Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16]>O1CCCC1>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: c1ccc(-c2ncc[nH]2)cc1
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1Cl)n1ccnc1-c1ccccc1

Procedure:
173 g of 2-phenylimidazole are dissolved in 600 ml of tetrahydrofuran. To this solution are added dropwise at boiling temperature 129.4 g of 2,6-dichlorobenzoyl chloride, dissolved in 400 ml of tetrahydrofuran, and the mixture is refluxed for 1 hour. The phenylimidazole hydrochloride which precipitates is separated at room temperature by vacuum filtration. The solvent of the filtrate is subsequently removed in the rotary evaporator, and the residue is recrystallised from 600 ml of acetonitrile. The yield after filtration with suction, washing with acetonitrile and drying is 153 g (80.4% of theory) of the product, m.p. 116°-117° C. There are obtained by concentrating the mother liquor by evaporation a further 22.3 g (11.7% of theory) of the product, m.p. 110°-114° C. For the analysis, 3.0 g of the compound are recrystallised from 5 ml of acetonitrile, washed with acetonitrile and dried at 60° C. in vacuo; yield: 2.6 g, m.p. 117°-118° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[C:13]([CH3:28])=[N:14][N:15]2[C:20]([Cl:21])=[C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18]([CH3:27])=[N:17][C:16]=12.C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[C:13]([CH3:28])=[N:14][N:15]2[C:20]([Cl:21])=[C:19]([CH:22]([OH:37])[C:23]([O:25][CH3:26])=[O:24])[C:18]([CH3:27])=[N:17][C:16]=12
Reactant: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2c(Cl)c(C)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 1.04 mL) in THF (5 mL) at −78° C. was added a solution of methyl 2-(3,7-dichloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.15 g, 0.5 mmol) in THF (5 mL) over 20 mins. The reaction mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.16 g, 0.63 mmol) in THF (5 mL) was added over 10 min and the resulted reaction mixture was stirred for an additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2 mL). The mixture was allowed to warm up to room temperature and diluted with EtOAc (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (80 mg, 30%). Used as is in the next step.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][O:24][CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].CCO>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.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][O:24][CH3:23])[CH:30]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: Cc1ccccc1
Solvent: CCO
Product: COCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[C:20](Cl)(=O)C(Cl)=O>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:20])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Solvent: CO
Product: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 89 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid is reacted with oxalyl chloride and methanol according to the procedure of Example 25 to give 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid, methyl ester in 89% yield; mp 132°-134° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1>>[CH:2]1(/[CH:1]=[N:8]/[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=CC1CC=CCC1
Product: C1=CCC(/C=N/Cc2ccccc2)CC1

Procedure:
In another aspect, a process is described for preparing a compound, or a salt of a compound, or a solvate thereof, of Formula (III). The process comprises steps of: (a) condensing benzylamine with cyclohex-3-enecarbaldehyde to form (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine; (b) contacting (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine with potassium tert-butoxide present in an amount ranging from about 0.05 molar equivalents to about 0.2 molar equivalents of potassium tert-butoxide to (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine to form (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine; (c) contacting (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine with paraformaldehyde present in an amount ranging from about 2.0 molar equivalents to about 5.0 molar equivalents of paraformaldehyde to (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine, in presence of formic acid and a reaction medium comprising water present in an amount ranging from about 0.1% to about 6.5% of the reaction medium to form a compound of Formula (I); (d) contacting a compound of Formula (I) with a hydrogen bromide solution comprising about 43% to about 53% w/w of hydrogen bromide and where the inorganic salt of a compound of Formula (II) is an HBr salt; (e) contacting aminothiourea and benzoic acid in presence of polyphosphoric acid to form 2-amino-5-phenyl-1,3,4-thiadiazole H3PO4 salt; (f) contacting 2-amino-5-phenyl-1,3,4-thiadiazole H3PO4 salt, CuBr2 and iso-amyl nitrite, in presence of a acetonitrile, to form 2-bromo-5-phenyl-1,3,4-thiadiazole; and (g) contacting a compound of Formula (II) with 2-bromo-5-phenyl-1,3,4-thiadiazole, in presence of a sodium bis(trimethylsilyl)amide and tetrahydrofuran, to form a reaction mixture, and optionally contacting the reaction mixture with citric acid. In another aspect, the reaction mixture comprises
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Cl:22]N1C(C)(C)C(=O)N(Cl)C1=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][C:7]=1[Cl:22]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(Cl)c(Cl)c2)CC1
Reaction time: 3 h

