Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)(=[O:35])=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (96 mg, 82%), MS (ISP) m/z=469.4 [(M+H)+], mp 130° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:23][CH:22]=1.O[Li].O>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(NCc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1)C1CC1
Yield: 91.1 %

Procedure:
Dissolve 7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg, 0.698 mmol) in MeOH (10 mL). Add LiOH.H2O (293 mg, 6.98 mmol) and stir overnight. Partition the reaction mixture between chloroform and water. Separate the aqueous phase and extract three times with chloroform and once with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to obtain 7-chloro-6-{-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (244 mg, 91%). MS (APCI+) m/z: 384 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:12])[C:8]2=[O:11])=[CH:4][C:3]=1[N+:13]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[C:8](=[O:11])[N:7]([CH3:12])[CH2:6]2
Reactant: CN1Cc2cc([N+](=O)[O-])c(Cl)cc2C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CN1Cc2cc(N)c(Cl)cc2C1=O
Temperature: 65 °C
Yield: 85.1 %

Procedure:
To 6-chloro-2-methyl-5-nitroisoindolin-1-one (340 mg, 1.5 mmol) in ethanol (9 mL) and water (0.9 mL) was added SnCl2.2H2O (1.35 g, 6 mmol) and the mixture was heated to 65° C. for 5 h. DCM (20 mL) and 2M NaOH(aq) (10 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-amino-6-chloro-2-methylisoindolin-1-one (251 mg, 85%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=197 at 2.31 min. 1H NMR (400 MHz, d6-DMSO): δ 7.45 (s, 1H), 6.90 (s, 1H), 5.99 (br s, 2H), 4.32 (s, 2H), 3.01 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH:17](O)=O>C=O>[ClH:1].[ClH:1].[CH3:17][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CO
Reactant: c1cncc(OCC[C@@H]2CCCN2)c1
Agent: C=O
Agent: Cl
Product: CN1CCC[C@H]1CCOc1cccnc1

Procedure:
A 400 mg sample of 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine dihydrochloride, from Example 102 above, was dissolved in 14 mL of 37% HCHO, 14 mL of HCOOH was added, and the reaction mixture was stirred at reflux for 2.5 hours. The solution was washed with ether, adjusted to basic pH with K2CO3 and extracted with methylene chloride. The extract was dried over MgSO4 and concentrated. The residue was purified on a column of silica gel, eluting with 10% methanol in methylene chloride. The compound was converted to the salt by the HCl in ether according to Example 14c to afford the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.71-1.98 (m, 1H), 2.00-2.23 (m, 3H), 2.37-2.45 (m, 1H), 2.50-2.63 (m, 1H), 2.98 (s, 3H), 3.13-3.25 (m, 1H), 3.53-3.67 (m, 1H), 3.68-3.78 (m, 1H), 4.31-4.48 (m, 2H), 8.00 (dd, J=11.0, 7.0 Hz, 1H), 8.20 (dd, J=10.5, 5.0 Hz, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H). Anal. Calc. for C12H18N2OF·1.9 HCl·1.1 H2O: C, 48.49; H, 7.46; N, 9,42; Found C, 48.51; H, 7.69; N, 9.61. [α]25D =+36.2820 (C=0.5, H2O).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21](=[O:23])[CH3:22])[C:12]3[C@@H:24]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:42][Mg]Br>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21]([OH:23])([CH3:42])[CH3:22])[C:12]3[C@@H:24]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C(C)(C)O)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
26 mg 1-((3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)ethanone are dissolved in 2 ml tetrahydrofurane cooled to −10° C. and treated with 110 μl of a 1.4 M solution of methylmagnesium bromide in toluene/tetrahydrofurane 75:25. The mixture is warmed to room temperature and stirred for 12 hours. The mixture is diluted with diethylether, washed with saturated aqueous ammonium chloride and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is directly used in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[S:11](Cl)(Cl)=[O:12].[CH3:15][C:16]1([CH3:26])[CH2:21][O:20][P:19]([NH:23][CH2:24][CH3:25])(=[S:22])[O:18][CH2:17]1>N1C=CC=CC=1>[CH3:15][C:16]1([CH3:26])[CH2:17][O:18][P:19]([N:23]([CH2:24][CH3:25])[S:11]([CH2:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4])=[O:12])(=[S:22])[O:20][CH2:21]1
Reactant: O=S(Cl)Cl
Reactant: CCNP1(=S)OCC(C)(C)CO1
Reactant: CNC(=O)ON=C(C)SC
Solvent: c1ccncc1
Product: CCN(S(=O)CNC(=O)ON=C(C)SC)P1(=S)OCC(C)(C)CO1

