Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([C:36](Cl)=[O:37])=[CH:31][CH:30]=[CH:29]3)[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:36]([C:32]2[C:33]3[C:28](=[CH:27][C:26]([O:25][C:21]4[CH:20]=[C:19]([Cl:18])[N:24]=[CH:23][N:22]=4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=2)=[O:37])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(F)cc2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)n(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
560 mg (2.4 mMol) 5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-ylamine and 763 mg (2.4 mMol) 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (see Step 19.3) are dissolved in 5 ml CH2Cl2 and cooled to 0° C. 193 μl (2.4 mMol) Pyridine are added dropwise and after complete addition the reaction is allowed to warm to rt. It is stirred for 2 h at ambient temperature. The reaction is concentrated under reduced pressure and the remaining crude product is purified by flash chromatography (combi-flash, 40 g column; CH2Cl2/MeOH; gradient 0-5% MeOH) to give the title compound as a yellow foam: MS: [M+1]+=517.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)=[O:36])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:33]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1CCN(CC(=O)Nc2ccc(N)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methylpiperazinomethylcarbonylamino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[C:5]([NH2:13])=[C:4]([Cl:14])[N:3]=1.[C:15](OC(OCC)OCC)(=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:13]=[CH:15][N:8]2[CH:9]2[CH2:10][CH2:11][CH2:12]2)=[C:4]([Cl:14])[N:3]=1
Reactant: Nc1c(Cl)nc(Cl)nc1NC1CCC1
Reactant: CCOC(OCC)OC(C)=O
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCC3)c2n1
Temperature: 80 °C
Yield: 53 %

Procedure:
2,6-Dichloro-N4-cyclobutylpyrimidine-4,5-diamine (crude, 5.65 mmol) in diethoxymethyl acetate (8 mL) was stirred and heated at 80° C. for 16 hr. The mixture was cooled to rt, diluted with EtOAc (80 mL) and washed with water (80 mL), sat. NaHCO3 (80 mL) and brine (80 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified via flash chromatography eluting with 20-50% EtOAc/heptanes to give the title compound as an off-white solid (727 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1 H, s) 5.07 (1 H, quin, J=8.56 Hz) 2.59-2.77 (2 H, m) 2.42-2.50 (2 H, m) 1.71-1.96 (2 H, m); m/z (APCI+) for C9H8Cl2N4 243.10 (M+H)+.
Reaction SMILES: [CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].CCN(C(C)C)C(C)C.CS(O[CH2:40][CH2:41][CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=2[N:45]=[N:44]1)(=O)=O>CN(C=O)C>[CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]([CH2:40][CH2:41][CH2:42][N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=4[N:45]=[N:44]3)[CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Reactant: CS(=O)(=O)OCCCn1nnc2cc(C=O)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCCn1nnc2cc(C=O)ccc21)[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Temperature: 75 °C
Reaction time: 7 h

Procedure:
To a solution of trans-4-(methylamino)cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate (Intermediate 172 from WO2011/141180A1, 318 mg, 0.93 mmol) in DMF (3 mL) was added sodium iodide (355 mg, 2.37 mmol) and DIEA (0.25 mL, 1.44 mmol). To this suspension a solution of 3-(5-formyl-1H-1,2,3-benzotriazol-1-yl)propyl methanesulfonate (Intermediate 99, 380 mg, 1.17 mmol) in DMF (2 mL) was added and the mixture was stirred at 75° C. for 7 hours. The reaction mixture was evaporated to dryness, the solid residue was re-suspended in CHCl3 (30 mL) and the suspension was filtered through Celite®. The solvent was removed under reduced pressure and the resulting yellow solid was purified by column chromatography over silica gel eluting with a mixture of CH2Cl2/EtOH (gradient from 0 to 100% of EtOH) to provide the title compound as a yellow solid (473 mg (70% purity by HPLC), 68% yield).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]2[O:21][CH2:20]2)=[CH:17][CH:16]=1.O>CS(C)=O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][CH:19]([OH:21])[C:18]2[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(OCC(O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a mixture of 65% sodium hydride (4.4 g, 0.12 mole) and dimethylsulfoxide (60 ml) was added dropwise a solution of 4-acetamidophenol (XV: R=CH3) (15.1 g, 0.1 mole) in dimethylsulfoxide (30 ml). After cooling the resulting mixture to 8° to 10° C., a solution of 4-methylstyrene oxide (XIX) (13.4 g, 0.1 mole) in dimethylsulfoxide (30 ml) was added dropwise thereto over 1 hour, followed by reaction at 15° C. for 4 hours. Water was added to the reaction solution, and the precipitated crystals were filtered and recrystallized from ethanol to obtain 17.5 g of β-(4-acetamidophenoxy)-α-(4-methylphenyl)ethyl alcohol (XIV: R=CH3) as white crystals (yield, 61.4%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N:24]4[CH2:28][N:27]=[C:26]([CH:29]([F:31])[F:30])[O:25]4)=[CH:19][C:18]=3[CH3:32])=[CH:9][CH:8]=2)OCC[O:3]1.C(O)(=O)C.Cl.C(=O)(O)[O-].[Na+]>O>[C:2]([C:7]1[N:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([CH3:32])=[CH:19][C:20]([N:24]3[CH2:28][N:27]=[C:26]([CH:29]([F:30])[F:31])[O:25]3)=[CH:21][C:22]=2[CH3:23])=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: Cc1cc(N2CN=C(C(F)F)O2)cc(C)c1OCCCc1ccc(C2(C)OCCO2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCCOc2c(C)cc(N3CN=C(C(F)F)O3)cc2C)nn1
Yield: 75.8 %

