Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([NH:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9]([C:6]1([NH:12][CH3:13])[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)=[O:11]
Reactant: CO
Reactant: CNC1(C(=O)O)CCN(OC)CC1
Solvent: O=S(Cl)Cl
Product: CNC1(C(=O)OC)CCN(OC)CC1

Procedure:
To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid (2.0 g, 10.63 mmol) in methanol (50 ml) at 0-10° C. was added thionyl chloride (2.29 ml, 3.76 g, 31.57 mmol) and the reaction mixture was heated at reflux overnight. After cooling, the mixture was concentrated, the residue diluted with ice water (20 ml) and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (4×25 ml) and dichloromethane (4×50 ml), the combined organic layers washed with aqueous sodium bicarbonate (15 ml) and brine (15 ml), dried over sodium sulfate and concentrated. Yield: 0.76 g of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (compound P5.4) as a viscous, orange oil. The spectral data of this crude material were identical to those described above under preparation example 6, step 2.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]1[C:18]2=[N:19][C:20]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[CH:21][CH:22]=[C:17]2[C:16]2[CH2:40][NH:41][CH2:42][CH2:43][C:15]1=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:42][CH2:43][C:15]2[N:14]([CH3:13])[C:18]3[C:17]([C:16]=2[CH2:40]1)=[CH:22][CH:21]=[C:20]([N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)=[CH:25][C:24]1=[O:39])[N:19]=3)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Triethylamine (40 μL, 0.28 mmol), DMAP (3.5 mg, 0.028 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added to a solution of 1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.14 mmol) in CH2Cl2 (8 mL) and the resulting solution was stirred at ambient temperature for 3 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 14 column volumes) gave the title compound (51 mg, 77%) as a yellow solid and a mixture of rotomers: mp 238-242° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.11-8.04 (m, 3H), 7.44-7.37 (m, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.86-6.83 (m, 1H), 4.73-4.68 (m, 2H), 3.90-3.83 (m, 2H), 3.71-3.69 (m, 3H), 3.01-2.86 (m, 2H), 2.16-2.12 (m, 3H); ESI MS m/z 468 [M+H]+; HPLC (Method A)>99% (AUC), tR=17.8 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH:8]([CH3:11])[CH2:7][S:6]1)=[O:4].Cl.[NH2:13]O.CCOCC>C(#N)C>[NH2:13][C:9]1[C:8]([CH3:11])=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1SCC(C)C1=O
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1scc(C)c1N

Procedure:
2-Methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene (l.74 g) was dissolved in acetonitrile (13 ml) and the resulting solution was brought to the boil. To this was added hydroxylamine hydrochloride (0.69 g) and the mixture was refluxed for 5 hours. The reaction mixture was cooled in ice and dry ether (50 ml) added whereby a sticky precipitate was produced which was filtered off with the aid of kieselguhr. The kieselguhr was slurried with water and filtered, and the filtrate was basified with ammonia and extracted with ether (2 ×). The combined extracts were dried over sodium sulphate, filtered and evaporated to give the title compound, 1.lg (64%) mp 82°-83°.
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[C:21]([O-])=[O:22].[Na+]>CN(C=O)C>[CH2:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCCCCCN(CCCCCC)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)c1ccc(C=O)cc1
Temperature: 95 °C
Yield: 84 %

Procedure:
To a solution of dry DMF (1.1. mL) under Argon at 0° C. was added of POC13(375 μL, 4 mmol). N,N-Dihexylaniline (1.04 g, 4 mmol) was added dropwise and the solution was mixed with rapid stirring to form a green solution. The reaction mixture was heated at 95° C. for 2 h. The solution quickly turned red/brown. After 2 h the solution was cooled. It was poured into ice/water 20 mL and aq. saturated NaOAc (20 mL) was added. The partially neutralized solution was partitioned between ether and water. The ether layer was washed with aq. saturated NaHCO3 and dried over sodium sulfate. After concentrating to approximately 20 mL. DMF oiled out of the solution. The solution was transferred from the oil and concentrated under reduced pressure. The resultant residue was purified via flash column chromatography, using a gradient of 0→20% ethyl acetate; petroleum ether as eluent to give N,N-Dihexyl-4-aminobenzaldehyde (32) (970 mg, 84%). 1H NMR (CDCl3) δ 9.72 (s, 1H CHO); 7.70 (d, 2H, ArH); 6.64 (d, 2H, ArH); 3.32 (t, 4H, 2×NCH2); 0.89 (t, 6H 2×CH2CH3). TLC (silica gel): Rf=0.75 (20% ethyl acetate;petroleum ether).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COC(C)CC(=O)O
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 50%), MS (ISP) m/z=431.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (RS)-3-methoxybutanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25]C)[N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:25])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[O:22])=[CH:23][CH:24]=1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C=O)cc3)c2n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C=O)cc3)c2n1
Temperature: 70 °C

