Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)CC>[Cu].C1(C)C=CC=CC=1>[Cl:13][C:11]1[CH:12]=[CH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[F:14]
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [Cu]
Solvent: CCC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Cl)c(F)c1
Temperature: 135 °C
Yield: 68.5 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with ethyl 2,4-dichloro-5-fluorobenzoate (5.09 g, 21.4 mmol) and copper powder (2.72 g, 42.8 mmol). Propionic acid (10 mL) was added, and the resulting mixture was heated to 135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (5 hours). Toluene (25 mL) was added as the reaction was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with toluene. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum to give 2.97 g of ethyl 4-chloro-3-fluorobenzoate as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C([O-])(=O)C.[NH4+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Yield: 92.2 %

Procedure:
Reaction of 2-chloronitrobenzene (10 g, 63 mmole), 4-methoxybenzylamine (52.1 g, 380 mmole) and ammonium acetate (4.6 g) substantially as described in 1C above producted 15 g (100%) of title compound as orange crystals: mp 75°-78°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:13]1([CH2:14][CH3:15])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH3:22]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Yield: 67.6 %

Procedure:
A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, 12 mmol), and p-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80° C. 1H NMR (300 MHz, CDCl3) δ 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (−) MS m/e=286 (MH−).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][N:13]=[CH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])=[C:4]([F:21])[CH:3]=1.[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:25](=[O:26])[C:24]([C:22]#[N:23])=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=[N:13]2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2ncc(C(F)(F)F)c(C#N)c2=O)c(F)cc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
After 4.345 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone) was dissolved in 20 mL of pyridine, 2.1 mL of ethyl cyanoacetate was added to the pyridine solution, which was followed by stirring for 4 hours at 120° C. After cooling to room temperature, the reaction solution was poured into 3N-hydrochloric acid and extracted with diethyl ether. After the organic layer was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane=2/8) to afford 2.858 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-5).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C[O:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:32]([CH:34]3[CH2:36][CH2:35]3)([OH:31])[O:22][N:21]=2)=[CH:9][CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=NOC(O)(C3CC3)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture consisting of Example 1, Compound B (3.0 g) in anhydrous tetrahydrofuran (14 mL) at −5° C. under a nitrogen atmosphere is added a solution consisting of 1.6 M n-butyllithium in hexanes (12 mL.) The mixture is stirred between −5 and 0° C. for 30 minutes. To the stirring mixture at 0° C. is added a mixture consisting of cyclopropanecarboxylic acid methyl ester (1.3 g) in tetrahydrofuran (7 mL) and the resultant mixture is stirred for two hours. The mixture is raised to room temperature and is stirred for 18 hours. The mixture is then treated with saturated aqueous ammonium chloride (50 mL) and diluted with ethyl acetate (300 mL.) The organic layer is separated and is washed sequentially with an additional portion of saturated aqueous ammonium chloride (50 mL) and brine solution (50 mL.) The organic layer is separated and is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with dichloromethane then with a mixture of hexanes-ethyl acetate (4:1 v/v) afforded the synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-cyclopropyl-4-phenyl-4,5-dihydro-isoxazol-5-ol (1.15 g.)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:24])[C:14](/[CH:16]=[C:17]1\[CH2:18][NH:19][CH2:20][CH2:21][CH:22]\1[OH:23])=[O:15].[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28](Br)[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28]([N:19]1[CH2:20][CH2:21][CH:22]([OH:23])/[C:17](=[CH:16]/[C:14](=[O:15])[N:13]([CH3:12])[CH3:24])/[CH2:18]1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: CN(C)C(=O)/C=C1\CNCCC1O
Reactant: COC(=O)C(Br)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1Cl)N1CCC(O)/C(=C/C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
7.95 g (23.3 mmol) of the (E)-3-(N,N-dimethylcarbamoyl)methylidene-4-hydroxypiperidine p-toluenesulfonate were dissolved in 50 ml of N,N-dimethylformamide (DMF), followed by the addition of 7.35 g (purity: 80.0%, 22.3 mmol) of 2-chloro-α-methoxycarbonylbenzyl bromide and 7.40 g (53.5 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, 150 ml water were added. The resulting mixture was extracted with toluene and ethyl acetate. The extract was distilled under reduced pressure. The residue was then purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=9/1 to 4/1), whereby 6.38 g (77.9%) of the title compound were obtained as a yellowish brown oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13]1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2H-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane: n-heptane (5:1) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluting with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][C:3]=2[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1cnn(-c2cc(C#N)ccn2)c1O
Reactant: OCc1ccc(F)cc1
Product: Cc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-4-methylpyrazol-1-yl)pyridine-4-carbonitrile and 4-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (300 MHz, CDCl3): δ 1.91 (3H, s), 5.14 (2H, s), 7.26 (2H, s), 7.33-7.37 (3H, m), 7.46 (1H, s), 7.99 (1H, s), 8.62 (1H, d, J=5.1 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylate (Step 55.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.59 min (HPLC 1); tR: 1.06 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=1[CH2:34][CH2:35][CH3:36])[C:9]=2[CH2:37][CH2:38][CH3:39])([O:3][CH2:4][CH3:5])=[O:2].C(O)C>O1CCCC1.[Ni]>[C:1]([CH:6]1[CH2:15][CH:14]([OH:16])[C:13]2[C:8](=[C:9]([CH2:37][CH2:38][CH3:39])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OCC)CC3O)ccc(C(C)=O)c1O
Reaction time: 24 h
Yield: 50 %

