(2-iodoethyl)pyrrolidine×HI 164 (4.85 g, 13.65 mmol) was added at 0° C., and the reaction mixture was allowed to warm to room temperature over a period of 4 hrs. EtOAc (50 mL) was added and the mixture was washed with NaHCO3 aqueous solution. The organic phase was separated and extracted with citric acid solution (3%), the acidic aqueous extract was basified with 2N NaOH solution to pH˜10, the resultant solid was collected by filtration to give the title compound 166 (1.75 g, 35%) as a light brown solid. MS (m/z): 543.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>O.CN(C=O)C>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
A mixture of 2 g (13 mmol) 2-chloro-5-nitro-pyridine and 0.76 g (6 mmol) N,N-diisopropylethylamine in 21 ml water and 4 ml DMF was heated to 80° C. During 2 min 1.73 g (15 mmol) N-ethylpiperazine was added and the mixture was kept for an additional hour at 80° C. The yellow precipitate was filtered off and washed three times with 4 ml water and dried for 16 h under vacuum to yield 2.48 g (83%) of the title compound as yellow crystals. (m/e): 237.1 (MH+; 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28](Cl)=[O:29]>>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28]([NH:23][C:10]1[S:11][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:29]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Product: O=C(Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1cc(F)cc(F)c1
Yield: 58 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and 3,5-difluorobenzoyl chloride prepared in the step 1 of Example 16 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 58.0%, mp: 216-218 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.44 (2H, s, CH2), 7.30 (2H, t, 3JFH=3JHH=8.96 Hz, ArH), 7.51 (2H, d, J=8.68 Hz, ArH), 7.30 (1H, t, 3JFH=9.00 Hz, ArH), 7.68 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.30 (2H, d, 3JFH=6.16 Hz, ArH), 8.20 (2H, d, J=8.68 Hz, ArH), 12.95 (1H, br, CONH); EI-MS m/e (%): 469.1 (M+, 77), 141.1 (100); HREI-MS Calcd. for C23H14F3N3O3S: 469.0708. found: 469.0710. Anal. Calcd. for C23H14F3N3O3S: C, 58.85; H, 3.01; N, 8.95. found: C, 58.42; H, 2.64; N, 8.80.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C1C=CC=CC=1>[C:14]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a well stirred solution of 3.62 g of trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (1:1) in 30 ml of water at 0-5° C is added 2.1 ml of benzoyl chloride in 10 ml of benzene. To this stirred two-phase mixture is added, over 30 minutes at 0°-5° C, a solution of 1.45 g of sodium hydroxide in 30 ml of water--precipitation of a pink solid begins immediately. After stirring the mixture for an additional 2 hours at 0°-5° C, the solid is filtered, washed with ether, and dried in vacuo to give 4.2 g of crude trans-3-benzamido-1,2,3,4-tetrahydro-2-naphthalenol.
Reaction SMILES: COC([C:5]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=O.[C-]#N.[Na+].Cl>CN(C)P(=O)(N(C)C)N(C)C>[CH3:35][O:34][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:5]1[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=[O:33]
Reactant: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1(CCCCCCC(=O)OC)C(=O)OC
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1CCCCCCC(=O)OC
Temperature: 25 °C
Yield: 82.5 %

Procedure:
1.00 g (1.98 mmol) of 3-methoxycarbonyl-3-(6-methoxycarbonylhexyl)-4-(1-phenylthio-trans-2-octenyl)-oxolane-2-one was dissolved in 23 ml of hexamethylphosphoric triamide followed by stirring. 194 mg (3.96 mmols) of sodium cyanide was then added to the solution and the mixture was heated at 75° to 80° C. for 15 hours while heating. The mixture was allowed to cool to room temperature and rendered neutral with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed three times with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation and the resulting residue was purified by silica gel column chromatography using ethyl acetate and n-hexane (1:9 by volume) as an eluent to obtain 730 mg (83% yield) of 3-(6-methoxycarbonylhexyl)-4-(1-phenylthio-trans-2-octenyl)-oxolane-2-one an an oily substance.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.O.[CH3:23]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:23])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoic acid (1.40 g) in methanol (50 mL) was added dropwise thionyl chloride (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.30 g) as a colorless oil. Ethyl acetate (250 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16](C(O)=O)=[C:15]3[N:10]([N:11]=[C:12]([O:20][CH3:21])[CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:29][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:20][CH3:21])=[N:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C(=O)O)c(-c3cccc(F)c3)nn2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(-c3cccc(F)c3)nn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (2.0 g) in anhydrous DMF (20 ml) was added n-bromosuccinimide (1.78 g) and the resulting solution stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (800 ml) and washed sequentially with water (10×100 ml) and sat. brine (25 ml), dried (Na2SO4), and concentrated to give the title compound as a buff solid (2.19, 93%).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:10][CH:11]([F:36])[CH2:12][NH:13][C:14]([C:16]1[C:20]2[CH:21]=[C:22]([CH:34]=O)[C:23]([N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[C:24]([F:25])[C:19]=2[O:18][N:17]=1)=[O:15]>>[F:36][CH:11]([F:10])[CH2:12][NH:13][C:14]([C:16]1[C:20]2[CH:21]=[C:22]3[C:23](=[C:24]([F:25])[C:19]=2[O:18][N:17]=1)[N:26]1[CH2:31][C@@H:30]([CH3:32])[O:29][C@@H:28]([CH3:33])[C@@H:27]1[C:7]1([C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9])[CH2:34]3)=[O:15]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)NCC(F)F)noc3c2F)C[C@H](C)O1
Product: C[C@@H]1CN2c3c(cc4c(C(=O)NCC(F)F)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: Barbituric acid and N-(2,2-difluoroethyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxamide were reacted (Intermediate 467) using a method similar to the one described for the synthesis of Example 134. The product was purified by reverse phase HPLC using a gradient of CH3CN in water with 0.1% TFA.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.[C-:12]#[N:13].[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: Fc1cc(I)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(I)cc1F
Yield: 96.4 %

