Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:2][CH3:3].[CH3:29][N:30]([S:32]([C:35]1[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:29][N:30]([CH3:31])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([C:15]2[CH:16]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:26][CH2:27][CH3:28])=[O:6])[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=2)=[CH:39][CH:40]=1)(=[O:33])=[O:34]
Reactant: CCCN(CCC)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)OC)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Temperature: 22.5 °C

Procedure:
A mixture of methyl 3-[(dipropylamino)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Step 1, 534 mg, 1.4 mmol), 4-bromobenzenedimethyl-sulfonamide (363 mg, 1.4 mmol), and sodium carbonate (2 mL of a 2 M mixture in water, 4.1 mmol) in toluene (10 mL) is degassed under reduced pressure for 15 minutes and then purged with argon. Palladium tetrakis(triphenylphosphine) (40 mg, 0.025 mmol) is added and the reaction mixture is degassed under reduced pressure for 15 minutes and then purged with argon. The reaction mixture is heated at reflux for 4 hours, cooled to 20-25 degrees C., filtered through a plug of diatomaceous earth and sodium sulfate, and the filtrate is concentrated under reduced pressure. Purification by flash column chromatography (silica; ethyl acetate/hexanes, 1/1) gives methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate (XXXVIII), ESI-MS (m/z) [M+H]+=447.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)C>[Pd].CCO>[CH2:13]1[NH:12][CH2:11][CH2:10][N:9]2[C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH:8]12
Reactant: CCOC(=O)CCCc1cnccn1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCC2CNCCN12
Yield: 57.3 %

Procedure:
4-Pyrazin-2-yl-butyric acid ethyl ester (1 g, 5.14 mmol) was dissolved in abs. EtOH (50 ml) and hydrogenated over 10% Pd/C (200 mg) at 50 psi for 20 hours. After filtration, the solvent was removed under vacuum and the residue was purified by flash chromatography (DCM/MeOH/32% NH4OH from 95/5/0.5 to 90/10/1 respectively) to afford the title compound (454 mg, 57% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Oc1ccc(-n2cccc2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccn(-c2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 39.4 %

Procedure:
To a 50 mL vial which contained a solution of 4-Pyrrol-1-yl-phenol (500 mg, 3.1 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (1.25 g, 6.2 mmol) in DMF (30 mL) was added K2CO3 (1.8 g, 13 mmol) at rt. The reaction mixture was heated to 85° C. and stirred at 85° C. for 72 h. After cooled to rt, the reaction mixture was poured into 30 mL ice-water mixture and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (30 mL), dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel eluting with ethyl acetate:hexane (1:4-1:1) to yield the title compound (330 mg 40%); 1HNMR (500 MHz, CDCl3) 7.29 (d, J=9.0 Hz, 2H), 6.99 (t, J=2.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.52 (br, 4H), 1.44-1.63 (m, 6H); LCMS; m/z (ESI+ 271.6, M+1); 98%;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]1([CH3:34])[CH3:33]>>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][C@@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[C:21]([CH3:34])([CH3:33])[CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Product: CCOC(=O)c1cc2c(N[C@@H]3CCN(C(=O)OC(C)(C)C)CC3(C)C)c(C(N)=O)cnn2c1
Yield: 98.6 %

Procedure:
Following the conditions described in Step 2 of Example 1, ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Intermediate 1, 0.7 g, 2.62 mmol,) was reacted with (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (Intermediate 6, 0.657 g, 2.88 mmol) to give (R)-ethyl 4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (1.187 g, 99% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.05 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 7.22 (d, J=1.5 Hz, 1H), 5.44 (br. s., 2H), 4.38 (q, J=7.1 Hz, 2H), 4.14-3.93 (m, J=9.6, 9.6, 3.7 Hz, 2H), 3.73 (br. s., 1H), 3.14 (br. s., 1H), 2.89 (br. s., 1H), 2.09-2.00 (m, 1H), 1.84-1.72 (m, 1H), 1.49 (s, 9H), 1.40 (t, J=7.2 Hz, 3H), 1.11 (s, 3H), 1.03 (s, 3H); MS (ES+) m/z: 460.3 (M+H); LC retention time: 4.250 min (analytical HPLC Method H).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCCBr
Product: C=CCCOc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 367 and 4-bromo-1-butene, white powdery N-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:5]([C:11]([OH:13])=O)[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[NH:36][CH:37]=[N:38][N:39]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[NH:38]1[CH:37]=[N:36][C:35]([NH:34][C:11]([C:5]2[N:6]([CH3:10])[C:7]([CH2:8][CH3:9])=[C:3]([C:1]#[N:2])[C:4]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)=[O:13])=[N:39]1
Reactant: Nc1nnc[nH]1
Reactant: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)O)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)Nc2nc[nH]n2)n1C
Temperature: 0 °C
Yield: 46 %

