Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>O>[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])=[CH2:1])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: C=C(C)c1ccc(-c2ccc(OC(C)=O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
10 ml of acetic anhydride was charged in a flask provided with a reflux condenser and a stirrer. Then, 1 g of 4-hydroxy-4'-isopropenylbiphenyl obtained in Example 2 was added thereto and the mixture was stirred at 80° C. for 1 hr to effect the reaction. The reaction solution was poured into water and the resulting crystals were separated and recrystallized from methanol to obtain 0.72 g of 4-acetoxy-4'-isopropenylbiphenyl (53) in the form of white crystals. ##STR158##
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH3:27][C:28]([N:30]([CH3:32])[CH3:31])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:31][N:30]([CH3:32])[C:28](=[N:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26])[CH3:27]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N=C(C)N(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.73 g of 5-amino-4-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole, prepared as described by Suzuki and Kumashiro, Chem. Abstracts 71, 12561n (1969), and dimethylacetamide (0.70 g) in acetonitrile (5 ml) is added dropwise phosphoryl chloride (0.61 g) and the mixture is stirred under nitrogen for 20 hours at room temperature. The mixture is poured into 5% aqueous sodium carbonate and extracted with ethyl acetate and the organic layer washed with saturated sodium chloride solution and dried over sodium sulfate. The organic extract is concentrated to dryness at reduced pressure to afford 5-[1-(dimethylamino)-ethylideneamino]-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole-4-carbonitrile as an oil.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)C>[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][CH:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(NC2c3ccccc3Oc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCNCC1
Temperature: 0 °C

Procedure:
A mixture of 5 g. of N-(N-ethoxycarbonyl-4- piperidinyl)-9-xanthenylamine, prepared as in Example 14, and 25 g. of potassium hydroxide in 125 ml. of aqueous ethanol is heated at reflux for three hours and then cooled and added with stirring to 1 liter of ice water. The mixture is extracted with ether and the extracts dried and concentrated in vacuo to give N-(4-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]2[NH:22][C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][CH:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH:12]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[NH:22]1
Reactant: O=c1[nH]c(C=Cc2cccc3ccccc23)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: ClC1NC(C=Cc2cccc3ccccc23)=Nc2ccccc21
Temperature: 25 °C

Procedure:
2-(2-Naphthalen-1-yl-vinyl)-3H-quinazolin-4-one (11 mmol), phosphorus oxychloride (20 ml) and N,N-diethylaniline (1.0 ml) is added to a round-bottomed flask. The mixture is heated at 110° for 12 h. After cooling to rt, the reaction is quenched with ice-water and the crude product is collected by suction filtration. The crude solid is dissolved in ethyl acetate. Customary working up afforded 4-chloro-2-(2-naphthalen-1-yl-vinyl)-3,4-dihydro-quinazoline.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])([OH:10])=[O:9].[H][H]>[Pd].O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])([OH:10])=[O:9]
Reactant: [H][H]
Reactant: CC(CN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(CN(CC(=O)O)CC(Cc1ccc(N)cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Yield: 125.5 %

Procedure:
To a Parr flask was added 3.40 g (3.84 mmol) of N,N,N′,N″,N″-Pentakis(carboxymethyl)-2-[(4-nitrophenyl)methyl-]-6-methyldiethylenetriamine trifluoroacetic acid salt and 50 ml of water followed by the addition of 0.3 g of 5% palladium on carbon. The flask was pressurized to 30 psi hydrogen and vented twice. The vessel was then pressurized to 45 psi hydrogen and shaken. Once hydrogen uptake ceased, typically after 2 to 4 hours, the flask was vented and the mixture filtered through a pad of celite. The celite was washed with 20 ml of water. The filtrate was concentrated under reduced pressure to afford 3.02 g of product with a yield of 92.03%. The spectral data obtained for this product are consistent with those of a reference standard.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:17]1([O:22][C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OC2CCCC2)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Product: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with the procedure described in Example 8(c) using 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester (see Example 3)5, Method 1, step (a)) and 4-cyclopentoxyphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)=O)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(C(C)=O)cccc2c1=O
Yield: 70.1 %

Procedure:
Ethyl 2-butyryl-3-(2-acetylphenylamino)acrylate (14.8 g, 48.8 mmol) was added to boiling diphenyl ether (50 ml) and heated at reflux for 3.5 hours. After cooling, the solution was poured into ether, and the solid filtered off and washed with ether to obtain 3-butyryl-8-acetyl-4(1H)-quinolone (8.8 g), contaminated with some diphenyl ether. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.CCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)CSc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1csc2ccc(Br)cc12
Temperature: 100 °C
Yield: 64.7 %

