Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>O.C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15][CH2:16][C:17]1=[O:18]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
4-Aminobenzoic acid (100 g, 0.73 mol) is suspended in water (400 mL) and toluene (200 mL), and thereto is added dropwise 30% aqueous sodium hydroxide solution (97 g, 0.73 mol) under ice-cooling. After confirming that pH is basic enough, 4-chlorobutyric chloride (103 g, 0.73 mol) and 30% aqueous sodium hydroxide solution (290 g, 2.2 mol) are added dropwise simultaneously while maintaining the pH range of 9-12 and temperature range of 15-20° C. over 1 hour. After stirring at room temperature for 1 hour, sodium hydroxide (88 g, 2.2 mol) is added to the mixture under ice-cooling. To the reaction solution is added conc. hydrochloric acid (370 g) at 30° C. or below and precipitated crystals are collected by filtration. The resulting crystals are washed with water and air-dried at 40° C. to give 4-(2-pyrrolidon-1-yl)benzoic acid (144 g, yield: 96.0%, purity: 98.3%). The purity was determined by HPLC analysis.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:6]2.[O:23]=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:6]2)[C:24](=[O:23])[CH3:31])[CH3:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)c1cc2c(Cl)ccc(-c3ccccc3C)c2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(C(C(C)=O)C(=O)OCC)ccc(-c3ccccc3C)c2[nH]1
Temperature: 93 °C

Procedure:
A mixture of ethyl 4-chloro-7-o-tolyl-1H-indole-2-carboxylate (EXAMPLE 166C) (0.93 g), ethyl 3-oxobutanoate (0.849 g), di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine (0.093 mg), K3PO4 (3.46 g), and palladium(II) acetate (0.033 g) in toluene (8 mL) was degassed via vacuum/nitrogen cycle three times. The reaction mixture was heated at 93° C. for 14 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash chromatography on silica gel (ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C(C)C)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.CO[C:26]1[CH:43]=CC(CNC2N=C(Cl)N=C3C=2NC=N3)=C[CH:27]=1.[H-].[Na+].IC(C)C>CN(C=O)C.O>[CH:26]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:43])[CH3:27]
Reactant: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Solvent: O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2) The 6-(4-methoxybenzylamino)-2-chloropurine (496 mg, 1.7 mmol) was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine (508 mg, 89%).
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:35]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=O)(=[O:37])[CH3:36].[NH2:48][C:49]1[CH:58]=[CH:57][C:56]([C:59]([C:61]2[N:69]3[C:64]([CH:65]=[CH:66][CH:67]=[CH:68]3)=[C:63]([NH2:70])[C:62]=2[CH3:71])=[O:60])=[CH:55][C:50]=1[C:51]([O:53][CH3:54])=[O:52]>CN(C)C=O.C(OCC)(=O)C.CC(C)=O>[C:35]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([NH:70][C:63]1[C:62]([CH3:71])=[C:61]([C:59]([C:56]2[CH:57]=[CH:58][C:49]([NH2:48])=[C:50]([CH:55]=2)[C:51]([O:53][CH3:54])=[O:52])=[O:60])[N:69]2[C:64]=1[CH:65]=[CH:66][CH:67]=[CH:68]2)=[O:44])(=[O:37])[CH3:36]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OC(C)=O)c3)c3ccccn23)ccc1N
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
0.95 ml (6.80 mmol) of triethylamine and 1.50 g (3.40 mmol) of BOP are added, at ambient temperature, to 0.61 g (3.40 mmol) of 3-acetoxybenzoic acid in suspension in 20 ml of N,N-dimethylformamide. After 15 minutes, 1.0 g (3.09 mmol) of methyl 2-amino-5-[(1-amino-2-methylindolizin-3-yl)carbonyl]benzoate (described in Patent Application WO2003084956) in 10 ml of N,N-dimethylformamide is added. The reaction medium is stirred for 16 hours under argon and then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in acetone and then filtered and dried. 0.86 g (57%) of a greenish yellow powder is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][C:4]=1[O:21][CH3:22])=[O:2].S(=O)(=O)(O)[OH:24].C([O-])([O-])=O.[K+].[K+]>>[CH:1]([C:3]1[C:4]([O:21][CH3:22])=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][N:9]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:24])=[CH:19][CH:20]=1)[CH2:8]2)=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1cc2c(cc1C=O)CN(c1ccc(C#N)cc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1C=O)CCN(c1ccc(C(N)=O)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 4-(7-formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzonitrile (200 mg, 0.68 mmol) and 96% (w/w) sulfuric acid (3 mL) was stirred at room temperature overnight. The next day poured onto ice-water (10 mL), the pH was adjusted with K2CO3 to 9 and the mixture was extracted with ethyl acetate. The residue was purified by column chromatography over silica, elating with a 95:5 mixture of chloroform and methanol. In this manner the title compound (85 mg, 0.27 mmol, 39.7%) was obtained as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[OH:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[O:26][CH:35]2[CH2:38][CH2:37][CH2:36]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccc(F)cc2C1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cc(Cl)cc(Cl)c2OC2CCC2)Cc2ccc(F)cc2C1
Yield: 51.8 %

Procedure:
To a suspension 2-(3,5-dichloro-2-hydroxy-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (19) (624 mg, 1.51 mmol), anhydrous Cs2CO3 (984 mg, 3.02 mmol), and KI (50 mg, 0.30 mmol) in DMF (20 mL) is added bromocyclobutane (711 μL, 7.55 mmol). The resulting reaction suspension is covered with argon and ran in a microwave reaction: 110° C., 2 h. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-50% EtOAc in heptane) to give a pure product (20) as white solid (365 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (800 mg) obtained in Reference Example 1(2) is dissolved in chloroform (30 ml), and thereto are added morpholine (560 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.24 g) and triethylamine (650 mg) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed successively with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=30/1) to give methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexanecarboxylate (897 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:15][CH2:14][C@H:13](/[CH:16]=[CH:17]/[C@@H:18]([O:24]C2CCCCO2)[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.C1COCC1>[OH:24][C@@H:18]([CH2:19][CH2:20][C:21]#[C:22][CH3:23])/[CH:17]=[CH:16]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][CH2:14]1
Reactant: CC#CCC[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
320 mg. of (5Z,13E)-(15S)-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours at room temperature with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), then evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 210 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH2:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[CH2:10]([C:9]1[NH:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C=CCCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylhept-6-ene-1,3-dione (3 g, 14.83 mmol) in ethanol (50 mL) was added hydrazine hydrate (2.228 g, 44.5 mmol) at room temperature. The reaction was refluxed for 10 h, cooled to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.78 (m, 2H), 4.01-4.12 (m, 2H), 4.83-4.95 (m, 2H), 5.82-5.93 (m, 1H), 6.42 (s, 1H), 7.23-7.82 (m, 5H), 12.6 (s, 1H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=O.[Mg+2].[I:45]Cl>ClCCl.C(#N)C>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[I:45])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:2][CH2:3][CH2:4]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)cc2c(=O)[nH]ncc21
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(I)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To 283 mg (0.593 mmol) of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 31-(a) were added 1.6 ml of dichloromethane and 5 ml of acetonitrile, then, 167 mg of sodium hydrogencarbonate and 367 mg of anhydrous magnesium sulfate were added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. Then, 3 ml of dichloromethane solution containing 267 mg of iodine chloride was added to the same, and the resulting mixture was further stirred at room temperature for 4 hours. After completion of the reaction, a filtrate obtained by removing insoluble material in the reaction suspension by filtration and a washed solution obtained by washing the filtered solid with ethyl acetate were combined and the combined solution was washed successively with 5% aqueous sodium thiosulfate solution and then with a saturated aqueous solution of sodium chloride. The organic layer after washing was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→0:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 314 mg of the title compound as a pale yellowish foam. (Yield: 88%)
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([C:10]1[N:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28][C:29](=[O:41])[C@@H:30]([N:32](C)[C:33](=O)OC(C)(C)C)[CH3:31])[CH2:24][O:23][C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9].CC#N.O>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([C:10]1[N:11]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28][C:29](=[O:41])[C@@H:30]([NH:32][CH3:33])[CH3:31])[CH2:24][O:23][C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9]
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)C1=O
Reaction time: 1 h
Yield: 93.5 %

Procedure:
TFA (1.48 g, 1 mL, 13.0 mmol, Eq: 178) was added to a solution of tert-butyl (S)-1-((S)-5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (45 mg, 72.7 μmol, Eq: 1.00) in DCM (1.7 mL) at 0° C. After 1 h, the mixture was concentrated and the residue triturated with Et2O/Hexanes to give a solid which was lyophilized from MeCN/H2O to give the title compound (43 mg, 93.5%) as a solid. MS m/z 519 (MH+)
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:16]([Si](C)(C)C)#[CH:17].C(N(CC)CC)C.[F-].[Cs+]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.CCCCCC>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][NH:10][C:3]1[C:2]([C:16]#[CH:17])=[CH:7][N:6]=[C:5]([C:8]#[N:9])[N:4]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#Cc1cnc(C#N)nc1NCC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