Procedure:
prepare a solution of 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid (200 mg, 0.57 mmol, prepared in example A-75) in 5 mL of methylene chloride and stir under nitrogen. Add 2 drops of dry DMF and cool the mixture to 0° C. Next, add oxalyl chloride (1.10 mmol) dropwise over five minutes. Remove the icebath and stir the reaction for one hour. Add another 1.10 mmol of oxalyl chloride and continue stirring for one hour. Then concentrate the reaction mixture under vacuum to provide the crude acid chloride. Dissolve the crude acid chloride in 3.5 mL of dry pyridine and add 2-amino-1,3,4-triazole (5.9 mmol) and stir overnight at room temperature. Pour into 100 mL of ice-water and extract with methylene chloride (3×50 mL). Dry the combined organic layers over anhydrous Na2SO4, filter and evaporate. Chromatograph the residue over silica gel (100/0-3/1 toluene/EtOAc) to give the title compound (110 mg, 46% yield). MS(ES+, m/e)=422 (M++1).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>CCOCC>[CH2:1]([NH:6][C:11]([NH:10][CH2:9][CH2:8][Cl:7])=[O:12])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C=NCCCl
Reactant: CC(C)CCN
Solvent: CCOCC
Product: CC(C)CCNC(=O)NCCCl
Reaction time: 1 h

Procedure:
Isopentylamine (8.7 g, 0.1 mol) was dissolved in 100 ml of anhydrous ether and cooled to less than 10° C. 2-Chloroethyl isocyanate (10.5 g, 0.1 mol) was dissolved in 20 ml of ether and added to the rapidly stirring reaction mixture at less than 10° C. Stirring continued 1 hr. longer and the preciptiate was filtered and washed with four 20 ml portions of chilled ether. After drying in vacuo overnight, 16.5 g (85%) of product obtained as a white powder, MP 58°-9° C. IR analysis showed peaks at 1620/cm (C=O) and 1575/cm (N--C=O). NMR showed a doublet (6H, J=7 Hz) at 0.9 ppm, a triplet (2H, J=7 Hz) at 1.4 ppm, a multiplet (1H) at 1.8 ppm, a multiplet (1H) at 3.2 ppm, a multiplet (4H) at 3.6 ppm, a singlet ( 1H) at 5.7 ppm, and a singlet (1H) at 6.0 ppm.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[N:6]([CH:9]=[CH:10][N:11]=2)[C:7]=1[CH3:8].[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:8][C:7]1[N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=[C:3]([CH3:12])[C:2]=1[C:13]#[N:14]
Reactant: Cc1cc2nccn2c(C)c1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc2nccn2c(C)c1C#N
Temperature: 120 °C
Yield: 99 %

