Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]12[CH2:36][CH2:35][CH2:34][N:33]1[CH2:32][CH2:31][CH2:30]2>CN(C)C=O>[CH2:1]([C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([NH:27][CH2:28][C:29]23[CH2:36][CH2:35][CH2:34][N:33]2[CH2:32][CH2:31][CH2:30]3)=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)O)c2ccccn12
Reactant: NCC12CCCN1CCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCC23CCCN2CCC3)c2ccccn12

Procedure:
3-Ethylindolizine-1-carboxylic acid is reacted with carbonyldiimidazole in dimethylformamide and subsequently with 7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound upon workup.
Reaction SMILES: O[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:29])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([Cl:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(Cl)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 ml of ether, 350 mg of ethyl 2-hydroxy-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate, 360 mg of thionyl chloride, and catalytic amount of pyridine are added and stirred at room temperature overnight. Then, saturated aqueous sodium bicarbonate solution is added and the ether layer separated is dried, evaporated, and purified with column chromatography. Ethyl-2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate is obtained with the yield of 300 mg. In IR and NMR, this product is in good agreement with the compound No. 1 in Example 7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:12]([C:10]1[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:20]2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Reaction time: 0.67 h

Procedure:
1248 mg (6.03 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 1000 mg (5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2291 mg (6.03 mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure. The reaction mixture is taken up in methanol and stirred together with acidic ion exchange resin (Dowex WX2-200) for about 40 min. The loaded ion exchanger is washed six times with in each case 100 ml of methanol. It is then eluted using methanol/triethylamine 99:1 to 90:10. The solvent is removed under reduced pressure. The product is taken up in 1N aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The extract is dried on magnesium sulfate. 1100 mg (69% of theory) of the title compound are isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[O:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[O:34][CH:27]([CH2:33][CH2:32]1)[CH2:28][N:29]([C:2]1[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]3[CH2:24][OH:25])[N:3]=1)[CH2:30]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16](=O)[CH:17](OC)[O:18]C.CC(=O)C.Cl>C(O)C>[CH:17]([C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[CH:14][CH:15]=1)=[O:18]
Reactant: N#Cc1ccc(NN)cc1
Reactant: COC(OC)C(=O)/C=C/N(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: N#Cc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-hydrazinylbenzonitrile hydrochloride (10.14 g, 59.78 mmol, 1.00 equiv), (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (17.6 g, 101.61 mmol, 1.70 equiv), propan-2-one (30 mL) and 6N hydrochloric acid (30 mL) in ethanol (300 mL) was stirred at 78° C. for 3.5 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Water (300 mL) and ethyl acetate (200 mL) were added to dissolve the residue. The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 4 g (34%) of 4-(5-formyl-1H-pyrazol-1-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.87 (s, 1H), 8.09-7.98 (m, 3H), 7.85-7.83 (m, 2H), 7.36 (d, J=1.5 Hz, 1H) ppm. LCMS (method A, ESI): RT=1.28 min, m/z=198.0 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[NH2:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=[O:33])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2-(3-{[(Tert-butoxycarbonyl-)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.17 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl-]4-methyl-1,3-thiazole-5-carboxylic acid hydrochloride (0.12 g, 92.3%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].N1CCCCC1>CCO>[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21]([C:22]2[C:23]([CH3:24])=[N:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=3)=[O:26])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(C=O)c(N)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2cc(C(=O)NCc3ccc(C(C)(C)C)cc3)c(C)nc2n1
Yield: 50.5 %

Procedure:
A solution of 200 mg (1.47 mmol) 2-amino-6-methylnicotinaldehyde, 400 mg (1.62 mmol) N-(4-tert-butylbenzyl)-3-oxobutanamide and 15 (0.15 mmol) piperidine in 3 ml EtOH was refluxed for 36 h. The reaction mixture was concentrated under reduced pressure. Flash chromatography (CH2Cl2/MeOH 20:1) afforded 258 mg (51%) of the title compound as a yellow-brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[O:18][N:17]=1)=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:51]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21](=[O:51])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[O:18][N:17]=1)=[O:15]
Reactant: C1CCOC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(Cc2cc(F)ccc2F)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(=O)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.0641 g; 0.154 mmol) was added to a solution of tetrabutylammonium fluoride in THF (1 M, 0.462 mL). The resulting mixture was stirred at room temperature overnight. As the reaction was not completed, tetrabutylammonium fluoride in THF (1 M, 2 mL) were added, the reaction mixture was stirred for four hours and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 20% methanol in dichloromethane) and by preparative HPLC method 2 to yield 0.013 g (19%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide as a yellow solid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:12](O)(=[O:14])C>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[NH:8])[O:14][CH3:12])[CH:3]=1
Reactant: CC(=O)O
Reactant: N#Cc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccnc1
Reaction time: 18 h