Procedure:
Methyl N-[[[[[(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)(ethyl)amino]sulfinyl]methylamino]carbonyl]oxy]ethanimidothioate was prepared by the procedure employed in Example 9, by reacting methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.43 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole), and 5,5-dimethyl-2-ethylamino-2-thioxo-1,3,2-dioxaphosphorinan (3.14 g, 0.015 mole) in pyridine (10 ml). Recrystallization from chloroform-hexane afforded 2.2 g of needles of the formula below, mp 136~138°. ##STR36##
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CC1CCCN1Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCCC5C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the title compound (16%).
Reaction SMILES: C(=O)(O)[O-].[K+].[NH2:6]OS(O)(=O)=O.[CH3:12][O:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:32](=[O:35])[C:33]#[CH:34])[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].[OH-].[K+]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]2[N:16]([N:6]=[CH:34][C:33]=2[C:32]([C:24]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:35])[N:15]=1
Reactant: COc1cccnn1
Reactant: C#CC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cnn2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Potassium bicarbonate (2.5 M) was added to a solution of hydroxylamine-O-sulfonic acid (64.7 mg, 0.57 mmol) until the pH value turned to 5. Then, 3-methoxypyridazine (42 mg, 0.38 mmol) was added at 70° C. over 10 min. The mixture was stirred at 70° C. for 2 h and then cooled to room temperature. The pH value of the mixture was adjusted to 8 by addition of 2.5M potassium bicarbonate. 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-one (42 mg, 0.19 mmol) in CH2Cl2 (10 mL) and potassium hydroxide (40 mg, 0.71 mmol) were added. The mixture was stirred at room temperature overnight, and then was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried over MgSO4, and concentrated to give a crude product, which was purified on a silica gel column eluting with CH2Cl2/MeOH (20:1) to afford compound 15 as a white solid (31 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH-:10].[Na+].O>C(#N)C>[C:5]([NH:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:10])=[O:8])(=[O:7])[NH2:4]
Reactant: [OH-]
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(NC(N)=O)C(=O)O
Reaction time: 3.5 h
Yield: 74.1 %

Procedure:
First, 4.0 g of 5,5-dimethylhydantoin was mixed with 4.0 g of sodium hydroxide and 4.0 g of water, and the mixture was stirred at 85° C. to 90° C. for 3.5 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=20/80, flow rate: 0.5 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) of the reaction mixture showed the production of 3.38 g (yield 74.1%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1>C(O)(=O)C>[CH3:19][C:17]1[NH:16][N:15]=[C:14]([NH:13][C:1]2[NH:2][C:6](=[O:7])[C:5]3[C:4]([CH:3]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]=1
Reactant: N#CCc1ccccc1C(=O)O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccccc3c(=O)[nH]2)n[nH]1
Temperature: 130 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
2-Cyanomethyl-benzoic acid (1.61 g, 0.01 mol), 3-amino-5-methylpyrazol (1 g, 0.01 mol) and acetic acid (15 ml) were sealed in a bottle. The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated, and the residue was dissolved in 5 ml methanol (MeOH). The resulting solution was added dropwise to 200 ml water. After stirred for 1 hour, the solid was collected, and dried to give product (1.8 g, 75% yield). LC-MS: 241 (MH+)
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[ClH:13].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>O.CC(O)=O.[Cu]Cl>[Cl:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[S:18]([Cl:13])(=[O:20])=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cl
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=S=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Yield: 50 %

Procedure:
To a suspension of methyl 4-amino-3-chlorobenzoate (33 g, 146 mmol, 1 eq) in a 1:1 mixture of concentrated HCl and water (140 ml) cooling in an ice/MeOH bath was added a solution of sodium nitrite (11.1 g, 160 mmol, 1.1 eq) in warm water (20 ml) dropwise, ensuring that the reaction temperature was maintained below 5° C. The mixture was filtered through a pad of Celite and the solids washed with water. The resulting filtrate was added portionwise to a mixture of sulphur dioxide (47 g, 729 mmol, 5 eq) and copper (I) chloride (catalytic) in AcOH, maintaining the reaction temperature below 10° C. The reaction mixture was extracted into DCM (600 ml), washed with water (600 ml), dried over sodium sulphate, filtered and the solvent evaporated in vacuo. The residue was redissolved in DCM, washed with saturated sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography eluting with 0-15% ethyl acetate:hexane then triturated with hexane to yield the title compound (19.6 g, 73.6 mmol, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH2:7]1)=[O:5])[CH3:2].C1COCC1>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reaction time: 4 h
Yield: 99.3 %

