Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:40])[O:14][CH2:15][C@@H:16]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:17][C@@H:18]([OH:25])[CH2:19][O:20][P:21]([OH:24])([OH:23])=[O:22])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:42]>>[P:21]([O-:24])([O-:23])([O:20][CH2:19][C@H:18]([OH:25])[CH2:17][C@H:16]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[Cl:38])=[O:28])[CH2:15][O:14][C:13](=[O:40])[NH:12][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1)=[O:22].[Na+:42].[Na+:42]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl 3-phenylisoxazol-5-ylcarbamate (48 mg, 0.08 mmol, 1.0 equiv.) at 0° C., was added NaOH (0.1 N, 1.6 mL, 2.0 equiv.) dropwise. The mixture was stirred at RT for 1 h followed by concentration to give sodium (2R,4S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-2-hydroxy-5-(3-phenylisoxazol-5-ylcarbamoyloxy)pentyl phosphate (55 mg, quant.) as a white solid. LRMS (M−2Na+3H+) ink 601.5.
Reaction SMILES: [CH2:1]([N:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](F)[CH:35]=[CH:36][C:30]=4[S:29](=[O:39])(=[O:38])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH:35]=[CH:36][C:30]=4[S:29](=[O:39])(=[O:38])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccc(F)cc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccc(N5CCOCC5)cc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine (100 mg, 0.16 mmol, prepared in analogy to N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine in Example 1-1 by using 2,4-dichloro-6-methylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine) and morpholine (0.5 mL) was heated with stirring in a sealed 2 mL of microwave process via for 3 hours at 120° C. under microwave irradiation. The resulting mixture was concentrated in vacuo to afford 111 mg of the crude product which was used in next step without purification. MS obsd. (ESI+) [(M+H)+] 704.
Reaction SMILES: [CH:1]1([C:4]2[C:8]3[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[O:15])=[CH:12][C:7]=3[N:6](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH:1]1([C:4]2[C:8]3[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[O:15])=[CH:12][C:7]=3[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCc1ccc(F)cc1)Nc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)Nc1cc2[nH]nc(C3CC3)c2cn1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of 1-(3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-fluorobenzyl)urea (70 mg, 0.123 mmol), TFA (1900 24.66 mmol), and triethylsilane (19.70 μl, 0.123 mmol) was stirred at room temperature. The reaction was concentrated, taken up in DMSO (2 mL) and purified by preparative HPLC (Reverse phase C-18, Waters SunFire PrepODB, 150×19 mm, 5u, eluting with 10-95% Acetonitrile/Water+0.1% TFA (20 mL/min) over 10 min.) to give 1-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-fluorobenzyl)urea (23 mg, 0.052 mmol, 42.5% yield) as an off-white solid. MS ESI calc'd. for C17H16FN5O [M+1]+ 326, found 326.
Reaction SMILES: [C:1]1([C:7]2[CH:8]([C:16]([O:18]CC)=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:10]1([C:9]2[CH:8]([C:16]([OH:18])=[O:17])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(c2ccccc2)=C1c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Ethyl 2,3-diphenyl-cycloprop-2-ene-1-carboxylate (1.75 g, 6.6 mol) and potassium hydroxide (1.79 g, 31.9 mmol) were dissolved in methanol (60 cm3) and heated to reflux for 5 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was partitioned between water (30 cm3) and ethyl acetate (30 cm3) The aqueous layer was separated and washed with ethyl acetate (2×30 cm3) before being acidified to pH=1 with dilute hydrochloric acid and extracted with dichloromethane (3×40 cm3). The combined dichloromethane extracts were dried (MgSO4) and evaporated to give the cyclopropene acid 1.22 g, 78%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:2]#[N:1])[C:14](=[O:15])[CH:13]=1
