Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C(Cl)Cl.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:7]=1[CH2:15][CH2:14][C:13]2=[O:16]
Reactant: Cc1ccc(C)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mL CH2Cl2 and 36 g anhydrous AlCl3 (Carlo Erba) were charged in a 3-neck 0.5-L round bottomed flask equipped with magnetic stirring bar, 250-ml dropping funnel, thermometer and reflux condenser. A solution containing 31 ml p-xylene and 21 ml acryloylchloride (Aldrich) in 100 ml CH2Cl2 was placed in the dropping funnel. This solution was added dropwise over 4 hours to the flask, the content of which was kept under stirring at the temperature of 0° C. with a bath of water and ice. Evolution of HCl was observed and the reaction mixture turned dark brick-red. After addition was complete, the mixture was allowed to warm to room temperature and stirring was continued overnight (18 hours). The reaction mixture was poured in a flask containing 250 g ice and 250 ml HCl 37%, the organic phase was separated and the acqueous phase was extracted with Et2O (3 times). All organic fractions were combined and washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and the solvent was removed in vacuo. 38.25 g of light yellow-orange oil were obtained. This product was used without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].[CH2:43]=O.O>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:26]([CH3:43])[CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:40][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=4)=[CH:12][C:13]=23)[C:20]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=2)=[N:21]1
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: C=O
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea.3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT aq. 1 N NaOH (1.1 mL, 1.1 mMol), 37 wt. % CH2O in water (50 uL, 0.67 mMol) and 20% Pd(OH)2/C (Pearlman's catalyst) (˜10 mg). A balloon of H2 was attached and the reaction stirred at RT for 3 days. The reaction was evaporated to dryness under vacuum, taken up in (9:1) CHCl3/iPrOH (15 mL) and treated with excess methyl isatoic anhydride polystyrene resin (˜500 mg, >1.8 mMol/g). After stirring at RT for 4 h the reaction was filtered, rinsed with (9:1) CHCl3/iPrOH, and the filtrate concentrated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (56.6 mg, 30%) as a white solid. ESMS [M+H]+: 551.6
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[CH3:12][N:13]([CH:21]1[CH2:22][CH2:23][N:24]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c12
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (1 g), 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.918 g, 8.95 mmol, commercially available from e.g. Fluorochem, Apollo or Butt Park) and N,N-diisopropylethylamine (2.61 mL, 14.92 mmol) was heated at 150° C. for 20 minutes. LC/MS showed incomplete reaction. Further NMP (2 mL) and DIPEA (1.3 mL) was added. The mixture was heated at 150° C. for 20 minutes. The mixture was partitioned between ethyl acetate (70 mL) and water (60 mL) and the organic phase washed with water (2×60 mL) and brine (50 mL). It was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, eluting 50-100% EtOAc in isohexane. The desired fractions collected and the solvent has been evaporated to give the desired product D22 in 0.793 g as a white solid. LCMS [M+H]+345.87@0.88 min (2 min run)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(C)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 2-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ 2.50 (3H, s), 4.58 (2H, s), 6.80 (1H, d, JH,H=11.88), 7.20-7.63 (9H aromatic+1H ethylenic).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([N:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:19]3=[O:34])[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 37 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate (12.6 mg, 0.020 mmol) in THF (1.2 mL) and methanol (0.5 mL) was added 1 M NaOH solution (0.3 mL, excess). The reaction mixture was stirred at 37° C. for 6 h. The reaction mixture was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30ClN4O4S: 613.17; Found: 613.2; 1H-NMR: 400 MHz, (CD3OD) δ 8.89 (dd, J=7.6, 2 Hz, 1H), 8.02 (s, 2H), 7.75 (s, 1H), 7.70-7.63 (m, 3H), 7.53-7.49 (m, 4H), 6.61 (t, J=7.2 Hz, 1H), 5.27 (s, 1H), 4.06 (s, 3H), 2.60 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][O:34][CH3:35])=[C:30]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][O:34][CH3:35])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCCN=C=S
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1CC1CCOCC1
Yield: 65 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 1-isothiocyanato-2-(methyloxy)ethane (50 mg) to give the title compound as beige solid (55 mg, 65%). LCMS (formate) Rt 0.68 min, MH+ 466
Reaction SMILES: [CH2:1]([C@:4]1([CH2:30][CH2:31][CH2:32][CH2:33][B:34]2[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]2)[C:9](=[O:10])[O:8][C@@H:7](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3].C(=O)=O.N.[Li]>CC#N.C1COCC1>[CH2:1]([C@:4]([NH:5][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:30][CH2:31][CH2:32][CH2:33][B:34]1[O:35][C:36]([CH3:41])([CH3:42])[C:37]([CH3:39])([CH3:40])[O:38]1)[C:9]([O:8][CH3:7])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 57.7 %

