Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1)=[O:27]
Reactant: [OH-]
Reactant: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(S(=O)(=O)NCCC2CCC(CC(=O)O)CC2)cc1
Yield: 72 %

Procedure:
by saponification of the ethyl 4-[2-(4-cyanobenzenesulphonylamino)-ethyl]-cyclohexylacetate with 2N sodium hydroxide solution in ethanol analogously to EXAMPLE 2c). Yield 72% of theory; m.p. 172-174° C. after recrystallisation from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24](C)[CH:23]=[C:22]4[CH:27]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:27][NH:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: CC(N)CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CC(=O)O)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (200 mg), 3-aminobutanoic acid (103 mg) and acetic acid (32 mg) in DCM (10 mL) was added NaBH(OAc)3 (223 mg). The reaction was stirred at 40° C. for 24 h. After cooled to room temperature, the mixture was diluted with DCM (10 mL), washed with water (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulphate, evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 3-({[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}amino)butanoic acid (E51) (55 mg, as TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (9H, m), 2.57 (1H, m), 2.91 (1H, dd), 3.57 (1H, m), 4.46 (2H, s), 4.91 (1H, m), 7.33 (1H, t), 7.47 (1H, d), 7.72 (1H, d), 8.03 (1H, d), 8.05 (1H, d), 8.22 (1H, dd), 8.39 (1H, d), 11.37 (1H, s), 12.81 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:29])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:15]=1)[N:6]=[C:5]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2.Br[CH2:48][CH2:49][Cl:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:50][CH2:49][CH2:48][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:29])[CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:15]=1)[N:6]=[C:5]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2
Reactant: ClCCBr
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C

Procedure:
A mixture of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.330 g, 0.527 mmol), 1-bromo-2-chloroethane (0.287 g, 2.00 mmol) and K2CO3 (0.330 g, 2.39 mmol) in DMF (3 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool to RT, upon which it was diluted with water (200 mL) and the resulting precipitate was collected via filtration. The solid was taken up in EtOAc (250 mL) and washed with water (1×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give tert-butyl 5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which was used without further purification (0.300 g, 0.436 mmol, 83%). HPLC retention time 5.842 mins.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:19]([O:18][CH3:17])[CH:20]=2)[N:7]=1
Reactant: Clc1ccc(Cc2nc(Cl)nc(Cl)n2)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(Cl)nc(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
2,4-Dichloro-6-(4-chloro-benzyl)-[1,3,5]triazine (0.78 g, 2.8 mmol) was added at 5° C. to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (0.61 g, 3.0 mmol) and triethylamine (0.36 ml, 0.26 mmol) in 15 ml of methanol. The mixture was stirred at 5° C. for 1 h and thereafter evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-100% ethyl acetate as eluent to give the title compound (0.53 g, 40%) as a yellow viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)CCC>[CH3:11][N:12]([CH2:14][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)[CH3:13]
Reactant: CNC
Reactant: C=O
Reactant: c1cc2[nH]ccc2cn1
Agent: Cl
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2ccncc12
Yield: 39 %

Procedure:
A solution of 5-azaindole (1.19 g, 10.0 mmol), dimethylamine hydrochloride (0.98 g, 12.0 mmol) and paraformaldehyde (0.36 g, 12.0 mmol-equivalents) in 1-butanol is heated at reflux temperature for 5 h and concentrated in vacuo. The concentrate is diluted with saturated aqueous NaHCO3 and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4, concentrated in vacuo and filtered. The filtercake is air-dried to afford the title compound as a yellow solid, 0.680 g (39% yield), identified by NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:23]=[C:24]([CH2:28][C:29](O)=O)C(O)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH:18]1([O:17][C:11]2[CH:10]=[C:9]([N:8]3[C:24](=[O:23])[C:28]([CH3:29])=[N:1][C:2]4[CH:7]=[CH:6][CH:5]=[N:4][C:3]3=4)[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Reactant: O=C(O)CC(=O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2c(=O)c(C)nc3cccnc32)cc1OC1CCCC1
Yield: 47.3 %

