Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35].N(CC)(CC)CC.[BrH:52].N(CC)(CC)CC.Cl>CN(C=O)C.CCN(CC)CC>[NH:1]([S:34]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[CH:32][CH:33]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[BrH:52]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
6.26 g (10 mM) of 2HBr.H-D-Leu-Gly-Arg-pNA (prepared according to Example 7f, see Table 3) were dissolved in 30 ml of distilled DMF. The solution was cooled to -15°, and first 2.80 ml (20 mM) of Et3N and immediately afterwards 1.91 g (10 mM) of tosyl chloride were added, while stirring, in the absence of humidity. After a reaction time of about 2 to 3 hours at -15°, the reaction mixture was allowed to further react overnight at room temperature. The reaction mixture was again cooled to -15°. The precipitated mixture of Et3N.HBr and Et3N.HCl was removed by filtration and washed with a small amount of cold DMF. The filtrate and the washing solution were combined and concentrated to dryness in vacuo at 50°. The residue was dissolved in 75 ml of 50% AcOH. The solution was purified on a column of "Sephadex" G-15 equilibrated with 50% AcOH. The main fraction of the AcOH eluate which was split by treatment with trypsin with release of p-nitroaniline was concentrated to dryness in vacuo at 40°. The residue was dissolved in 100 ml of MeOH, and the solution was again concentrated to dryness. The residue was dried in a vacuum desiccator at 60° over P2O5 to obtain 6.65 g (95.0% of the theory) of amorphous compound Tos-D-Leu-Gly-Arg-pNA.HBr which was homogeneous in the SS as shown by TLC. Elementary analysis and calculation from the empirical formula C27H39N8SO7Br gave the following values: C=46.85% (46.35%), H=5.66% (5.62%), N=16.28% (16.02%), S=4.43% (4.58%) and Br=11.22% (11.42%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C1(C)C=CC=CC=1>[C:8]1([S:14][CH:17]2[CH2:16][C:15](=[O:21])[O:20][C:18]2=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CC(Sc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
Triethylamine (0.8 ml) was added dropwise to a solution of benzenethiol (9.3 ml, 91 mmol) and maleic anhydride (8.9 g, 91 mmol) in toluene (125 ml). After stirring at room temperature for 12 hr the solvent was evaporated to leave 20 g of crude 3-phenylsulfanyl-dihydro-furan-2,5-dione as a brown oil. 1H NMR (CDCl3) δ 7.20-7.70 (5H, m), 4.20 (1H, dd), 3.40 (1H, dd), 2.90 (1H, dd).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCCC[C@@H](O)c1ccc(CC(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC[C@H](Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (275 mg), (R)-1-(4-isobutylphenyl)pentan-1-ol (179 mg) and triphenylphosphine (213 mg) in a mixture of tetrahydrofuran and toluene (1:4, 10 ml) was added diethyl azodicarboxylate (0.13 ml) at -25° C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The concentrate was chromatographed on silica gel using hexane and ethyl acetate (3:1) to give ethyl (S)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indol-1-yl]butyrate (279 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH2:26])=O)[CH2:19]1.O>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH2:26])[CH2:19]1
Reactant: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 66 °C

Procedure:
To a suspension of LiAlH4 (0.62 g, 16.30 mmol) in dry THF (15 ml) was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid amide (0.45 g, 01.63 mmol) in dry THF (5 ml). The reaction mixture was heated under microwaves at 66° C. for 1 h. Water was slowly added and the mixture extracted with EtOAc (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the desired product, which was purified by column chromatography (DCM/MeOH, 98:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:16]([O-])=O)=[N:13][O:14][CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1.N>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12](=[N:13][O:14][CH3:15])[NH2:16])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1
Reactant: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]
Agent: N
Solvent: CO
Product: CON=C(N)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
A mixture of 1.5 g (0.004 mole) of 7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine and 20 ml of methanol containing 20% (v/v) of ammonia was allowed to sit at room temperature for 41/2 hours. After partial evaporation the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer was dried and evaporated. The residue was passed over neutral alumina using ether. Crystallization of the combined eluates from ether/hexane gave end product as colorless crystals with mp 120°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:17])[C:6]=1[O:5]2.[Br:18]N1C(=O)CCC1=O>>[Br:18][CH2:17][C:7]1[C:6]2[O:5][C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c(=O)c3ccc(Cl)cc3oc12
Reactant: O=C1CCC(=O)N1Br
Product: O=c1c2ccc(Cl)cc2oc2c(CBr)cccc12