Procedure:
A three-necked RBF equipped with nitrogen inlet tube and dry ice condenser was charged with (3R,5R,6S)-tert-butyl 3-allyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (4.60 g, 8.00 mmol) and THF (10 mL). After cooling the condenser to −78° C. and the flask to −45° C. (CO2 (s), CH3CN), ammonia (80 mL) was condensed into the flask. Once complete, lithium metal (0.55 g, 80 mmol, small pieces) was carefully added over 10 min. After stirring an additional 40 min, the reaction mixture was carefully quenched with NH4Cl (s) until the solution became clear. The bath was removed and the ammonia was allowed to evaporate over night. The resulting residue was diluted with ethyl acetate and washed successively with 0.5 N HCl and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 50% methanol in toluene (80 mL, 0.1 M) and treated with TMSCHN2 (2.0 M in hexanes) until the pale yellow color persisted. With TLC indicating the reaction complete, the excess TMSCHN2 was quenched with acetic acid until the solution became clear. The solution was concentrated, diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (R)-methyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as colorless oil (1.9 g, 58%). Rf 0.46 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 5.70-5.52 (m, 1H), 5.49-5.36 (m, 1H), 5.05 (dd, J1=13.8 Hz, J2=1.2 Hz, 1H), 3.73 (s, 3H), 3.09-2.96 (m, 1H), 2.50 (dd, J1=13.8 Hz, J2=7.8 Hz, 1H), 2.29-2.10 (m, 1H), 1.78-1.65 (m, 1H), 1.43 (s, 9H), 1.42-1.26 (m, 4H), 1.23 (s, 12H), 0.74 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C21H38BNO6: expected 411.3. found 412.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>O.C1COCC1.CO>[C:3]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.9 %

Procedure:
A solution of sodium hydroxide in water (2N, 50 mL) was added to a suspension of compound 1022 (3.5 g, 11.9 mmol) in THF (50 mL) and methanol (50 mL). The reaction mixture was stirred at room temperature for 14 hours and then concentrated to approximately 1/10 of its original volume (15 mL). The concentrated solution was adjusted to pH 2-3 using 2N aqueous hydrochloric acid solution and extracted with a mixture of DCM and ethanol (7:3 ratio, 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound 1023 (2.7 g). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.41 (d, 1H), 7.46-7.51 (m, 2H), 7.63-7.64 (d, 1H), 7.71-7.85 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3.[OH-].[Na+].Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23][S:30]([C:33]5[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=5)(=[O:32])=[O:31])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Reaction time: 48 h
Yield: 19 %

Procedure:
At ambient temperature, to a stirred suspension containing 4-(2, 3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol (0.317 g, 0.919 mmol) and 0.O1M aq. Borax (6 mL) in THF (9 mL) was added 2.5N NaOH (0.397 mL). To the reaction was added dropwise a solution of 4-chlorosulphonyl-2-hydroxybenzoic acid (0.653 g, 2.76 mmol) in THF (12 mL) while maintaining the pH at 10 with the simultaneous addition of 2.5N NaOH. After 48 h, additional 4-chlorosulphonyl-2-hydroxybenzoic acid (0.440 g, 1.86 mmol) in THF (12 mL) was added dropwise while maintaining the pH at 10 with the simultaneous addition of 2.5N NaOH and the reaction was stirred for an additional 48 h. The reaction was quenched with 1N HCl and extracted with ether. The combined ethereal extracts were washed with brine (1×), dried (Na2SO4) and concentrated. Purification on 2% H3PO4 /MeOH treated silica gel eluting with 2% EtOAc/hexane followed by recrystallization (EtOAc/hexane) gave 95 mg (19%) of the title compound as an off white solid, mp 222-227° C. 1H NMR (DMSO-d6) δ 1.09 (t, 6 H), 1.55 (s, 3 H), 2.40 (s, 3 H), 2.55-2.60 (m, 4 H), 7.21 (s, 2 H), 7.37-7.39 (m, 1 H), 7.43-7.49 (m, 3 H), 7.53 (d of d, 1 H), 7.99 (s, 1 H), 8.01-8.04 (m, 1 H), 8.08 (d, 1 H). mass spectrum (-ESI) m/z 543 (M-H). Anal. Calcd. for C31H28O7S.0.5H2O: C, 67.25; H, 5.28; N, 0.00. Found: C, 67.14; H, 5.21; N, 0.08.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[C:17]([CH:27]([OH:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:16][N:15]=1
Reactant: O=Cc1ccccn1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccccn1)c1cnc(Cl)nc1Cl
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a 1.6 M solution of n-butyl lithium in hexane 19.3 ml is dropped over a period of 10 minutes a solution of diisopropylamine 3.1 g in tetrahydrofuran 80 ml in a dry ice-acetone bath and the mixture is stirred for 30 minutes. To the mixture is dropped over a period of 2.5 hours a solution of 2,4-dichloropyrimidine 2 g in tetrahydrofuran 70 ml and the mixture is stirred at the same temperature for 1 hour. To the mixture is dropped pyridine-2-aldehyde 2.2 g in tetrahydrofuran 20 ml over a period of 50 minutes, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into a 10% aqueous citric acid solution and the organic layer is separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; chloroform:methanol=10:1, hexane:ethyl acetate=3:2, hexane:ethyl acetate=2:1) to give crude 2,4-dichloro-5-[(hydroxy)(2-pyridyl)methyl]pyrimidine 480 mg.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18](O)=O)=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][S:21][C:7]=12.B.CSC.CO>O1CCCC1>[CH3:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2](=[O:1])[N:3]2[C:8]=1[C:7]1[S:21][CH:22]=[CH:23][C:6]=1[CH2:5][CH2:4]2
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Temperature: 25 °C

