Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH3:35]>O>[F:22][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH3:35])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4]
Reactant: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2[nH]c(C(=O)NC)c(CCNC(=O)C(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (102 mg) and N,N-dimethyl formamide (3.00 mL) were added potassium carbonate (55.2 mg) and ethyl iodide (0.0318 mL), followed by stirring at room temperature for 2 hours, then warming to 60° C., and stirring overnight. To this mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and subsequently dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane:ethyl acetate=2:1 to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-ethoxy-N-methyl-1H-indole-2-carboxamide (9.00 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])=[O:26])(=[O:21])[CH3:20]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cc1C

Procedure:
To a stirred solution of 4-chloro-2-methylaniline, 1-1, (10.0 g 0.071 moles) in toluene was added (24.7 mL 0.014 moles) of N,N-diisopropylethylamine, followed by slow addition of acetylsalicyloyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 9.4 grams of 1-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 88% pure, M+1 peak m/e 304.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:26]=[C:27](/[C:31](/[CH3:35])=[CH:32]/[CH2:33]O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[Br:20][CH2:33]/[CH:32]=[C:31](/[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1)\[CH3:35]
Reactant: BrBr
Reactant: C/C(=C\CO)c1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (5.15 g, 19.7 mmol) in acetonitrile (140 ml) was added dropwise over 5 minutes a solution of bromine (3.15 g, 19.7 mmol) in acetonitrile (5 ml) at a rate such that the temperature did not exceed −10° C. The mixture was allowed to warm to room temperature, then to this was added a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 4 g, 20.7 mmol) in acetonitrile (5 ml). The mixture was warmed gently to 65° C. for 1 h, cooled to room temperature and then poured onto diethyl ether (50 ml). The mixture was concentrated in vacuo, then diethyl ether (200 ml) was added. The mixture was filtered, concentrated again in vacuo and the residue purified by silica column (300 g) chromatography, eluting with 3:1 hexane/dichloromethane then 1:1 hexane/dichloromethane. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (4 g, 75%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])=[C:20]([Cl:31])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([O:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][CH2:1][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCC)cc23)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCN4CCOCC4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A starting compound (N-(4-{[6-(3-propoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propylurea, 54 mg), potassium carbonate (138 mg), and morpholine (0.017 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 42 mg (yield 77%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][O:21]2)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(C2CO2)ccc1OCc1ccccc1
Yield: 96.2 %

Procedure:
2-(Benzyloxy)-5-(2-bromoacetyl)benzamide (11.3 g, 32.30 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL) and cooled in an ice bath. The solution was diluted with ethanol (250 mL). Sodium borohydride (1.2 g, 32.3 mmol) was added in three portions. Following addition the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield crude title compound (1 0.88 g, 31.06 mmol).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](Br)[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].[Br-].[CH2:14]([Zn+])[CH2:15][CH3:16]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: CCC[Zn+]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Agent: [Br-]
Product: CCCc1cc(C=O)cc(C(=O)O)c1

Procedure:
The title compound is prepared in analogy to 3-formyl-5-ethyl-benzoic (582 mg) from 3-formyl-5-bromo-benzoic acid (1.00 g, 4.37 mmol) using propyl zinc bromide. LC-MS*: tR=0.56 min, [M−H]−=191.32; 1H NMR (D6-DMSO): δ 0.91 (t, J=7.3 Hz, 3H), 1.65 (h, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 7.97 (s, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 10.07 (s, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([NH:17][C:18]2[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=2[O:50][CH3:51])=[O:16])[NH:7]1)=O)C.[NH3:52].CO>>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([NH:17][C:18]2[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=2[O:50][CH3:51])=[O:16])[NH:7]1)(=[O:3])[NH2:52]
Reactant: CCOC(=O)C1Cc2c(cccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3OCCCCCC(=O)N3CCN(C)CC3)cc2OC)N1
Reactant: N
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1CC(C(N)=O)N2