Procedure:
Polyphosphoric acid (7 g) was added to a solution of 1-(4-bromo-phenylsulfanyl)-propan-2-one (I-24a: 2.0 g, 8.163 mmol) in toluene (10 mL) and the resulting mixture was heated to 100° C. for 5 hours. The reaction was monitored by TLC (100% hexane). The reaction mixture was cooled to room temperature, quenched with ice, basified with potassium carbonate (pH˜8) and extracted with ethyl acetate. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 1.2 g of product (66% yield)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH:13]([CH2:14][CH3:15])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CCC(Oc1ccccc1[N+](=O)[O-])C(NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CCC(Oc1ccccc1N)C(NC(=O)OC(C)(C)C)C(=O)O
Yield: 94.7 %

Procedure:
6.03 g (17.0 mmol) 2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-pentanoic acid in 110 ml methanol were hydrogenated with 0.21 g Palladium 10% on charcoal. Filtration and removal of the solvent by distillation yielded 5.22 g (95%) 3-(2-amino-phenoxy)-2-tert-butoxycarbonylamino-pentanoic acid as red oil, MS m/e (%): 325.3 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[CH:36]1([O:42][C:43](=[O:48])[O:44][CH:45](Cl)[CH3:46])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C>[CH:36]1([O:42][C:43]([O:44][CH:45]([O:15][C:14](=[O:16])[CH2:13][CH2:12][O:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=2[N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]3[CH:25]=[N:26][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:29]=3[C:30]#[N:31])[CH:4]=2)[CH3:21])[CH3:46])=[O:48])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(OC(=O)CCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)OC(=O)OC1CCCCC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (500 mg, 0.95 mmol), carbonic acid 1-chloroethyl cyclohexyl ester (393 mg, 1.9 mmol), triethylamine (399 μL, 2.85 mmol), and NaI (142.5 mg, 0.95 mmol) in DMF (5 mL) were stirred at 60° C. for 1 day. Ethyl acetate was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 37-1. MS [M+H]+: 674.2; tR=35.7 min (method 5).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].ClCCl>CO>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCNC(=O)c1cnc2ccc(Br)cn12

Procedure:
Add 6-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (0.11 g, 0.41 mmol) to a sealed tube containing N,N-dimethyl-ethane-1,2-diamine (5 mL). Heat the reaction at 150° C. for 24 h. Flash chromatography using appropriate mixtures of dichloromethane/2M ammonia in methanol gives 0.14 g of the product as a yellow oil. This material is progressed further without characterization. MS ES− m/e 269.0, 311.0 (M−1).
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:4]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:3]1.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[NH:6][C@@H:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:4]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc(C3CCC3)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N[C@H]1Cc1cccc(C2CCC2)c1
Yield: 90.4 %

Procedure:
According to example 82, 1.87 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-cyclobutylbenzyl)-4-morpholinecarboxylate was treated with 3.1 mL of TFA in 30 mL of CH2Cl2 for 4 h. Neutralization with 8 mL of Et3N and work-up in the usual manner gave a light yellow residue. Purification of the crude material by flash chromatography on 85 g of silica gel (8:2 hexane:EtOAc) afforded 1.35 g (91%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-cyclobutylbenzyl)morpholine as a thick, transparent semi-solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:41][C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][S:45][CH3:46]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:41][C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][S:45][CH3:46]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CSCC[C@H](N)CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
2.0 g of Boc-Tyr-(D)Ala-Gly-Phe-methioninol are dissolved in 20 ml of TFA-CH2Cl2 (1:1) and left to stand for 30 minutes at 0°. After reducing the volume under vacuum, the title compound is precipitated with ether and filtered off. The title compound is obtained as an amorphous salt.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:12]=[N:13][C:14]([C:28]#[N:29])=[C:15]([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:19][CH2:18]2)[N:16]=1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:12]=[N:13][C:14]([C:28]#[N:29])=[C:15]([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:19][CH2:18]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nnc(NCCN)nc1N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 60 mg (0.15 mmol) of {2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester as prepared in example 8 in 2 ml of dichloromethane were added 0.2 ml of trifluoroacetic acid. The reaction mixture was stirred at room temperature for one hour and then evaporated under reduced pressure. The solid residue was dispersed in ether. The resulting solid was filtered and gave 30 mg (47% of theory) of 3-(2-amino-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile trifluoro-acetate as an off-white solid; MS: 310 (M+H)+.
Reaction SMILES: [K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[F:14][C:15]([F:35])([CH:18]([F:34])[O:19][C:20]([F:33])([F:32])[C:21]([F:31])([F:30])[C:22]([F:29])([F:28])[O:23][C:24]([F:27])([F:26])[F:25])[CH2:16][OH:17].[O-]Cl.[Na+].S(=O)(=O)(O)[OH:40]>CC#N.O>[F:14][C:15]([F:35])([CH:18]([F:34])[O:19][C:20]([F:33])([F:32])[C:21]([F:30])([F:31])[C:22]([F:28])([F:29])[O:23][C:24]([F:25])([F:26])[F:27])[C:16]([OH:40])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C