Procedure:
The above compound (VI: R1 =6-Cl; Z=CH3) was then treated with N-bromosuccinimide as in Example A to give 4-bromomethyl-6-chloroxanthenone (VII: R1 =6-Cl, Z=CH2Br), mp (benzene/petroleum ether) 217°-218° C. Anal. (C14H8BrClO2) C, H,N.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH2:29]([N:31]=[C:32]=S)[CH3:30].C(Cl)CCl>CO.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:32]([NH:31][CH2:29][CH3:30])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: CCN=C=S
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1CC1CCOCC1
Temperature: 50 °C
Yield: 32.5 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (100 mg, 0.261 mmol) was dissolved in methanol and ethyl isothiocyanate (45.6 mg, 0.523 mmol) was added. The mixture was heated at 50° C. for 6 h, cooled and evaporated in vacuo to give a beige solid residue. This was re-dissolved in THF (5 ml) and EDC (100 mg, 0.523 mmol) was added, then the mixture heated at 60° C. overnight. The solvent was evaporated in vacuo and the residue dissolved in DCM (10 ml) and washed with water (10 ml), the organic layer dried and evaporated and the residue dissolved in DCM (2 ml) and loaded onto a 10 g silica column, then eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinolin-2-amine (37 mg, 0.085 mmol, 32.5% yield) as a colourless glass. LCMS (formate) Rt 0.71 min, MH+ 436
Reaction SMILES: [NH2:1][CH:2]([CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>C1COCC1.C(O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][CH:2]([CH:8]2[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)CC(N)C1CCC1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CC(Nc1nc(Cl)ncc1F)C1CCC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
To a racemic solution of methyl 3-amino-3-cyclobutylpropanoate, 49a, (0.354 g, 2.252 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.414 g, 2.477 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.628 mL, 4.504 mmol). The reaction mixture was heated and stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to approximately 5 mL final volume. The crude residue was purified via silica gel chromatography (0-100% EtOAC/hexanes gradient) to afford 289 mg (45%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 5.80 (s, 1H), 4.71-4.38 (m, 1H), 3.68 (s, 3H), 2.84-2.37 (m, 3H), 2.23-1.67 (m, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.08 minutes (M+H) 287.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)[N:7]([CH3:24])[C:6]2=1.[O:25]=[C:26]1[NH:31][C:30]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:36]([C:33]4[CH:34]=[CH:35][C:29]5[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=5[CH:32]=4)=[O:37])[CH2:19][CH2:18]3)[N:7]([CH3:24])[C:6]2=1
Reactant: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as an orange semisolid following Scheme 5 and in analogy to Example 27 using trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: COCCOC1C=C2C(NC3C=CC=C(C#C)C=3)=NC=NC2=CC=1OCCOC.Cl.C[O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43]C)[N:39]=[CH:38][NH:37][C:36]2=[O:45].[BrH:46].Cl.N1C=CC=CC=1>>[BrH:46].[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[OH:43])[N:39]=[CH:38][NH:37][C:36]2=[O:45]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: Br
Agent: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1[nH]cnc2cc(O)c(O)cc12