Procedure:
0.646 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid was dissolved in 20 ml of tetrahydrofuran. The solution was treated at -15° with 0.4 ml of a 10M solution of borane/methyl sulfide in tetrahydrofuran, left to warm to room temperature and subsequently heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was treated with methanol and evaporated in vacuo. The mixture was heated to boiling in 2N hydrochloric acid for a short time and extracted with chloroform. The organic extracts was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. After recrystallization from ethyl acetate/diethyl ether there was obtained pure 4,5-dihydro-10-methyl-8-phenyl-7H-thieno-[2,3-a]quinolizin-7-one of m.p. 80.5°-81°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:16])=[CH:6][C:5]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(C)cc1OC(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.00 g, 4.8 mmol), N-bromosuccinimide (0.940 g, 5.28 mmol), 2,2′-azo-bis-isobutyronitrile (50 mg, 0.30 mmol) and carbon tetrachloride (20 mL) is stirred under a bright lamp for 3 h. The mixture is concentrated and the residue is purified via flash chromatography (0 to 50% EtOAc-heptane) to provide the title compound (0.85 g, 62%) as an orange oil. ES/MS m/e 288.7 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([NH:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
HATU (2.510 g, 6.60 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.269 g, 5.5 mmol), (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate HCl (1.172 g, 6.60 mmol), and Hunig's Base (3.84 ml, 22.00 mmol) in DCM (20 ml) and was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then brine and evaporated on rotovap, then purified via silica gel chromatography to get the product (1R,2S)-methyl 1-((2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (2.68 g, 5.00 mmol, 91% yield) as a light orange foam. MS: MS m/z 558.16 (M++23).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH:18]=[O:19]
Reactant: CN1CCCCC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCCC1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.5 %

Procedure:
Dimethyl sulfoxide (3.3 mL, 46 mmol) was dissolved in 15 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (2.6 mL, 31 mmol). After stirring for 45 minutes, a solution of (1-methyl-2-piperidyl)methanol 6a (1 g, 7.74 mmol) in 5 mL of dichloromethane was added dropwise to the solution. The reaction mixture was stirred for 45 minutes, then added with triethylamine (7.2 mL, 52 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure then the resulting residue was purified by alkaline alumina column chromatography with elution system A to obtain the title compound 1-methylpiperidine-2-carbaldehyde 6b (300 mg, yield 31.0%) as a brown oil, which was directly used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.OS(O)(=O)=O.[OH-].[Na+].[CH3:22][CH2:23]O>>[CH2:22]([O:13][C:12]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14])[CH3:23]
Reactant: CCO
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Yield: 82 %

Procedure:
5-Methoxy-1H-indole-2-carboxylic acid (10 g, 52.3 mmol) in EtOH (400 ml) containing 36% H2SO4 (7 ml) was heated under reflux for 18 hr. After cooling the mixture was neutralised with 2N NaOH (to pH 7) and extracted with EtOAc (3×150ml), the combined extracts were washed with 10% NaHCO3 (2×25 ml), dried (MgSO4), filtered and evaporated to afford 5-methoxy-1H-indole-2-carboxylic acid ethyl ester as a brown solid (9.52 g, 43.3 mmol, 82%) Mp. 154-155° C., MS: m/e=219.1 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[C:13]([Cu])#[N:14].[O-]S([O-])(=O)=O.[Na+].[Na+].CC(OC)(C)C>CN1C(=O)CCC1>[F:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: N#C[Cu]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 160 °C
Reaction time: 7.5 h
Yield: 68.1 %

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160° C. oil-base and stirred at 160° C. under N2 over 450 min. The mixture was cooled to RT, charged with Na2SO4 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The material was recrystallized from EtOH/water (2/1) to yield 2,5-Difluoro-4-nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.95 (dd, 1H), 7.67-7.64 (dd, 1H).