Reactant: N#Cc1cccc(CN)c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A nitrogen flushed pyrex reaction tube was charged with 3-(aminomethyl)benzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-methyl-2-pyrone (1 g, 7.9 mmol) and water (20 mL). The tube was capped and was heated to reflux. After 1.5 h, the product precipitated from solution. The reaction mixture was cooled to room temperature, filtered and washed with water. The product was used without further purification (1.67 g, 88%) 1H NMR (400 MHz, dmso-d6) δ 10.53 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.52 (t, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 5.79 (dd, J=1 and 2.5 Hz, 1H), 5.56 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 2.14 (s, 3H) ppm. ES-HRMS m/z 241.0968 (M+H calcd for C14H13N2O2 requires 241.0972).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH:15][C:16]([C:24]([F:27])([F:26])[F:25])([CH:20]=[C:21]([CH3:23])[CH3:22])[C:17]([OH:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:21]([CH3:23])([CH3:22])[CH2:20][C:16]([OH:15])([C:24]([F:25])([F:26])[F:27])[C:17]([OH:19])=[O:18])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2c(c1)CCO2
Reactant: CC(C)=CC(O)(C(=O)O)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)cc2c1OCC2
Temperature: 0 °C

Procedure:
A solution of 0.07 mol 5-fluoro-2,3-dihydro-benzofurane in 21 ml of dichloromethane is cooled to 3° C. To this solution 0.1 mol of AlCl3 is added over a period of 30 minutes. After this addition 0.05 mol of 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid is added dropwise over 30 minutes. The mixture is stirred for at least 6 h under reflux conditions. After complete reaction the solution is poured on a mixture of ice (50 ml) and 1M HCl (10 ml) and stirred for at least 1 hour. The aqueous phase is extracted three times with 51 ml of ethylacetate. The combined organic phases are washed with water, saturated sodium chloride solution (brine) and dried over magnesiumsulfate. The solvent is evaporated under vacuum. The product may be recrystallized from n-heptane. As the title compound is yielded in highly pure form the recrystallization is not necessary. The title compound may be used directly to start the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](OC)=O)=[CH:17][C:16]=3OC)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.COC1C=C(C(OC)=O)C=CC=1CP(=O)(OCC)OCC.ClC1C=CC(C([N:57]2CCC(=O)CC2)=O)=CC=1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:57])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(OC)c1
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: CCOP(=O)(Cc1ccc(C(=O)OC)cc1OC)OCC
Product: N#Cc1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
1-(4-chlorobenzoyl)-4-(2-methoxy-4-methoxycarbonylbenzylidene)piperidine from diethyl 2-methoxy-4-methoxycarbonylbenzylphosphonate and N-(4-chlorobenzoyl)-4-piperidone. Colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[CH3:17][NH:18][C:19]([NH:21][CH2:22][CH:23]([O:25][CH3:26])[CH3:24])=[S:20]>>[BrH:1].[Cl:16][C:6]1[CH:7]=[C:8]([Cl:15])[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]=1[C:3]1([OH:4])[CH2:2][S:20][C:19](=[N:21][CH2:22][CH:23]([O:25][CH3:26])[CH3:24])[N:18]1[CH3:17]
Reactant: CNC(=S)NCC(C)OC
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Product: Br
Product: COC(C)CN=C1SCC(O)(c2cc(S(N)(=O)=O)c(Cl)cc2Cl)N1C

Procedure:
was obtained in a manner analogous to the method described in Example 10 from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoylacetophenone and 1.6 g of 1-methyl-3-(2-methoxypropyl)-thiourea. M.p. 196° C (decomposition).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:43]=[CH:42][CH:41]=[CH:40][C:29]=1[NH:30][C:31]([CH2:38][CH3:39])=[CH:32][C:33]([O:35]CC)=O>CCCCCC>[CH2:38]([C:31]1[CH:32]=[C:33]([OH:35])[C:40]2[C:29](=[C:28]([O:27][CH3:26])[CH:43]=[CH:42][CH:41]=2)[N:30]=1)[CH3:39]
Reactant: CCOC(=O)C=C(CC)Nc1ccccc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCc1cc(O)c2cccc(OC)c2n1
Temperature: 232.5 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a mixture of diphenyl ether (30 ml) and biphenyl (30 g) was added ethyl 3-(2-methoxyanilino)-2-pentenoate (15.1 g) during which time the internal temperature was maintained 230-235° C. The mixture was stirred at 235° C. for 1 hour. To the reaction mixture was added hexane (150 ml). The precipitate was collected by vacuum filtration and washed with hexane to give 2-ethyl-4-hydroxy-8-methoxyquinoline (10.37 g) as crystals.
