Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:33])[CH3:31]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87.0 mg, 0.213 mmol) and propan-2-amine (18.89 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (62.1 mg, 0.138 mmol, 64.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.84-2.01 (m, 3 H) 2.12-2.22 (m, 1 H) 2.41 (d, J=4.29 Hz, 4H) 3.36-3.47 (m, 1H) 3.49-3.64 (m, 5 H) 3.95-4.10 (m, 2 H) 6.81 (d, J=8.84 Hz, 1 H) 6.99 (d, J=2.02 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.94 (dd, J=9.09, 2.53 Hz, 1H) 7.97 (d, J=7.83 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H31N7O2, 450; found, 450.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]=1)[CH3:2].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([CH3:15])[C:10]([O:14][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:29][CH:28]=3)[S:31][C:32]=2[CH3:38])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C)c(O)c(C)c1)OCC
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3,5-dimethyl-phenyl)-propionic acid ethyl ester was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH:20][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CC1

Procedure:
20 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was dissolved in 3 mL of toluene, and added with 20 μl of triethylamine and 10 μl of cyclopropanecarbonyl chloride at room temperature and stirred all day and night. The reaction solution was added with saturated aqueous sodium hydrogen carbonate, extracted with sodium acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 20 mg of the title compound as a colorless powder.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2nc(-c3ccccc3)sc12
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (105 mg, 0.33 mmole) and glycine (500 mg, 6.65 mmole) in 0.5 M sodium methoxide/methanol (12.6 ml) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.08 (br s, 1H), 9.22 (t, 1H), 8.13 (m, 2H), 7.61 (m, 3H), 4.02 (d, J=6.2 Hz, 2H), 2.72 (s, 3H); MS: (+) m/z 344.26 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of compound 10b (66 mg, 0.15 mmol) and pyridine (24 μL, 0.29 mmol) in DCM (5 mL) was added methanesulfonyl chloride (23 μL, 0.29 mmol). The resulting mixture was stirred at rt for 3 days. The mixture was then diluted with DCM (20 mL), and washed with 1 N HCl solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The orange solid obtained was washed with methanol (2×5 mL), and dried in vacuo to give the title compound 47. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.09-10.17 (m, 1H), 8.64-8.83 (br.s., 1H), 8.25 (br.s, 1H), 8.06-8.22 (m, 3H), 7.83-8.06 (m, 3H), 7.63-7.80 (m, 3H), 7.36-7.48 (m, 2H), 6.46 (d, J=5.9 Hz, 1H), 4.04-4.18 (m, 4H), 3.79-3.97 (m, 4H), 3.14 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H26N6O3S: 527.2 (M+H). Found 527.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:31](Cl)(=[O:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:31](=[O:42])[O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (200 mg, 0.45 mmol) in DCM (2 mL) was added 4-nitrophenyl carbonochloridate (226.9 mg, 1.13 mmol) followed by the addition of K2CO3 (620.6 mg, 4.5 mmol). The reaction mixture was stirred at room temperature for 18 h and filtered through a small silica pad. The filtrate was diluted with DCM (20 mL), washed with saturated NaHCO3 (8×15 mL) till the aqueous layer only showed light yellow color. The organic layer was dried over MgSO4, filtered and concentrated to give (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamate as a yellow oil (273 mg, crude 100%). This yellow oil was used directly to the next step without further purification. LCMS RT=2.213 min [M+H] 607.94 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2([CH2:16][CH3:17])OCCO2)=[C:5]([NH2:18])[N:4]=1.Cl>>[CH2:16]([C:11]1[NH:18][C:5]2[NH:4][C:3]([S:2][CH3:1])=[N:8][C:7](=[O:9])[C:6]=2[CH:10]=1)[CH3:17]
Reactant: CCC1(Cc2c(N)nc(SC)nc2O)OCCO1
Agent: Cl
Product: CCc1cc2c(=O)nc(SC)[nH]c2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 2-(methylthio)-6-amino-5-(2-ethyl-1,3-dioxolan-2ylmethyl)-4-pyrimidinol (2.50 g, 9.21 mmol) was combined with 69 mL of 0.2 M HCl and stirred at ambient temperature for 18 hours. The solids were collected by filtration, washed with 20 mL of water and dried in vacuo (40° C., 10 torr) to provide a quantitative yield of 1,7-dihydro-6-ethyl-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-4-one as a white solid. nmr (500 MHz, dmso-d6) δ1.17 (t, J=7.5 Hz, 3H), 2.49 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 6.03 (s, 1H), 11.61 (s, 1H), 11.95 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide as a yellow solid (50 mg, 38%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Cl>C(O)C>[CH3:3][O:4][C:5]([CH:7]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
Sodium hydroxide (4.56 g, 0.114 mol) was dissolved in ethanol (210 mL), and trimethyl phosphonoacetate (11.4 g, 0.062 mol) added with stirring. The mixture was stirred for 30 min at room temperature. Tert-butyl 4-oxopiperidine-1-carboxylate (11.35 g, 0.057 mol) was added with stirring at room temperature, and the reaction was allowed to stand overnight. Then, the mixture was acidified with diluted hydrochloric acid until the pH was 4, filtered, concentrated, and partitioned into water and chloroform. Phases were separated. The aqueous phase was extracted once with chloroform. Chloroform phases were combined, washed once with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound.
Reaction SMILES: [Br-].[CH:2]([C:5]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[CH:28]=[C:27]([CH:34]([CH3:36])[CH3:35])[C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[CH2:37]([O:41][C:42](=[O:53])[CH:43]=[C:44]([CH3:52])[CH:45]=[CH:46][CH:47]=[C:48]([CH:50]=O)[CH3:49])[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42](=[O:53])[CH:43]=[C:44]([CH3:52])[CH:45]=[CH:46][CH:47]=[C:48]([CH3:49])[CH:50]=[CH:7][C:6]1[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:30][C:29]([CH:31]([CH3:33])[CH3:32])=[CH:28][C:27]=1[CH:34]([CH3:36])[CH3:35])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)c1cc(C(C)C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C(C)C)c1
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Br-]
Product: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C(C)C)cc(C(C)C)cc1C(C)C

