Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.C([Sn](CCCC)(CCCC)[C:23]1[C:27]([CH3:28])=[CH:26][S:25][C:24]=1[CH3:29])CCC>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>[CH3:29][C:24]1[S:25][CH:26]=[C:27]([CH3:28])[C:23]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([CH3:17])[C:12]=1[C:15]#[N:16]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)csc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (40 mg, 0.12 mmol), tributyl(2,4-dimethylthiophen-3-yl)stannane (140.3 mg, 0.35 mmol) and PdCl2(PPh3)2 (24.55 mg, 0.03 mmol), were mixed with 0.5 mL degassed dioxane and 0.5 mL degassed DME under nitrogen in a microwave vial. The reaction was run at 145° C. in the microwave for 30 min. Water was added, the mixture was extracted with CH2Cl2 and the organic layer was concentrated. The crude product was purified on HPLC to give 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 34%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[S:6][CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.CO>CN(C)C=O>[Si:13]([O:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[S:6][CH:7]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1csc(N2CC(O)C2)n1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a solution of 1-(4-hydroxymethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (226.5 mg, 1.22 mmol) (obtained as described in Reference Example 12(1)) in dimethylformamide (11.5 ml) were added t-butyldimethylsilyl chloride (220 mg, 1.46 mmol) and imidazole (120 mg, 1.76 mmol) in an ice bath. The reaction mixture was then brought to room temperature in 10 minutes, and stirred for 5 hours. After checking the completion of the reaction, methanol (2 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (300.4 mg, yield 82%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:16])=O)=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCCl>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:16])=[CH:12][N:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 95 %

Procedure:
Heat at its boiling point a mixture of 10 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide and 16.5 g of phosphorus oxychloride in 100 ml of 1,2-dichloroethane for 1 hour. Pour the resulting solution onto ice, and adjust the pH-value to 4 with saturated caustic soda solution. Separate the organic phase. Wash it with water and then evaporate it to dryness to obtain a 95% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH:32]3[CH2:33][O:34]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: ClCC1CO1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) was added K2CO3 (0.066 g, 0.474 mmol). The resulting mixture was stirred at room temperature for 30 minutes, after which time epichlorohydrin (0.044 g, 0.474 mmol) was added. The reaction was heated to 100° C., stirred at this temperature for 2 h and then diluted with EtOAc before being washed with water and brine. Drying over Na2SO4 and removal of solvent under vacuum gave 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.102 g, 0.274 mmol, 87%) as a golden oil. LCMS (1) 2.00 min; m/z (ES+) 374.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34](O)=[O:35])[CH:26]=[CH:27][CH:28]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:34]([C:30]3[N:31]=[CH:32][O:33][C:29]=3[C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:24]=3)=[O:35])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COCCc1cccc(-c2ocnc2C(=O)O)c1
Product: COCCc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by C, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-[3-(2-methoxy-ethyl)-phenyl]-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=435.45.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:5]1)[CH2:2][CH3:3].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][NH:25][CH:26]([CH3:28])[CH3:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][N:25]([CH:26]([CH3:28])[CH3:27])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)=[O:23]
Reactant: CCCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-propyl-1H-indol-3-yl)acrylic acid (160.0 mg, 0.70 mmol), 3-fluoro-N′-isopropylbenzohydrazide (206.0 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-3-fluoro-N′-isopropyl-N′-(3-(1-propyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (136.0 mg, 47.7%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.Br[CH:38]([C:41]([F:44])([F:43])[F:42])[CH2:39][OH:40].CN(C)C=O>C(#N)C.O>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH:38]([C:41]([F:44])([F:43])[F:42])[CH2:39][OH:40])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: OCC(Br)C(F)(F)F
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(CO)C(F)(F)F)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.04 mmol, chiral intermediate from peak 1 of Example 1, step 7) and triethylamine (19 μL, 0.13 mmol) in acetonitrile (0.6 mL) was added 2-bromo-3,3,3-trifluoropropan-1-ol (from Synquest Labs, 9.2 mg, 0.048 mmol). N,N-dimethylformamide (0.3 mL) was added, which created a clear solution that was stirred at 70° C. overnight. The mixture was diluted water and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.6 mg (30%) of the desired product. The product was isolated as a mixture of diastereomers. LCMS calculated for C22H27ClF3N6O2 (M+H)+: m/z=499.2; Found: 499.1.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH:5]4[CH2:7][CH2:6]4)=[O:11])=[CH:14][N:15]=3)=[C:25]([CH3:26])[O:24][N:23]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of cyclopropanemethylamine (0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (56 mg, 70%) which was obtained as a white solid. MS: m/e=398.4 [M+H]+.
Reaction SMILES: C(O[C:9](=O)[N:10]([C@H:12]([C:14](=[O:43])[NH:15][C:16]1[C:17](=[O:42])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=2)[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[CH3:13])C)C1C=CC=CC=1.[H][H]>C(O)C>[C:22]1([C:19]2[N:18]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:30]=3)[C:17](=[O:42])[C:16]([NH:15][C:14](=[O:43])[C@@H:12]([NH:10][CH3:9])[CH3:13])=[CH:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: C[C@@H](C(=O)Nc1ccc(-c2ccccc2)n(Cc2cccc(Oc3ccccc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Solvent: CCO
Product: CN[C@@H](C)C(=O)Nc1ccc(-c2ccccc2)n(Cc2cccc(Oc3ccccc3)c2)c1=O
Yield: 11.7 %

