Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1ccc(Cl)cc1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NCC1OCCO1
Reaction time: 26 h

Procedure:
2-Methyl-5-chloroaniline (75 grams), 2-chloromethyl1,3-dioxolane (25 grams), potassium carbonate (22 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 26 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-methyl-5chloroaniline having a boiling point of 116° to 118°C at 0.1 mm of Hg pressure.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)[CH:7]=1.S(=O)(=O)(O)[OH:27].N([O-])=O.[Na+].NC(N)=O>O.S([O-])([O-])(=O)=O.[Cu+2].C(OCC)(=O)C>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([OH:27])[CH:3]=[CH:4][C:5]=2[CH3:25])[N:10]=1)=[O:24]
Reactant: Cc1ccc(N)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(O)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To N-{1-[(5-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 48) (0.312 g, 0.911 mmol) in an ice-water bath was added sulphuric acid specific gravity 1.84 (3 ml, 56.3 mmol). To the stirred suspension was slowly added water (5 ml). To the slight suspension was added a solution of sodium nitrite (0.132 g, 1.91 mmol, Aldrich) in water (1 ml). The solution was maintained at 0-5° C. for 20 min. To the solution was added urea (0.350 g, 5.83 mmol, Aldrich) and then copper (II) sulphate (50 mg, 0.313 mmol, Fluka). The mixture was heated to 90° C. for 30 min. The mixture was allowed to stand at ambient temperature overnight. The mixture was diluted with water (100 ml) and then ethyl acetate (50 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (25 ml). The combined organic extracts were concentrated in vacuo to leave a brown gum (0.3 g). The residue was loaded in dichloromethane and purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (206 mg); LCMS (System 4) MH+=344, tRET=2.36 min.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:14]([CH3:22])=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:19][C:16]1[N:15]=[C:14]([CH3:22])[C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:23])[CH3:1])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A mixture of 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (5.2 g, 16.4 mmol) in MeOH (60 mL) and THF (60 mL) was treated with NH4Cl (26.3 g, 492 mmol) and stirred vigorously at RT. Zinc dust (10.72 g, 164 mmol) was added portion-wise and the mixture was stirred at RT for 2 h. Additional portions of NH4Cl (5 g, 93 mmol) and zinc dust (1 g, 15 mmol) were added and stirring was continued overnight. The mixture was diluted with EtOAc and filtered. The filtered solids were washed with EtOAc. The combined filtrates were further filtered (2×) and concentrated to dryness. THF (150 mL) and thiol-modified silica gel (1.4 mmol/g loading, 22 g, 31 mmol) were added and the mixture was stirred at RT overnight. The solids were removed by filtration and washed with THF. The combined filtrates were concentrated to dryness to give 3-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (4.54 g, 96%) as a foam. MS (ESI) m/z: 288.1 (M+H+).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][Si](C)(C)N[Si](C)(C)C.C[Si](Cl)(C)C.CI>C(O)(=O)C>[CH3:10][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)O
Solvent: CI
Product: Cc1cn(C)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Thymine (2.0 g, 16 mmol), hexamethyl-disilazane (32 mL) and trimethyl silylchloride (4.1 mL) were added in 100 mL mad apple-type flask with a magnetic stirrer and allowed to stir for 17 hr. at 140° C. until the reaction solution became transparent. After the reaction solution was cooled to 60° C., the solution was added with methyl-iodide (10 mL) and was allowed to stir for 29 hr. at 60° C. Then, the reaction solution was added with 6 N aqueous acetic acid solution (6 mL×10) and subjected to evaporation under reduced pressure. The residues were dissolved by the addition of 2-propanol and insolubles were filtered out. The filtrate was added with ethanol-water mixture. The object was recrystallized in ethanol-water mixture to give white solids (1.6 g, yield, 72%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:16][CH3:17])[N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[CH3:17][NH:16][C:13]1[N:14]([CH3:15])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=1
Reactant: N
Reactant: CNc1nc2c(Cl)nc3ccccc3c2n1C
Solvent: CO
Product: CNc1nc2c(N)nc3ccccc3c2n1C
Temperature: 145 °C

Procedure:
4-Chloro-N,1-dimethyl-1H-imidazo[4,5-c]quinolin-2-amine (0.280 g, 0.88 mmol) and ammonia (15 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 145° C. for two days. An analysis by LC/MS indicated the presence of starting material, and heating at 145° C. was continued for a total of two weeks. The solvent was removed under reduced pressure, and the residue was purified by automated flash chromagraphy (silica cartridge, eluting with 1-20% methanol in dichloromethane with 1% aqueous ammonium hydroxide added) to provide 153 mg of N2,1-dimethyl-1H-imidazo[4,5-c]quinoline-2,4-diamine.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][NH2:10])([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4]1.C([O-])(=O)C.[Na+].[Cl:16][Pt-2:17](Cl)(Cl)[Cl:18].[K+].[K+]>O>[C:3]1([CH2:9][NH2:10])([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4]1.[Pt:17]([Cl:18])[Cl:16]
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: NCC1(CN)CCC1
Solvent: O
Product: Cl[Pt]Cl
Reaction time: 8 h