Procedure:
A mixture of 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (180 mg) and 2-oxosuccinic acid (90 mg) in ethanol (4 ml) was stirred under reflux for 1.5 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with ethanol to give 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[OH-].[K+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)OC)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(F)cc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of ester (5) (300 mg, 0.78 mmol) in methanol (25 mL) and THF (8 mL) was added 1N KOH (12 mL, 12 mmol). After stirring overnight the solvent was partially removed under reduced pressure, the mixture was acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and were dried (MgSO4). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 5% methanol/CH2Cl2) to give the acid (6) as a white solid (270 mg, 93%): 1 H NMR (CDCl3) δ 7.60 (d, J=15.8 Hz, 1 H), 7.13 (m, 11 H), 6.87 (d, J=8.5 Hz, 2 H), 6.28 (d, J=15.8 Hz, 1 H), 2.47 (q, J=7.3 Hz, 2 H), 0.93 (t, J=7.3 Hz, 3 H); APcI m/z: 414 (M+H+CH3CN+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:18][CH:19]=1
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 3.5 °C
Yield: 89.4 %

Procedure:
A mixture of (S)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide (IIIa) (150 g), prepared as described in Example 16a), and methanol (900 mL) is cooled under stirring to 2-5° C. Sodium borohydride (19.0 g) is added in small portions in 2 hours to the previously prepared cold mixture keeping the temperature below 5° C. The mixture is then stirred for additional 20 min at 5° C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to give 135 g (89.2% yield) of (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (Ia) with a HPLC purity of 98.8 (area % determined according to the method of Example 25A and a C,O-dialkylated (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide content of 0.005% by weight determined by HPLC, according to the method of Example 25B.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH3:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:17][C:16]1[N:13]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[O:12][CH:15]=1
Reactant: CC(=O)CBr
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1coc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (15.0 g), 1-bromo-2-propanone (19.03 g), and N,N-dimethylformamide (2 mL) was stirred at 120° C. for 3 hrs. Water, potassium carbonate and ethyl acetate were added to basify the reaction mixture and the mixture was extracted with ethyl acetate. Insoluble materials were filtered off, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-methyl-2-(4-nitrobenzyl)-1,3-oxazole as orange crystals (1.50 g, yield 8.2%) from a fraction eluted with hexane-ethyl acetate (2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 67-68° C.
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([C@@H:9]([NH:20][C:21]([NH2:23])=[S:22])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O.[CH3:36]C#N>>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:26][C:25]1[N:23]=[C:21]([NH:20][C@H:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[S:5][CH:6]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:22][CH:36]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CC#N
Reactant: NC(=S)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(C2CC2)n1
Product: COc1cccc(Cc2csc(N[C@@H](Cc3ccc([N+](=O)[O-])cc3)c3csc(C4CC4)n3)n2)c1