Procedure:
6-Bromo-5,7-dimethyl-imidazo[1,2-a]pyridine (985 mg, 4.26 mmol) was dissolved in DMF (15 ml). To this solution was added Zn(CN)2 (512 mg, 4.36 mmol), Pd2(dba)3 (40 mg, 0.044 mmol) and DPPF (49 mg, 0.088 mmol). The mixture was heated at 120° C. for 48 h. The mixture was then concentrated under vacuum and the residue was taken into CH2Cl2 (40 ml) and washed with H2O (30 ml×2) and brine (20 ml). The organic layer was concentrated and the residue was purified by column chromatography on silica gel (CH2Cl2/CH3OH, 18:1) to give 5,7-dimethyl-imidazo[1,2-a]pyridine-6-carbonitrile (747 mg, 99%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:19][CH3:20])=[N:13][C:14]([CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[CH2:20]([NH:19][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:21])[NH:5][N:6]=3)=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:18])[N:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CNc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Solvent: CS(C)=O
Product: Cc1nc(NCc2ccccc2)c2ccc(C3=NNC(=O)CC3C)cc2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 0.76 g of Compound 64 obtained in Example 66, 15 ml of benzylamine and 15 ml of dimethylsulfoxide was stirred at 150° C. for 3 hours, and then concentrated. The residue was subjected to partition between water and chloroform, and the organic layer was dried and concentrated. The residue was purified by column chromatography using 100 g of silica gel to give 0.31 g (32%) of 6-(4-benzylamino-2-methylquinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (Compound 65).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:16])[C:8]=1[O:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[NH2:5].C1(C)C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].O1CCOCC1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:24]=[O:25])[CH:6]=[C:7]([Cl:16])[C:8]=1[O:9][C:10]([F:14])([F:15])[CH:11]([F:13])[F:12]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: Clc1ccccc1
Product: O=C=Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1

Procedure:
33.4 g of 3,5-dichloro-4-(1,1,2,2,-tetrafluoroethoxy)aniline are dissolved in 130 ml of chlorobenzene. With stirring, this solution is added dropwise at 22° C. to a solution consisting of 90 g of toluene containing 20% by weight of phosgene and of 100 ml of dioxane and 300 ml of chlorobenzene. The reaction mixture is stirred for 1 hour at room temperature, 1 hour at 50° C. and then 1 hour at 80° C. The reaction mixture is subsequently concentrated in a water-jet vacuum and then distilled under high vacuum, affording the title compound of the formula ##STR8## as a colourless oil. Boiling point 81°-83° C./2.5 mbar.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([S:34]([F:39])([F:35])([F:36])([F:37])[F:38])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25.0 mg (0.100 mmol) 95% sodium hydride were given to a solution of 216 mg (0.100 mmol) 4-(4-[Imidazol-1-yl]-butyl)-phenol in 5.0 ml DMF and stirred for 15 min. 346 mg (0.100 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued overnight. After addition of 10 ml water the resulting precipitate was isolated and washed with 2×10 ml water, 2×10 ml methanol and with diethyl ether. Yield 411 mg (78%). MS: M=526.2 (ESI+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.B(O)(O)[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CCOC(C)=O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cc(Cl)nc(-c2nccs2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Cl)cc(-c3nccs3)n2)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-(4,6-dichloropyridin-2-yl)thiazole (50 mg, 0.22 mmol), p-tolylboronic acid (29 mg, 0.22 mmol), Pd(dppf)Cl2 (8 mg, 11 μmol) and K3PO4 (344 mg, 1.62 mmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added THF (1 mL) and water (0.5 mL). The mixture was placed in a 60° C. oil bath with stirring for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and brine (1 mL). The mixture was shaken; the aq. phase was decanted away via pipet. The organic phase was dried over MgSO4; filtered; and the filtrate was concentrated in vacuo to afford a dark amber solid. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 60:40) to afford 2-(4-chloro-6-(p-tolyl)pyridin-2-yl)thiazole as a white solid (28 mg, 45%). 1H-NMR (400 MHz, CDCl3) δ 8.12 (d, J=1.8 Hz, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.96 (d, J=3.3 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.50 (d, J=3.3 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C=O.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:12]([O:11][C:9]([N:4]1[CH2:3][CH:2]([CH3:1])[N:7]([CH3:21])[CH:6]([CH3:8])[CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)O
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(C)N1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1CN(C(=O)OCc2ccccc2)CC(C)N1C
Reaction time: 0.17 h

Procedure:
Benzyl 3,5-dimethylpiperazine-1-carboxylate (1 eq, 2.04 mmol, 0.5 g) and formaldehyde (37% in H2O, 5 eq, 10.07 mmol, 0.277 ml) are dissolved in MeOH (10 ml). After 10 mins at room temperature, acetic acid (5 eq, 10.07 mmol, 0.576 ml) and sodium triacetoxyborohydride (5 eq, 10.07 mmol, 2.13 g) are added and the reaction mixture stirred overnight. The reaction is quenched with 5M HCl (15 ml) and the solvent evaporated under vacuo. The residue is taken to pH 13 by addition of sodium hydroxide (4M) and extracted with EtOAc. This organic portion is washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:17])[CH3:18])[CH:12]=[CH:13][CH:14]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)Cc1cccc(OCCCN=C=S)c1