Procedure:
The compound of Example 2, 14.3 g (0.027 mole), was dissolved in 150 ml tetrahydrofuran and 150 ml ethyl alcohol and hydrogenated using Raney Nickel (4.2 g) at 2 psi. After 24 hours at room temperature, the catalyst was separated by filtration and the solvent stripped to give crude (14.4 g oil). 2.4 of the crude was chromatographed (50% ethyl acetate-hexane) to give 1.4 g (50% yield based on crude taken) of the title compound as an oil. Calc: C, 68.61; H, 7.80. Found: C, 68.34; H, 7.74.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([N:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])[C:7]([F:17])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23].[F-].[K+]>CS(C)=O>[C:4]([C:3]1[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:9][C:8]([N:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])=[C:7]([F:17])[CH:6]=1)#[N:5]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: CN(CC(C)(C)C)c1nc(Cl)c(C#N)cc1F
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(F)cc2C#N)c1
Temperature: 150 °C
Yield: 4 %

Procedure:
A mixture of 2-chloro-6-[(2,2-dimethyl-propyl)-methyl-amino]-5-fluoro-nicotinonitrile (120 mg, 0.47 mmol), 3-amino-N-methoxy-4-methyl-benzamide (120 mg, 0.66 mmol) and potassium fluoride (30 mg, 0.51 mmol) in DMSO (1 mL) was heated to 150° C. overnight. The reaction mixture was allowed to cool down to room temp and then partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (7.5 mg, 4%) was obtained after purification by silica gel chromatography with 30% EtOAc in hexane as eluent. C21H26FN5O2 MS m/e=400 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]#[N:15])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCn1cc(C#N)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.3 %

Procedure:
To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH2Cl2 (40 mL) is added a 1M solution of BBr3 in CH2Cl2 (28.5 mL, 28.5 mmol) at 0° C. The mixture is allowed to warm to room temperature and kept for 2.5 h. The dark reaction mixture is then poured onto ice and sufficient 1M NaOH is added until the pH is 8-9. The product is extracted with CH2Cl2 (3×) and the combined organic phases are washed with saturated NaHCO3, H2O and saturated NaCl. After drying over MgSO4, the solution is concentrated and the product is purified by chromatography (EtOAc/CH2Cl2, 0-10%) to afford 2.15 g (82%) of 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:24]([NH:25][C:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:16])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: NCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 2-phenylethylamine.
Reaction SMILES: [CH2:1](C1C2C(=CC=CC=2)NC=1)[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(O[CH2:28][CH3:29])(OCC)OCC.S(=O)(=O)(O)O>CO>[CH:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]3[CH:1]=[C:2]4[C:3](=[N:4][C:5]5[C:10]4=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:29]=[C:28]3[C:6]=12
Reactant: CCOC(OCC)OCC
Reactant: c1ccc2c(Cc3c[nH]c4ccccc34)c[nH]c2c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: c1ccc2c(c1)N=c1cc3c(cc1-2)=Nc1ccccc1-3
Temperature: 25 °C
Yield: 139.7 %