Procedure:
(S)-1-(1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea, 32, (350 mg, 1.00 mmol) and 2-bromo-3′-methoxy-acetophenone (253 mg, 1.10 mmol) are combined in 3 mL CH3CN and heated to reflux for 24 hours. The mixture is concentrated and chromatographed to afford 0.172 g of the product as a yellow solid. LC/MS ESI+479 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH:6]([CH3:15])[CH2:5]2.Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][CH:6]1[CH2:5][C:4]2[C:8](=[C:9]([CH3:12])[C:10]([CH3:11])=[C:2]([O:1][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:3]=2)[N:7]1[CH:13]=[O:14]
Reactant: Cc1c(O)cc2c(c1C)N(C=O)C(C)C2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)C(C)C2
Temperature: 60 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-2,6,7-trimethyl-1H-indole-1-carbaldehyde (0.5 g, 2.4 mmol), 3-chloro-2-methyl-1-propene (0.29 mL, 2.9 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in DMF (6 mL) was stirred at 60° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel columns chromatography (hexane-ethyl acetate 3:1) to obtain 0.60 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[CH:48]=[CH:47][NH:46][C:43]3=[N:44][CH:45]=2)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.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>[CH3:12][C:8]1[C:6]2[N:7]=[C:2]([C:40]3[CH:41]=[C:42]4[CH:48]=[CH:47][NH:46][C:43]4=[N:44][CH:45]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[S:10][C:9]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2cccc(S(C)(=O)=O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.3 g, 0.8 mmol), 3-(methylsulfonyl)phenylboronic acid (0.3 g, 1.5 mmol), and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 40 μmmol) in 1 M aqueous Na2CO3 (1.5 mL) and acetonitrile (1.5 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.4 g, 1.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 40 μmol) were added into the same pot. The reaction mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 395 after reverse phase HPLC purification (82 mg). MS (Q1) 506 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH3:28].[Cl-].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[CH3:28][C:14]1[N:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[S:17][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
5-Hydroxyindole (200 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL) with the chloride 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.50 g, 1.7 mmol) and Cs2CO3 (2.37 g, 7.27 mmol) The reaction mixture was stirred at RT overnight. Ether (50 mL) and H2O were added and stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organics was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product as a white solid (0.3 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)=[O:42])[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: CC1(COc2ccc(N3CCNCC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(c3ccc(OCC4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)CC2)CC1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 2-methyl-6-nitro-2-(4-piperazin-1-yl-phenoxymethyl)-2,3-dihydro-imidazo[2,1-b]oxazole (200 mg, 0.34 mmol) and 4-carboxymethyl-piperazine-1-carboxylic acid tert-butyl ester (136 mg, 0.55 mmol) in DMF is treated with TBTU (179.8 mg, 0.55 mmol), triethyl amine (0.23 ml, 1.65 mmol) and stirred for 2 h. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by preparative TLC (10% methanol in dichloromethane to give 4-(2-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as yellow oil (152 mg, 78%). ESI MS m/z 585 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.48 (d, J=Hz), 4.18 (d, J=Hz, 1H), 4.14-4.02 (m, 2H), 3.82-3.71 (m, 4H), 3.56-3.38 (m, 4H), 2.91 (s, 2H), 2.52-2.42 (m, 4H), 1.75-1.62 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc2scnc2c1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nc3ccccc3s2)CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
To a solution of 2 mL (18.3 mmol) of benzothiazole in 20 mL of tetrahydrofuran was added 11.4 mL (18.2 mmol) of 1.6 M n-BuLi at −78° C. After 45 min, 1.6 mL (18.1 mmol) of cyclopentanone was added at the same temperature. The reaction was let warm to room temperature over 1 h. Water was added to quench the reaction and the mixture was extracted with ether (3×). The ether layer was washed with brine (3×) and dried over magnesium sulfate. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (4:1) gave 2.8 g (71%) of 1-(1,3-benzothiazol-2-yl)cyclopentanol as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 2.25 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[CH3:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)Nc2nc(CC(=O)N3CCN(CC(=O)N4CCCC4)CC3)cs2)s1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-methylthiophene-2-carboxylic acid, using general method D, to give 5-methyl-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow solid. MS 462.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(N)c1N
Yield: 97.4 %

Procedure:
2-Methyl-6-nitroaniline (15.2 g, 0.1 mol) was dissolved by heating in ethanol (150 mL). The solution was cooled, 10% palladium on carbon (1.0 g) was added and the solution was hydrogenated (50 lb initial hydrogen pressure) until uptake of hydrogen ceased (1 hour). The catalyst was filtered off and the ethanol was removed under reduced pressure to give 11.9 g (98%) of 3-methyl-l,2-benzenediamine as a solid which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C1CCN2C(=[N:15]CCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Cl)nc1
Temperature: 65 °C
Yield: 107 %

Procedure:
A solution of 4-fluoroaniline (1.00 ml, 10 mmol) and diisopropylethylamine (1.74 mL, 10 mmol) in anhydrous DMF (10 mL) was warmed to 60° C., then a solution of tert-butyl bromoacetate (1.47 mL, 10 mmol) in anhydrous DMF (10 ml) was added drop-wise over 1 hour. After addition, the reaction mixture was kept at 60° C. for 4 hours. The reaction mixture was then concentrated by rotary evaporation, then partitioned between EtOAc and water. The organic layer was washed with water, then evaporated to yield a dark brown liquid (1.96 g, 87%) TLC (EtOAc/hexanes, 1:4) Rf=0.31; ESI-MS m/z=225.9 [M+H]+. The disubstituted aniline derivative (0.41 g, 2.31 mmol) and was then coupled to 6-chloronicotinoyl chloride (0.52 g, 2.31 mmol) in anhydrous DMF (2 mL) using DBU (344 ml, 2.31 mmol). The reaction mixture was heated to 65° C. for 48 h. The reaction mixture was diluted with EtOAc, and the organic layer washed with H2O. The crude material was concentrated by rotary evaporation, and purified by flash chromatography (EtOAc/hex 1:2) to yield 387 mg (46%) of 6-chloronicotinamide intermediate XIV as a clear oil. TLC (EtOAc/hexanes, 1:2) Rf=0.28; ESI-MS m/z=364.9 [M+H]+.