Procedure:
A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1, 2.56 g, 8.15 mmol) in ethanol (55 mL and water (10 mL) was treated with sodium cyanide (2.15 g, 43.86 mmol) and refluxed for 0.5 h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic extract was washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a pale yellow solid (2.05 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:26][NH2:27])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
20 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbonyl chloride in 100 ml of ethanol are placed under nitrogen and the mixture is heated at reflux for 2 hours. It is allowed to return to a temperature of 20-25° C., then 50 g of hydrazine hydrate are added and the mixture is again heated at reflux for 3 and a half hours. The reaction medium is filtered while hot and then the ethanol is evaporated. The reaction medium is concentrated, then taken up in 150 ml of DCM and separated by settling. The aqueous phase is discarded, the organic phase is washed twice with 100 ml of water and then the DCM is evaporated. After drying under vacuum, 16.9 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[S:8][C:9]3[C:10](=[N:11][CH:12]=[C:13]([C:23]#[N:24])[C:14]=3[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C=O>[Br:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:14]1[C:13]([C:23]#[N:24])=[CH:12][N:11]=[C:10]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:25](=[O:28])[CH:26]=[CH2:27])[C:7]=3[S:8][C:9]=12
Reactant: N#Cc1cnc2c(sc3c(N)cccc32)c1Nc1cccc(Br)c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cccc2c1sc1c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 43 %

Procedure:
A 0.138 g (0.349 mM) portion of 6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile is dissolved in 2 mL of tetrahydrofuran and 2 mL of dimethylformamide at 0C. To this is added 0.042 g (0.583 mM) of acrylic acid, 0.105 g (0.575 mM) of N,N-diisopropylethylamine and 0.106 g (0.554 mM) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride with stirring under nitrogen. The reaction mixture is stirred for 48 hours at room temperature, and the solvent is removed under reduced pressure. The residue is worked up with water (3 mL) and extracted with methylene chloride (10 mL), dried with sodium sulfate and evaporated. Purification of the product is carried out by silica gel chromatography, eluting with 20:1 chloroform/methanol. Further purification is achieved by preparative thin layer chromatography, eluting with the same solvent system. Finally, the product is washed with ether to provide 0.068 g (43%) of N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide, m.p. 286-287° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(O)C.[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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2cccc(Br)c2)s1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccc(-c3cccs3)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
To a suspension of 10.0 mg (0.0086 mmol) tetrakis(triphenylphosphine)-palladium(0) in 2 ml dry dimethoxyethane, 100 mg (0.272 mmol) 5-[1-(3-Bromo-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester were added and stirred for 10 min at room temperature under nitrogen atmosphere. 52.5 mg (0.410 mmol) thiophene-2-boronic acid in 0.5 ml ethanol and 285 μl (0.570 mmol) of a 2 M aqueous solution of Na2CO3 were added and the mixture was heated in the microwave oven (Emrys Optimizer) at 100° C. for 25 min. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with ethanol. The solvent of the combined filtrates was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate, the solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/n-heptane 1:2) to yield 81 mg (0.218 mmol) 5-[1-(3-thiophen-2-yl-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Br.C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[CH2:14]Br)[N:8]=1)(=O)C.[NH2:17][C:18](=[N:20][C:21]([NH2:23])=[S:22])[NH2:19]>CO>[NH2:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[N:23]=[C:21]([N:20]=[C:18]([NH2:19])[NH2:17])[S:22][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1cccc(C(=O)CBr)n1
Reactant: NC(=S)N=C(N)N
Agent: Br
Solvent: CO
Product: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 42.4 %

Procedure:
A mixture of 2-(acetylaminometyl)-6-bromoacetylpyridine hydrobromide (3.34 g) and diaminomethylenethiourea (1.01 g) in methanol (50 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected, dissolved in water (50 ml) and the solution was made basic with aqueous potassium carbonate. The separated product was collected and washed with water to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.90 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34][CH3:35])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[O:18][CH2:17][C@H:16]([CH2:28][CH2:29][NH:30][CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([O:40][C:41]([N:43]([CH3:49])[CH2:44][CH2:45][C:46]([OH:48])=O)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]([CH3:49])[CH2:44][CH2:45][C:46]([N:30]([CH3:31])[CH2:29][CH2:28][C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:32]([O:34][CH3:35])=[O:33])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[O:18][CH2:17]1)=[O:48])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CNCC[C@H]1COc2c(OC)cccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](CCN(C)C(=O)CCN(C)C(=O)OC(C)(C)C)COc1c(OC)cccc1-3

Procedure:
The title compound was prepared in analogy to Example 13, Step 6 from methyl (7R)-14-cyclohexyl-4-methoxy-7-[2-(methylamino)ethyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate and N-(tert-butoxycarbonyl)-N-methyl-β-alanine