Procedure:
A mixture of 1-(5-chloro-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (1.56, 5.0 mmol), 1,3-dichloro-5,5-dimethylhydantoin (0.985 g, 5.0 mmol) and dichloromethane (50 ml) was stirred for 180 minutes. The crude mixture was evaporated and purified by chromatography on silica gel using ethyl acetate:petroleum (3:1) as solvent. Yield 0.46 g, 27%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=O)[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[S:32])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=S)N3C)C(=O)O1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in dry dioxane (25 mL) is added Lawesson's reagent (2.37 g, 5.861 mmol). This reaction mixture is heated at 70–80° C. for 1.5–2 h at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is washed with EtOAc (15 mL×3), sonicated and filtered to give the title compound as a yellow solid (1.18 g, 89%), MS (m/z): 339.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20]I)[CH3:18]>CN1CCCC1=O>[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC(CC)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCC(CC)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 43 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-nitrophenol (27.14 grams, 0.195 moles), potassium carbonate (51.13 grams, 0.370 moles), 2-ethylhexyl iodide (45.63, 0.185 moles) in 1-methyl-pyrrolidin-2-one(180 ml). The contents of the flask were heated at 100° C. for 3 hours; cooled to room temperature; partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed with a 1 N sodium hydroxide solution (4×75 ml), brine (3×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 29.9 grams of crude product as a yellow oil. Excess 2-ethylhexyl iodide was removed from the product using Kugelrohr distillation apparatus to afford 20 grams of pure product as a yellow oil. 1H NMR (CDCl3) δ 8.2(d, 2H), 6.95(d, 2H), 3.95(d, 2H), 1.75(heptet, 1H), 1.2-1.6(m, 8H), 0.85-1.0(m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17]([Cl:32])=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 1.0 g (2.5 mmol) of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionic acid and 1.07 ml (12.5 mmol) of oxalyl chloride in 2 ml of tetrahydrofuran was heated at 500 for 18 hours. Thereafter, the reaction solution was evaporated under reduced pressure. The residue was taken up twice in 30 ml of toluene each time and again evaporated under reduced pressure each time. (RS)-2-[[2-[(Benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride was obtained as a yellowish oil in quantitative yield and was used in the following step without purification and characterization.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH3:1][NH:2][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methylamine (5.7 mL of a 2.0 M in THF, 11.4 mmol) was added to a solution of 4-phenylcyclohexanone 1 (2.0 g, 11 mmol) in anhydrous THF (30 mL), and the mixture was stirred at room temperature for 4 hours. BH3—SMe2 1.6 mL, 16 mmol) was added, and stirring was continued overnight. After quenching the reaction with MeOH, the solvents were removed under reduced pressure. The crude solid was dissolved in MeOH (10 mL), HCl (15 mL of a 1.0 M solution in Et2O, 15 mmol) was added, and the mixture concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1:0.1 CH2Cl2: MeOH:NH4OH) gave trans-1-(methylamino)-4-phenylcyclohexane 6 (0.80 g, 39%) as a white solid: 1H NMR (300 MHz, CD3 OD) δ 7.27-7.11 (m, 5H), 2.64 m, 1H), 2.51 (obs m, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.11 (br d, J=11 Hz, 2H), 1.93 (br d, J=11 Hz, 2H), 1.59 (dddd, J=11, 11, 2, 2 Hz, 2H), 1.42 (dddd, J=11, 11, 2, 2 Hz, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[N:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](CS)=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:18][S:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])=[C:6]([O:20][CH3:21])[CH:7]=3)[C:12](=[O:19])[N:13]=2)=[CH:27][CH:26]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: COc1cc(-n2ccc(SC)nc2=O)ccc1OCC(C)(C)O
Solvent: ClCCl
Product: COc1cc(-n2ccc(SCc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 145 °C
Yield: 69.8 %