Procedure:
The equipment of example 9 was used. 5.5 mL water, 20 ml MeCN, 0.36 g KBr, 0.12 g TEMPO (0.00077 mol) and 10 g 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol were placed in the flask. 15% (wt) aq. NaOCl buffered to pH 8-9 (48 ml) were added via the dropping funnel in 3 portions during 18 hours of stirring at room temperature. Then concentrated sulphuric acid (1-2 ml 95%) were added to make the reaction mixture acidic. After extraction with diethyl ether, the organic phases were collected and dried over magnesium sulphate. The solvent was evaporated to give a colorless liquid (12.24 g), which was distilled using a water pump (15 mmHg, 92° C.) to give 8.54 g of pure acid. Yield: 82%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH2:3]1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[CH:29]=[N:28]1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([NH:16][C:9]2[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:36]([C:32]4[CH:31]=[C:30]5[C:35](=[CH:34][CH:33]=4)[NH:27][N:28]=[CH:29]5)=[O:37])[CH2:3]3)[N:8]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5[nH]ncc5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
To a solution of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.27 mmol) and 1H-indazole-5-carboxylic acid (44 mg, 0.27 mmol) in dichloromethane (20 mL) were added the solution of 1-methyl-1H-imidazole (88 mg, 1.1 mmol) and EDCI (206 mg, 1.1 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid formed during the reaction was collected by filtration and washed with MeOH to afford N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-5-carboxamide (78 mg, 56.1%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 13.25 (s, 1H), 9.58 (s, 1H), 8.81 (s, 1H), 8.61 (d, 1H, J=6.3 Hz), 8.36 (s, 1H), 8.19 (s, 1H), 7.88-7.86 (m, 2H), 7.56 (d, 1H, J=8.7 Hz), 7.50 (s, 1H), 6.91 (d, 1H, J=8.4 Hz), 4.61-4.59 (m, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.62 (brs, 3H), 2.28-2.09 (m, 2H). LC-MS: 517 [M+H]+, tR=1.34 min. HPLC: 95.89% at 214 nm, 97.39% at 254 nm, tR=4.52 min
Reaction SMILES: C(C(C(C(O)=O)O)O)(O)=O.C([O:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH2:24][O:25][CH:26]=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:17]1)=[O:15])C.[OH-].[Na+].[ClH:44]>C(O)C>[ClH:44].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:27]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[CH:26][O:25][CH2:24][CH2:23][CH2:22][N:18]2[CH2:19][CH2:20][CH2:21][C@@H:16]([C:14]([OH:15])=[O:13])[CH2:17]2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOC=C(c2ccc(F)cc2)c2ccc(F)cc2)C1
Agent: Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCOC=C(c2ccc(F)cc2)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 4.8 h
Yield: 100 %

Procedure:
(R)-1-(3-((2,2-bis(4-Fluorophenyl)ethenyl)oxy)-1-propyl)-3-piperidinecarboxylic acid ethyl ester tartrate (3.8 g, 0.0065 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (25 ml) and 12 N sodium hydroxide solution (2.2 ml) was introduced at 5° C. After stirring the solution at room temperature for 4.8 h, pH of the reaction mixture was adjusted to ca. 7 with 4 N hydrochloric acid solution, and the mixture was evaporated to a residue in vacuo. Water (25 ml) was added, and the mixture was extracted with dichloromethane (3×50 ml). The combined extacts were dried (MgSO4) and evaporated to a foam, which was dissolved in toluene (1.5 ml) and warmed to 40° C. Methanol (0.27 ml) was introduced followed by chlorotrimethylsilane (0.83 ml). The product precipitated slowly, and after the suspension had been allowed to stand for 18 h at room temperature it was collected by filtration. The title compound (2.9 g, 100%) was obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2[S:6][C:7]([S:11][CH3:12])=[CH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Cl.C(NCC)C.C=O.[C:22](=O)([O-])[O-:23].[K+].[K+]>CO.O.C(O)(=O)C>[Cl:1][C:2]1[S:13][C:5]2[S:6][C:7]([S:11][CH3:12])=[C:8]([CH2:22][OH:23])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(=O)c2cc(Cl)sc2s1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CSc1sc2sc(Cl)cc2c(=O)c1CO
Temperature: 0 °C
Yield: 46.5 %

Procedure:
2-Chloro-6-methylthio-4-oxo-4H-thieno[2,3-b]thiopyran (6.64 g, 0.027 mol), diethylamine hydrochloride (19.65 g, 0.24 mol) and paraformaldehyde (17.16 g) were added to an aqueous solution of 80% acetic acid and refluxed under heating for 30 hours. The solvent was removed under reduced pressure. The residue was added with ice water and stirred for a while, and supernatant was removed. The remaining viscous matter was dissolved in dimethylformamide (150 ml), filtered for removal of the insoluble matter. Then, the filtrate was added with water (40 ml), methanol (100 ml) and potassium carbonate (37 g, 0.7 mol) and stirred for 35 minutes. Then, ice water (700 ml) was added and the resulting precipitates were collected by filtration. The precipitates were recrystallized from ethanol to obtain 3.5 g (yield: 46.5%) of 2-chloro-5-hydroxymethyl-6-methylthio-4-oxo-4H-thieno[2,3-b]thiopyran.