Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([N:23]1[CH2:28][C@@H:27]2[CH2:29][C@H:24]1[CH2:25][NH:26]2)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][C@@H:27]2[CH2:29][C@H:24]1[CH2:25][N:26]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])([CH3:7])[CH3:6])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (155 μL, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL) The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a pale brown oil. To a solution of (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (1 mmol) in anhydrous THF (5 mL) at 0° C., a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 3.37 (bs, 1H); 3.31 (d, J=10.2 Hz, 1H); 3.21 (d, J=10.2 Hz, 1H); 3.15-3.00 (m, 2H); 2.81-2.61 (m, 2H); 2.45 (s, 2H); 1.76 (d, J=10.0 Hz, 1H); 1.56 (d, J=10.0 Hz, 1H); 1.46 (t, J=5.02 Hz, 1H); 1.03 (s, 3H) and 1.00 (s, 2H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[C:15]1([CH2:14][CH2:13][CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCc2ccccc21
Reactant: BrCCCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 3-bromo-propyl-benzene (0.119 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.100 g, 80%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.99 (m, 2H), 2.66 (t, 2H), 3.68 (t, 2H), 4.38 (s, 2H), 7.18-7.56 (m, 8H), 7.92 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1

Procedure:
3-Acetylphenylboronic acid (7.10 g, 43.3 mmol) was coupled with (E)-3-(4-bromophenyl)-but-2-en-1-ol (5.76 g, 25.0 mmol) by a procedure analogous to that described in example 54a to give (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an off-white solid; 5.33 g (79%). This solid was recrystallised from aqueous ethanol to give a first crop of very pure (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as colourless platelets; 2.78 g (41%) and a second crop of (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an amorphous off-white solid; 2.53 g (37%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:28]=[C:27]([NH2:29])[C:26]4[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)=[N:8][CH:7]=1>CO.O>[NH2:29][C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=2)[N:20]=[C:19]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:34])=[O:4])=[CH:7][N:8]=3)[CH2:14][CH2:15]2)[N:28]=1
Reactant: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cn4)CC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 103.2 %

Procedure:
Potassium hydroxide (1.18 g, 21.1 mmol) was added to a solution of (3) (0.5 g, 1.05 mmol) in MeOH/H2O (20 mL, 10%; v/v). The reaction mixture was heated to 85° C. for 12 h, then cooled to room temperature. The mixture was concentrated, acidified with HCl (aq) (20 mL, 3M) and the desired product was filtered and rinsed with cold H2O to give 0.46 g (quantitative yield) of the title compound: 1H NMR (DMSO) δ 12.36 (br s, 1H), 9.56 (br s, 1H), 8.78 (br s, 2H), 8.36 (s, 1H), 8.07 (d, 1H, J=9.2), 7.75 (s, 1H), 7.61 (s, 1H), 7.11 (d, 1H, J=9.3), 4.64 (m, 2H), 4.29 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.37 (m, 2H), 2.12 (m, 2H), 1.60 (m, 2H); 13C NMR (DMSO) δ 164.7, 161.3, 155.2, 154.4, 151.0, 146.7, 141.8, 140.1, 136.3, 115.2, 112.4, 105.2, 101.6, 99.3, 56.3, 56.0, 48.4, 43.3, 30.4; HRMS (FAB) m/z 425.1948 (M+H)+ (C21H24N6O4 requires 425.1937); Anal. (C21H24N6O4 ·2HCl·2H2O) C, H, N.