Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(OCC)(=O)C>[I:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: C1COCCN1
Reactant: BrCc1ccc(I)cc1
Solvent: CCOC(C)=O
Product: Ic1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
1-Bromomethyl-4-iodobenzene (320 mg, 1.08 mmol) and morpholine (1 mL, 11.47 mmol) were combined. The reaction mixture was heated at 70° C. for 4 hours and then diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated and dried. The residue was then dissolved in dichloromethane (10 mL), washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated to give the product as an off-white solid ±300 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.64 (d, 2H), 7.09 (d, 2H), 3.7 (t, 4H), 3.43 (s, 2H), 2.43 (t, 4H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>C1COCC1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -50 °C
Yield: 50 %

Procedure:
To a mixture of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.59 mmol) and THF (6 mL) was added triethylamine (165 μL, 1.18 mmol) to form a clear solution. The mixture was cooled to −50° C. external temperature, and a 1:1 mixture of 2-methoxyethyl chloroformate (65 μL) and THF (65 μL) was added dropwise. After complete addition, the reaction was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 gave (R)-2-methoxyethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-Page 66 of 141 yl)pyrrolidin-3-ylcarbamate (compound 1) (130 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.7 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.58 (s, 1H), 7.33 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.69 (m, 1H), 4.22 (m, 1H), 4.04 (m, 5H), 3.84 (m, 1H), 3.48 (t, J=4.6 Hz, 2H), 3.23 (s, 3H), 2.52 (s, 3H), 2.20 (m, 1H), 2.02 (m, 1H) ppm. LC/MS: m/z 441.5 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:45])=[O:46])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
A solution of triphenylphosphine (194 mg, 0.74 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (132 mg, 0.74 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (200 mg, 0.57 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (143 mg, 1.43 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) to afford pure 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propionamide (178 mg, 72%) as a light yellow foam: mp 61–64° C. (foam to gel); EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0790.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18](C1SC(C#N)=CC=1)=[O:19])[CH2:10]2>>[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:19])[CH2:10]2
Reactant: COc1cccs1
Reactant: N#Cc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1
Agent: Cl
Product: COc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1

Procedure:
This compound is prepared from 2-methoxythiophene according to the procedure used to make the compound of Example 18, making non-critical variations. Yield for 2 steps 33%. HRMS (FAB) calculated for C13H18N2O2S+H 267.1167, found 267.1167.
Reaction SMILES: P(=O)(O)(O)O.C([C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:9](=[O:12])[CH2:10][CH3:11])#N.Br>C(O)(=O)C>[CH3:17][C:15]1([CH3:16])[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:13][CH2:14]1
Reactant: CCC(=O)C(C#N)(CC=C(C)C)c1ccccc1
Agent: Br
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 105 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
In a 3-liter flask provided with a thermometer and stirrer 200 g of phosphorus pentoxide are added while cooling to 500 g of 85% phosphoric acid and subsequently 150 g of 4-cyano-7-methyl-4-phenyl-oct-6-en-3-one are added at ca. 50° C. The mixture is stirred at 105° C. until starting material is no longer present (gas chromatography/thin-layer). 1000 g of 48% hydrobromic acid and 500 g of glacial acetic acid are then added. After 12 hours, a further 200 g of 48% hydrobromic acid and 100 g of glacial acetic acid are added and the temperature is raised to 110° C. After a total reaction time of 30 hours, the mixture is cooled, ice is added and the mixture is extracted with ether, washed neutral with water, with 10% sodium hydroxide and again with water, dried over sodium sulphate and evaporated. Vacuum distillation gives 32 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 24%. Odour: see (3).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[NH:12]1[CH2:15][CH:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][C:25]4[S:24][C:23]([C:29]5[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=5)=[N:22][C:21]=4[C:20]=3[CH:37]=2)[CH2:13]1>C1COCC1>[CH:34]([N:30]1[C:29]([C:23]2[S:24][C:25]3[CH2:26][CH2:27][O:28][C:19]4[CH:18]=[CH:17][C:16]([CH:14]5[CH2:13][N:12]([CH2:8][C:9]([CH3:11])([OH:7])[CH3:10])[CH2:15]5)=[CH:37][C:20]=4[C:21]=3[N:22]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: CC1(C)CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(C)(C)O)C3)cc1-2
Reaction time: 0.21 h
Yield: 35.7 %