Procedure:
The product of example 7 (800 mg) is combined with sodium iodide (504 mg) and acetonitrile (40 mL), and then chlorotrimethylsilane (0.5 mL) is slowly added. The mixture is heated at 70° C. for 3.5 h, cooled and filtered. The solid product is washed with water, then ether to yield 406 mg. NMR, UV, MS are consistent with structure assignment. This material is suitable for conjugation reactions between linkers and auxiliary groups.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C@H:31]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:32][OH:33]>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH3:20])[N:3]=[C:2]([NH:30][C@H:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:32][OH:33])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Cc1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-5-nitropyrimidin-4-amine (Method 75; 1.0 g, 3.4 mmol), DIEA (0.57 g, 4.4 mmol), and (R)-2-amino-2-(4-fluorophenyl)ethanol (0.58 g, 3.7 mmol) in n-BuOH (15 ml) was heated to 60° C. for 2 hours. The reaction was then cooled to 25° C., concentrated, and treated with hexane. The resulting solid was collected by filtration to give the title compound (1.3 g, 93%). MS: Calcd.: 413; Found: [M+H]+ 414.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH2:29])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH:29][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)=[O:12])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(O)c1noc2ccccc12
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2noc3ccccc23)C[C@@H]2CCC[C@@H]21

Procedure:
prepared by reaction of Benzo[d]isoxazole-3-carboxylic acid with (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester. LC-MS: tR=1.11 min; [M+H]+=386.6.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH2:14])=[C:9]([F:15])[CH:8]=1.[CH:16]([NH:19][C:20](=O)[CH3:21])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH:14][C:20](=[N:19][CH:16]([CH3:18])[CH3:17])[CH3:21])=[C:9]([F:15])[CH:8]=1
Reactant: CC(=O)NC(C)C
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Temperature: 15 °C
Yield: 84.7 %

Procedure:
Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES+): m/z=292 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:14][CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:16]1=[O:17]>CCCCCC>[Br:14][CH:15]([CH2:20][C:19]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:21])[C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CC(Br)C(=O)O1
Solvent: CCCCCC
Product: CCCCCCCCCCCCNC(=O)CC(Br)C(=O)O
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 9.3 g. (0.05 mole) of dodecylamine in 30 ml. of hexane is added dropwise to a stirred mixture of 9.0 g. (0.05 mole) of 2-bromosuccinic anhydride in 70 ml. of hexane at 5°-10° C. over a period of 15 minutes. Reaction is exothermic and the mixture is stirred for an additional 15 minutes while still in cooling bath. As a result, the temperature rises to 15° C. and the reaction takes the appearance of a white emulsion. Hexane (100 ml.) is added and stirring is continued at ambient temperature for 24 hours. The white insoluble solid is filtered off, washed several times with hexane then dried at about 50° C. and reduced pressure to obtain 16.1 g. (89% yield) of a white slightly waxy solid product of this example; m. p. 62°-70° C. (opaque).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>O1CCCC1>[CH:11]1([CH:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[OH:6])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: OC(c1cc(F)cc(F)c1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3,5-difluorobenzaldehyde (1.0 g, 7.0 mmol) was dissolved in tetrahydrofuran (10 mL) was cooled in an ice bath. cyclopropylmagnesium bromide (0.5 M in THF, 1.2 equiv., 8.4 mmol) was added slowly and the mixture was stirred at 0° C. for 60 min. The reaction was quenched with sat. ammonium chloride and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound of sufficient purity to be used directly.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The solution of 1.0 g of N-(4-nitro-o-tolyl)-4-methoxyphthalimide in 70 ml of ethyl acetate is hydrogenated over 0.35 g of platinum oxide at 2.5 atm. and room temperature for 2 hours. It is filtered, the filtrate concentrated and the precipitate formed collected, to yield the N-(4-amino-o-tolyl)-4-methoxyphthalimide melting at 158°-161°.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH:15](O)[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[NH:24][N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[N:24]([CH:15]2[CH2:16][CH2:17][CH2:18][C:19]3[N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:2])=[O:3])[N:12]=[CH:13][C:14]2=3)[N:23]=1
Reactant: COc1ccc(CNc2ncnc3[nH]nc(Br)c23)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2c(Br)nn3C2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
A solution of 1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (4.05 g, 11.13 mmol), 3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.9 g, 13.35 mmol) and PPh3 (4.38 g, 16.70 mmol) in dry THF (110 mL) at 0° C. was added dropwise DIAD (3.37 g, 16.70 mmol) over a period of 5 minutes under a nitrogen atmosphere, then the mixture was stirred at room temperature for 4 hours. Removed the solvent under reduced pressure and then extracted with DCM, the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC separation to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.3 g, yield 32.4%). MS-ESI (m/z): 640 (M+2)+ (Acq Method: 10-80AB_2 min; Rt: 1.357 min)
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[O:25][CH3:26])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:34][C@H:35]1[CH2:39][NH:38][C@H:37]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[CH2:36]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:38]1[CH2:39][C@H:35]([OH:34])[CH2:36][C@H:37]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[O:25][CH3:26]
Reactant: COc1ccc(N2CCCCC2)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCCCC2)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.10 g of the compound obtained in Step 193-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (1.83 mmol) as starting materials, respectively 202 mg (Isomer A, brown amorphous) and 343 mg (Isomer B, brown amorphous) of two species of diastereoisomers of the title compound were obtained by a similar procedure to Step 4-2.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].CN(C)C=O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[CH3:2][CH2:1][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:17]([CH3:18])=[O:19]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(C)=O
Reaction time: 1 h