Procedure:
A mixture of 0.24 g (0.538 mmol) of 6-(2-methyl-1,3-dioxolan-2-yl)-3-[3-[2,6-dimethyl-4-(5-difluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine from example 8d, 20 mL of acetic acid, 5 mL of water, and 5 mL of 2M HCl solution was heated to reflux for 24 hr. The reaction mixture was added to a freshly prepared sodium bicarbonate solution, the aqueous layer was extracted with ethyl acetate (4×50 mL), and the combined organic layer was washed with water (50 mL) and brine (100 mL), dried and concentrated in vacuo. The residue was purified by chromatography on MPLC eluting with 30% ethyl acetate/hexane followed by recrystallization from ethyl acetate/hexane to afford 165 mg (76%) of 6-acetyl-3-[3-[2,6-dimethyl-4-(5-difluoromethyl-1,2,4-oxadiazol-2-yl)-phenoxy]-propyl]-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 -6-acetyl, R4 =hydrogen, R5 =5-difluoromethyl-1,2,4-oxadiazolyl, Y=1,3-propylene), m.p. 95°-96° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:19]=[N-:20]
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc2c1cnn2C1CCCCO1
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-bromomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150 mg, 0.508 mmol) and sodium azide (132 mg, 2.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a 90° C.-oil-bath for 30 min, then allowed to cool, and poured into water (5 mL). The mixture was extracted with ether (2×10 mL), dried (MgSO4), filtered, evaporated, and dried under high vacuum overnight to give 4-azidomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (124 mg, 95%) as a yellow oil.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CC(C)=O>[CH3:3][CH:11]([C:10](=[O:9])[CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
Methyl iodide (6.86 mL, 1.1 eq) and K2CO3 (17.97 g, 1.3 eq) were added to an acetone (400 mL) solution of tert-butyl 3-oxobutanoate (15.82 g, 100 mmol) at room temperature. After 15 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 mL), washed with water (30 mL) and brine (300 mL), dried (MgSO4) and concentrated. The crude residue was purified by silica gel chromatography (5-10% EtOAc-hexanes) to give tert-butyl 2-methyl-3-oxobutanoate as a colorless oil (9.56 g, 56%). MS found: (M+Na)+=195.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:26])=[O:17])=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Yield: 74 %

Procedure:
To a solution of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, and iced water was poured into the residue. The precipitated crystals (1.70 g, yield 74%) of methyl 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionate were collected by filtration. The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 68–69° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([SH:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([S:20][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:19])([CH3:18])[CH3:16]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccccc1C=O
Temperature: 50 °C
Yield: 40.3 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and 2-methyl-2-propanethiol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 50° C. for 4 days. After cooling, the mixture was added to 50 ml of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent to give a yellow oil (1.26 g, 40%). 1H NMR (200 MHz, CDCl3): δ 1.26 (s, 9H), 7.43-7.63 (m, 3H), 7.96 (dd, J1=6.9, J2=2.5, 1H), 10.76 (s, 1H) ppm.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCC3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCC3