Procedure:
Lithium perchlorate (52 mg, 0.49 mmol) was added to THF (5 mL) followed by 1,2-epoxy-2-methylpropane (0.43 mL, 4.9 mmol) and the mixture was stirred for 10-15 minutes giving a clear solution. 9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) was added and the reaction mixture was stirred for 72 hours then concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-10% MeOH in EtOAc) and the resulting solid extracted several times with ether. The ether extracts were concentrated in vacuo to give 377 (77 mg, 97%). LCMS: RT=7.45 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.28 (1 H, d, J=2.34 Hz), 7.90 (1 H, s), 7.16 (1 H, dd, J=8.29, 2.35 Hz), 7.02 (1 H, d, J=8.27 Hz), 5.93-5.83 (1 H, m), 4.40-4.34 (2 H, m), 4.04-3.95 (2 H, m), 3.89-3.79 (1 H, m), 3.46-3.36 (4 H, m), 2.55 (2 H, s), 1.63 (6 H, d, J=6.64 Hz), 1.15 (6 H, s). 1 Exchangeable proton not seen
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:6]1[NH:18][N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(F)c1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(F)c2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13 g of 3-fluorobenzylhydrazine, on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 11.3 g, corresponding to 55% of theory, of the compound identified above as colorless crystals of melting point 129°.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:27]#[C:28]Br.N>CO>[NH2:27][C:28]1[O:4][CH2:3][CH:2]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)[N:1]=1
Reactant: NC(CO)c1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=NC(c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To a stirred suspension of 1-[4-(1-amino-2-hydroxy-ethyl)-phenyl]-3-(4-chloro-phenyl)-urea (160 mg) and sodium acetate (129 mg) in methanol (8 ml) was added dropwise a solution of cyanogen bromide (72 mg) in methanol (0.5 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. Aqueous ammonia solution (0.4 ml, 25%) was added dropwise and stirring was continued for a further hour. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/dichloromethane/methanol) to give (RS)-1-[4-(2-amino-4,5-dihydro-oxazol-4-yl)-phenyl]-3-(4-chloro-phenyl)-urea (91 mg, 53%) as a white solid. MS (ISP): 333.2 ([{37Cl}M+H]+), 331.1 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(O)C.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of methyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) [1]benzothieno[2,3-d]pyrimidin-7-yl]acrylate (100 mg, 0.19 mmol) in THF (3 vmL) were added ethanol (1 mL) and lithium hydroxide (2 N, 0.5 mL, 1 mmol, 5 equiv). The contents were stirred at rt for 16 h. The mixture was concentrated to dryness and the residue was triturated with ether and ethyl acetate to remove organic impurities. To the solid was added some water and 1N HCl to adjust the pH to ˜6. The solid was filtered and dried to obtain (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylic acid (50 mg, 51%). 1H-NMR (DMSO-d6) δ 9.10 (s, 1H), 8.56 (d, 1H), 8.52 (s, 1H), 8.39 (d, 1H), 7.87 (dd, 1H), 7.74 (d, 1H), 7.42-7.59 (m, 3H), 7.30 (m, 2H), 7.23 (d, 1H), 7.17 (m, 1H), 6.69 (d, 1H), 5.26 (s, 2H); LCMS RT=3.77 min, [M+H]+=506.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:36]1[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=1>C(#N)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:7]1[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:36]2[N:41]=[C:40]([NH2:42])[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][CH:37]=2)[CH:6]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ccc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nc(NCCNc2ccc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
The amine hydrochloride salt 10 (35 mg) in acetonitrile (2 ml) is treated with N,N-diisopropylethylamine (54 eq) and 6-chloro-3-nitro-2-pyridylamine 11 (1.2 eq) and stirred at 90° C. for 2 h. The mixture is concentrated under reduced pressure and dried under vacuum. The crude product is purified by chromatography starting with 3% MeOH in methylene chloride and finishing with, 5% MeOH in methylene chloride to provide 12 as yellow solid (50–70%). The material is acidified with 2 equivalents of HCl and lyophilized to a dry powder.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CCOCC>[I:13][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Ic1cccc(I)c1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Ic1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
n-Butyllithium (2.0 M in cyclohexane, 8 cm3) was added dropwise to a solution of 1,3-diiodobenzene (5.19 g, 16 mmol) in ether (50 cm3), cooled in a salt-ice bath, and the solution was stirred for 10 minutes. 2-Fluoropyridine (1.4 cm3, 16 mmol) was added, at which the pale yellow cloudy solution turned dark brown, and the reaction was allowed to warm to room temperature over 1 hour. Water (50 cm3) and ether (20 cm3) were added, and the layers were separated. The aqueous layer was extracted with ether (3×50 cm3). The combined organic extracts were washed with brine (150 cm3), and dried over magnesium sulfate. The solvent was removed to leave a brown oil. Purification of the crude product by column chromatography over silica using dichloromethane: light petroleum (1:1) as eluent gave (15) as an orange oil (1.04 g, 24%).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:18][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1cccs1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1cccs1
Yield: 77.5 %