Procedure:
A solution of nicotinonitrile (11.35 g) and sodium methoxide (1.1 g) in methanol was allowed to stand at ambient temperature under nitrogen for 18 hours, then acetic acid (1.2 ml) was added, and the solvent was removed in vacuo. The residue was triturated with cyclohexane, undissolved solid was removed by filtration, and the solvent was removed in vacuo to leave methyl pyridine-3-carboximidate as an orange oil (10.6 g).
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][NH2:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:19][CH2:20]O>>[ClH:1].[CH2:19]([NH:15][CH2:14][C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:16]([OH:18])=[O:17])[CH3:20]
Reactant: CCO
Reactant: NC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Agent: Cl
Product: CCNC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
HCl gas was rapidly bubbled through a suspension of acid 5-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bath was removed and the reaction was heated to 60° C. After 18 h, the reaction was concentrated to provide ester 5-4 as a white solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:30][C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccc(C(F)(F)F)cc3)(CC1)CC2
Yield: 74.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and 4-trifluoromethylbenzyl bromide (16.2 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-trifluoromethylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.2 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:29])=[C:19]([F:28])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:29][C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[O:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:19]=1[F:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4)c3O2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2c(F)c(F)cc(-c3ccccc3)c2O1
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.40 mmol) in N,N-dimethylformamide (25 mL) was added sodium azide (0.781 g, 12.02 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 3 h. The reaction mixture was allowed to cool and the solvent was removed in vacuo to provide a crude solid. The residue was suspended in ethyl acetate (100 mL) and washed with water (50 mL) and aqueous sodium chloride (50 mL), was dried (sodium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.68 g (99%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide as a white solid. Rf=0.93 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.65 (d, 2H); 7.41 (m, 3H); 7.31 (t, 1H); 5.15 (m, 1H); 3.64 (m, 2H); 3.46 (dd, 1H); 3.10 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=O)=[CH:17][CH:16]=1.[CH2:36]([P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:36]/[P:45](=[O:52])([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a mixture of 5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]ethenylphosphonate as colorless crystals (0.41 g, yield 62%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Br:25]N1C(=O)CCC1=O>CN(C=O)C>[Br:25][C:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[C:5]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:6]=2[C:12](=[O:13])[NH:11][CH:10]=1
Reactant: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]cc(Br)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 20 mL reaction vessel was charged with 2-(methylthio)-4-(3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (135 mg, 0.38 mmol), and N-bromosuccinimide (68 mg, 0.38 mmol) in 7 mL dry DMF. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressuring yielding yellow residue. The residue was recrystallized from acetonitrile providing yellow solid (100 mg, 74%). MS m/z: 431, 433 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC(OP(O[NH2:29])(OC2C=CC=CC=2)=O)=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C(OCC)C>[NH2:29][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc[nH]1
Reactant: NOP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccn1N
Temperature: -5 °C
Yield: 82.5 %

Procedure:
Sodium hydride (4.40 g, 0.11 mol, 60% in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at −5° C., methyl 1H-pyrrole-2-carboxylate (11.0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277 ml more of DMF was added and then 0-(diphenylphosphoryl)hydroxylamine (32.8 g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4 h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (×5H2O) was added and the mixture was warmed to 80° C. for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81.1% yield) of the final compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C1C=CC=CC=1>[CH3:12][N:13]([CH3:22])[CH2:14][CH2:15][O:16][CH:17]1[CH2:21][CH2:20][N:19]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:11])[CH2:18]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN(C)CCOC1CCNC1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N2CCC(OCCN(C)C)C2)cc1
Reaction time: 2 h

Procedure:
A solution of 3.0 g. (0.02 mole) of p-methoxyphenyl isocyanate in 10 ml. of dry benzene was added dropwise to a stirring solution of 3.2 g. (0.02 mole) of 3-(2-dimethylaminoethoxy)pyrrolidine in 100 ml. of dry benzene under anhydrous conditions. When the addition was complete, the reaction mixture was allowed to stir for two hours. The mixture was concentrated under reduced pressure to give 4.9 g. (80%) of product which crystallized upon standing. Recrystallization from benzeneisooctane gave 4.8 g. of solid melting at 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][OH:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)-2-hydroxyethanone (18 mg, 0.048 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (18 mg, 0.062 mmol) followed by formation of the dihydrochloride salt to afford the desired product (9.1 mg, 33%) as an off-white solid. 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.13 (s, 2H), 5.78-5.68 (m, 1H), 4.91 (s, 2H), 3.10 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.49-2.42 (m, 2H), 2.10-2.00 (m, 3H), 1.76-1.66 (m, 2H), 1.48-1.36 (m, 2H).; ESI MS m/z 503 [M+H]+; HPLC>99% (AUC), tR=9.40 min.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:11][CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH3:16]>CO>[CH3:16][CH:15]1[C:14](=[O:17])[CH2:13][CH:12]([CH3:11])[CH:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: CC=CC(=O)CC
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)CC(C)C(C#N)C1=O
Temperature: 25 °C
Yield: 68.2 %

Procedure:
To a solution of sodium methoxide (162 grams, 3 moles) in 400 mls of anhydrous methanol is added, dropwise, 276 grams (3.2 moles) of methylcyanoacetate over a period of 1 hour at 60° C. with stirring. The resulting slurry is stirred at 60° C. for 10 minutes, whereupon 288 grams (3.0 moles) of 2-hexen-4-one is added over a 20 minute period. The resulting reaction mixture is stirred and heated at reflux for six hours, whereupon a distillation take-off condenser is affixed to the reaction flask and 240 mls of methanol are removed under reduced pressure (65 mm Hg). The reaction mixture is then cooled to room temperature and poured into 2 liters of water. Toluene (500 ml) is added and the mixture is transferred to a separatory funnel. The aqueous layer is removed and again extracted with toluene (500 mls). To the aqueous solution, 500 mls of 18% HCl are added with external cooling at 25° C., whereupon a solid material precipitates. The solid is filtered, dried and recrystallized from aqueous methanol to afford colorless needles of 3,6-dimethyl-2,4-dioxocyclohexanecarbonitrile (338 grams, 68.3% yield based on 2-hexen-4-one); m.p. 178°-179° C. The resulting product is represented by the following equilibrium mixture: ##STR21##
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f20) and commercially acetyl chloride the title compound is obtained as colorless solid.