Reaction SMILES: [Br-].O1CCCCC1O[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.C([Li])CCC.[CH2:42]([CH:47]1[CH2:52][CH2:51][CH:50]([CH:53]=O)[CH2:49][CH2:48]1)[CH2:43][CH2:44][CH2:45][CH3:46].[OH2:55]>COC(C)(C)C>[CH2:42]([C@H:47]1[CH2:48][CH2:49][C@H:50]([CH:53]=[CH:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=2[OH:55])[CH2:51][CH2:52]1)[CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: c1ccc([P+](CCCc2ccc(OC3CCCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O
Reactant: CCCCCC1CCC(C=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CCCCC[C@H]1CC[C@H](C=CCCc2ccccc2O)CC1
Reaction time: 0.5 h

Procedure:
To a solution of [3-(4-[2-Tetrahydropyranyloxy]phenyl)propyl]triphenylphosphonium bromide 3D (R=pentyl) (1.68 g) in tert-butyl methyl ether at room temperature is added, dropwise, a 2.6 M solution of butyllithium (1.25 mL). The orange reaction mixture is stirred for 30 minutes, then a solution of cyclohexanal 3F (R=pentyl) (0.558 g) in tert-butyl methyl ether (3 mL) is added dropwise. The reaction is stirred a further 30 minutes, then poured into water and extracted with ether. The combined organic layers are washed with brine, then dried over sodium sulfate. The solvent is removed in vacuo and the residual material is flash chromatographed using 10% ethyl acetate in hexanes as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]1>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([O:28][CH2:11][CH2:6][CH2:7][CH3:8])=[O:27])[CH2:20][CH2:19]2)[N:3]=1
Reactant: O=C(O)CCC1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CCC1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Yield: 114.7 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (24.9 g) and 3-(4-piperidinyl)propionic acid, hydrochloride (20 g) in n-butanol (1000 ml) were stirred under reflux for 20 hours. The hot suspension was filtered and the insoluble material discarded. The filtrate was cooled in ice/water, the precipitated solid collected and the filtrate evaporated in vacuo. The resulting solid and the precipitated solid were combined and crystallised from isopropanol to give 4-amino-2-[4-(2-{n-butoxycarbonyl}ethyl)piperidino]-6,7-dimethoxyquinazoline, hydrochloride (27.0 g) with m.p. 250°-252°.
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1OC(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:18]1[C:17](=[O:20])[CH:16]=[CH:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C2[C@@H]1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C(N=[N+]=[N-])=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 73 %

Procedure:
To a stirred solution of 0.5 g of 6β-bromo-7α-acetoxyandrosta-1,4-dien-3,17-dione in 30 ml of dimethylformamide and 1.2 ml of water are added 0.11 g of sodium azide. The reaction mixture is heated at 100° C. for 45 minutes, cooled, poured into 500 ml of iced water and extracted with ethyl acetate. The combined extracts are washed with water, dried over sodium sulphate, filtered and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel. Elution with n-hexane:ethyl acetate 70:30 yields 0.28 g of the title compound, m.p. 123°-125° C. (dec.);
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[NH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1>O1CCCC1>[N:3]1([C:1]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=2)=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1csc(NC(=O)n2ccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 25 g of carbonyldiimidazole, 30.87 g of ethyl 2-aminothiazol-4-ylglyoxylate and 300 ml of tetrahydrofuran was stirred at room temperature for 1 day. After completion of the reaction, the crystals which precipitated out were collected by filtration and washed with ethyl acetate to give crude ethyl 2-(1-imidazolylcarbonylamino)thiazol-4-ylglyoxylate.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:22][CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])/[C:22](/[CH3:23])=[CH:9]/[CH:8]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/C=C(c1ccccc1)c1ccccc1
Yield: 95.9 %

Procedure:
As in the Example 99, a solution of 3,3-diphenyl-2-propenal (2.08 g) in ethanol (25 mL) was reacted with (carbethoxyethylidene)triphenylphosphine (4.0 g) for 30 minutes at room temperature. The reaction was worked up in the usual manner to give 2.8 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid ethyl ester as the sole product. The crude ester (2.89) in methanol (25 mL) was treated with 2N potassium hydroxide (10 mL) and the mixture was heated at reflux until the oil dissolved. Then it was cooled and left at ambient temperature overnight. The reaction was diluted with water (20 mL) and most of the methanol was removed under reduced pressure. The solution was acidified with 2N hydrochloric acid (12 mL) and the resulting solid was recovered by filtration washed with water and dried. The crude acid was triturated with hot hexane to furnish 2.08 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid. mp 184°-186° C. A sample was crystallized from 2-propanol to afford the analytical specimen. mp 185°-186.5° C. Anal. Calculated for C18H16O2 : C, 81.79; H. 6.10 Found: C, 81.73; H. 6.17.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([OH:27])=O)=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25](=[O:27])[NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:32]=3[O:31][CH3:30])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ocnc3C(=O)O)cc2)CC1(C)C