5-Bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (7.58 mmol) and ethynyl-trimethyl-silane (22.74 mmol) in DMF (20 ml) are treated with triethylamine (38.0 mmol), copper (I) iodide (0.76 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.38 mmol) at room temperature. The mixture is stirred for 1.5 h at room temperature, poured into an ice water and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is dissolved in methanol (60 ml) water (10 ml) and cesium fluoride (4.2 mmol) is added at room temperature and the mixture is stirred at room temperature for 5 min. The reaction mixture is evaporated, then water and CH2Cl2 are added. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 76% yield. Rf=0.67 (n-hexane:AcOEt=2:1)
Reaction SMILES: F[C:2](F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.C=O.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([CH3:2])[CH2:15][C:13]=2[N:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a stirring solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) (2.16 g, 2.0 mmol) in DMF, was added aqueous formaldehyde (0.3 ml, 4.0 mmol) and Et3N (560 uL, 4.0 mmol). The reaction mixture was stirred at room temperature (20° C.) for 45 minutes, before adding sodium triacetoxy borohydride (848 mg, 4.0 mmol). The reaction mixture was then stirred over-night at room temperature (20° C.). The reaction mixture was basified (with 2M NaOH) before partitioning between water (25 ml) and DCM (50 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo, affording the title compound as a pink solid, which was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C@@H:25]([C:37]([O:39]C(C)(C)C)=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[C:18]=4[CH3:44])[CH2:13][CH2:12]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][C@@H:25]([C:37]([OH:39])=[O:38])[NH:26][C:27]([O:29][CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:28])[C:18]=4[CH3:44])[CH2:15][CH2:16]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A mixture of 38 mg (0.06 mmoles) of (1,1-dimethylethyl) 3-[[6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenyl methoxy)carbonyl]alaninate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane is stirred at ambient temperature for 3 hours. Then 5 ml of toluene is added followed by evaporating the mixture to dryness. 26 mg (Yield=76%) of expected product is obtained in the form of an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl.FC1C=CC(C(Cl)=O)=CC=1.N1C=CC=CC=1>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a suspension of 30.0 gm (0.217 mole) 4-nitroaniline in 225 mL dichloromethane were added 17.57 mL (0.217 mole) pyridine. The suspension was cooled to 0° C. and then 25.66 mL (0.217 mole) 4-fluorobenzoyl chloride were added slowly. Within 15 minutes the reaction mixture became homogeneous and was allowed to warm to room temperature. After an hour an additional 2.56 mL (21.7 mMol) 4-fluorobenzoyl chloride and 1.75 mL (21.7 mMol) pyridine were added and the reaction continued at room temperature for an additional hour. The reaction mixture was then washed with 200 mL water at which point a precipitate formed. The solid was filtered, washed with 100 mL hexane, washed with 200 mL water and dried under reduced pressure at 60° C. to give 56.6 gm (100%) of the desired compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:22])(=O)C.O[Li].O>C1COCC1.CO.O>[Br:22][C:7]1[CH:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CCOc1ccc(Cc2ccc(COC(C)=O)c(Br)c2)cc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(Cc2ccc(CO)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-bromo-4-(4-ethoxybenzyl)benzyl acetate (0.215 g, 0.59 mmol) in 10 mL of THF/MeOH/H2O (2:3:1) was added LiOH.H2O (0.051 g, 1.21 mmol). After the reaction mixture was stirred at 25° C. for 3 hours, the volatiles were removed using a rotary evaporator. The residue was dissolved in EtOAc, washed once with brine and dried over Na2SO4. The volatiles were removed using a rotary evaporator to yield 0.175 g of the title compound, which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.38-7.36 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.71 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.88 (s, 2H), 1.92 (bs, 1H), 1.40 (t, J=7.2 Hz, 3H); MS ESI (m/z) 320 [M+], calc. 320.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:9]1[CH:8]=[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 0.18 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (20 mL) and then 1080 ul of LiOH 1N was added to it. After 16 h of stirring at temperature of 100° C., solvents were removed and then partitioned between 10 ml of H2O, 2 ml of KHSO4 5% and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4) and concentrated to obtain 43 mg (63%) of 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid 1H-NMR (DMSO, 400 MHz): δ 7.65 ppm (m, 3H, Haro); 7.43-7.32 ppm (m, 5H, Haro); 7.23 ppm (s, 1H, Haro); 4.61 ppm (d, 2H, N—CH2).