Procedure:
By the procedure of Example 6: 2,4,6-triisopropyl-benzyl-triphenylphosphonium bromide is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester to form 9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester (oil); which is hydrolyzed by the procedure of Example 7 to form: 9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid m.p.: 221° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.[S:29]1[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30]1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:34]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[O:35])[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: O=C(Cl)c1ccsc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccsc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
0.20 g (0.50 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 5 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. A solution of 0.07 g (0.50 mmol) of thiophene-3-carbonyl chloride (prepared according to FR 2 411 188) in 2.0 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.074 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.14 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.013 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam, along with 0.11 g of an impure batch, which is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.62 (s, 9H); 1.71 (s, 6H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.70 (d, J=2.0 Hz, 2H); 8.50 (t, J=2.0 Hz, 1H); 8.70 (s, 1H); 11.25 (s, 1H). LC-MS-DAD-ELSD: 510(−)=(M−H)(−); 512(+)=(M+H)(+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CN(C=O)C>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: BrCCCOC1CCCCO1
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1cccc(N2CCN(CCCOC3CCCCO3)CC2)c1
Yield: 49.4 %

Procedure:
712 mg (4 mmol) 3-Piperazin-1-yl-phenol are dissolved in 30 mL DMF under argon and cooled below 5° C. After addition of 1.38 g (2.5 eq.) K2CO3, 166 mg (0.25 eq.) KI and 888 mg (1 eq.) 2-(3-bromo-propoxy)-tetrahydro-pyran, the suspension is stirred at room temperature for 20 hours, then extracted with AcOEt after dilution with saline. The organic phase is dried over sodium sulfate, evaporated and the residue column chromatographed (silica gel, AcOEt/EtOH 95:5) to yield 630 mg (48%) desired product as a light yellowish resin.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 47.6 %

Procedure:
The title compound (73 mg) was prepared according to Example 263 using 201 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 122 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C18H20F3N3, 335.16; found, m/z 336.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.86-7.85 (m, 2H), 7.52-7.50 (m, 2H), 4.65-4.58 (m, 1H), 3.45-3.41 (m, 2H), 3.22-3.20 (m, 2H), 2.81-2.79 (m, 2H), 2.67-2.62 (m, 2H), 2.30-2.24 (m, 2H), 1.84-1.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:52][CH2:51]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[S:19][C:18]([CH:51]=[O:52])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: COCCOCc1csc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COCCOCc1c(C=O)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 210 mg of N-(4-chlorobenzyl)-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 5.0 mL of dry THF is heated to boiling under argon to dissolve the solid, then is cooled to −78° C. Into this mixture is cannulated a solution of LDA in THF, prepared in the usual manner from 0.35 mL of diisopropylamine and 0.80 mL of 2.5 M (in hexane) butyllithium in 4.0 mL of THF. The resulting deep blue mixture is stirred at −78° C. for 15 min, then 0.25 mL of dry DMF is added and the mixture allowed to warm to ambient temperature. The mixture is then partitioned between CH2Cl2 and dil HCl, and the organic phase dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica gel using 2% MeOH in CH2Cl2 provides 146 mg of the title compound as an orange solid. Recrystallization of a sample from EtOAc provides an analytical sample as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)([Cl:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:39]([Cl:41])=[O:40])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of cis-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole (5 g, 10.98 mmol, example 2) in methylene chloride (50 mL) cooled to 0° C. were added triethylamine (3 mL, 21.96 mL) and phosgene (8.7 mL, 16.47 mmol, ˜20% solution in toluene), respectively. The reaction mixture was stirred at 0° C. for 30 min then the excess reagents and solvent were removed under reduced pressure. The residue was taken in methylene chloride (˜100 mL) and the solution was filtered through a plug of silica gel (˜50 g). The silica gel was washed with 20% ethyl acetate in hexanes. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel, eluting with 5%, 10%, 20% ethyl acetate in hexanes) to give rac-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride as white solids (4.31 g, 76%).