Procedure:
In a 2,000-ml three-necked flask that had been deaerated and filled with nitrogen were placed 50.69 g (205.8 millimoles) of 3,3′-methylenediindole and 30.55 g (206.1 millimoles) of triethyl orthoformate, then 640 g of methanol was added, and the mixture was stirred. To this mixture was added dropwise 5.0 g (51.5 millimoles) of concentrated sulfuric acid over 3 minutes and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature and the reddish-brown crystals formed were collected by filtration and washed twice by reslurrying in 500 ml of methanol. The solvent was stripped off under reduced pressure and 36.8 g (143.8 millimoles, 69.9% yield) of indolo[3,2-b]carbazole was obtained as a reddish-brown powder.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:18])(=O)C.[OH-].[Na+]>Cl>[CH3:18][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][NH2:4])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)NCCCCn1c(C)nc2cnccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cnccc2n1CCCCN
Yield: 85.6 %

Procedure:
N-Acetyl-4-(2-methylimidazo[4,5-c]pyrid-1-yl)butylamine (1 g) was dissolved in 2M hydrochloric acid (100 ml) and heated at reflux for 8 hours. The solution was basified to pH8 with 2M sodium hydroxide solution and then extracted with methylene chloride using a continuous extractor. The organic extract was evaporated under vacuum to give the title product, (0.71 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2Cl2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Cl2 (40 mL) at 0° C. The resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40° C. to afford N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205° C.; 1H-NMR (DMSO-d6) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)+).
Reaction SMILES: N[CH:2]1[N:6]2[C:7](=[O:20])[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:5]2[C:4]2[S:21][CH:22]=[CH:23][C:3]1=2.O>C(O)(=O)C.[Zn]>[O:20]=[C:7]1[N:6]2[CH2:2][C:3]3[CH:23]=[CH:22][S:21][C:4]=3[C:5]2=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=[C:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1c2ccsc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1C2
Yield: 97.3 %

Procedure:
A suspension of 45.7 g of 4-amino-4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]pyrrolo[1,2-a]pyridine-9-carboxylic acid in 915 ml of acetic acid was treated with 27.6 g of zinc powder and heated to boiling under reflux for 2 hours. The suspension was then cooled and poured into 3,000 ml of water. The excess zinc was for the most part removed by decantation. The separated crystals were filtered off under suction and dried in a vacuum. There was obtained 42.4 g of 4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]-pyrrolo[1,2-a]pyridine-9-carboxylic acid with a m.p. of >300° (purity 85-90%). This material was purified further by recrystallization from methanol/N,N-dimethylformamide.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:10]S(O)(=O)=O.N([O-])=O.[Na+]>O>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:10])=[CH:7][N:6]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 5-amino-2-cyano pyridine (1.0 g, 8.38 mmol), conc. H2SO4 (4.2 mL), water (15 mL) and the mixture was cooled to 0° C. A solution of NaNO2 (636 mg, 9.22 mmol) in water (5.7 mL) was added slowly at 0° C. Then the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was poured into a boiling mixture of water (11 mL) and H2SO4 (1 mL) and stirred for 30 min. The mixture was cooled and extracted with EtOAc. The organic layer was washed with water, dried and concentrated to give 2-cyano-5-hydroxy pyridine (900 mg, 89%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(OCC)(=O)C.[ClH:28]>C(OCC)C>[ClH:28].[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, 1-Boc-4-[2-(4-pyridinyl)ethyl]piperazine (1.0 g, 3.43 mmol) was dissolved in ethyl ether. Ethyl acetate (15 mL) saturated with HCl was added, and the mixture stirred for 30 min at room temperature. The mixture was concentrated under vacuum and provided 1-[2-(4-pyridinyl)ethyl]piperazine hydrochloride (900 mg, 87%) as a tan solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:12])[CH2:10][CH2:9]1.Cl>ClCCl>[C:14]([CH:13]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:12])[C:17]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([F:27])([F:29])([F:25])([F:26])[F:28])=[CH:22][CH:23]=1)=[O:16])#[N:15]
Reactant: O=C(c1cnoc1-c1ccc(S(F)(F)(F)(F)F)cc1)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1

Procedure:
Triethylamine (0.73 g) was added to a stirred solution of 4-cyclopropylcarbonyl-S-(4-pentafluorosulphanylphenyl)isoxazole (Compound 2, 0.4 g) in dichloromethane. After 16 hours the solution was washed (2M hydrochloric acid), dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography eluting with ethyl acetate/hexane to give a residue which was suspended in dichloromethane and shaken with hydrochloric acid until dissolved. The organic phase was evaporated and triturated with hexane to give 2-cyano-3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)propan-1,3-dione as a white solid (Compound 3, m.p.108-110° C.