Procedure:
A solution of 1.87 g of the above amine in 30 ml of water was treated with 1.64 g of solid sodium acetate followed by 4.15 g of potassium tetrachloroplatinate. The mixture was stirred overnight and filtered. The filtrate was concentrated, giving as a solid 1,1-cyclobutanedimethanamine, compound with platinum chloride.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[N:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]2=[N:28][N:29]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[N:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]4=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nnc2ccccn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4ccccn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
2.72 g (0.01 mol) of 7-aminocephalosporanic acid was suspended in 18 ml of water, and a suspension of 2.1 g (0.025 mol) of sodium bicarbonate in 20 ml of water was added dropwise thereto over a period of time of 10 minutes. The inside temperature of the reactor was then increased to 50° C., and a suspension of 1.81 g (0.0125 mol) of 3-mercaptopyrido[2,1-c]-s-triazole in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 4 hours at a stable inside temperature of the reactor of 63° C. followed by ice cooling the mixture. After the inside temperature of the reactor reached 4° C., the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid. One hour after the stirring, the precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.31 g (yield: 61%) of the titled compound having a melting point (decomposition) of 173° to 175° C.
Reaction SMILES: C[O:2][C:3]1(C(O)=O)[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.[C:18]([OH:21])(=[O:20])C.Br(O)(=O)=O>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:18]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COC1(C(=O)O)C=CC(c2ccccc2)=CC1
Reactant: CC(=O)O
Agent: [O-][Br+2]([O-])O
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(O)cc1

Procedure:
A mixture of 25 g of 4-methoxybiphenyl-4-carboxylic acid, 1 1 of acetic acid and 200 ml of 48% bromic acid was refluxed for 12-14 hours and then thrown into 2.5 l of water. After cooling, the resultant crystal was collected to obtain 4'-hydroxybiphenylcarboxylic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].[OH-].OP(O)(O)=O>CO.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[C:12]([OH:14])=[O:13])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)c1cccc2cnccc12
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1cccc2cnccc12

Procedure:
4-Tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate (1.00 g, 3.04 mmol) and LiOH (0.29 g) were stirred in MeOH:H2O (3:1, 20 mL) at room temperature for 5 hours. The solution was poured into aqueous H3PO4 (0.1M, 30 mL) and extracted with CHCl3:IPA (3:1, 30 mL×3). The extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 302 (M+H)+; MS (ESI−) m/z 300 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.28 (s, 9H), 2.74 (dd, J1 16.7, J2 6.1, 1H), 3.10 (dd, J1 9.5, J2 6.1, 1H), 4.68 (dd, J1 16.7, J2 9.5, 1H), 7.70 (m, 2H), 8.05 (m, 2H), 8.57 (d, J 6.1, 1H), 9.33 (s, 1H); Anal. Calcd for C17H19NO4+1.25H2O: C, 63.05; H, 6.69. Found: C, 63.27; H, 6.95.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@H:4]([OH:6])[CH3:5].[CH:38]([Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])Cl)([CH3:40])[CH3:39].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:6][C@H:4]([CH3:5])[C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[CH2:2][O:1][Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:38]([CH3:40])[CH3:39]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
N-[(2R,3R)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.10 g, 3.93 mmol) synthesized in Example (110a) was dissolved in methylene chloride (50 mL), and triisopropylchlorosilane (1.50 mL, 7.01 mmol), 4-dimethylaminopyridine (1.50 g, 12.27 mmol) and triethylamine (5.00 mL, 35.87 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25-40%) to afford the desired compound (2.52 g, yield 93%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]([CH3:40])=[C:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>C1COCC1.O>[CH:35]1([C:34]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:40])[CH3:33])[CH:39]=[CH:38][CH:37]=[CH:36]1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CC(C)=C1C=CC=C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(C)(C)C3C=CC=C3)c1C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3.0 g(10.8 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 7.0 ml (11.3 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 6 hours. From the reaction mixture, the solvent was removed under reduced pressure, and the residue was washed with pentane and dried to obtain a white solid. To a solution of the solid in 30 ml of THF, a solution of 1.4 g (13.2 mmol) of 6,6-dimethylfulvene in 30 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring for 5 hours. Then, 30 ml of water was added. The organic phase extracted with diethyl ether and separated was dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was recrystallized from methanol to obtain 2.9 g of a slightly yellow solid. The analyzed values are given below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)=[C:20]([CH3:30])[S:19][C:14]=3[NH:15][C:16](=O)[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(Cl)([Cl:39])=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:39])[N:15]=[C:14]3[S:19][C:20]([CH3:30])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Product: COc1cccc(-c2c(C)sc3nc(Cl)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
A solution of 3-chloro-N-{2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 116) (150 mg, 0.325 mmol) in phenylphosphonic dichloride (1.5 mL, 10.72 mmol) was heated to 200° C. under a nitrogen atmosphere. The reaction mixture was cooled to RT, poured dropwise onto ice and left for ca. 30 min. The aqueous layer was extracted with DCM (ca. 25 mL×2), the combined organics passed through phase separator and the solvent removed in vacuo. The residue was then purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to afford the title compound (37 mg). LCMS (A) m/z: 479 [M+1]+, Rt 1.62 min (acidic).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:5][C:6]([S:22][CH3:23])=[N:7][C:8]=1[CH2:9][CH2:10][CH:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:2].[Sn](Cl)(Cl)(Cl)Cl.O.CCOC(C)=O>C(Cl)Cl>[NH2:2][C:1]1[C:3]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[N:5][C:6]([S:22][CH3:23])=[N:7][C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCc1nc(SC)nc(-c2cccc(OC)c2)c1C#N)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(N)c2c(nc(SC)nc2-c2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-(1,1-bis(ethoxycarbonyl)prop-3-yl)pyrimidine (example 25b, 81 mg) was dissolved in dry CH2Cl2 (1 ml). A 1M solution of tin(IV) chloride in CH2Cl2 (1 ml) was added dropwise and the mixture was stirred at room temperature for 1 h. H2O (10 ml) and EtOAc (10 ml) were then added to the reaction mixture. The organic layer was washed with H2O (10 ml) and sat. aq. NaCl (10 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=1/0 to 3/2 (v/v) as eluent.
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:27])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1CCC(O)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5° C. and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH3:28])=[C:17]([O:21][C:22]4[CH:23]=[N:24][CH:25]=[N:26][CH:27]=4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([OH:31])=O)=[N:10][CH:9]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH3:28])=[C:17]([O:21][C:22]4[CH:23]=[N:24][CH:25]=[N:26][CH:27]=4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([NH2:41])=[O:31])=[N:10][CH:9]=1
Reactant: Cc1cc2[nH]c3c(C(=O)O)ncc(-c4ccccc4F)c3c2cc1Oc1cncnc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2[nH]c3c(C(N)=O)ncc(-c4ccccc4F)c3c2cc1Oc1cncnc1
Reaction time: 1 h
Yield: 30 %