Procedure:
A solution of carbon disulphide (8.36 g) in acetone (16 ml) was added dropwise to a stirred solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (20.8 g) in acetone (60 ml) at -10° to 0° during 15 minutes. A solution of mercuric chloride (27.2 g) in acetone (40 ml) was added slowly at -15° and after the addition the suspension was warmed to 0° and triethylamine (23 g) added dropwise. The suspension was refluxed for 45 minutes then filtered and evaporated to give an oil which was chromatographed (alumina,grade 3/ether). The appropriate eluate was evaporated to a yellow oil consisting of the title compound (8.7 g).
Reaction SMILES: [Cl-].C([Al+]CC)C.[Br:7][C:8]1[N:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.[CH3:17][C:18]([CH3:25])([CH2:22][CH:23]=[CH2:24])[C:19](Cl)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[Br:7][C:8]1[N:9]=[C:10]2[C:16]([C:19](=[O:20])[C:18]([CH3:25])([CH3:17])[CH2:22][CH:23]=[CH2:24])=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: C=CCC(C)(C)C(=O)Cl
Agent: CC[Al+]CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
Diethylaluminum chloride (1.0 M in CH2Cl2, 23.4 mL, 23.4 mmol) was added to a 0-5° C. mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1.55 g, 7.80 mmol) and 30 mL of dichloromethane in a sealed tube, and the mixture was stirred at 0-5° C. for 20 min. The solution of crude 2,2-dimethyl-4-pentenoyl chloride prepared in the previous step was added dropwise. The resulting mixture was stirred at 60° C. for 64 h, then cooled to 0-5° C. A sat. aq. NaHCO3 solution (50 mL) was carefully added, and the mixture was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→50% EtOAc/hexanes) afforded 1.033 g (43%) of impure 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-pent-4-en-1-one as a brown solid, which was used without further purification. The major impurity is s.m. (typically 15-30% of the mixture).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16](=[O:37])[CH:17]=[P:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:46](=[O:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48].O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16](=[O:37])[C:17](=[P:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:46](=[O:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)C(C(=O)c1cc(Cl)ccc1OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-Benzyloxy-5-chloro-phenyl)-2-(triphenyl-λ5-phosphanylidene)-ethanone (0.49 g, 0.94 mmol), NEt3 (96 mg, 0.94 mmol) and DMAP (12 mg, 0.09 mmol) in dry toluene (20 ml) at room temperature, ethyl chlorooxoacetate (0.38 g, 2.78 mmol) in toluene (5 ml) was added. The mixture was stirred for 2 hours and poured into water (50 ml). The organic layer was separated and the aq. layer was extracted with EtOAc (2×40 ml). The combined organic layers were then washed with sat. NaHCO3 solution (2×40 ml), sat. citric acid (1×40 ml), brine (1×40 ml) and dried. Crude oil (0.36 g) was purified by chromatography, eluted with EtOAc. Rf=0.88. 1H NMR (d6-acetone) δ=7.75-7.40 (15H, m); 7.30 (1H, dd); 7.15 (1H, d); 7.05 (1H, d); 5.10 (2H, s); 3.60 (2H, q) and 1.10 (3H, s). LCMS: (M+1)+=621.2 (RT=6.49 min.)
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH2:8]([CH:10]1O[CH2:11]1)[Cl:9]>>[Cl:9][CH2:8][C@@H:10]1[O:4][CH2:3][C@@H:2]2[CH2:5][CH2:6][CH2:7][N:1]2[CH2:11]1
Reactant: ClCC1CO1
Reactant: OC[C@@H]1CCCN1
Product: ClC[C@H]1CN2CCC[C@H]2CO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(S)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH˜8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): 1H NMR (400 MHz, CDCl3): 4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15 (dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+). (3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54 g, 8.77 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 3.94-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+).