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N+:8]=2[O-])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16]C(OC)=O>C1COCC1>[Cl:16][C:7]1[N:8]=[C:9]2[C:4]([CH:3]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:1]2)=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cc2ccc[n+]([O-])c2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a stirred solution of ethyl 7-azaindole-2-carboxylate-7-oxide (1.32 g, 6.4 mmol) and hexamethyldisilazale (1.4 mL, 6.6 mmol) in THF (30 mL) at 0° C. was added dropwise over 30 min a solution of methyl chloroformate (1.2 mL, 15.5 mmol) in THF (5 mL). The mixture was warmed to room temperature, stirred for 2 h and partitioned between ether (50 mL) and water (50 mL). The aqueous layer was extracted with ether (30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and purified by column chromatography [SiO2; heptane-ether (3:1)] to give ethyl 6-chloro-7-azaindole-2-carboxylate as a white solid (0.38 g, 26%). mp 144–145° C. Found: C, 53.69; H, 4.05; N, 12.39%. C10H9N2ClO2 requires: C, 53.47; H, 4.04; N, 12.46%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].Br[CH2:35][CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:37]([CH2:36][CH2:35][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]3[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:32]=[C:31]([F:33])[CH:30]=4)[CH:12]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)#[N:38]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
60 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 221) was dissolved in 0.6 mL of N,N-dimethylformamide, to which 45 mg of 3-bromopropionitrile and 57 mg of potassium carbonate were added, and stirred at 80° C. for 4 hours. After cooling, the solvent was evaporated, the residue was dissolved in chloroform, and the insoluble substances were filtered off. Chloroform was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 52 mg (77%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1([CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[CH2:3]1
Reactant: c1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)c2ccccc21
Yield: 73 %

Procedure:
A solution of 25.0 g (0.25 moles) of 3,3-dimethyl acrylic acid in 250 ml of benzene was cooled to 0° C. in an ice bath. To this solution, 99 g (0.75 moles) of anhydrous aluminum chloride was slowly added using a spatula over a period of 20 minutes with stirring, after which the ice bath was removed and the reaction mixture was gradually heated to reflux. The reaction mixture was refluxed for ˜7-8 h, then excess benzene was distilled off and the mixture was quenched with ice-cold dilute hydrochloric acid (HCl). The mixture was then diluted with ethylacetate (100 ml), the organic layer was separated and the aqueous layer was again washed with ethyl acetate (50 ml). The combined organic layer was washed with water (3×100 ml) until the pH was neutral, and then dried over anhydrous sodium sulfate and concentrated under vacuum. 43.0 g of reddish brown liquid was obtained, which was distilled under vacuum to give 29 g of the desired product, 3,3-dimethyl-indan-1-one (distilled at 82-84° C. at ˜10 mm). Yield=73%, purity=99%. 1H NMR (DMSO-d6, 300 MHz): δ 7.3-7.8 (m, 4H, Ar—H), δ 2.5 (s, 2H, O═C—CH2), δ 1.3 (s, 6H, —CH3). LC/MS: 161 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[Br:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1>>[Br:18][C:19]1[N:20]=[CH:21][N:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH:15]3[CH2:17][CH2:16]3)[N:3]=2)[CH:23]=1
Reactant: Clc1ccc(-c2cc(C3CC3)nc(Cl)n2)cc1
Reactant: Brc1c[nH]cn1
Product: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example A.13) (0.80 g, 3.0 mmol) and commercially available 4-bromo-imidazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.71 g, 63%). MS (ISP) 375.1 [(M+H)+].
