Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1[CH:12]=[C:11](OCC2C=CC(B(O)O)=CC=2)[C:10]2[CH2:9][CH2:8]CC[C:5]=2[N:4]=1)C.[CH2:24]([C:26]1[C:31]([C:32](OC)=O)=[C:30]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:41](C(OC)=O)=[CH:40][CH:39]=2)[CH:29]=[C:28]([CH2:48]C)[N:27]=1)C.C(=O)([O-])O.[Na+].OO>CO.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.C1(C)C=CC=CC=1>[C:5]([C:10]1[CH:11]=[CH:12][C:32]([C:31]2[C:26]([CH3:24])=[N:27][C:28]([CH3:48])=[CH:29][C:30]=2[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:46][CH:47]=2)=[CH:8][CH:9]=1)#[N:4]
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reactant: CCc1cc(OCc2ccc(C(=O)OC)cc2)c(C(=O)OC)c(CC)n1
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: OO
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c(-c2ccc(C#N)cc2)c(C)n1
Reaction time: 0.5 h

Procedure:
A solution of compound C (188 mg) in methanol (1 ml) was added to a mixture of compound B (170 mg), tetrakis(triphenylphosphine)palladium (30 mg), 2M sodium hydrogen carbonate solution (2 ml) and toluene (10 ml). The mixture was heated under reflux for 12 hours and then allowed to cool. Hydrogen peroxide solution (30 wt. % solution in water; 0.1 ml) was added and the mixture was stirred for 30 minutes. The aqueous phase was separated and extracted with ethyl acetate (2×25 ml). The combined organic solutions were dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (4:1 v/v) to give 3-(4-cyanophenyl)-2,6-dimethyl-4-(phenylmethoxy)pyridine (D), as a gum; NMR (CDCl3): 2.3(s,3H), 2.6(s,3H), 5.1(s,2H), 6.7(s,1H), 7.1-7.2(m,2H), 7.25-7.35(m,5H), 7.7(d,2H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:18]1[O:31][C:30]2[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][N:25]=[C:26]=[O:27])=[CH:21][C:20]=2[O:19]1.C(N(CC)CC)C.O>C1COCC1>[O:31]1[C:30]2[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][NH:25][C:26]([N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[C:8]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:7]=3)=[O:27])=[CH:21][C:20]=2[O:19][CH2:18]1
Reactant: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Reactant: O=C=NCCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2CCCN2C(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Yield: 90.1 %

Procedure:
A solution of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine (21.8 mg, 0.095 mmol), 3,4-methylenedioxyphenethyl isocyanate (29 mg, 0.151 mmol) and triethylamine (0.4 mL) in anhydrous THF (1.5 mL) was reacted for 10 min. Water was added and the solution was extracted with ethyl acetate (2×3 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent and purification by TLC plate gave 36 mg (90%) of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide as a white solid. [M+H]+ 421.15; 1H-NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.99 (s, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.65 (m, 3H), 5.88 (s, 2H), 4.98 (m, 1H), 3.62 (m, 1H), 3.55 (m, 1H), 3.34 (m, 2H), 2.69 (m, 2H), 2.56 (s, 3H), 2.41 (m, 1H), 2.03 (m, 3H); 13C-NMR (100 MHz, CD3OD) δ 173.9, 170.3, 166.5, 157.7, 147.6, 145.9, 133.2, 128.9, 121.3, 115.0, 108.6, 107.6, 106.9, 61.4, 46.4, 41.8, 35.7, 32.4, 23.3, 22.8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-2-(phenylsulfonyl)pyridine (6.00 g), ethynylbenzene (2.87 mL), dichlorobis(triphenylphosphine)palladium (II) (140 mg) and CuI (38 mg) in DMF (90 mL) was added triethylamine (8.42 mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3 to CHCl3-EtOAc 10:1) to give 5-(phenylethynyl)-2-(phenylsulfonyl)pyridine (6.33 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH:15]([C:19]2[S:20][C:21]([C:24]3[C:32]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[CH:22][CH:23]=2)[C:16]([OH:18])=O)=[O:13])[C:7]1=[O:33].C[N:39](C)C=O.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[C:16]([CH:15]([NH:14][C:12]([C:8]1[C:7](=[O:33])[N:6]([CH2:5][C:4]2[CH:34]=[CH:35][C:36]([F:37])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:19]1[S:20][C:21]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[CH:22][CH:23]=1)(=[O:18])[NH2:39]
Reactant: O=C(NC(C(=O)O)c1ccc(-c2c[nH]c3ncccc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-acetic acid (0.039 g, 0.000075 mol;) was dissolved in N,N-Dimethylformamide (3 g, 0.04 mol;) and Ammonium chloride (0.010 g, 0.00019 mol;), N,N-Diisopropylethylamine (65.2 uL, 0.000374 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.037 g, 0.000097 mol;) were added. After 2 hours the reaction was found to be complete by LC-MS 1.18 520.03. The crude reaction was directly injected onto the Gilson for purification to give the pure product. ES (+) MS m/e=520.03; NMR (400 MHz, DMSO-d6) δ ppm 5.22 (m, 2H), 5.83 (d, 1H, J=8 Hz), 6.60 (t, 1H, J=8 Hz), 7.07 (d, 1H, J=4 Hz), 7.14-7.21 (m, 2H), 7.23 (d, 1H, J=8 Hz) 7.38-7.49 (m, 3H), 7.81 (m, 1H), 8.19-8.30 (m, 3H), 8.37 (dd. 1H), 10.53 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[H-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(=O)[nH]c(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7.1 g) was added portion wise to a stirred suspension of 60% sodium hydride (2.4 g) in dry N,N-dimethylformamide (70 ml). After 1 hour a solution of 2,3-Difluorobenzyl bromide (10 g) in dry N,N-dimethylformamide (10 ml) was added. Stirred over weekend at room temperature. Poured on to ice/water and the precipitate was collected by filtration to give 9.6 g of product. 81% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6]([C@H:8]([O:10][C:11]2[C:12]([NH2:26])=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[CH3:9])[CH:7]=1.Br[C:33]1[CH:34]=[CH:35][C:36]2[CH:40]([OH:41])[CH2:39][S:38](=[O:43])(=[O:42])[C:37]=2[CH:44]=1.[F-].[Cs+]>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].CO>[NH2:26][C:12]1[N:13]=[CH:14][C:15]([C:33]2[CH:34]=[CH:35][C:36]3[CH:40]([OH:41])[CH2:39][S:38](=[O:42])(=[O:43])[C:37]=3[CH:44]=2)=[CH:16][C:11]=1[O:10][C@@H:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:27]1[N:28]=[CH:29][CH:30]=[N:31]1)[CH3:9]
Reactant: O=S1(=O)CC(O)c2ccc(Br)cc21
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1cc(F)ccc1-n1nccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)S(=O)(=O)CC3O)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 120 °C

Procedure:
To a mixture (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine of preparation 109 (100 mg, 0.235 mmol), 6-bromo-2,3-dihydrobenzo[b]thiophen-3-ol-1,1 dioxide (92.6 mg, 1.5 eq), and CsF (126 mg, 3.5 eq) was added MeOH (2 mL). The mixture was thoroughly degassed and Pd(dppf)Cl2 (9.8 mg, 0.05 eq) was added. The mixture was heated in the microwave at 120° C. for 1 hr. LCMS showed the desired product mass. Mixture was filtered and purified with reverse phase preparative HPLC to give the title compound (66.08 mg, 58.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[BH4-].[Na+].C(Cl)Cl.C(OCC)(=O)C.CO>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH:9]=[C:8]3[N:7]([CH2:20][CH2:19][C:18]4[CH:17]=[C:16]5[O:21][CH2:22][O:23][C:15]5=[CH:14][C:13]=43)[CH2:6][C:5]=2[C:4]=1[O:24][CH3:25]
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1OC)CN1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of berberine hydrochloride (3,718 g, 10 mmol) in pyridine (30 mL) was added portionwise sodium borohydride (450 mg, 12 mmol) and the mixture was stirred at room temperature for 30 min. More sodium borohydride (380 mg, 10 mmol) was added and stirring was continued for 1 h. The reduction was monitored by TLC (DCM-ethyl acetate-methanol 4:4:2). The mixture was poured onto ice water. The precipitate was filtered, the residue washed with water and then dried under vacuum over calcium chloride to give 2.860 g of title compound in about 85 % yield.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][CH:41]4[CH2:43][CH2:42]4)[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:46][CH3:47].C(O)(C(F)(F)F)=O>>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:45]=[CH:44][C:24]([C:25]([NH:27][C@H:28]5[CH2:29][CH2:30][C@H:31]([N:34]6[CH2:39][CH2:38][N:37]([CH2:40][CH:41]7[CH2:43][CH2:42]7)[CH2:36][CH2:35]6)[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:46][CH3:47])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 1) (0.13 g, 0.43 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 1 (0.10 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative 4) then finally preparative RP-HPLC-MS (Preparative 1) to give 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 26%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]3[C:22]=2[CH3:23])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[CH3:23][C:22]1[N:16]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]2=[N:14][C:13]=1[CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:1]([CH3:2])[O:3][C:10]=2[CH:9]=1
Reactant: CC(=O)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: Cc1ccn2c(C)c(CCc3ccc4nc(C)oc4c3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixture of 2-[2-(4-acetamido-3-hydroxyphenyl)-ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.5 g) and phosphorus oxychloride (1.4 ml) in sulfolane (25 ml) was stirred for 1 hour at 100° C. The reaction mixture was added to a mixture of water and ethyl acetate and the separated aqueous layer was adjusted to pH 8 with potassium carbonate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by a column chromatography on silica gel eluting with a mixture of chloroform and methanol (39:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and diethyl ether to give 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-methylbenzoxazole (0.67 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][OH:37])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:47][S:48]([O:37][CH2:36][C@@H:12]1[CH2:13][C@H:14]([S:16][C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:39][CH:38]=1)=[O:10])(=[O:50])=[O:49]
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (22.33 g: 41.37 mmole) is diluted with dichloromethane (300 ml) and the mixture is cooled to -30° C. To this mixture, triethylamine (6.92 ml: 1.2 eq.) and methanesulfonyl chloride (3.52 ml: 1.1 eq.) are added, and the mixture is stirred for 20 minutes. The reaction mixture is successively washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and filtered. The filtrate is concentrated in vacuo to give crude (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g: 45.02 mmole). Yield: 100%. NMR δ(CDCl3) ppm: 2.89(s, 3H), 3.81, 3.83(2×s, 3H), 4.85 to 5.07(m, 2H). IR ν (CHCl3) cm-1 : 1725, 1690, 1610.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Yield: 14.7 %

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)-2-pyridinol (0.59 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (146 mg, 15% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16]O)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Br:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N+:32]([O-:34])=[O:33])[NH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][N:25]2[C:26]3[C:31](=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][CH:27]=3)[C:23]([Br:22])=[N:24]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cc1nc(CO)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)ccc1OCc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
To (5-(benzyloxy)-6-methylpyridin-2-yl)methanol (3.51 g, 15.3 mmol, Prepared as described in U.S. Pat. No. 3,952,101) in DCM (10 mL) was added sulfurous dichloride (10.9 g, 91.9 mmol). The reaction mixture was stirred for 3 hours, and then solvent was removed under reduced pressure. To the resulting solid was added 3-bromo-4-nitro-1H-indazole (3.71 g, 15.3 mmol), K2CO3 (6.35 g, 45.9 mmol) and anhydrous DMF (20 mL). The reaction mixture was stirred for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), and concentrated, and the residue was purified by silica gel flash chromatography (1:3 EtOAc/hexanes) to give desired product (87%).
Reaction SMILES: [C:1]([C:9]1[N:13]2[C:14]3[C:19]([CH:20]=[CH:21][C:12]2=[C:11]([C:23]#[N:24])[CH:10]=1)=[C:18]([OH:22])[CH:17]=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:1]([C:9]1[N:13]2[C:14]3[C:19]([CH:20]=[CH:21][C:12]2=[C:11]([C:23]#[N:24])[CH:10]=1)=[C:18]([O:22][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH:17]=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C(=O)c2ccccc2)n2c1ccc1c(O)cccc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)c2ccccc2)n2c1ccc1c(OCCN3CCOCC3)cccc12
Temperature: 60 °C
Yield: 42.3 %

Procedure:
A mixture of 1-benzoyl-3-cyano-6-hydroxy-pyrrolo[1,2-α]quinoline (31 mg, 0.10 mmol), N-(2-chloro-ethyl)-morpholine hydrochloride (25 mg, 0.13 mmol), potassium carbonate (138 mg, 1.0 mmol) and potassium iodide (18 mg, 0.11 mmol) in anhydrous acetone (10 mL) was heated in 60° C. oil bath for 2.5 days. The solvent was evaporated, and the residue was stirred with EtOAc (25 mL) and filtered. The EtOAc filtrate was evaporated and the crude product was purified by chromatography (SiO2, EtOAc/hexanes 50 to 100%) to give a light yellow solid (18 mg, 42%): 1H NMR (CDCl3): 8.21 (d, J=9.6, Hz, 1H), 8.08 (m, 1H), 8.05 (m, 1H), 7.71–7.47 (m, 6H), 7.42 (s, 1H), 6.94 (d, J=7.2 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 2.97 (t, J=6.0 Hz, 2H), 2.65 (t, J=4.5 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH:18]([C:24](=[O:26])[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1.CO.C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5]1)[C:24](=[O:26])[CH3:25])[CH3:23]
Reactant: Cc1nc(C(F)(F)F)n[nH]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)n1nc(C(F)(F)F)nc1C
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazole (2 g, 13.24 mmol) in THF (60 ml) is added K2CO3 (3.66 g, 26.5 mmol). The mixture is allowed to stir for 20 minutes at 40° C. before adding ethyl 2-chloro-3-oxobutanoate (2.61 g, 15.88 mmol) and leaving to stir. The reaction mixture is filtered to remove solids, before concentrating under vacuum to yield a dark orange/red oil. The oil is taken up in 2% MeOH in DCM and purified on silica eluting with 2% MeOH in DCM to afford the title compound as a pale yellow oil. MS m/z 280.0 [M+H]+
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[Br-].[Na+].CN1CCCC1=O.C([Br:22])C>O>[CH:1]([CH:3]([Br:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: CCBr
Reactant: C=CC(Cl)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CC(Br)c1ccccc1
Yield: 73 %

Procedure:
Vinylbenzyl chloride (50.60 g, 0.33 mol, 60:40 mixture of p,m isomers), sodium bromide (6.86 g, 6.67×10−2 mol), N-methylpyrrolidone (300 ml, passed through a short column of basic alumina), ethyl bromide (260 g), and 3-t-butyl-4-hydroxy-5-methyl phenyl sulfide (1.00 g, 2.79×10−3 mol) were combined in a 1 liter round bottomed flask fitted with a reflux condenser and a nitrogen inlet and the mixture was heated at reflux for 72 hours at which point the reaction was found to have proceeded to >95% conversion by gas chromatography. The reaction mixture was poured into 1 liter of water and extracted twice with 300 ml of diethyl ether. The combined ether layers were extracted twice with 1 liter of water, dried over MgSO4, and the solvents were stripped by rotary evaporation to yield yellowish oil. The crude product was purified by vacuum distillation to afford 47.5 g of product (53.1% yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH:15]([O:18][Si](C)(C)C)[C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:24]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=CN=[C:26]([S:35][CH3:36])[N:25]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:15]([C:16]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][N:25]=[C:26]([S:35][CH3:36])[N:17]=1)(=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (−78° C.) freshly-prepared solution of lithium diisopropylamide (2.62 mmol) in THF (5 mL) was added a solution of 2-phenyl-2-(trimethylsilyloxy)acetonitrile (0.5 ml, 2.382 mmol) in THF (4 mL). The solution was stirred for 2 hours, and a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (554 mg, 2.382 mmol) in THF (3 mL) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (15 mL), and a solution of tetrabutyl ammonium fluoride (3.0 mmol, 3.0 mL, 1 M in THF) was added. The reaction mixture was stirred for 1 hour, and quenched by the addition of saturated sodium bicarbonate solution (15 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer extracted with addition ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of hexane to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 302.9 [M+H]+.