Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:16]2[CH:17]=[CH:18][N:19]=[C:14]([NH2:13])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cn1
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccnc(N)n2)cn1
Temperature: 0 °C
Yield: 119.6 %

Procedure:
A mixture of commercially available (6-methoxypyridin-3-yl)-methanol (CAS 58584-63-7, 1 g, 7.19 mmol) and dry THF (9.3 mL) was cooled to 0° C. and sodium hydride (0.38 g of a 60% dispersion, 9.58 mmol) was added portionwise. Stirring was continued at 0° C. before portionwise addition of 2-amino-4-chloropyrimidine (0.62 g, 4.79 mmol). The mixture was heated at 100° C. (bath temperature) for 2 hours. On cooling, the mixture was poured onto ice, extracted with EtOAc (4×) and the combined organic phase washed with brine, dried and concentrated to give the title compound as a beige solid (1.33 g, 65% purity) which was used without further purification in the next step.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=O)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(COC)OC>[CH2:1]1[CH:13]2[CH:4]([C:5](=[S:24])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccccc2C2CCCC12
Solvent: COCCOC
Product: S=C1Nc2ccccc2C2CCCC12
Reaction time: 3 h

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinolin-4-one (153 mg, 0.82 mmol) and Lawesson's reagent (363 mg, 0.9 mmol) are stirred in dimethoxyethane (20 ml) at room temperature. After 3 hours, another portion of Lawesson's reagent (363 mg, 0.9 mmol) is added to it. After 3 hours, the batch is concentrated by evaporation, and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:26]=[CH:27][N:28]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:26]=[CH:27][N:28]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCC(C(=O)O)C3)nn3ccnc23)nc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.2 %

Procedure:
A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxylic acid (80 mg, 0.21 mmol), tert-butyl 4-aminobenzoate (40 mg, 0.21 mmol), EDCI (159 mg, 0.08 mmol) and 1-methyl-1H-imidazole (68 mg, 0.8 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 h. The residue was concentrated to give crude tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoate (200 mg, crude) as brown liquid that was used directly without purification. LC-MS: 560 [M+1]+, tR=1.510 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[O:20][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)CCc1cc(Cl)c(O)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)OCC)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Yield: 102.2 %

Procedure:
To a stirring solution of (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (66 mg, 0.21 mmol) and ethyl 3-[3-chloro-4-hydroxy-5-(methyloxy)phenyl]propanoate (78 mg, 0.30 mmol) in THF (4 mL) at 0° C. under nitrogen was added ADDP (100 mg, 0.40 mmol) followed by nBu3P (0.10 mL, 0.40 mmol). The resulting mixture was then stirred at 0° C. with slow warming to ambient temperature over 19 h and then reduced under vacuum (Genevac). The residue was then purified by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) to afford the title compound (118 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+]>CO>[OH:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CC(O)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (727 mg, 3.41 mmol, Small Molecules Inc.) in MeOH (6.0 mL) at 0° C. was added sodium borohydride (193 mg, 5.11 mmol, Aldrich) in several portions. The reaction mixture was stirred at 0° C. for 1 hr and warmed up to room temperature and continuously stirred for another 2.5 hrs. The resulting mixture was then quenched with saturated NH4Cl aqueous solution and evaporated under reduced pressure to remove MeOH followed by extraction with CH2Cl2 (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (745 mg) as a colorless sticky oil which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[CH:4]=[C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: C1CNCCNC1
Reactant: COc1cc2ccc(CCl)cc2c(OC)c1OC
Product: COc1cc2ccc(CN3CCCN(Cc4ccc5cc(OC)c(OC)c(OC)c5c4)CC3)cc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxynaphthalene (222 mg) and homopiperazine (42 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Agent: [Ni]
Product: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1