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si](O[C:27]1[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:31][CH:30]=[C:29]([O:47][Si](C(C)(C)C)(C)C)[C:28]=1[O:55][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C(O)(=[O:65])C.O>C1COCC1>[OH:65][C:30]1[C:29]([OH:47])=[C:28]([OH:55])[CH:27]=[C:32](/[CH:33]=[CH:34]\[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:31]=1
Reactant: CC(=O)O
Reactant: COc1cc(/C=C\c2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cc(O)c(O)c(O)c2)cc(OC)c1OC
Temperature: 25 °C
Yield: 122.9 %

Procedure:
Tetrabutylammonium fluoride (1.37 mL, 1.37 mmol, 1M in THF) was added to a solution of 32 (0.45 g, 0.69 mmol) and glacial acetic acid (78 μL, 1.37 mmol) in THF (6 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was partitioned between CH3CN and cyclohexane and the CH3CN layer was separated and concentrated in vacuo to give the crude product (0.27 g). Purification by column chromatography (SiO2 1:1 EtOAc:cyclohexane) gave ZSB-79 (0.127 g, 58%) as a 86:14 mixture of Z:E isomers:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].O.[OH-].[Na+]>CO.CC(O)=O>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][CH:4]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)[C:3]([OH:35])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@H](O)CC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@H](O)CC1)C(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-(trans-4-hydroxy-cyclohexylmethyl)-butyric acid methyl ester (f1) (27.4 mg, 0.045 mmol) in MeOH (0.50 mL) was added water (32 μL) and 10N NaOH (32 μL, 0.32 mmol). The mixture was heated at 50° C. After 15 h, the reaction mixture was cooled to RT, dissolved in 50% aqueous AcOH (6 mL) and purified by preparative HPLC to give the title compound (13.8 mg) as a lyophylized powder. (m/z): [M+H] calcd for C27H42N2O5 475.32. found 475.2. 1H NMR (CD3OD, 400 mHz) δ (ppm) 7.78 (d, J=1.6 Hz, 1H), 7.72 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 4.09 (m, 1H), 3.57 (dd, J=16.7, 5.9 Hz, 1H), 3.52 (s, 3H), 3.52-3.42 (m, 3H), 3.23 (m, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.31 (m, 1H), 2.05-1.60 (m, 10H), 1.40-1.15 (m, 4H), 1.00 (m. 2H), 0.79 (t, J=7.5 Hz, 3H), 0.70 (dt, J=7.3, 1.3 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].CS(C)=[O:20].C(=O)([O-])[O-].[K+].[K+].OO>O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:20])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: CS(C)=O
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol), dimethylsulfoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3 mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature. Dilute with 100 mL of water, extract with ethyl acetate (3×100 mL). Wash the organic phase with 100 mL of water, and 50 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via a Biotage Flash 40L system using 75:25 hexanes/ethyl acetate as eluting solvent to give 3.0 g (77%) of the title compound: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (br m, 2H).
Reaction SMILES: [C:1]([C:4]1[N:9]2[C:10](=[O:25])[N:11]([CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.[CH2:36]1COCC1>>[OH:3][C:1]([C:4]1[N:9]2[C:10](=[O:25])[N:11]([CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)([CH3:36])[CH2:2][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc2nn(CCc3ccc4ccccc4n3)c(=O)n12
Product: COc1ccc(CC(C)(O)c2cccc3nn(CCc4ccc5ccccc5n4)c(=O)n23)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
In a flame-dried, 5 mL microwave vial was placed 7-1 (20 mg, 0.054 mmol) in THF (0.54 mL) under dry N2 gas. The reaction mixture was cooled to −78° C., and a 0.5 M solution of (4-methoxyphenyl)magnesium bromide in THF (0.119 mmol, 0.24 mL) was added. After stirring for 15 min, the reaction was quenched with sat. aq. NH4Cl (0.25 mL) and diluted with CH2Cl2 (2 mL). The mixture was transferred to a phase separator column, and the organic layer was collected and dried under a stream of N2 gas. The crude product was purified by reversed phase HPLC (eluting with 20-60% acetonitrile/water with 0.1% NH4OH modifier). Pure fractions were pooled and dried to give 6.3 mg (26%) of 7-2. HRMS (ES) 441.1911 found (M+H) found, 441.1923 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH:12]2CBr)=[O:8])=[CH:5][CH:4]=1.[C-:18]#[N:19].[K+].[C:21](=O)(O)[O-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:21][C:18]#[N:19])[CH2:12][CH2:13]2)=[O:8])=[CH:16][CH:17]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)OCC2CC2CBr)cc1
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)OCC2(CC#N)CC2)cc1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
