Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCNCC1

Procedure:
A solution of 4-ethoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester in 90% trifluroacetic acid (5 ml) was stirred for 3 h. The mixture was basified with saturated sodium bicarbonate solution and concentrated. The residue was triturated with ethylacetate (30 ml) and filtered. The filtrate was concentrated to leave piperazin-1-yl-acetic acid ethyl ester as a yellow oil (ca 1.5 g)
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([F:15])[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)C>[C:21]([O:20][C:18]([NH:17][CH2:16][C:12]1([F:15])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC1(F)CCN(C(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(F)CCNCC1
Yield: 58.2 %

Procedure:
A mixture of N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 3 of Example 15) (4.42 g, 13.1 mmol), NaOH (2.62 g, 65.5 mmol), H2O (9.00 mL) and ethanol (90.0 mL) was refluxed for 15 h and concentrated in vacuo. To the resulting residue were added water and chloroform. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the resulting solid with hexane-CH2Cl2 afforded a colorless solid 1.77 g (58%) as the titled compound.
Reaction SMILES: Cl.CN(CCCN=C=NCC)C.[C:13]([C@H:16]([CH:25]=[CH:26][CH3:27])[C@H:17]([O:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])([OH:15])=O.ON1C2N=CC=CC=2N=N1.Cl.[NH2:39][C@@H:40]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:41]([NH:43][C@@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45])=[O:42].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:54][C:52]([CH3:53])([CH3:55])[C@H:40]([NH:39][C:13]([C@H:16]([CH2:25][CH:26]=[CH2:27])[C@H:17]([O:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:41]([NH:43][C@@H:44]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH3:45])=[O:42]
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Reactant: CC=C[C@@H](C(=O)O)[C@H](OCC)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](OCC)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) was added to a stirred mixture of methyl (2S, 3R)-3-carboxy-2-ethoxy-hex-4-enoate (Preparation 7) (210 mg, 0.97 mmol) and 1-hydroxy-7-azabenzotriazole (139 mg, 1.02 mmol) in anhydrous dimethylformamide (4 mL) under nitrogen at 0° C. After 1 h, (2S)-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(276 mg, 1.02 mmol) was added, followed by diisopropylethylamine (0.18 μL, 1.02 mmol). After another 30 min, the mixture was allowed to warm to room temperature. After 17 h at room temperature, the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2×20 mL). The combined organic solutions were concentrated under reduced pressure, dissolved in ether (50 mL), washed with water (3×20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=60:40) to give methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (181 mg, 43%), as a colourless solid (single diastereomer by 1H NMR).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(C=O)cn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-ethoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-ethoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH2:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[CH:18][CH:17]=1.O>CO.CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:1](=[O:6])[CH:2]=[C:3]([CH3:5])[C:27]3[C:26](=[O:28])[N:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:24][C:23]2=3)=[CH:20][CH:21]=1
Reactant: COc1ccc(NC2=NN(c3ccccc3)C(=O)C2)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(-n2c(=O)cc(C)c3c(=O)n(-c4ccccc4)[nH]c32)cc1
Yield: 48.6 %