Procedure:
Prepared from (4′-ethyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B4) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (311 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17]Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(OCC)(=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CCl
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A mixture of ethyl 2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60° C. for 30 min. The reaction mass is diluted with water and extraction is carried out with ethyl acetate. After decanting, the organic phase is washed with water, followed by drying over magnesium sulphate, filtering and evaporating under reduced pressure. The residue is taken up in water, agitated for 15 minutes, filtered, washed with water and dried under vacuum. The residue is purified by column chromatography (SiO2, MeOH/CH2Cl2: 5/95 to 8/92). 6.7 g of product, a beige solid, is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[N:3]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncsc3n2)cn1

Procedure:
4-(5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 131 after purification by reverse HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].C(N(CC)CC)C.[CH3:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](Cl)=[O:45]>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:44](=[O:45])[CH2:43][C:42]([CH3:48])([CH3:47])[CH3:41]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 9.9 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazin-1-yl)methanone (100 mg, 0.209 mmol) was stirred in dichloromethane (1 mL) with triethylamine (53 mg, 0.073 mL, 0.521 mmol) at 0° C. 3,3-Dimethylbutanoyl chloride (42 mg, 0.313 mmol) was added and the reaction allowed to stir for 2 hours. The reaction mixture was washed with water and the organic phase was purified by reverse phase acidic preparative HPLC to afford the title compound (12 mg). MS (ESI) m/z 578.5 [M+H]+
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[C:1]([NH:8][C:9]1[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]([F:17])([F:18])[F:19])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A solution of N-ethoxalyl-4-chloro-2-trifluoromethylaniline in concentrated sulphuric acid (125 ml) was added to a stirred mixture of 100% nitric acid (120 ml) and concentrated sulphuric acid (240 ml). The temperature was kept between 8°-10° C. during the addition. After the addition was completed, the solution was stirred for additionally 20 min. without external cooling, whereafter it was poured onto icewater. This afforded precipitation of the title compound as an oil, which crystallized as light yellow crystals upon standing. The crystals were filtered off and washed extensively with water. M.p. 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.C([O-])(=O)C.[Zn+2:15].C([O-])(=O)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O-:10])=[O:9])[CH:3]=1.[Zn+2:15].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O-:10])=[O:9])[CH:3]=1
Reactant: Cc1ccnc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: Cc1ccnc(C(=O)[O-])c1
Yield: 82.3 %

Procedure:
To a solution of 0.49 g (3.6 mmol) of 4-methylpicolinic acid dissolved in 2.5 ml of water, a solution of 0.40 g (1.8 mmol) of zinc acetate.dihydrate dissolved in 1.5 ml of water was dropwise added while stirring. After the dropwise addition, the mixture was stirred at room temperature for one hour. Because no solid was precipitated, the mixture was evaporated to dryness under a reduced pressure, and the solid obtained was washed with acetone under heating to give 0.50 g of the desired zinc salt. No recrystallization was possible from either water or ethanol (yield 79.1%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[S:11][C:12]([Br:15])=[CH:13][CH:14]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:16]12CC(C=C1)C=[CH:17]2>O1CCOCC1>[Br:15][C:12]1[S:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:17]=[CH:16][N:3]=[N:2]3)[O:9][N:8]=2)=[CH:14][CH:13]=1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)s2)=NO1
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)s1

Procedure:
5-Azidomethyl-3-(5-bromo-thien-2-yl)-4,5-dihydro-isoxazole (500 mg, 1.74 mmol) and bicyclo[2.2.1]hepta-2,5-diene (1 ml) were combined with dioxane (2 ml) and subjected to microwave radiation in a Smith Personal Synthesizer for 900 seconds at 125° C. The reaction mixture was concentrated in vacuo and ethyl acetate (5 ml) was added. The precipitate was filtered and washed with ethyl acetate (2×5 ml) to give the desired product (234 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[N:31]=[C:30]([CH3:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[CH3:32][C:30]1[NH:29][C:26]2=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:24]=[C:25]2[N:31]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)cnc2[nH]1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2[nH]1