Procedure:
The solution of 4-[(2-ethoxycarbonylindolin-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (175 mg) in ammonia-methanol solution (8.0 ml) was stood overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent; 8-10% methanol in chloroform) to give 4-[(2-carbamoylindolin-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (160 mg).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(P(N(C)C)(N(C)C)=O)C.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>C1COCC1.[Li]CCCC>[CH2:26]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:25][CH2:24][CH2:23][CH2:22][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: ICCCCCOC1CCCCO1
Reactant: C#CCCCCCCC
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCC#CCCCCCOC1CCCCO1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
1-Nonyne 11 (1.0 g, 8.06 mmol) in THF (20 ml) was treated with n-BuLi (1.7 M in hexanes, 6.6 ml, 0.011 mmol) at 0° C. and the resulting pale yellow solution stirred for a 15 min. HMPA (15 ml) was then added and the mixture stirred for a further 15 min at 0° C. To the resultant dark yellow/orange solution was then added 10 (3.6 g, 0.0121 mol) at 0° C. which resulted in a immediate colour change in the solution to light yellow. This light yellow solution was stirred at r.t. overnight at which stage it was triturated with water and extracted with hexanes. The hexane extract were well washed with water, dried (MgSO4) and concentrated invacuo to afford a light yellow residue which was purified by flash column chromatography (eluent—8.5% EtOAc in hexanes) to yield a the pure 12 (1.6 g, 70%); δH(270 MHz, CDCl3); 0.86 (3H, t, J 6.2), 1.15-1.85 (13H, m), 2.11 (4H, m), 3.30-3.55 (2H, m), 3.69-3.90 (2H, m) and 4.56 (1H, m); δC(67.5 MHz, CDCl3) 14.17, 18.82, 18.82, 19.74, 22.71, 25.57, 25.57, 28.91, 28.91, 29.08, 29.24, 29.38, 30.49, 30.84, 31.84, 62.40, 62.40, 67.57, 67.57, 98.90. MS (EI) 295 (M+H)+; HRMS: Found 295.2616 [M+H]+. Calc. for C19H35O2: 295.263706 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3,4-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (50.1 mg) with purity >90%. LCMS (pos) m/z 395.0, 397.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:13])=[N+:10]([O-])[CH:11]=1)=[O:5])[CH3:2].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:13][C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(C)[n+]([O-])c1
Product: CCOC(=O)c1ccc(COC(C)=O)nc1
Yield: 59.2 %

Procedure:
A mixture of 13.7 g of 5-ethoxycarbonyl-2-methyl-pyridine-1-oxide and 15 g of acetic anhydride was stirred under reflux. Excess acetic anhydride was removed under a reduced pressure, and the residue was purified by distillation under a reduced pressure (110° C./0.1 mmHg) to obtain 10.0 g of ethyl 6-acetoxymethylnicotinate. ##STR7##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:19]=[CH2:20].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:18]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:19]=[CH2:20]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCNc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a round bottom flask was added 2-(tert-butoxycarbonylamino)-3,3-dimethylpent-4-enoic acid (120 mg, 0.493 mmol), N-allylaniline (0.134 mL, 0.986 mmol), EtOAc (5 mL) and Hunig's Base (0.258 mL, 1.48 mmol). The reaction mixture was cooled to 0° C. 1-propanephosphonic acid cyclic anhydride (314 mg, 0.986 mmol) was added and the reaction was stirred at 0° C. for 5 min and then at rt for 3 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give tert-butyl 1-(allyl(phenyl)amino)-3,3-dimethyl-1-oxopent-4-en-2-ylcarbamate (70 mg, 0.20 mmol, 40% yield) as clear oil. Anal. Calcd. for C21H30N2O3 m/z 358.2. found: 359.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(OCC)(=O)C>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:1]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.25 g (29.5 mmol) of diethyl 3,5-pyrazoledicarboxylate (1) in 225 mL of acetone was added 11.7 g (36 mmol) of cesium carbonate, followed after 10 min by the addition of 5.3 mL (36 mmol) of t-butyl bromoacetate and the mixture was stirred overnight at room temperature. Since TLC analysis confirmed that the reaction was complete (Rf product=0.6 (7:3 hexanes:ethyl acetate)), the mixture was filtered and concentrated to give quantitatively 1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (2) as a clear oil as indicated by 1H NMR (containing a trace of t-butyl bromoacetate). (δ(300 MHz, CDCl3) 7.14 (s, 1H), 5.15 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (s, 9 H), 1.27 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H)). This material was used without further purification in the next reaction.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[C:33]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:26][CH:25]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)sc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Yield: 52.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (3.50 g, 15.9 mmol, RN-59216-82-9), oxalyl chloride (1.52 mL, 17.5 mmol), N,N-dimethylformamide (2 drops) tin(IV) chloride (2.04 mL, 17.5 mmol) and 2-(4-bromobenzyl)4,5-dimethylthiophene (4.46 g, 15.9 mmol). Purification on silica gel eluting 5% EtOAc/pet. ether gave 4.05 g (53%) of the title compound as yellow oil. (DMSO-d6) δ 1.43-1.47 (m, 2H), 1.61-1.75 (m, 4H), 1.81 (s, 3H), 1.91-1.99 (m, 2H), 2.28 (s, 3H), 3.24 (quintet, 1H), 3.84 (s, 2H), 3.88 (s, 3H), 7.02 (d, 2H), 7.06 (d, 1H), 7.40 (d, 2H), 7.52 (dd, 1H), 7.57 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH:29]=[CH2:30])=[O:27]>ClCCCl>[CH3:24][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]2[CH:15]([CH2:16][N:8]([C:26]([O:28][CH:29]=[CH2:30])=[O:27])[CH2:9]2)[C:14](=[O:17])[CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2)CCC(=O)C2CN(Cc3ccccc3)CC21
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1

