Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC[N:32]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:32])=[O:23])=[CH:20][CH:19]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc1OC
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a mixture of 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (210 mg, 0.52 mmol), EDCI (147 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol) and Et3N (104 mg, 1.07 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (38 mg, 22%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.14 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.32-7.28 (m, 1H), 6.92 (d, 1H, J=9.0 Hz), 3.75 (s, 3H), 3.72 (s, 3H). LC-MS: 599 [M+H]+, tR=1.54 min. HPLC: 95.59% at 214 nm, 95.99% at 254 nm, tR=4.594 min. LC-MS: 408 [M+H]+, tR=1.392 min. HPLC: 95.38% at 214 nm, 96.23% at 254 nm, tR=5.259 min.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)(Cl)Cl.O[C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29]C)=[O:28].[ClH:31]>C(Cl)(Cl)(Cl)Cl>[Cl:31][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([OH:29])=[O:28]
Reactant: Cl
Reactant: COC(=O)c1sccc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sccc1Cl

Procedure:
14.5 liters of absolute carbon tetrachloride (refluxed for 1 hour with 500 g of P2O5 and then distilled) is placed in a 25 liter apparatus equipped with stirrer, dropping funnel, drainage cock and reflux condenser with gas outlet; while stirring, 2,200 g (10.05 moles) of PCl5 is added. Upon refluxing the mixture the PCl5 goes into solution (a small amount of PCl5 settles in the drainage cock). 660 g (4.18 moles) of methyl 3-hydroxythiophene-2-carboxylate (prepared as described in German Pat. No. 1,020,641) dissolved in 2 liters of absolute carbon tetrachloride is allowed to flow at a just continuous rate over a period of 4 hours into the boiling solution (vigorous evolution of HCl).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN4CCN(C)CC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 54 mg (yield 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)([C:9]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[NH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)([C:9]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:11]([CH2:32][CH2:33][CH3:34])[CH:10]=2)[N:3]=1
Reactant: CCCI
Reactant: CCC(=O)c1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C(=O)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-amino-5-(3-bromo-phenyl)-3-methyl-5-(5-propionyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one (0.2 g, 0.51 mmol) in DMF (5 mL) was added Cs2CO3 (0.33 g, 1.02 mmol) and iodopropane (0.12 g, 0.70 mmol). The reaction mixture was sealed and stirred at room temperature for 20 hours. DMF was removed in vacuo, the residue was taken back CHCl3 and filtered. Evaporation and purification by combi flash chromatography (methylene chloride/methyl alcohol/triethyl amine, 9.5/0.4/0.1) gave the title compound as a white solid (0.16 g, 72% yield), mp 260° C., 1H NMR (400 MHZ, CDCl3) δ 0.73 (t, 3H), 1.01 (t, 3H), 1.03 (q, 2H), 2.66 (m, 2H), 2.91 (s, 3H), 4.12 (q, 2H), 6.6 (bs, 2H), 6.87 (s, 1H), 6.98 (s, 1H), 7.23 (m, 1H), 7.37 (m, 1H), 7.45 (m, 1H), 7.57 (m, 1H), MS m/e (M−H)− 429.1.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CCN(C(C)C)C(C)C.[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41]>C(Cl)Cl>[CH2:40]([NH:42][C:43]([N:21]1[CH2:22][CH2:23][C:17]2[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])=[N:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=3)=[N:19][C:18]=2[CH2:20]1)=[O:44])[CH3:41]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)NCC)C3)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 13 as a hydrochloride salt) (99 mg, 0.25 mmol) in DCM (3 mL) at room temperature (20° C.) was added DIPEA (44 uL, 0.26 mmol) followed by ethyl isocyanate (22 uL, 0.27 mmol). The reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford a brown solid (55 mg, 47%).
Reaction SMILES: [C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][N:39](C(OCC2C=CC=CC=2)=O)[C:40](=[NH:52])[NH:41]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:17]C(OCC2C=CC=CC=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:64].O1CCOCC1.[H][H]>CN(C=O)C.[C].[Pd]>[ClH:64].[ClH:64].[C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:52])[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH2:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Oc1cccc2ccccc12
Reaction time: 4 h
Yield: 78 %

Procedure:
In DMF was dissolved 935 mg of the above ester, and to the resulting solution were added 0.5 g of 10% palladium-carbon (Pd-C) and 0.98 ml of a 2 N hydrochloric acid-dioxane solution, after which hydrogen gas was passed through the resulting mixture with ice-cooling and with stirring for 4 hrs. After the reaction, the Pd-C was removed by filtration, and 300 ml of anhydrous diethyl ether was added dropwise to the filtrate, upon which a powder was precipitated. The powder was collected by filtration to obtain 450 mg (yield 78%) of L-phenylalanyl-L-arginine 1-naphthyl ester dihydrochloride, m.p. 215° C. (decomp.).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(C)=O>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCc4ccccc4)nc32)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and benzylamine (0.14 ml) in dry 1,4-dioxane (3 ml) were heated at 60° C. for 36 h. After this time benzylamine (0.14 ml) and dry dimethylsulphoxide (2 ml) were added and the mixture was heated at 60° C. for a further 72 h. The solvent was removed under reduced pressure. Purification was by trituration with diethyl ether and water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:4]=1[C:10]([CH3:20])([CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH:13]2[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 3.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 288 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 90 mg of the imine is reacted by reaction with 0.4 ml of titanium tetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and 25 mg of the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)=[C:6]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>>[OH:18][C@@H:17]1[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:4]([CH2:3][CH2:2][NH:1][S:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:46])=[O:45])=[N:5][C:6]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 56.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)-tetrahydro-3,4-furandiol (example 11) (200 mg, 0.40 mmol), phenylsulfonyl chloride (70 mg, 0.40 mmol) and triethylamine (0.15 ml, 1.08 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (145 mg) as a powder. MS: 645 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1sc(Cl)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSCCC(=O)N(C(=O)OC(C)(C)C)c1sc(Cl)nc1Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of (2,4-dichloro-thiazol-5-yl)-carbamic acid tert-butyl ester (1.0 g, 3.7 mmol) in dichloroethane (20 mL) stirring at room temperature was added triethylamine (935 mg, 9.25 mmol), followed by dropwise addition of methylsulfanyl-propionyl chloride (776 mg, 5.6 mmol) and the mixture was stirred for 5 min before DMAP (45 mg, 0.37 mmol) was added. The mixture was stirred at 75° C. for 4 h. The reaction mixture was cooled, quenched with H2O (30 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layer was dried over Na2SO4 and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a colorless oil (1.11 g, 81%): 1H NMR (300 MHz, CDCl3) δ 3.32 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.46 (s, 9H); ESIMS m/z 371.2 (M+1).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:50]([O:54][CH2:55][CH2:56][OH:57])(=[O:53])[CH:51]=[CH2:52].[N-]=C=O>>[C:50]([O:54][CH2:55][CH2:56][O:57][C:48](=[O:49])[NH:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:53])[CH:51]=[CH2:52]
Reactant: O=C=Nc1ccccc1
Reactant: C=CC(=O)OCCO
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1ccccc1
Temperature: 60 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 0.25 g of 2,6-di-tert-butyl-4-methylphenol, 0.12 g of Desmorapid Z and 126.4 g of phenyl isocyanate, and the mixture was heated to 60° C. Subsequently, 123.3 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept at 60° C. until the isocyanate content had fallen below 0.1%. This was followed by cooling. The product was obtained as a crystalline solid (preparation described in DE 2329142). The product has a melting point of 66-68° C. (Bowman, Macromolecules, 2004, 37 (11), 4062-4069).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.O.[NH2:12][NH2:13]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:12][NH2:13])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: NN
Reactant: COc1ncc(Br)nc1Br
Solvent: O
Solvent: CCO
Product: COc1ncc(Br)nc1NN
Temperature: 80 °C

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromo-2-methoxypyrazine (0.50 g, 1.9 mmol), hydrazine hydrate (0.47 g, 9.4 mmol) and ethanol (5 mL). The resulting mixture was heated at 80° C. for 4 h. TLC indicated a complete conversion. Work-up: the reaction solution was concentrated in vacuo, to afford 0.5 g (crude) of the product as a brown solid, which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:16]([O:24][CH2:25][C:26]#[CH:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.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)I>[C:16]([O:24][CH2:25][C:26]#[C:27][C:6](=[O:7])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1cccs1
Reactant: C#CCOC(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(OCC#CC(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A solution of 2-thiophenecarbonyl chloride (549 mg, 3.75 mmol) in anhydrous dioxane (15 mL) was bubbled with argon for 10 minutes. Triethylamine (1.31 mL, 9.36 mmol) was added and the bubbling was maintained for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.12 mmol), copper iodide (48 mg, 0.25 mmol) and propargyl benzoate (0.45 mL, 3.12 mmol) were added, and the reaction mixture was stirred for 1 hour at room temperature, under argon atmosphere. The solution was filtered and water (20 mL) was added to the filtrate. Layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5) to provide 4-oxo-4-(thiophen-2-yl)but-2-yn-1-yl benzoate (3a) (333 mg, 1.23 mmol, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:20]([OH:21])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)Nc1cc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CCC(CC)n1c(O)nc2ncc(Br)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
To a 100° C. solution of 5-bromo-N3-(pentan-3-yl)pyridine-2,3-diamine (2.0 g, 8.1 mmol, 1.0 equiv) in dioxane (10 mL) was added CDI portionwise until starting material was consumed as judged by TLC (50% EtOAC/Hexanes; UV). Approximately 10 equiv of carbonyldiimidazole were required. The resulting reaction mixture was cooled to room temperature, and the excess carbonyldiimidazole was quenched by the careful addition of water. The mixture was diluted with dichloromethane, and the layers were separated. The organic layer was washed with satd. aq. NaHCO3 twice, and brine once. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC provided 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol as a white solid (2.0 g, 74%). m/z=284.0 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([O:34]CC)=[O:33])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([OH:34])=[O:33])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Yield: 46.7 %

Procedure:
{1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.737 g, 1.42 mmol), potassium hydroxide (0.260 g, 4.63 mmol) in THF (9 mL) and water (9 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 88° C. furnished the title compound as a white solid (0.326 g, 47%), mp: 206-207° C. Mass spectrum (+APCI, [M+H]+) m/z 492; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.5 (s, 1H), 8.25 (s, 2H), 8.1 (s, 1H), 7.75 (s, 2H), 7.25-7.35 (m, 5H), and 5.6 ppm(s, 2H). Elemental Analysis for C25H15F6NO3: Calculated: C, 61.11; H, 3.08; N, 2.85. Found: C, 60.91; H, 2.87; N, 2.83.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[CH:23]=[C:22]([CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:21]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C>CO.ClCCl>[CH2:1]([O:4][NH:5][C@@H:18]1[CH:23]=[C:22]([CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:28])[CH3:29])[C@@H:21]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: ClCCl
Solvent: CO
Product: C=CCON[C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Yield: 85.5 %

Procedure:
The title compound was prepared from N-(allyloxy)-N-((3R,6S)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)-2-nitrobenzenesulfonamide (Intermediate 283, 6.49 g, 10.11 mmol) according to the procedure described for Intermediate 12. Silica gel chromatography (0%-5% methanol/dichloromethane) afforded the desired product (3.95 g, 86%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>Cl.C(OCC)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: OCc1ccccc1Br
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Brc1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ten drops of concentrated hydrochloric acid were added to a mixture of 2-bromophenylmethanol (34 g, 0.18 mol) and 3,4-dihydro-2H-pyran (18 g, 0.22 mol), and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with diethyl ether, and the organic phase was neutralized with a saturated NaHCO3 aqueous solution. Further, the resultant was dried over anhydrous MgSO4 and was concentrated under reduced pressure to obtain 2-(2-tetrahydro-2H-pyranoxymethyl)bromobenzene, to which dissolved in THF (450 mL) was added a 1.6 M n-BuLi solution in hexane (124 mL, 0.20 mol) at −78° C. over 40 minutes. The resulting solution was stirred for 50 minutes at −78° C., and chlorodimethylsilane (20 g, 0.22 mol) was added thereto. The mixture was warmed gradually at room temperature overnight and then was quenched with water. After evaporation of THF, the residue thereof was extracted with diethylether, and the combined organic layers were washed with brine, and then the resultant was dried over anhydrous MgSO4. The dried resultant was distilled under reduced pressure, thereby obtaining dimethyl[2-(2-tetrahydro-2H-pyranoxymethyl)phenyl]silane (5) (38 g, yield of 83%) as a colorless oil, bp: 135° C. (1.0 mmHg). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.40-7.36, (m, 1H), 7.31-7.27 (m, 1H), 4.87 (d, J=12.0 Hz, 1H), 4.74 (s, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.58-4.50 (m, 1H), 4.00-3.95 (m, 1H), 3.62-3.54 (m, 1H), 1.94-1.50 (m, 6H), 0.36 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 143.6, 136.5, 134.7, 129.4, 128.3, 127.0, 98.1, 69.1, 62.1, 30.6, 25.5, 19.3, −3.0, −3.1; Anal. Calcd for C14H22O2Si; C, 67.15; H, 8.86. Found: C, 67.44; H, 8.91.