Procedure:
Ethyl acetoacetate (8.5 g) and acetic acid (75 ml) were added to 3-(4-methoxyphenylamino)-1-phenyl-2-pyrazolin-5-one (14 g) and refluxed while heating for 6 hours. The reaction solution was poured into 150 ml of water, and the resulting solid was dissolved in a mixture of methanol (500 ml) and acetone (150 ml) while heating. The solution was cooled to obtain 8.4 g of 7-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo(3,4-b)pyridine-3,6-dione (melting point 189°-190° C.). In a solution prepared by adding methanol (40 ml) and triethylamine (2.8 ml) to these crystals (3.47 g) was dissolved, 1,7-diphenyl-1,7-diaza-1,3,5-heptatriene hydrochloride (2.85 g), and then acetic anhydride (1.88 ml) was added thereto, and stirred at room temperature for one hour. The resulting precipitate was collected by filtration, washed with methanol and dried to obtain 5-[5-(N-acetylanilino)-2,3-pentadienylidene]-7-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo(3,4-b)pyridine-3,6 -dione (4.1 g). N,N-dimethylformamide (40 ml), 7-(4-methoxyphenyl)-4-methyl-1-phenyl- 2-pyrazolin-5-one (2.4 g) and triethylamine (0.98 ml) were added to these crystals (3.8 g), and stirred at 50° C. for 2 hours. After filtration of the reaction solution, 10-fold volume of ethyl acetate was added for crystallization. The crystals were recrystallized from acetonitrile to obtain compound II-3 (1.0 g). Melting point 260° C. (decomposed).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([F:11])[C:9]=1[F:10])=[O:4].[OH-:15].[Na+].Cl>>[F:10][C:9]1[C:8]([F:11])=[C:7]([CH3:12])[NH:6][C:5]=1[C:3]([OH:4])=[O:15]
Reactant: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c(F)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-Trichloro-1-(3,4-difluoro-5-methyl-1H-pyrrol-2-yl)ethanone (Intermediate 80; 1.03 g) was added to an aqueous solution of NaOH (18 ml) at 0° C. under N2. The mixture was stirred at room temperature for a further 2 h, cooled to 0° C. and acidified with HCl to ˜pH 2. A brown precipitate of product was collected by filtration. The crude product was purified by column chromatography on silica gel elution with EtOAc/hexanes (1:1). Trituration with DCM (1 ml)/pentane (6 ml) gave the title compound as a pale brown solid (306 mg). M.p. 140° C. (dec.). MS (ES) MH+: 160, 161 for C6H5F2NO2; NMR (CDCl3): 2.15 (s, 3H), 11.5 (s, 1H), 12.8 (brs, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: c1c[nH]cn1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCn1ccnc1)\c1nc2ccccc2o1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with Example 18 starting with (D) of Example 18 (2.5 g, 7.6 mmol) and using imidazole in place of dibutylamine to produce 1.1 g (40% yield) of the title compound as the HCl salt, mp 204°-205° C. IR(KBr): 3400, 1600 cm-1. MS: 360(MH+). 1H NMR (CD3OD): δ 9.02 (s, 1H), 7.89-6.89 (m, 12H), 4.38 (t, J=5.3 Hz, 2H), 4.08 (t, J=5.4 Hz, 2H), 1.97 (m, 4H).
Reaction SMILES: C(C1C=CC(SC[N+]([O-])=O)=CC=1)(C)(C)C.[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([S:24]CC(O)=O)=[C:19]([CH3:29])[CH:18]=1>>[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([SH:24])=[C:19]([CH3:29])[CH:18]=1
Reactant: Cc1cc(SCC(=O)O)c(C)cc1Cl
Agent: CC(C)(C)c1ccc(SC[N+](=O)[O-])cc1
Product: Cc1cc(Cl)c(C)cc1S

Procedure:
The thioether (A) was obtained as an oil having a satisfactory NMR spectrum (200 MHz/CDCl3): 2.33 (s, 3H), 2.42 (s, 3H), 5.37 (s, 2H), 7.26 (s, 1H), 7.35 (s, 1H) from (4-chloro-2,5-dimethylphenylthio)aceti acid, itself obtained from 4-chloro-2,5-dimethylbenzenethiol, in both cases using analogous procedures to those described in Example 13.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C(OC([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].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>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:33]3[CH:34]=[N:30][NH:31][CH:32]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 50 mg, 0.160 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (70.5 mg, 0.240 mmol), Pd(PPh3)2Cl2 (5.61 mg) and 2 M K2CO3 (0.216 mL, 0.423 mmol) in DME (1 mL) was stirred at 90° C. for 3 h. The Boc protecting group felt off during the course of the reaction. The mixture was diluted with EtOAc/NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/DCM/MeOH 19:1=100:0->0:100) to afford the title compound (tR 3.22 min (conditions 3), MH+=345.1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:21]>C1COCC1>[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])(=[O:3])[NH2:21]
Reactant: N
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(N)(=O)=O
Yield: 80.5 %

Procedure:
A solution of 11 g (32 mmol) of methyl 2-chlorosulfonyl-4-methanesulfonylaminomethylbenzoate in 200 ml of THF is treated at 0° C. with 1.1 g (64 mmol) of NH3 gas. For work-up, the mixture is concentrated in vacuo. Extracting the residue by stirring with water and then filtration and drying in vacuo give 8.3 g (80%) of methyl 2-sulfamoyl-4-methanesulfonylaminomethylbenzoate of melting point 185-187° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:31][CH2:32]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N[C@H]3CC[C@H](O)CC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide (42 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), trans-4-amino-cyclohexanol (23 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 506.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.82-7.64 (m, 2H), 7.47 (d, 1H), 7.36 (d, 1H), 4.57 (d, 1H), 3.81-3.68 (m, 1H), 3.64 (bs, 3H), 3.46-3.35 (m, 1H), 1.92-1.78 (m, 4H), 1.39 (q, 2H), 1.26 (q, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClCCl.N1C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>C(OCC)(=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CCOC(=O)C(N)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)Cc1ccccc1F)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.50 g (12.1 mmol) of ethyl amino(pyridin-2-yl)acetate [G. van Zyl et al., J. Org. Chem. 1961, 26, 3373] are introduced into 20 ml of dichloromethane and, after addition of 4.9 ml (60.3 mmol) of pyridine, cooled to 0° C. A solution of 1.86 g (12.1 mmol) of (2-fluorophenyl)acetyl chloride is then slowly added, and the mixture is stirred at 0° C. for 30 min and then at RT for 2 h. It is diluted with ethyl acetate, washed with sodium bicarbonate solution and dried over sodium sulfate. The crude product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1). 2.9 g (76% of theory) of the desired product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1.C=O.[C:14](O)(=O)C>O.CO>[CH3:11][N:2]([CH3:1])[C:3]1[S:4][C:5]2[CH2:14][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc(CCN)cs1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Solvent: O
Product: CN(C)c1nc2c(s1)CNCC2
Reaction time: 2.5 h
Yield: 219.2 %