Procedure:
Compound 20D (55 mg, 0.094 mmol) in ethanol (2 mL) is hydrogenated under 10% palladium on carbon (10 mg) and hydrogen (balloon pressure). The reaction is monitored by LCMS. Upon completion the mixture is filtered and the filtrate is concentrated and purified by HPLC to afford the title compound (5 mg, 12%):
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(O)CCC.O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:19]2[N:18]=[N:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccc(Cl)nn1
Solvent: O
Solvent: ClCCl
Solvent: CCCCO
Product: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 4-amino-1-benzylpiperidine (4 g, 21 mmol) and 3,6-dichloro-pyridazine (1.56 g, 10.5 mmol) was stirred for 1 h at 120° C., before n-butanol (10 ml) was added and the reaction mixture stirred for a further 1 h at 120° C. After addition of water and dichloromethane, the organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was crystallized from acetonitrile and the resulting solid was filtered off and dried to yield D1 (1.3 g, 41%) as a solid. C16H19ClN4 requires 302. Found 303 (MH+); mp: 208.2-209.3° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=O)(=[O:8])=[O:7].[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:26]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:13]1[C:12]1[CH:11]=[C:10]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cccs2)c1
Reactant: Nc1cccnc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(-c2nc3ncccc3[nH]2)c1)c1cccs1

Procedure:
3-(thiophene-2-sulfonamido)benzoic acid (242b) was reacted with 2,3-diaminopyridine, HBTU and TEA in DMF followed by microwave as described previously for example 235. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.45 (d, 1H, J=4.6 Hz), 8.20 (d, 1H, J=7.3 Hz), 8.11 (m, 1H), 7.92 (m, 2H), 7.61 (dd, 1H, J=1.4, 3.7 Hz), 7.52 (t, 2H, J=8.0 Hz), 7.40 (dd, 1H, J=5.0, 7.8 Hz), 7.33 (dd, 1H, J=1.3, 8.0 Hz), 7.12 (dd, 1H, J=3.8, 5.0 Hz); Calc'd for C16H12N4O2S2; (M+H)=357; found 357.
Reaction SMILES: [C:1]([O:18]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:27]([N:26]([CH2:25][CH2:24][O:23][CH2:22][CH2:21][OH:20])[C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CCCCCCCCCCCCCCCCNCCOCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCOCCO)C(=O)CCCCCCCCCCCCCCC
Temperature: 120 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
Into a 250 ml-flask equipped with reflux condenser, were introduced 14.3 g of methyl palmitate and 16.5 g of N-(2-hydroxyethoxy)ethyl-n-hexadecyl amine prepared in Example 1, and thereto was added 2.6 g of sodium carbonate. Then, the mixture was stirred violently for 3 hours at 120° C. After the termination of the reaction, the mixture was cooled to a room temperature and 100 ml of chloroform was added thereto to be dissolved. The precipitates were removed and the solvent was evaporated off under reduced pressure. The produced solid was recrystallized from hexane to give 23.2 g of the title compound(Yield: 82%) as white powder, which was identified by IR and NMR. The results are shown in Table 1.
Reaction SMILES: ClC1C2C=C(C3CCN(C(OC(C)(C)C)=O)CC=3)NC=2N=CN=1.Cl[C:25]1[C:26]2[CH:33]=[C:32]([I:34])[NH:31][C:27]=2[N:28]=[CH:29][N:30]=1.[S:35]1[C:39]2[CH:40]=[C:41]([NH2:44])[CH:42]=[CH:43][C:38]=2[N:37]=[CH:36]1>>[S:35]1[C:39]2[CH:40]=[C:41]([NH:44][C:25]3[C:26]4[CH:33]=[C:32]([I:34])[NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH:42]=[CH:43][C:38]=2[N:37]=[CH:36]1
Reactant: Nc1ccc2ncsc2c1
Reactant: Clc1ncnc2[nH]c(I)cc12
Agent: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Product: Ic1cc2c(Nc3ccc4ncsc4c3)ncnc2[nH]1

Procedure:
Following the General method for the reaction of amines with tert-butyl 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate to generate compounds of Formula I-B-Boc, but using 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine and benzothiazol-6-ylamine, one obtained the title compound. MS (ES+): m/z 393.88 (100) [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6](=[O:23])[CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([OH:23])[CH:7]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 66.5 %