Procedure:
1.5 g of ethyl 3-benzoylamino-3-(2-thienylcarbonyl)propionate, 10 ml of dimethylformamide and 0.5 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.1 g of ethyl 2-[2-phenyl-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].CCCCCC.C([Li])CCC.Cl[C:28]([O:30]CC)=[O:29]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cc1c(-c2cccs2)n[nH]c1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(-c2ccc(C(=O)O)s2)n[nH]c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
4-Methyl-3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole was allowed to react with an n-butyl lithium-n-hexane solution (1.6 M). Further, ethyl chloroformate was added at −50° C. or below. After stirring at −50° C. or below for 30 minutes, it was subjected to purification in the usual way to give a yellow oil. By hydrolyzing this in the usual way, 5-(4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acid was obtained as colorless powder crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CN1CCOCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(NS(C)(=O)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a slurry of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11B) (14 mg, 0.035 mmol) in CH2Cl2 (2 ml) was added N-methyl morpholine (12.3 μl, 0.113 mmol) followed by MsCl (4.5 μl, 0.057 mmol). The reaction mixture was stirred overnight, 10% citric acid (3 ml) was added. The resulting mixture was extracted with CHCl3 (10 ml), the organic layer was separated and dried with Na2SO4, concentrated to give the title compound (6.9 mg, 45%). It has a retention time of 6.01 min (standard LCl method, 8 min run). MS Found: (M+H)+=434.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15]
Reactant: Cc1ccc(C)c(CC(=O)CC(C)(C)CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(C)(C)CC(=O)Cc1cc(C)ccc1C
Yield: 78 %

Procedure:
Utilizing the procedure of EXAMPLE XX 6-(2',5'-dimethylphenyl)-5-keto-3,3-dimethyl hexanoic acid was esterified with absolute ethanol in the presence of a catalytic amount of concentrated sulfuric acid to provide 15.52 g (78% yield) of ethyl 6-(2',5'-dimethylphenyl)-5-keto-3,3-dimethylhexanoate as a pale viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].[CH3:54][O:55][C:56]1[CH:79]=[CH:78][C:59]([CH2:60][O:61][C:62]([NH:64][C@H:65]([C:75](O)=[O:76])[CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[O:63])=[CH:58][CH:57]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:53])[C@H:4]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:5][C:6](=[O:48])[C@@H:7]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH:17][C:75](=[O:76])[C@H:65]([CH2:66][O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[NH:64][C:62]([O:61][CH2:60][C:59]1[CH:78]=[CH:79][C:56]([O:55][CH3:54])=[CH:57][CH:58]=1)=[O:63]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1ccc(COC(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-Tryptophyl-L-seryl-L-tyrosyl-D-phenylalanyl-L-leucine methyl ester (example 1, h), 1.6 g., is dissolved in 30 ml. of dimethylformamide and treated with 0.789 g., of Nα -p-methoxybenzyloxycarbonyl-O-benzyl-L-serine and cooled in an ice bath. 1-Hydroxybenzotriazole, 326 mg., and finally 500 mg., of dicyclohexylcarbodiimide are added and the reaction mixture stirred to room temperature overnight and for twenty-four additional hours. The reaction mixture is filtered and the solvent removed under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.25 N hydrochloric acid, saturated sodium chloride solution, 5% sodium bicarbonate solution, and finally, saturated sodium chloride solution. The ethyl acetate solution is refrigerated for several days and a gelatinous precipitate separated. After triturating with ether for two hours, the above named product is separated and dried, 1.7 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH2:12][C:13](O)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:11][CH2:12][C:13]([O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: OCCCc1ccccc1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OCCCc1ccccc1

Procedure:
Into a 100 ml flask equipped with reflux condenser, thermometer, hot plate (including magnetic stirring apparatus within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4 grams of mercaptoacetic acid; and 0.1 grams para-toluene sulphonic acid.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[OH-:29].[K+]>C(O)(C)(C)C>[F:15][C:13]1[CH:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[CH:19][CH:18]=2)[CH:10]=[C:9]([C:3]2([C:1]([NH2:2])=[O:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C#N)CCOCC3)c2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Yield: 31.2 %

Procedure:
To a solution of 4-cyano-4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 25, 1.71 g, 4.36 mmol) in tert-butanol (20 ml) was added powdered potassium hydroxide (85%, 860 mg, 13 mmol). The resulting mixture was heated at reflux temperature for 4 h, cooled and concentrated in vacuo . Water (50 ml) was added and the precipitates were collected by filtration and washed with 50 ml of ethyl acetate. After drying in vacuo, 560 mg (31%) of the titled compound was obtained as a yellow powder.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[Cl:11]>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([N:9]1[C:10]([Cl:11])=[C:6]([CH3:5])[N:7]=[CH:8]1)=[O:4]
Reactant: CN=C=O
Reactant: Cc1nc[nH]c1Cl
Solvent: ClC(Cl)Cl
Product: CNC(=O)n1cnc(C)c1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
104 g of methyl isocyanate were added dropwise to 233 g of 4-methyl-5-chloroimidazole in 1 liter of chloroform in a stirred flask provided with a thermometer and a reflux condenser. During the addition, the temperature increased to 40° C. Refluxing was carried out for 2 hours, the reaction solution was evaporated down under reduced pressure, the hot residue was dissolved in 400 ml of toluene, the solution was filtered with carbon and cooled, and the precipitated crystals were filtered off under suction, washed with toluene and dried to give 237 g (68.3%) of 1-N-methylcarbamyl-4-methyl-5-chloroimidazole of melting point 94.1°-94.4° C.