Procedure:
2-Dimethylamino-4-(2-aminoethyl)thiazole (1.7 g, see preceding preparation), formaldehyde (0.78 ml of a 37% solution in water, 9.6 mmol) and acetic acid (0.15 ml, 2.6 mmol) were combined in methanol (100 ml). After 2.5 hours at room temperature, the reaction mixture was treated with additional formaldehyde (0.15 ml, 1.8 mmol) and allowed to stir for an additional 16 hours. The reaction was then filtered, and the filtrate was concentrated in vacuo and purified by column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide), providing the title product as a white solid (1.04 g, 5.7 mmol).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=3.[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]1[C:5]2[N:6]([C:2]([C:32]3[CH:33]=[C:28]([NH:27][C:24](=[O:26])[CH3:25])[CH:29]=[CH:30][CH:31]=3)=[CH:3][N:4]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=2
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(Br)cnc12
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1cccc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
To a solution of 3-(1-Bromo-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (375 mg; 0.96 mmol; 1 eq) in a mixture of 1,2-dimethoxyethane and water (3.4 mL/1.4 mL), 3-acetamidophenylboronic acid (242 mg, 1.35 mmol; 1.4 eq) is added under argon followed by potassium carbonate (266 mg; 1.93 mmol; 2 eq) and tetrakis(triphenylphosphine)palladium (89 mg; 0.08 mmol; 0.08 eq). The solution is allowed to stir for 17 hours at 90° C. until the reaction is complete on TLC. The crude mixture is cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (10 mL). The resulting organic phase is dried over sodium sulfate, filtered and concentrated under vacuum to afford a grey powder. This solid is passed through two successive columns (eluent column 1: ethyl acetate 100%; eluent column 2: methylene chloride/methanol 9:1) to afford the title compound as an off-white powder (256 mg; 0.58 mmol; 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[OH-].[K+]>O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 67.8 %

Procedure:
A mixture of 0.5 mole each of p-nitrochlorobenzene (79.0 g), p-hydroxyanisole (62.0 g), and potassium hydroxide (33.0 g, 86% pure), in 100 ml water was heated at 140° C. for about 3.5 hours. The resulting solid, collected by filtration, had a melting point of 100°-107° C. Reactants were further removed from the crude product by steam distillation, and the remaining solid was washed with copious amounts of water to afford a brown, granular mass of 4-methoxy-4'-nitrodiphenyl ether (83 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[C:34]1([C:43]2[CH:48]=[CH:47]C=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:37](C(O)=O)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20]([C:21]4[CH:45]=[CH:44][C:43]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:48][CH:47]=4)=[O:22])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), [1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate and isopropyl ether (1:5), to give the titled compound (36.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1=c2cnc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of Example 69e (0.02 g, 0.053 mmol), triethylamine (53.6 mg, 0.53 mmol), and acetyl chloride (0.019 mL, 0.265 mmol) in dichloromethane (2 mL) was stirred at ambient temperature for 2 hours. Additional acetyl chloride (0.057 mL, 0.795 mmol) and triethylamine (161 mg, 1.59 mmol) were added, and the reaction mixture was stirred for additional 3 hours. The solvent was evaporated, and the residue was treated with dioxane (3 mL) and 2.0 NaOH (1 mL). The reaction mixture was heated at 80° C. for three hours. The solvents were partially removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC(C18, CH3CN/water (0.1% TFA), 0-100%) to afford 0.018 g (67.3%) of the title compound as the TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (d, J=5.8, 1H), 10.31 (s, 1H), 8.53 (d, J=2.75 Hz, 1H), 8.42 (d, J=2.44 Hz, 1H), 7.74 (s, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.03-7.07 (m, 2H), 6.57-6.60 (m, 2H), 4.65 (br s, 2H), 4.07 (s, 3H), 2.13 (s, 3H). MS (DCI+) m/z 420.2 (M+H)+.