Procedure:
PCT Patent Publication No. WO 2007/060691 A2 describes an improved process for the preparation of erlotinib hydrochloride, which comprises: i) reacting 6,7-dimethoxy-4-(3H)-quinazolinone with aqueous hydrobromic acid or pyridine hydrochloride at an elevated temperature to get a hydrobromide or hydrochloride salt of 6,7-dihydroxy-4-(3H)-quinazolinone which on neutralization with a base gives 6,7-dihydroxy-4-(3H)-quinazolinone; ii) acylating the dihydroxy compound using an acylating agent at a temperature in the range of 20-150° C. and in the presence of a catalyst to give 6,7-diacetoxy-4-(3H)-quinazolinone; iii) reacting the diacetoxy compound with oxalyl chloride at a temperature of 10-100° C. to give 4-chloro-6,7-diacetoxy-quinazoline; iv) condensing the reaction mass containing the chloro compound with 3-ethynylaniline in an organic solvent selected from chloroform, methylene chloride, acetonitrile, isopropyl alcohol, toluene, tetrahydrofuran, dioxane, cyclohexane and dimethylformamide, at a temperature of 10-100° C. to give N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride which on further treatment with a base such as aqueous sodium or potassium hydroxide, or aqueous ammonia solution in alcohols at a temperature of 20-60° C. gives N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine; v) reacting the N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine with 2-halo-ethylmethyl ether in the presence of a base at a temperature of 25-100° C. to give crude erlotinib base; vi) recrystallizing the crude erlotinib base from different solvents like ethyl acetate, acetonitrile, isopropyl alcohol, methanol, ethanol, acetone, methyl ethyl ketone, water or a mixture thereof to give pure erlotinib base; vii) reacting pure erlotinib base by dissolving or suspending in an organic solvent or water or a mixture thereof with aqueous hydrochloric acid or hydrogen chloride gas dissolved in an organic solvent selected from chloroform, toluene, ethanol, methanol, isopropyl alcohol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl ether, diethyl ether and tetrahydrofuran to give erlotinib hydrochloride.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:10])[CH2:8][CH3:9].CO[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1>O1CCCC1>[C:7]([CH:8]([CH3:9])[C:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)=[O:22])#[N:10]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C#N)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
Potassium-tert-butoxide (7.76 g, 69.2 mmol) and propionitrile (4.84 mL, 69.2 mmol) was added to a solution of 4-cyano-benzoic acid methyl ester (11.15 g, 69.2 mmol) in tetrahydrofuran (100 mL). This mixture was stirred at room temperature for 16 hours, and then quenched onto an aqueous 10% solution (weight/volume) citric acid (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulphate, filtered, and evaporated under reduced pressure. This crude residue was triturated with tert-butyl methyl ether to give the title compound as a solid (7.00 g, 55%). 1H NMR (400 MHz, CDCl3): δ 1.65 (d, 3H), 4.35 (m, 1H), 7.85 (d, 2H), 8.10 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:23]([NH:22][CH2:21][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:28])[F:27])=[CH:26][CH:25]=3)=[O:24])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][CH3:14])[N:3]=1
Reactant: CCc1cc2c(N)cccc2c(Cl)n1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: CCc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2c(Cl)n1

Procedure:
Prepared from 1-chloro-3-ethylisoquinolin-5-amine (Description 66) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 408, 410 (M+H)+.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([NH:14][C:15](=[O:33])[NH:16][C:17]3[N:22]=[C:21]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[C:29]([O:31]C)=[O:30])[CH:20]=[CH:19][CH:18]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl>CO>[N:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:11]=[C:12]([NH:14][C:15](=[O:33])[NH:16][C:17]3[N:22]=[C:21]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[C:29]([OH:31])=[O:30])[CH:20]=[CH:19][CH:18]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCCN1Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cccc(CN2CCCC2C(=O)O)n1)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.0 N NaOH solution (0.40 mL) was added to a solution of methyl 1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}pyrrolidine-2-carboxylate (3 mg, 6.84 μM, Example 77) in MeOH (1 mL) and the resulting mixture was stirred at RT for 12 h. The mixture was adjusted to pH 7 with 1N HCl solution and concentrated in vacuo. The residue was dissolved in CH2Cl2 and a few drops of MeOH. A precipitate formed and was collected to give a white solid. MS m/z: 423.5 (M−H) Calc'd for C20H20N6O3S-424.48.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]=1.[OH-:16].[Na+]>S(=O)(=O)(O)O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:14]([NH2:15])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]=1
Reactant: N#CC1(Nc2cccnc2)CCCCC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(Nc2cccnc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.23 g (6.11 mmol) of 1-(pyridin-3-ylamino)-cyclohexanecarbonitrile are dissolved in 20 ml of concentrated sulfuric acid. The reaction medium is stirred at room temperature for 72 hours. It is then poured slowly into ice and the pH is brought to 14 with sodium hydroxide, and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is chromatographed on silica gel (ethyl acetate and then 90/10 ethyl acetate/methanol). 1-(Pyridin-3-ylamino)-cyclohexanecarboxylic acid amide is obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH:26]=[CH:27][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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:35][C:34]([F:36])([F:37])[CH2:33][NH:32][C:30](=[O:31])[NH:29][C:25]1[CH:24]=[C:23]([C:11]2[N:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]3=[N:13][CH:12]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(C(=O)O)ccn23)c1
Temperature: 80 °C