Procedure:
A sealed vial containing 4-(2-fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.0456 g, 0.110 mmol), ammonium chloride (0.024 g, 0.440 mmol), benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.063 g, 0.143 mmol), DIPEA (0.092 mL, 0.528 mmol) and N-methylmorpholine (0.047 mL, 0.429 mmol) in DMF (0.8 mL) was stirred. After 1 hr, the reaction was diluted with MeOH (1 mL) and subjected to autoprep reverse phase HPLC purification. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. It was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0137 g, 0.033 mmol, 30.1% yield) as a light tan solid, LC/MS (M+H)=414.10; 1H NMR (500 MHz, DMSO-d6) δ ppm 11.87 (br. S, 1 H), 8.98 (s, 1H), 8.47 (s, 2H), 8.33 (br. S, 1H), 8.26 (s, 1H), 7.81 (s, 2H), 7.59 (dd, J1=7.49, J2=1.39 Hz, 1H), 7.48-7.54 (m, 1H), 7.22-7.33 (m, 2H), 6.72 (s, 1H), 2.35 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1ccccn1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1ccccn1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [CH:1](/[C:4](=[CH:8]\[CH:9]=[C:10]([CH3:12])[CH3:11])/[C:5](O)=[O:6])([CH3:3])[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O.C(OCC)(=O)C>[CH:1](/[C:4](=[CH:8]\[CH:9]=[C:10]([CH3:12])[CH3:11])/[CH2:5][OH:6])([CH3:3])[CH3:2]
Reactant: CC(C)=C/C=C(/C(=O)O)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=C/C=C(/CO)C(C)C
Yield: 98 %

Procedure:
In a nitrogen atmosphere, a mixture of 48.1 g of 2-isopropyl-5-methyl-2,4-hexadienoic acid (2) having a purity of 98.0% and an (E)-isomer purity of 98.1% and 300 ml of tetrahydrofuran was added dropwise to a mixture of 20.0 g of lithium aluminum hydride and 500 ml of tetrahydrofuran over 70 minutes, which was stirred under ice cooling. The reaction mixture was stirred under ice cooling for 30 minutes and then stirred at room temperature for 17.5 hours, and subjected to careful and sequential additions of 50 g of ethyl acetate, 20.7 g of water, 12.42 g of 25% aqueous sodium hydroxide solution, and 70.38 g of water. The crystals thus formed were filtered. The filtrate was dried and concentrated to obtain 54.99 g of crude intended product having a purity of 76.8% and containing 16.4% of the solvent. The yield was 98%.