Procedure:
A solution of 74.5 parts of 2,6-diethylaniline in 200 parts of dimethylformamide is treated with 56 parts of acetic anhydride at 10°C. The mixture is stirred at 40° for one hour, poured into ice and water and stirred. The solid 2,6-diethylacetanilide is filtered, washed with water and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COCCN
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: COCCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 2-methoxyethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 18.8 mg of 188. MS (Q1) 439.1 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:19]([C:5]2[S:4][C:3]([CH2:1][CH3:2])=[CH:7][CH:6]=2)[OH:20])[CH:21]=1
Reactant: CCc1cccs1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2OC)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran (36 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml). The mixture was stirred at the same temperature for 30 minutes, and cooled to −78° C., and thereto was added dropwise a suspension of 5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml). The mixture was stirred at the same temperature for 2 hours, warmed to 0° C., and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-85:15) to give 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol (5.99 g) as a pale yellow syrup. APCI-Mass m/Z 309/311 (M+H—H2O). (2) The above 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol was treated in a manner similar to Reference Example 1-(2) to give 5-bromo-(5-ethyl-2-thienylmethyl)-2-methoxybenzene as oil. APCI-Mass m/Z 311/313 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:18])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Reactant: CN(C)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 3-bromo-11-oxo-11H-pyrido[2,1-b]quina-zoline-6-carboxylic acid was dissolved in dichloromethane (25 ml). To the reaction mixture was added N,N-dimethyl-ethylenediamine (1 g; 0.0023 mol), followed by the BOP reagent (1 g, 0.0023 mol). The reaction mixture was stirred at room temperature for 30 minutes, diluted with water and extracted with dichloromethane. The combined organic phases were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 10% methanol/chloroform) to provide product as a yellow solid: 0.338 g.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>N1C=CC=CC=1.ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:3]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:2]=2[NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][O:45][CH3:44])=[CH:13][CH:14]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2N)cc1
Reactant: COCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCCC(=O)Nc1cc(C)ccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
The solution of 0.278 g of tert-butyl 3-(2-amino-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.046 ml of pyridine and 2.3 ml of dichloromethane is cooled to 0° C. and admixed slowly with 0.078 g of 4-methoxybutyryl chloride. The reaction mixture is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1)=[O:28])[CH3:31]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: CCOC(=O)CCCBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.47 g), ethyl 4-bromobutyrate (0.32 g), triton B (0.5 ml) and chloroform was stirred for 2 days under room temperature. The reaction mixture was evaporated and the residue was subjected to a column chromatography on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound were combined (20 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered off. The filtrate was evaporated to give 3-[2-(3-ethoxycarbonylpropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.49 g).