Reactant: COc1ccc(CN)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ncoc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-[4-(4-Carboxy-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 30 mL DMF. To the solution was added 2,4-dimethoxybenzylamine (1.26 g, 7.6 mmol), HATU (2.8 g, 7.4 mmol) and TEA (1 g, 10 mmol). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to DCM:MeOH=200:1) to afford the title compound (1.6 g, 3 mmol, yield: 54% over two steps).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OCCN1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((S)-3-tert-butoxycarbonylaminopiperidin-1-yl)ethyl ester (2.54 g, 7.73 mmol) in DCM (80 mL) was added TFA (20 mL) and the mixture was stirred at RT for 2 h. Toluene was added and volatiles removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 1M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a pale yellow oil (1.567 g, 89%). 1H NMR (CDCl3, 300 MHz): 4.18 (2H, t, J=6.0 Hz), 2.89-2.77 (2H, m), 2.68-2.59 & 2.62 (3H, m & t, J=6.0 Hz), 2.20-2.12 (1H, m), 2.00-1.94 (1H, m), 1.82-1.65 (2H, m), 1.60-1.46 (1H, m), 1.28 (2H, bs), 1.20 (9H, s), 1.15-1.03 (1H, m).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[NH2:13].Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].O>CS(C)=O.ClCCl>[NH2:13][C:9]1[C:8]2[C:12](=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[O:14][CH3:15])[N:11]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:10]=1
Reactant: N#Cc1cccc(CCl)c1
Reactant: COc1ccc(F)c2[nH]nc(N)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(F)c2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a fine suspension of ground potassium hydroxide (566 mg, 10.09 mmol) in dimethyl sulfoxide (5 mL) at room temperature under nitrogen was added a solution of 7-fluoro-4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 43) (727 mg, 4.01 mmol) in dimethyl sulfoxide (2 mL). After 5 min the resulting dark brown solution was treated with 3-(chloromethyl)benzonitrile (730 mg, 4.82 mmol). The reaction mixture was stirred for 30 min and then the mixture was poured into water, forming an emulsion. This was extracted with DCM and the combined extracts were washed with water and passed through a hydrophobic frit. The aqueous was extracted with ethyl acetate and the combined organic solutions were washed with water and brine, dried (Na2SO4) and then combined with the initial DCM extracts and concentrated in vacuo to leave a brown oil. The residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the required product (665 mg, 56%) as a yellow powder. LCMS (System A) RT=1.02 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([CH2:8][N+:9]([O-])=O)([OH:7])[CH:4]([CH3:6])[CH3:5].[ClH:14]>CCO.CO.[Pd]>[Cl-:14].[OH:7][C:3]([C:2]([F:1])([F:12])[F:13])([CH:4]([CH3:6])[CH3:5])[CH2:8][NH3+:9]
Reactant: CC(C)C(O)(C[N+](=O)[O-])C(F)(F)F
Reactant: Cl
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)C(O)(C[NH3+])C(F)(F)F
Product: [Cl-]
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 1,1,1-trifluoro-3-methyl-2-(nitromethyl)butan-2-ol (753 mg, 3.74 mmol) in EtOH (10 ml) in a 25 ml medium pressure glass hydrogenation vessel under N2, 10% Pd on carbon (39.8 mg, 0.374 mmol) was added. The vessel was flushed with N2, followed by H2 (22.64 mg, 11.23 mmol) at 5 bar pressure and stirred at RT for 6 days. The mixture was filtered through Celite® and washed through with EtOH(30 ml), followed by DCM (10 ml). The filtrate was concentrated under vacuum to give a colourless oil. The crude product was taken up in methanol (20 ml) and treated with a 1.25M HCl in methanol solution. The resulting colourless solution was stirred at RT for 1 hour and concentrated under vacuum to afford the title compound;
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([CH:21]=O)([CH3:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([C:21]#[CH:1])([CH3:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
K2CO3 (5.25 g) and 4-formyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (5.23 g) are added to an ice cold mixture of dimethyl (1-diazo-2-oxopropyl)-phosphonate (5.50 g), molecular sieves (2 g), and methanol (30 mL). The mixture is stirred in the cooling bath for 30 min and then at room temperature overnight. The mixture is filtered and aqueous NH4Cl solution is added to the filtrate. The resulting mixture is extracted with dichloromethane and the combined extracts are concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound.