Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N([O-])=O.[Na+].[Cu]C#N.[ClH:20]>C(O)(=O)C.O>[Cl:20][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: Cl
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2oc(S)nc2c1
Solvent: CN(C)C=O
Product: COc1ccc2oc(Cl)nc2c1

Procedure:
The mixture containing 5-methoxybenzoxazole-2-thiol was heated in thionyl chloride with a drop of DMF. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried and concentrated. Purification on a silica gel column gave 2-chloro-5-methoxybenzoxazole as a white solid. MS: MH+=184.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)[C:26]([OH:28])=[O:27])=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)OC)c3)cn2)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)O)c3)cn2)C1
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a solution of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoate (60 mg, 0.11 mmol) in THF:H2O (1:1, 5 mL) at 20-25° C. was added LiOH.H2O (15 mg, 0.34 mmol). The mixture was stirred for 18 hours, and then was concentrated under reduced pressure. The resulting residue was diluted with water (5 mL) and washed with ethyl acetate (3 times with 5 mL). The aqueous layer was acidified to pH 2 with 1N HCl (5 mL), and then was extracted with ethyl acetate (3 times with 5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoic acid (40 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.91 (m, 1H), 8.78 (s, 2H), 7.49 (s, 1H), 7.34 (s, 1H), 7.02 (m, 2H), 6.89 (m, 3H), 4.45 (d, 2H), 4.32 (m, 1H), 4.20 (d, 1H), 3.91 (m, 5H), 3.78 (s, 3H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 507.1 (M+H).
Reaction SMILES: [NH3:1].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])=[CH2:4].[Cl-].[NH4+]>CCOCC>[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:1])(=[O:13])=[O:12])=[CH2:4]
Reactant: N
Reactant: C=C(C)c1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)c1ccccc1S(N)(=O)=O
Yield: 101.4 %

Procedure:
A solution of anhydrous ammonia (1 ml, 40 mmol) in ether (25 ml) was cooled to 0° and to this was added 2-(1-methylethenyl)benzenesulfonyl chloride of Example 13 (2.9 g, 13 mmol). After stirring for 2 hours at 0° to 5° the ammonium chloride was removed by filtration of the filtrate concentrated to an oil which crystallized on standing to give 2.6 g of the title compound, m.p. 76°-85°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br.[H][H]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: [H][H]
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above-prepared 2-(3,5-dimethoxyphenyl)-5-(p-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen gas (approximately one-half hour). The reacion was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(-p-fluorophenylpentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:18][C@H:19]1[C@@H:23]([F:24])[CH2:22][NH:21][CH2:20]1>>[F:18][C@H:19]1[C@@H:23]([F:24])[CH2:22][N:21]([C:10]([C@@H:9]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])[CH2:20]1
Reactant: F[C@@H]1CNC[C@@H]1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1C[C@@H](F)[C@@H](F)C1
Yield: 67.1 %

Procedure:
(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.31 g, 10 mmol), was coupled with (3R,4S)-rel-3,4-difluoropyrrolidine hydrochloride (1.44 g, 10 mmol, Preparation 4), in a manner analogous to that described in Preparation 1, Step 1, to afford 2.15 g (67%) of the title product as an off-white foam. MS m/z 321 (MH+).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36].[CH2:41](I)[CH3:42]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:41][CH3:42])[C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCI
Reactant: CCCC(CCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)OC(=O)N(CC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 1-propylbutyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 75%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=3[N:15]=[C:14](N)[C:13]=2[N:12]=[C:11]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Product: CCCCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 83.2 %

Procedure:
tert-Butyl[2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl{2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:30]([NH2:33])[CH2:31][CH3:32].[BH4-].[Na+]>CO>[CH2:30]([NH:33][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)[CH2:31][CH3:32]
Reactant: O=C1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Reactant: CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNC1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of N-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(piperidon-4-yl)methyl]urea (50 mg, 0.12 mmol, Example 175) in MeOH (10 mL) was added propylamine (0.1 mL, 1.22 mmol). The resulting mixture was heated at 50° C. for 4 h under N2. After the mixture was cooled to RT, NaBH4 (83 mg, 2.20 mmol) was added. The mixture was stirred at RT under N2 for 3 h. Solvent was removed in vacuo and the crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH (90:10) gave the title compound as a white solid. MS m/z: 451.7 (M+H). Calc'd. for C23H29N7OS-451.6.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[CH:11]=2)[CH:2]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example 28, 65 mg of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[3-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 7 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].NN>[Pd].C(O)C>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:24]#[N:25])=[C:11]2[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
Added 0.5 g 10% palladium on carbon to a flask under N2 and covered with 250 ml ethanol. To this added 4.818 g (14.5 mmol) 4-[(3-isopropylphenyl)amino]-6-nitro-3-quinolinecarbonitrile and 1.14 ml (36.2 mmol) anhydrous hydrazine and heated to reflux. At 1.5 hours, filtered hot mixture through celite, stripped solvent, and dried in vacuo, giving 4.30 g of yellow solid: mass spectrum (electrospray m/e): M+H=303.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([CH:12](C(C)(C)C(C)C)O[SiH](C)C)=[CH:5]2.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([CH3:35])[N:7]2[C:8]3[CH:9]=[C:10]([F:11])[C:2]([Br:1])=[CH:3][C:4]=3[CH:5]=[C:6]2[CH2:12]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1cc2cc(Br)c(F)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3cc(Br)c(F)cc3n21

Procedure:
The title compound, ISP-MS: m/e=383.2 ([M+H]+) and m.p. 116-118° C., was prepared in accordance with the general method of example 26b) and c) from 5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-fluoro-1H-indole and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7](=O)[C:8](=[O:10])[CH3:9]>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:8](=[O:10])[CH3:9])[N:4]=1
Reactant: CC(=O)C(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.1 %

Procedure:
To a solution of thiourea (6.79 g, 89.2 mmol) in absolute ethanol (100 mL) was added 1-chloro-butane-2,3-dione (prepared as described by Bonnema, J. et al., Rec. Trav. Chim. Pays-Bas 1960, 79, 1137) (10.75 g, 89.2 mmol) and the mixture stirred at room temperature for 72 hours. The dark brown suspension was concentrated in vacuo, the residue taken up in water (350 mL), acidified with 1M aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (2×100 mL). The aqueous layer was then neutralized with solid sodium bicarbonate to form a light brown solid which was isolated by filtration. The precipitate was washed with 1:1 hexanes/ether (100 mL), 1:1 hexanes/ethyl acetae (100 mL) and then dried in vacuo over potassium hydroxide to give 1-(2-amino-thiazol-4-yl)-ethanone as a light brown solid (9.91 g, 78%).
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.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: COc1ccccc1C=O
Product: COc1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methoxybenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[Br:27]Br.O>C(O)(=O)C>[Br:27][C:3]1[C:4]([OH:26])=[C:5]([CH:24]=[O:25])[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]=1[CH3:1]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)c(Br)c(O)c(C=O)c1O2
Temperature: 25 °C

Procedure:
To a solution of psoromic acid (1 mmol) in glacial acetic acid (5 ml) was dropwise added a solution of bromine (3 mmol, 0.15 ml) in glacial acetic acid (3 ml). After stirring at room temperature for several hours, the redbrown reaction mixture was poured into water (50 ml), extracted with ethyl acetate (100 ml), dried with MgSO4, filtered, and evaporated by a rotatory evaporator to give a redbrown solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.CN(C)C=O>[C:7]1([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-n2cncn2)cc1
Yield: 93 %

Procedure:
Using the general procedure, 1,2,4-triazole (0.069 g, 1.00 mmol) was coupled with iodobenzene (134 μL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %) and dimethylformamide (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 3:1) provided 0.135 g (93% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ8.58 (s, 1H), 8.10 (s, 1H), 7.66 (m, 2H), 7.47 (m, 2H), 7.37 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([CH3:6])[C:3](=[NH:5])[CH3:4].[C:12]1([CH3:29])[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:13]=1.CCCCCC>C(OCC)C.COCCOCCOC>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:2]([C:3]1[N:5]=[C:24]([OH:25])[C:18]([C:14]2[CH:13]=[C:12]([CH3:29])[CH:17]=[CH:16][CH:15]=2)=[C:19]([OH:20])[CH:4]=1)([CH3:1])[CH3:6]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(C)c1
Reactant: CC(=N)C(C)(C)c1cccs1
Solvent: CCOCC
Solvent: COCCOCCOC
Solvent: CCCCCC
Product: Cc1cccc(-c2c(O)cc(C(C)(C)c3cccs3)nc2O)c1
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 2a (0.83 g, 5.5 mmol) in anhydrous diethyl ether (5 mL) was added under argon 1.6M methyl lithium in diethyl ether (21 mL, 33.00 mmol) and the mixture was stirred for 3 hrs. at room temperature. After quenching with water, the mixture was extracted with diethyl ether. The extracts were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to afford a colorless oil (0.86, 95%). A solution of the intermediate product (3-methyl-3-(thiophen-2-yl)butan-2-imine; 0.73 g, 4.36 mmol) and diethyl 2-m-tolylmalonate (0.70 g, 4.36 mmol) in 1 mL diglyme was refluxed at 135° C. for 3 hours. The reaction mixture was cooled and poured into hexane to afford a yellow precipitate, which was collected and crystallized from ethyl acetate/hexane mixture. Off white powder, Yield: 52% MS: (ESI, Neg) 323.90 (M−1) 1HNMR (500 MHz, DMSO-d6): ∂(ppm) 10.69(s, 1H), 10.19(s, 1H), 7.46(d, 1H), 7.11-7.19(m, 3H), 6.99-7.05(m, 3H), 5.78(s, 1H), 2.28(s, 3H), 1.72(s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[S:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[S:33][CH:34]=3)[CH:21]=[CH:20][CH:19]=2)=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)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: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cs1

Procedure:
A mixture of 3-bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol in 2.4 mL DME), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL), and (Ph3P)4Pd (8 mg, 6.94 μmol) in a sealed vial were subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated to dryness under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=2.37 min, m/z=422.3 [M+H]+.