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (3.02 g, 10 mmol) in DME (200 ml) was added 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (4.13 g, 12 mmol), 1M Na2CO3 (80 ml) [reaction degassed by bubbling N2 through] followed by tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol). The mixture was heated at 80° C. overnight, then diluted with water and extracted with CH2Cl2. The aqueous layer was neutralised and loaded onto a reverse phase (C18) SPE (Solid Phase Extraction) cartridge. The cartridge was washed with H2O (2 column volumes) and eluted with MeOH (2 column volumes), the organic solvent removed in vacuo to afford the product as an off-white solid: 1H NMR (400 MHz, DMSO-d6): 12.31 (1H, s), 9.77 (1H, s), 8.85 (1H, d), 8.12 (1H, d), 8.04 (1H, s), 7.94 (1H, s), 7.84 (1H, s), 7.76 (1H, d), 7.39 (1H, t), 7.21 (1H, d), 4.05-3.90 (2H, m). MS: [M+H]+ 379.
Reaction SMILES: [OH-].[Na+].O.C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC([C:22]([C@:24](C(O)=O)([OH:39])[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:23])=CC=1.[F:44][C:45]1[C:50]([C@@H:51]([NH:53][CH2:54][C@@H:55]([OH:57])[CH3:56])[CH3:52])=[CH:49][CH:48]=[C:47]([F:58])[N:46]=1>C1(C)C=CC=CC=1>[F:44][C:45]1[C:50]([C@@H:51]([N:53]2[CH2:54][C@H:55]([CH3:56])[O:57][C:22](=[O:23])[C:24]2=[O:39])[CH3:52])=[CH:49][CH:48]=[C:47]([F:58])[N:46]=1
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Reactant: C[C@H](O)CN[C@@H](C)c1ccc(F)nc1F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Temperature: 145 °C
Reaction time: 3 h
Yield: 115.4 %

Procedure:
A 5 N sodium hydroxide aqueous solution (450 mL), water (1000 mL), and 50% toluene-THF (2000 mL) were added to (S)-1-[(S)-1-(2,6-difluoropyridin-3-yl)ethylamino]propan-2-ol (+)-di-p-toluoyl-D-tartrate (199 g). The organic layer was separated. The water layer was extracted with 50% toluene-THF (800 mL) three times. All the organic layers were combined and concentrated under reduced pressure. To the residue, diethyl oxalate (200 mL) was added. The resulting reaction solution was heated to and stirred at 140 to 150° C. After 3 hr, the reaction solution was diluted with toluene (500 mL) and cooled with ice while stirring. The precipitated crystal was filtered, washed with toluene and diethyl ether, and dried in air to give 103 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[C:12]([F:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[F:3][C:4]1[C:12]([F:13])=[C:11]([NH:2][CH3:1])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reaction time: 3 h

Procedure:
A mixture of methylamine (40% aq solution, 0.68 mL, 6.7 mmol), 2,3,4-trifluoro-5-nitro-benzoic acid (0.50 g, 2.3 mmol) and 5 mL water is stirred for 3 h in an ice bath. Then the mixture is acidified with 6M aq HCl and the resulting precipitate is collected by filtration washed with water and dried.