Procedure:
To a solution of 9 g of (3aRS,7SR,7aRS)-2-benzyl-7-methyl-7-phenyl-4-perhydroisoindolone in 100 cm3 of 1,2-dichloroethane are added, at room temperature, 2.84 cm3 of vinyl chloroformate, followed by heating for 2 hours at reflux. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is purified by chromatography on a Column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 23 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 100 cm3 fractions. Fractions 17 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 4.27 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-vinyloxycarbonyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][C:29]([CH:35]1[CH2:40][O:39][CH2:38][CH2:37][NH:36]1)([CH3:34])[CH2:30][C:31]([OH:33])=[O:32]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:35]2[C:29]([CH3:34])([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)(CC(=O)O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(C)(C)CC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 41 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 3-methyl-3-(morpholin-3-yl)butanoic acid hydrochloride (1.34 g, 6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.5 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[CH2:3][N+:4]([O-:6])=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[N+:4](/[CH:3]=[CH:2]/[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-:6])=[O:5]
Reactant: N#Cc1cccc(C(O)C[N+](=O)[O-])c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(/C=C/[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(1-Hydroxy-2-nitroethyl)benzonitrile (3.32 g, 17.3 mmol) and triethylamine (4.37 g, 43.2 mmol) were stirred in anhydrous dichloromethane (100 mL) at 0° C. To the resulting solution was added methanesulfonyl chloride (2.77 g, 24.2 mmol) dropwise via syringe, after which time the reaction was warmed to ambient temperature and stirred for 15 min. The resulting reaction mixture was diluted with additional dichloromethane (200 mL) and partitioned with H2O (100 mL). The dichloromethane layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was filtered through silica gel eluting with hexane:EtOAc (4:1) to afford 3-[(E)-2-nitroethenyl]benzonitrile as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18](O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:18]([C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[Cl:10])[CH3:19])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(O)c1cc(F)ccc1Cl
Reactant: Nc1ncc(Br)cc1O
Product: CC(Oc1cc(Br)cnc1N)c1cc(F)ccc1Cl
Reaction time: 18 h

Procedure:
The title compound was prepared by a similar method to that of preparation 18 using commercially available 5-bromo-3-hydroxy-2-amino-pyridine and 1-(2-chloro-5-fluoro-phenyl)-ethanol (prepared according to WO 2009087305 A1) except the reaction time was 18 hr and the crude reaction was purified by chromatography on silica gel eluting initially with ethyl acetate in dichloromethane (2:98) followed by a second purification on silica gel eluting with tert-butyl methyl ether in heptane (45:55) to give a white solid (3.82 g, 49%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[C:3]#[C:4][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: Ic1ncccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C#Cc1ncccn1)Oc1ccc(C#N)cc1
Yield: 64.8 %

Procedure:
0.63 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile, 0.75 g of 2-iodopyrimidine, 18 mg of triphenylphosphine, 12 mg of palladium(II) chloride and 3.5 mg of copper(I) iodide were stirred overnight in 20 ml of triethylamine under nitrogen. The mixture was evaporated to dryness and then ethyl acetate and water were added. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and subsequently ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 580 mg of 4-[1,1-dimethyl-3-(2-pyrimidinyl)-2-propynyloxy]benzonitrile as an oil.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:10](=O)[CH2:11]OCC)\C(OC)=O)[CH3:3].CN(/C=C(/C(=O)CCCC)\C(OC)=O)C.Cl[C:32]1[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([N:39]2[C:43]([CH2:44][O:45][CH2:46][CH3:47])=[C:42]([C:48]([NH:50][CH2:51][C:52]3[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=3)=[O:49])[CH:41]=[N:40]2)[N:33]=1>>[CH2:46]([O:45][CH2:44][C:43]1[N:39]([C:34]2[N:33]=[C:32]([N:2]3[CH2:4][CH2:5][CH2:10][CH2:11][CH2:3]3)[C:37]([CH3:38])=[CH:36][N:35]=2)[N:40]=[CH:41][C:42]=1[C:48]([NH:50][CH2:51][C:52]1[N:56]([CH3:57])[CH:55]=[N:54][CH:53]=1)=[O:49])[CH3:47]
Reactant: CCOCC(=O)/C(=C/N(C)C)C(=O)OC
Reactant: CCOCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(Cl)n1
Agent: CCCCC(=O)/C(=C/N(C)C)C(=O)OC
Product: CCOCc1c(C(=O)NCc2cncn2C)cnn1-c1ncc(C)c(N2CCCCC2)n1

Procedure:
The title compound 99 was prepared by following the synthetic sequence and conditions described in Example 14 and Example 16 with the following modifications. First in Step 2 of Example 14, intermediate D.2 (R2=methyl, R3=H) was treated with (Z)-methyl 2-((dimethylamino)methylene)-4-ethoxy-3-oxobutanoate, instead of (Z)-methyl 2-((dimethylamino)methylene)-3-oxoheptanoate, to give D.3 (R2=methyl, R4=ethoxymethyl). This intermediate D.3 was converted to the corresponding D.5, 1-(4-chloro-5-methylpyrimidin-2-yl)-5-(ethoxymethyl)-N-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazole-4-carboxamide, in three steps (Steps 3-5).