Procedure:
A mechanically stirred solution of 4-tert-butoxycarbonylamino-3-oxo-5-phenyl-pentanoic acid ethyl ester (115 g, 0.343 mol) in ethanol (450 ml) at 0° C. under nitrogen was treated portionwise with sodium borohydride (4.43 g, 0,117 mol) over 30 minutes, producing a thick slurry. The reaction mixture was quenched by the dropwise addition of glacial acetic acid (26 ml) at 0° C. under nitrogen. The slurry was then poured onto a mixture of dichloromethane (400 ml) and a 1M aqueous hydrogen chloride solution (400 ml) in a separating funnel. The organic layer was removed and the aqueous solution extracted with dichloromethane (180 ml). The combined organic solutions were washed sequentially with water (200 ml), 5% aqueous sodium hydrogen carbonate solution (200 ml) and brine (200 ml, and dried (anhydrous magnesium sulfate). The solvents were removed in vacuo to give an off-white solid which was recrystallised from methylcyclohexane/ethyl acetate providing 4-tert-butoxycarbonylamino-3-hydroxy-5-phenyl-pentanoic acid ethyl ester (77 g, 66%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([CH:15]1[CH2:25][CH2:24][C:18]2([O:22][CH2:21][C:20](=O)[CH2:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>O.O1CCCC1>[C:11]([CH:15]1[CH2:25][CH2:24][C:18]2([O:22][CH2:21][C:20](=[N:2][OH:3])[CH2:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)CO2
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)CC(=NO)CO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (6.9 g, 0.1 mol) and triethylamine (10.0 g, 0.1 mol) in 10 ml of water was added 8-t-butyl-1-oxaspiro(4,5)decane-3-one (16.0 g, 0.076 mol) in 30 ml tetrahydrofuran. The mixture was stirred at room temperature for 3 hours and at 60° C. for 1 hour. The solvent was then evaporated in vacuo and the residue was partitioned between toluene and brine (100 ml each). The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo to yield a colourless oil (17.0 g) which crystallised on standing. Recrystallisation from light petroleum gave two fractions of colourless crystals (6.6 g and 5.3 g) mp.: 118-120 and 105°-108° C. 1H-NMR indicated mixtures of geometric isomers (E/Z) in ratios of 1:1 and 2:1 respectively.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([F:15])[C:12]([Cl:16])=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[CH2:6][C:7]([OH:9])=O.P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].[H][H]>[Pd].CO.O>[Cl:16][C:12]1[C:13]([F:15])=[CH:14][CH:2]=[C:3]2[C:11]=1[C:7](=[O:9])[CH2:6][CH:5]([CH3:10])[NH:4]2
Reactant: [H][H]
Reactant: CC(CC(=O)O)Nc1cc(Cl)c(F)cc1Br
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Solvent: CCOP(=O)(OCC)OCC
Solvent: O
Product: CC1CC(=O)c2c(ccc(F)c2Cl)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
6.0 g of (+)-3-(2-bromo-5-chloro-4fluoroanilino)butyric acid obtained in Example 5 was added to 60 g of a triethyl phosphate-phosphorus pentoxide mixture (in a weight ratio of 3:2). The resulting mixture was stirred at 80°-90° C. for 15 minutes and then cooled to room temperature. After the addition of 600 ml of water, the resulting mixture was stirred and then extracted twice with 150 ml-portions of chloroform. The extract was washed twice with 200 ml-portions of water, dried and then concentrated under reduced pressure. The residue thus obtained was mixed with 0.1 g of 10% palladium-active carbon, 20 ml of a 1N aqueous solution of sodium hydroxide, and 200 ml of methanol. The resulting mixture was stirred at ordinary temperature and pressure for an hour with hydrogen gas passed therethrough. This reaction mixture was filtered to remove the palladium-active carbon therefrom, the filtrate was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The extract was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography [using n-hexane-ethyl acetate (5:1) as the eluent]. Fractions containing the desired compound were collected and concentrated under reduced pressure to obtain 2.2 g of (-)-5-chloro 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[CH2:29]([Mg]Cl)[CH:30]=[CH2:31].O1CCCC1>C(OCC)C>[CH2:31]([CH:10]1[N:11]2[CH2:20][CH2:19][C:18]3[C:13]([C:12]2=[C:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)[CH:30]=[CH2:29]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: C=CC[Mg]Cl
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of allylmagnesium chloride in tetrahydrofuran (1.7 M, 2.5 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-allyl-13-ethyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (160 mg, 98%). LC/MS m/e calcd for C25H27NO4 (M+H)+: 406.5, observed: 406.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.20 Hz, 3 H) 2.11-2.20 (m, 1 H) 2.25-2.35 (m, 1 H) 2.55-2.65 (m, 2 H) 2.66-2.76 (m, 2 H) 3.23-3.30 (m, 2 H) 3.80 (d, J=4.55 Hz, 6 H) 4.68-4.81 (m, 3 H) 5.63-5.75 (m, 1 H) 6.04 (d, J=11.87 Hz, 2 H) 6.85 (s, 1 H) 6.90 (s, 1 H) 6.94 (s, 2 H).