Procedure:
To a stirred solution of 3.2 g. of 1-isopropyl-3,4,6,7-tetrahydro-4-phenyl-furo[3,2-g]quinazolin-2(1H)-one in 150 ml. of dioxane cooled to 8°±5°C. is added dropwise a solution of 2.0 g. of potassium permanganate in 130 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The resulting precipitated solids are removed by filtration and the filtrate concentrated in vacuo to give an oil of 1-isopropyl-6,7-dihydro-4-phenyl-furo[3,2-g]quinazolin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]12([CH2:23][CH2:24][C:25]3[NH:29][C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[N:27][C:26]=3[C:36](O)=[O:37])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][CH2:24][C:25]3[NH:29][C:28]([CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[N:27][C:26]=3[C:36]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=3)=[O:37])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)CCc1ccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
3-(4-Amino-phenyl)-propionic acid acid benzyl ester (prepared in two steps from 4-nitrocinnamic acid) was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.28 (1H, br s), 7.63 (1H, d), 7.14 (1H, d), 2.86 (2H, m), 2.76 (2H, t), 2.64 (1H, m), 2.62 (2H, m), 2.49 (2H, m), 1.93-1.30 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.77; H, 8.69; N, 7.49%; C38H58N4O8.3.0 H2O requires: C, 60.62; H, 8.57; N, 7.44%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:26]>COCCOC>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][Br:26])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CO)c1
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [3-(4-chloro-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester (0.9 g, 2.6 mmol) in DME was added phosphorus tribromide (0.37 mL, 3.9 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was worked-up to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: Nc1cnccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccncc1N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To an ice-cold suspension of 3-aminoisonicotinic acid (8 g, 58 mmol) in ethanol (36 mL) and toluene (36 mL) was added concentrated sulfuric acid (6.4 mL), and the mixture was stirred for 24 h. The solvents were removed under reduced pressure, the residue was dissolved in water, and the solution was adjusted to pH 8 with concentrated ammonium hydroxide to give ethyl 3-aminoisonicotinate (6.5 g). MS (ESI): m/z 167 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:21])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:21])[CH3:12])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: COC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.0 g) and 6-(dimethylamino)hex-4-ynylamine (0.79 g) were reacted to give a solution of 3-methoxy-4-[6-dimethylaminohex-4-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia and purification as in Example 1 gave the title compound (0.62 g), m.p. 183°-5° C. (recrystallisation from acetonitrile).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30].[CH2:32](I)[CH3:33]>C1CCCCC1.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([N:11]([CH2:32][CH3:33])[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Reactant: CCI
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCN1C(=O)C(C)(C)c2cc(N(CC)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-N-ethyl-3-phenyl-propionamide is prepared from N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (214 mg) and ethyl iodide (46 μl; 0.57 mmol) as described in Example 57b. The compound (55 mg) is obtained by flash chromatography on silica gel eluting with cyclohexane/EtOAc.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17](OC)[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[CH3:30][NH2:31]>C(O)C>[CH3:1][C:2]([NH:4][CH:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([NH:31][CH3:30])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reactant: CN
Solvent: CCO
Product: CNc1ccc2c(cc1=O)C(NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 84.3 %

Procedure:
A mixed solution of colchicine (5.00 g, 12.5 mmoles), an aqueous 40% methylamine solution (10 ml, 130 mmol) and ethyl alcohol (10 ml) was subjected to reaction at 120° C. for 20 hours under stirring in a sealed tube. The solvent was distilled off, water (10 ml) was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography [chloroform: methanol (20:1)]. Thereby, 4.20 g of N-methylcolchiceinamide was obtained as yellow crystals (yield 84%). ##STR13##
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C=O)C>[CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CO1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, prepared as described in Procedure 59, (20 mg, 0.039 mmol) in DMF (0.1 mL) was added K2CO3 (12 mg, 0.086 mmol), followed by 2,2-dimethyloxirane (28 mg, 0.39 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was washed with H2O, sat. NaCl and dried over Na2SO4 and filtered. The organic solvent was evaporated under reduced pressure and the residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (Example 304) as white lyophillate (11 mg, 56% yield). LCMS: RT=4.066 min [M+H] 577.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm (retention time, column type, size, solvent, flow rate, gradient) NMR: 400 MHz 1H (CD3OD) ppm 1.27 (d, J=2.20 Hz, 6H), 1.32-1.49 (m, 2H), 1.54-1.76 (m, 4H), 1.81-1.98 (m, 2H), 3.53 (d, J=9.23 Hz, 1H), 3.69 (d, J=9.23 Hz, 1H), 3.78 (d, J=12.74 Hz, 1H), 3.91 (t, J=6.15 Hz, 1H), 4.02 (d, J=12.74 Hz, 1H), 6.63-6.70 (m, 1H), 6.72-6.79 (m, 3H), 7.01 (dd, J=10.99, 8.79 Hz, 1H), 7.09-7.20 (m, 3H), 7.27-7.42 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1>[C:36]([C@:17]1([OH:27])[CH:16]=[CH:15][C@@H:14]2[C@@:19]34[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]2[CH2:12][C:11]2[C:20]3=[C:21]([O:22][C@@H:18]14)[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:9][CH:10]=2)(=[O:38])[CH3:37]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3CC4=CCC(O)(Cc5ccccc5)C5=C4[C@@]2(CCN3C)[C@H]1O5
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH2CI2 (300 ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride (7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). The reaction mixture was heated under reflux for 2 hr, cooled with an ice--H2O bath, then transferred to a separatory funnel, and washed with cold 10% aqueous NaHCO3 solution (3×100 ml). The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave 6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(ν, cm-1): 2900 (m, sharp), 1727 (s, sharp, AcO); NMR (δH)(CDCl3): 7.47-7.20 (5, m, --C6H5), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2, 1-H), 5.63(1, dm, J, 10.1, 7-H), 5.43 (1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15(1, m, 6-H), 5.14 (2, s, --OCH2Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J, 6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-Hβ), 2.79-2.70 (1, m, 14-H), 2.59 (1, dd, J, 12.1 & 3.4, 16-He), 2.43 (3, s, N--CH3), 2.37 (1, td, J, 11.8 & 3.6, 16-Ha), 2.27 (1, dd, J, 18.8 & 6.6, 10-Hα), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-Ha), 1.86 (1, dm, J, 12.5, 15-He).