261 mg of compound 10a was dissolved in 5 ml ethanol. A solution of 98 mg potassium cyanide in 5 ml water was added and the mixture was stirred at 35° C. for two days. 10 ml of a saturated aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The combined extracts were dried with sodium sulfate and evaporated to give a yellow liquid. Purification with column chromatography (heptane/ethyl acetate 3/1) gave the title compound (38 mg) confirmed by NMR and LC/MS
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([O-:17])=[O:16])=[N:8][C:7]=12)=O.[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].N1CCCC[CH2:29]1>CCO>[O:26]=[C:25]1[C:27](=[CH:1][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=4)[C:15]([O:17][CH3:29])=[O:16])=[N:8][C:7]=23)[S:21][C:22](=[S:23])[NH:24]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cnn2ccc(-c3cccc(C(=O)[O-])c3)nc12
Reactant: C1CCNCC1
Solvent: CCO
Product: COC(=O)c1cccc(-c2ccn3ncc(C=C4SC(=S)NC4=O)c3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)benzoate (40 mg, 0.14 mmol) in 0.5 mL EtOH was added rhodanine (19 mg, 0.14 mmol) and piperidine (14 μL, 0.14 mmol). The mixture was stirred at room temperature overnight for three nights. The solid formed was isolated by filtration and purified by preparative TLC (1% MeOH/DCM) to yield methyl 3-(3-((4-oxo-2-thioxothiazolidin-5-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate. LCMS (M+1=397)
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH:12]([CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)=[O:13].O>C1COCC1.C(OCC)(=O)C>[OH:13][CH:12]([C:11]1[N:7]([CH3:6])[N:8]=[N:9][CH:10]=1)[CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: Cn1ccnn1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nncc1C(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (9.60 mL, 24.0 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (2.00 g, 24.0 mmol, prepared according to PCT Int. Appl., 2008098104) in dry THF (100 mL) at −50° C. The reaction became heterogeneous and yellow during addition. After 15 minutes, a solution of tert-butyl 3-formylazetidine-1-carboxylate (4.45 g, 24.0 mmol) in dry THF (10 mL) was added dropwise by syringe. The reaction mixture became homogeneous and was allowed to slowly warm to 0° C. Water (10 mL) and ethyl acetate (100) mL were added. The biphasic mixture was warmed to 23° C. The mixture was partitioned between half-saturated aqueous sodium chloride solution (100 mL) and ethyl acetate (300 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Celite® (14 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with ethyl acetate initially, grading to 5% methanol-ethyl acetate provided the title compound as a white foam.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][CH:7]3CC(N(CCC)CCC)C[C:5]=1[C:6]=23)(=O)C.C([N:25]([CH2:28]C)CC)C.ClC(OCC(Cl)(Cl)Cl)=[O:32]>C(Cl)Cl>[C:28]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:32])[NH2:25]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCCN(CCC)C1Cc2c(C(C)=O)ccc3c2C(CN3)C1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (2.3 g, 7.7 mmol) and triethylamine (1.1 ml, 8 mmol) in 90 ml CH2Cl2 under N2 was added dropwise a solution of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at room temperature for 1 hr. The CH2Cl2 solution was extracted with water and 1N HCl. The organic solution was washed with a saturated NaHCO3 solution and with a brine solution. The CH2Cl2 solution was dried (MgSO4) and concentrated in vacuo to give 3.3 g of the 1-carbamylindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:4]2[CH:5]=[C:6]([Cl:32])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Mix Trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 19) (1.70 g, 2.64 mmol), (4-methoxycarbonylphenyl)boronic acid (0.576 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium(0) (0.305 g, 0.26 mmol) and 1.32 ml of 2M solution of K2CO3 in DME (10 mL). Stir for 12 hours at 80° C. Quench the reaction with water and extract with ethyl acetate. Wash the extract with brine and dry over magnesium sulfate. Flash chromatography affords 1.32 g (80%) of the title compound: Mass spectrum (apci) m/z=632 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:18]1([C:23]#[N:24])[CH2:22]CC[CH2:19]1>O>[N:2]1([C:18]([CH3:22])([CH3:19])[C:23]#[N:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCNCC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCCCCC1
Yield: 80 %

Procedure:
The title compound (6.6 g: 80%) was prepared from homopiperidine hydrochloride (6.7 g; 49 mmol), acetone (3.67 ml; 50 mmol), and potassium cyanide (3.25 g; 50 mmol) in water (25 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ 1.43 (6H, s), 1.50-1.65 (8H, m), 2.66 (4H, m).