Procedure:
A mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(methylthio)pyrimidin-2(1H)-one (90 mg, 0.268 mmol) and (4-chlorophenyl)methanethiol (707 μl, 5.35 mmol) was heated to 145° C. (neat) for 30 min. The mixture was diluted with methylene chloride, washed with water, dried (Na2SO4) and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes:ethyl acetate 100:0 to 0:100 gradient) to afford the title compound 4-(4-chlorobenzylthio)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one A-1 (83.5 mg, 0.187 mmol, 69.8% yield) as a yellow solid. LC/MS 447 (M+H)+, tR 0.93 (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.33-7.44 (3H, m), 7.24-7.31 (2H, m), 6.91-6.99 (2H, m), 6.86 (1H, dd, J=8.53, 2.51 Hz), 6.24 (1H, d, J=7.03 Hz), 4.48 (2H, s), 3.86 (3H, s), 3.85 (2H, s), 1.35 (6H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.[NH3:26]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[S:6][C:5]=1[C:3]([NH2:26])=[O:2])[CH3:12]
Reactant: COC(=O)c1sc(-c2cccnc2)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-c2cccnc2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 54 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-pyridin-3-yl-thiophene-2-carboxylic acid methyl ester (58 mg, 0.16 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The reaction was allowed to cool to ambient temperature, the solvent removed in vacuo and purified by tritruation with MeOH to give the title compound as an off-white solid (30 mg, 0.08 mmol, 54%); 1H NMR (400 MHz, d-6 DMSO) δ 1.72 (3H, d), 6.00 (1H, q), 7.10 (1H, br s), 7.35-7.52 (5H, m), 7.67 (1H, dd), 7.75 (1H, br s), 7.97-8.01 (1H, m), 8.56 (1H, dd), 8.84 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC21CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyridine (Intermediate 157, 265 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (245 mg, 4.45 mmol) and then ammonium chloride (238 mg, 4.45 mmol) were added and the reaction mixture was stirred overnight at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (203 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(O)cc2OCc2ccccc2)S1(=O)=O
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(OCCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 5-(2-benzyloxy-4-hydroxyphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (90 mg, 0.21 mmol), phenethyl alcohol (37.9 mg, 0.31 mmol), DIAD (0.0612 mL, 0.31 mmol), and triphenylphosphine (81.5 mg, 0.31 mmol) in (THF 5 mL) is stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue chromatographed on a Biotage 40S column using a gradient of 80:20 to 60:40 hexane/EtOAc as eluent to afford the title compound: 1H NMR (CDCl3δ7.30 (m, 11H), 6.62 (d, J=2.8 Hz, 1H), 6.43 (dd, J=8.6, 2.8 Hz, 1H), 5.00 (s, 2H), 4.25 (s, 2H), 4.11 (t, J=7.1 Hz, 2H), 3.51 (m, 2H), 3.03 (t, J=7.1 Hz, 2H), 0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [ClH:1].[I:2][C:3]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[ClH:1].[F:10][C:9]1[C:3]([I:2])=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1I
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cccc(F)c1I
Temperature: -10 °C
Reaction time: 4 h

Procedure:
2-Iodo-3-fluoroaniline hydrochloride (5.7 g, 0.021 mol) was stirred in 7.4 mL of concentrated HCl and cooled to -10° C. An aqueous solution of sodium nitrite (1.63 g, 0.024 mL) in 5 mL water was added dropwise over a 20 minute period, stannous chloride (9.95 g, 0.044 mol) in 12 mL of 6N HCl added at -5° C., warmed to room temperature and stirring continued for 4 hours. The reaction mixture was cooled to 0° C., and made basic with 50% NaOH (pH 10-11), extracted with ether, washed with water, brine, dried (MgSO4), filtered and concentrated to give the hydrazine. Addition of ethereal HCl (pH 1-2) gave 4.6 g of the title compound, m.p. 165°-167° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:11][CH:12]=O>CCO>[N:1]1[CH:11]=[CH:12][N:9]2[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=12
Reactant: N#Cc1cccnc1N
Reactant: O=CCCl
Solvent: CCO
Product: N#Cc1cccn2ccnc12
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a solution of 2-aminonicotinonitrile (1.0 g, 8.39 mmol) in EtOH (10 ml) in a 20 ml sealed vial was added 2-chloroacetaldehyde (1.611 ml, 9.23 mmol) vial was then sealed and heated to 120° C. overnight. Reaction was cooled to RT and quenched with 2N Na2CO3, removed EtOH in vaccuo and extracted with DCMx3. Combined organics and washed with water then brinex2. Dried over sodium sulfate and removed solvent to give title compound as a yellow brown solid (1.2 g, 8.38 mmol, 100% yield) was verified by MS (ES+) C8H5N3 requires: 143 found: 144 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C1(O)C=CC=CC=1>CN(C=O)C>[F:37][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C

Procedure:
To a mechanically stirred slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (16.6 g, 32.8 mmol) and potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4-(3-chloropropyl)-morpholine hydrochloride (13, 7.92 g, 39.6 mmol). The resulting mixture was heated at 90° C. for 5 hours (until phenol completely consumed). The reaction mixture was allowed to cool to room temperature, then dumped into water (900 mL), followed by extraction with EtOAc (3×). The combined extracts were washed with 5% LiCl (aq.) (3×) and brine (1×) followed by drying over MgSO4 and concentration in vacuo. The crude (18.8 g) obtained as brown solid was further purified by flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc; 2) EtOAc:MeOH:7N N3/MeOH (95:5:0.5); 3) DCM:MeOH:7N N3/MeOH (95:5:0.5); 4) DCM:MeOH:7N N3/MeOH (93:8:1)], affording N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin 4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was obtained as an off white solid (15.0 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (t, 1H), 7.40 (s, 1H), 7.16 (m, 2H), 6.42 (d, 1H), 4.20 (t, 2H), 3.96 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (br, s, 4H), 1.98 (m, 2H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+ 633.3. found 633.0.