Procedure:
This compound was prepared according to a process similar to that described in Example 1.2, starting with 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in Example 1.1 and 6-amino-2-methyl-3H-imidazo[4,5-b]pyridine, prepared in the preceding step.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[NH3:23].CO>O1CCOCC1>[NH2:23][C:13]1[N:12]=[C:11]([C:9]2[S:10][C:5]3[C:4](=[O:21])[NH:3][C:2]([CH3:22])([CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:16]=[CH:15][N:14]=1
Reactant: N
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(N)n3)cc2N1
Yield: 53 %

Procedure:
A mixture of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.044 g, 0.13 mmol) and 7 M ammonia in methanol (2.0 mL, 14 mmol) in 1,4-dioxane (8 mL) was microwave-irradiated at 120° C. for 75 min. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified twice by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.019 g, 53%) as a yellow solid:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH2:49][C:50](O)=[O:51]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:45]3[S:44][CH:48]=[CH:47][CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccs1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyo)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-2-yl-acetamide (0.7 g, 78%) as a white solid: mp 171-173° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.24 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.77 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.95-6.97 (m, 2H), 7.35-7.38 (m, 1H), 7.65-7.69 (m, 1H), 7.78-7.84 (m, 2H), 8.70 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 36.35, 37.87, 48.84, 121.91, 124.90, 126.22, 126.60, 127.13, 131.52, 133.21, 134.68, 137.33, 138.97, 166.89, 167.42, 169.61, 169.78, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.41; H, 4.01; N, 10.07; S, 7.62.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:26].B(Br)(Br)Br>C(Cl)Cl>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)(=[O:17])=[O:16])[C:6]([CH3:26])=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:13]=12
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2nccc(Cl)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of [4-chloro-1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester (40 mg, 0.09 mmol) in CH2Cl2 (1 mL), is added 1M BBr3 in CH2Cl2 (536 μL, 0.54 mmol). The solution is subjected to microwave irradiation in a sealed reaction vessel with stirring at 60° C. over 45 minutes. The reaction mixture is evaporated to dryness in vacuo. Water is added and the suspension sonicated then filtered, washed with water and dried in vacuo, furnishing [4-chloro-1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid; MH+=433.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[C:3]=1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C(OC(C)(C)C)=O)[C:21]1=[O:33].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH:5]=3)[CH:10]=[CH:11][C:2]=2[Br:1])[C:21]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(Br)ccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccc(Br)c(N3CC[C@H](N)C3=O)c2c1
Reaction time: 0.5 h

Procedure:
(S)-1-[2-Bromo-7-(tert-butyldimethylsilyloxy)naphthalen-1-yl]-3-(tert-butoxycarbonylamino)-2-oxopyrrolidine, as described above in Step I, (245 mg, 0.458 mmol) was dissolved in a 10% TFA solution in CH2Cl2 (5 mL). After 30 min, the mixture was poured into saturated aqueous Na2CO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 4% MeOH—0.1% to 0.4% NH4OH, to yield the above-titled compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:14][C:15]([SH:18])([CH3:17])[CH3:16].CCN(CC)CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1COCC1>[C:15]([S:18][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)S
Reactant: COC(=O)C(C)(C)CCC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCC(=O)CSC(C)(C)C

Procedure:
A solution of the α-chloroketone (1 eq) from Step 5, 2-methyl-2-propanethiol (1.2 eq), Et3N (1.5 eq) and n-Bu4NBr (catalytic amount) in THF at room temperature under nitrogen was stirred for 24 hours. The mixture was filtered and the solvent removed in vacuo. Chromatography of the oily residue on silica gel (hexane/EtOAc 10:1) provide the title compound as an oil.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(C)ccn1
Solvent: CO
Product: Cc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 72 h
Yield: 47 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (101 mg, 0.3 mmol) in MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:7) to furnish III as a colourless oil (46 mg, 47%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([N:14]([CH3:15])[C:12]2[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]3[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:17]1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2)C1CC1

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M70) (215 mg, 0.42 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (87 mg).