Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: CCOC(=O)CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and ethyl 4-bromobutyrate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (80%) as a gummy material: 1H NMR (300 MHz, CDCl3) δ 7.29 (t, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.11 (q, 2H), 3.88-3.71 (m, 2H), 2.40 (t, 2H), 2.03 (t, 2H), 1.21(t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4, 172.8, 156.0, 148.9, 142.4, 142.2, 132.4, 129.0, 124.0, 123.3, 119.4, 108.7, 103.0, 101.5, 93.6, 80.5, 60.7, 58.2, 39.6, 31.2, 22.6, 14.3; MS (ES+) m/z 418.08 (M+23), 396.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]2[O:46][CH2:45][O:44][CH2:43][C:42]=2[CH:47]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]2[CH:39]=[C:40]([CH2:48][CH3:49])[C:41]3[O:46][CH2:45][O:44][CH2:43][C:42]=3[CH:47]=2)[NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:30][CH:31]=2)=[N:11]1)=[O:4]
Reactant: COC(=O)c1scnc1NN
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncsc3C(=O)OC)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After adding 71 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 300 μl of triethylamine to a solution of 198 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (27b)) in 6 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue was dissolved in 6 ml of DMF, and then 0.3 ml of triethylamine was added and the mixture was stirred at 80° C. for 6 hours.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:18][C:19]([N:21]([CH2:29][CH2:30][O:31][NH:32][C:33]([NH2:42])=[N:34]C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:43])[N:14]([CH2:18][C:19]([NH:21][CH2:29][CH2:30][O:31][NH:32][C:33]([NH2:42])=[NH:34])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N=C(N)NOCCN(C(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NOCCNC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 3-benzylsulfonylamino-1-{[N,N′-di(tert-butoxycarbonyl)] [(2-guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (155 mg, 0.25 mmol), as prepared in the preceding step, and trifluoroacetic acid (2 mL) in methylene chloride (3 mL) was stirred at room temperature for 2 h. After evaporation of the solvent in vacuo, the residue was purified by Waters Sep-Pak (10 g, 10% methanol in methylene chloride) to give the title compound as a colorless foam (160 mg, 92%). 1H-NMR (300 MHz, DMSO c6) δ 11.00 (s, 1H), 8.66 (s, 1H), 8.45 (t, J=5.3 Hz, 1H), 7.72 (br s, 4H), 7.40 (d, J=6.9 Hz, 1H), 7.33 (m, 5H), 7.19 (d, J=7.0 Hz, 1H), 6.19 (d, J=7.0 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.39 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H22N6O5S: 423.1 (M+H), 445.1 (M+Na); Found: 423.3, 445.0.
Reaction SMILES: [NH2:1][C:2](=[C:6]([OH:10])[CH2:7][O:8][CH3:9])[C:3]([OH:5])=[O:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][CH:2]([CH:6]([OH:10])[CH2:7][O:8][CH3:9])[C:3]([OH:5])=[O:4])(=[O:13])[CH3:12]
Reactant: COCC(O)=C(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COCC(O)C(NC(C)=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of amino acid 7 (34 g, 0.23 mol) in 300 ml of water cooled to 0° was added dropwise with stirring, 10 ml of acetic anhydride. After 1 hr, an additional 10 ml of acetic anhydride was added. The process was continued until a total of 35 ml of acetic anhydride had been added. The reaction mixture was allowed to stand at 0° for 3 hrs. The solvent was then removed in vacuo at 50°. Water was added to the residue and after a homogeneous solution was obtained, the water was removed in vacuo at 50°. The addition and removal of water was repeated 3 more times. The resultant residue was subjected two more times to the entire sequence beginning with the addition of 35 ml of acetic anhydride in portions. The residue resulting from this treatment was dried in vacuo (0.1 mm) for 48 hr yielding 2-Acetamido-3-hydroxy-4-methoxybutanoic acid as a glass. This material was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1.C1(C)C=CC=CC=1>C(#N)C>[C:1]([C:5]1[N:6]=[C:7]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: O[C@H]1CCNC1
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (10 g, 29.7 mmol, Eq: 1.00) was dissolved in Acetonitrile (54.6 g, 70.0 ml). N-Ethyldiisopropylamin (7.84 g, 10.3 ml, 59.5 mmol, Eq: 2) was added dropwise over 5-10 min. After 10 min at RT, a solution of (S)-pyrrolidin-3-ol (2.94 g, 2.8 ml, 32.7 mmol, Eq: 1.1) in Acetonitrile (2.27 g, 2.91 ml) added dropwise over 30 min at 20° C. After 2 h30 reaction, toluene (86.5 g, 100 ml) was added and the reaction mixture was concentrated under reduced pressure to remove most of the acetonitrile. A 10% aqueous citric acid solution (100 ml) was added. The aqueous phase was separated and extracted with toluene (86.5 g, 100 ml). The organic phases were washed sequentially with half saturated aqueous NaHCO3 (50 ml) and half saturated aqueous NaCl (50 ml). The organic phases were combined dried over MgSO4 and rotavaped at 45° C./10 mbar. The crude product was taken up in ethanol (150 ml) and concentrated under reduced pressure. This was repeated twice in order to remove toluene and gave 11.1 g of the crude title compound as a light yellow solid/foam.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(C)cc1Cl
Yield: 35 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (15.0 g, 72.4 mmol) and 2-chloro-4-methylaniline (20.5 g, 144.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (8.37 g, 35%) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:10]([N:36]2[CH2:41][CH2:40][CH2:39][C@@H:38]([N:42](C(OC(C)(C)C)=O)[CH3:43])[CH2:37]2)=[C:11]2[C:17]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:16][N:15](C(OC(C)(C)C)=O)[C:12]2=[N:13][CH:14]=1.C(Cl)[Cl:52]>>[ClH:52].[Br:8][C:9]1[C:10]([N:36]2[CH2:41][CH2:40][CH2:39][C@@H:38]([NH:42][CH3:43])[CH2:37]2)=[C:11]2[C:17]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)c2ccc(=O)n(C)c2)cn3C(=O)OC(C)(C)C)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(=O)n(C)c4)c23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
TFA (0.020 mL, 0.26 mmol) was added to (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonyl(methyl)amino)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.034 g, 0.052 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give (R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (25 mg, 91%) as a solid. 1H NMR (400 MHz, D2O) δ 8.34 (s, 1H), 8.30 (s, 1H), 7.97 (dd, 1H), 7.35 (s, 1H), 6.60 (d, 1H), 3.88 (m, 1H), 3.53 (s, 3H), 3.39 (m, 2H), 3.08 (m, 2H), 2.55 (s, 3H), 2.04 (m, 1H), 1.68 (m, 1H), 1.60 (m, 1H), 1.35 (m, 1H). LCMS (APCI+) m/z 459 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH2:9]([O:11][C:12](=[O:30])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=O)[CH3:10].[OH-].[NH4+]>C(O)=O>[ClH:28].[CH2:9]([O:11][C:12]([C:13]1[N:6]([CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:16]2[C:15]=1[CH:20]=[CH:19][CH:18]=[CH:17]2)=[O:30])[CH3:10]
Reactant: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Product: CCOC(=O)c1c2ccccc2c(-c2ccc(Cl)cc2)n1CCN(CC)CC
Product: Cl

Procedure:
A mixture of 0.83 g. of formic acid and 1.05 g. of 2-diethylaminoethylamine is treated at room temperature with 0.95 g. of [o-(p-chlorobenzoyl)phenyl]-glyoxylic acid ethyl ester and subsequently stirred at 140° C. for 2 hours. After cooling, the obtained solution is made alkaline with 2-N ammonium hydroxide with addition of ice and extracted with ether. The extract, shielded from daylight, is washed with water, dried over sodium sulfate, concentrated and chromatographed on 70 g. of silica gel with ether as the eluant. The homogeneous fractions are combined, concentrated to a volume of 15-20 ml. and treated with ethereal hydrochloric acid. The crystallized hydrochloride is removed by filtration and washed with ether, and there is obtained 3-(p-chlorophenyl)-2-[2-(diethylamino)ethyl]isoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 202°-204° C. (decomposition). Recrystallization from methylene chloride/ether does not increase the melting point.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].C[CH2:17][O:18]CC>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH2:17][OH:18])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CCOCC
Product: CCOC(OCC)c1ccc(CCO)cc1
Yield: 97 %

Procedure:
To a solution of 4-(diethoxymethyl)benzaldehyde (5.0 g, 24 mmol) in ether (65 ml), cooled to -10° C., was added dropwise a 1.5M toluene-THF methylmagnesium bromide solution (64 ml, 96 mmol) at such a rate that the temperature remains below 0° C. After the addition the reaction was quenched with saturated ammonium chloride (80 ml) and the solution was diluted with water (50 ml) and extracted with ether (2×75 ml). The combined extracts were washed with water (50 ml) and brine (50 ml), dried over sodium sulfate and concentrated in vacuo, leaving present title product (5.2 g, 97%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH3:9])[S:4][N:3]=1.S(=O)(=O)(O)[OH:11]>>[OH:1][C:2]1[C:6]([C:7](=[O:11])[NH2:8])=[C:5]([CH3:9])[S:4][N:3]=1
Reactant: Cc1snc(O)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1snc(O)c1C(N)=O
Temperature: 113 °C

Procedure:
A mixture of 60 g of 3-hydrox-4-cyano-5-methyl-isothiazole and 150 ml of concentrated sulfuric acid (d = 1.838) was heated for 15 minutes at 113°C and after allowing the temperature to return to 45°C, the mixture was added to ice with stirring. The precipitate formed was recovered by vacuum filtration, was washed with water and then with acetone and dried to obtain 51.5 g of 3-hydroxy-4-carbamoyl-5-methyl-isothiazole melting at 248°-250°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[CH2:16])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(COC)OC.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[CH2:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(c1cccc(OC2CCCCO2)c1)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: C=C(c1cccc(OC2CCCCO2)c1)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)-3-(3'-tetrahydropyranyloxyphenyl)-3-butenoate (0.40 g) in dimethoxyethane (10 ml) and water (2 ml) is treated with solid lithium hydroxide monohydrate (0.02 g). After stirring for 2 hours at room temperature, the mixture is diluted with water and acidified with 0.1 N hydrochloric acid to ca pH 4. Extraction with ether gives essentially pure racemic 2-(tert-butoxycarbonylamino)-3-(3'-tetrahydropyranyloxyphenyl)-3-butenoic acid (0.25 g): colorless solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O-])[O-:23].[Na+].[Na+]>CN(C)C=O>[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCCCCc1ccco1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
6.13 g of phosphorous oxychloride were added, while stirring, to 2.93 g of dimethyl formamide at 5°-10° C for 5 minutes. The mixture was kept at 0°-5° C for 40 minutes and then heated to room temperature. Immediately, and with vigorous stirring, 8.96 g of 8-(2-furyl)-octanoic acid methyl ester were added, whereupon the mixture was cooled to 5°-10° C in an ice-salt bath during 1 hour. After further 1 hour at room temperature, 40 g of ice were added, whereupon the mixture was neutralized with 10 g of sodium carbonate. The two phases were then separated, and the aqueous phase was extracted with ether. The combined organic phases were dried and then distilled. Boiling point 144° C at 0.2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[N:11]=[C:12]([NH:15][C:16]([CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2C(OC(C)(C)C)=O)=[O:17])[S:13][CH:14]=1>ClCCl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[N:11]=[C:12]([NH:15][C:16]([CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19]2)=[O:17])[S:13][CH:14]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3C(=O)OC(C)(C)C)n2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3)n2)c(C)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
35 g of N-[4-(2,4,6-trimethylphenyl)-2-thiazolyl]-1-tert-butoxycarbonyl-indoline-2-carboxamide are dissolved in 200 of dry dichloromethane and 40 ml of trifluoroacetic acid are added dropwise. The reaction mixture is kept at ambient temperature for 2 hours and then evaporated to dryness. The residue obtained is taken up in 150 ml of ethyl acetate. The organic solution is washed with 1N aqueous sodium hydroxide solution and then with water saturated with NaCl and dried over anhydrous magnesium sulphate. After removal of the ethyl acetate, the final product is obtained, from which the salt is prepared by the action of gaseous HCl in isopropanol. The hydrochloride melts at 212° C. Yield 88%. Salt: 1H NMR: 80 MHz(DMSOd6) δ(ppm): 2.1(s,6H); 2.4(s,3H); 3.2-3.8(m,2H); 5.0(m,1H); 6.0(s,1H 6.0(s,1H); 6.9-7.6(m,7H); 12.1(s,1H).