Procedure:
The above (S)-3-(5-nitropyridine-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (2.59 g, 9.25 mmol) was suspended in ethanol (50 mL) and THF (10 mL) was added. The mixture was gently heated to give a clear solution and 10% palladium on carbon (250 mg) was added. The mixture was hydrogenated at 45 psi for 4 hrs and then filtered. The filtrate was concentrated to give a purple solid as (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (2.3 g, 100% yield). LCMS for C12H18N4O2 calcd (m/e) 250, obsd 251 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([O-])=[O:23])[S:21][C:14]=12.[Li+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[Cl:12])[CH:19]=2)=[O:23])[CH2:4][CH2:3]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN1CCN(CCCN)CC1
Agent: [Li+]
Product: CN1CCN(CCCNC(=O)c2cc3nccc(Cl)c3s2)CC1

Procedure:
The title compound was prepared from 3-(4-methylpiperazin-1-yl)-propylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 353/355 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[CH2:58][N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1>CN(C=O)C.ClCCl>[N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:53]4[CH2:57][CH2:56][CH2:55][C@H:54]4[CH2:58][N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)N3CCCC3)s2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1)N1CCCC1
Yield: 57.1 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 5 mL 20% DMF/dichloromethane using 4-[5-(Pyrrolidine-1-carbonyl)-thiophen-2-yl]-benzoic acid (121 mg, 0.40 mmol), EDC-HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), DIEA (0.17 mL, 1.0 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (52 mg, 0.34 mmol) to give the title compound (85 mg, 57% yield). MS (ES+) 438.3 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5].[Li+].[OH-].O>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[C:15]([OH:16])[C:10]([C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:24])=[O:2])=[O:9])=[N:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester, 20, (0.082 g, 0.24 mmol) in THF (4 mL) is added LiOH (0.024 g, 0.98 mmol) and H2O (1 mL) and the resulting solution stirred for 3 days at room temperature. The solvent is removed under reduced pressure and the pale yellow solid that remains is then acidified with 1M HCl to until the pH is approximately 1 and the solution extracted twice with EtOAc. The combined organic layers are combined, dried (Na2SO4), filtered and concentrated under reduced pressure to afford 0.064 g (81% yield) of the desired compound as a white solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 12.99 (1 H, br s), 12.25 (1 H, s), 9.05 (1 H, s), 8.53 (1 H, d, J=2.0 Hz), 7.91 (1 H, s), 7.74-7.83 (2 H, m), 7.51-7.58 (2 H, m), 1.58 (6 H, s). HPLC-MS: m/z 335 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([CH:39]=[CH:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)C=Cc4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-phenyl-ethenesulfonyl chloride. Purity (ELSD, based on MW=587.7)=97%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1>CN1CCCC1=O>[NH2:33][C:29]1[CH:28]=[C:27]([NH:34][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cccc(N)c1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(N)c1
Yield: 50.4 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), 1,3-phenylenediamine (288 mg), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave device at 200° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added thereto for extraction. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1), and was washed with ethyl acetate to obtain 5-[(3-aminophenyl)amino]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (120 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[CH2:23](O)[CH3:24]>>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:24]
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (3-Bromo-4-methoxy-phenyl)-acetic acid (24 g, 97.9 mmol) in ethanol (240 mL) was added thionyl chloride (78 mL, 107.7 mmol) and the reaction was stirred at room temperature for 1.5 hours. Once no starting material was seen by analytical LCMS, saturated sodium bicarbonate (aqueous) was added until the reaction was of basic pH. The mixture was extracted twice with dichloromethane and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30]1[CH2:40][CH2:39]N2C(=NCCC2)C[CH2:31]1.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:30]1([CH2:31][O:28][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])=[O:18])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:29])[CH2:39][CH2:40]1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1
Reaction time: 8 h

Procedure:
A 0.12 g quantity of the compound obtained in Example 229 and 0.14 ml of DBU were dissolved in 3 ml of ethanol, 0.12 g of (bromomethyl)cyclopropane was then added to the obtained solution, and heating and refluxing were conducted overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from ethanol, thereby yielding 80 mg of white powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.