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][CH3:12])=[C:6]([CH3:14])[CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Cu](Br)Br>[Br:1][CH:11]([CH3:12])[C:10]([C:7]1[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH3:14])=[O:13]
Reactant: Br
Reactant: CCC(O)c1cnc(OC)cc1C
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)C(C)Br)cn1
Temperature: 70 °C

Procedure:
To a stirred suspension of copper (II) bromide (499 mg, 2.23 mmol, 2 eq.) in EtOAc is added HBr (33% in acetic acid, 0.368 ml, 2.25 mmol, 2 eq.) followed by 1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-ol (200 mg, 1.12 mmol, 1 eq.). The mixture is heated at 70° C. for 12 hrs. After cooling to RT the mixture is poured into 2M Na2CO3 (50 ml) and extracted with EtOAc (2×50 ml). The combined extracts are washed successively with 2M Na2CO3, water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue is purified by column chromatography on silica gel eluting with 10% EtOAc/iso-hexane to yield 2-bromo-1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-one as a clear oil. MS: m/z 257.9 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.90 (d, 3H), 2.50 (s, 3H), 4.0 (s, 3H), 2.33 (s, 3H), 5.20 (q, 1H), 6.65 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])C=CC=CC=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O.CC(C)([O-])C.[K+]>CS(C)=O>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1/[CH:39]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CCC/C=C\c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
Triphenyl (5-carboxypentyl)phosphonium bromide (937 mg, 2.1 mmole) and 2-napthaldehyde (300 mg, 1.92 mmole) were dissolved in DMSO (50 mL, freshly distilled from CaH2) and potassium t-butoxide (540 mg, 4.8 mmole) was added. After stirring for 30 minutes the reaction was quenched with saturated NH4Cl solution (25 mL) and poured into ether. The ether layer was dried with saturated NaCl and MgSO4 and the solvent was evaporated. The resulting 1:1 mixture E/Z isomers were separated with flash chromatography eluting with ether/hexane/formic acid (10:89:1).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15]>Cl.O1CCCC1>[ClH:1].[C:8]([O:9][CH2:10][C:11]([NH2:12])([CH3:14])[CH3:13])(=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC(c2ccccc2)=N1
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 8.7 g (0.041 mol) 2-phenyl-4,4-dimethyl-1,3-oxazoline hydrochloride suspended in 120 ml anhydrous hydrogen chloride in tetrahydrofuran (1 M) was added 3.6 ml (0.20 mol) water. The mixture was warmed to cause solution and heated under reflux with stirring for 1 hour. The tetrahydrofuran was removed under reduced pressure to afford a nearly colorless oil which crystallized at 0° following the addition of anhydrous ether. The solid was triturated with anhydrous ether overnight and isolated by filtration under a nitrogen atmosphere. After drying in vacuo over calcium sulfate, 6.9 g (0.30 mol), 73%, 2-amino-2-methyl-1-propyl benzoate hydrochloride was obtained as a white solid, mp 225°-228° (dec.) acetone:hexane, ir (KBr) 1725 (c=o) cm-1, pmr (D2O) δ 1.50 (s, 6H), 4.4 (s, 2H) and 7.0-8.3 (m, 5H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)[CH:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(O)(=O)C>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][NH:24][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:19]=[CH:18][C:17]=1[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CN1CCCC1CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncc1CC(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
37.9 mg of 6-[(4-morpholinophenyl)amino]-4-[(pyrrolidin-2-ylmethyl)amino]pyridine-3-carboxyamide (the compound of Example 358) was dissolved in 2 mL of methylene chloride, to which, under ice cooling, 19.4 mg of 37% formaldehyde in water, 40.5 mg of sodium triacetoxyborohydride and acetic acid were sequentially added, and stirred at room temperature for 2 hours. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform:methanol=10:1, the extract washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-ether to obtain 27.5 mg (70%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.O1C2=N[CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([CH2:26][C:27]#[CH:28])[NH2:25])=N1.O1C2=NC=CC=C2[C:31](C2C=CC=CC=2C=O)=[N:30]1>>[C:31]([C:15]1[CH:1]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH:24]([CH2:26][C:27]#[CH:28])[NH2:25])[CH:12]=[CH:17][CH:16]=1)#[N:30]
Reactant: C#CCC(N)c1ccccc1-c1noc2ncccc12
Reactant: O=C(O)/C=C\C(=O)O
Reactant: O=Cc1ccccc1-c1noc2ncccc12
Product: C#CCC(N)c1ccccc1-c1cccc(C#N)c1

Procedure:
2-(isoxazolo[5,4-b]pyridin-3-yl)-a-2-propynyl-benzenemethanamine (Z)-butenedioate starting from 2-(isoxazolo[5,4-b]pyridin-3-yl)-benzaldehyde, melting at 180-185° C. (dec).