Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[N:8]2)=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2nc(-c3ccc(NS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3)cc2N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(-c3ccc(NS(=O)(=O)c4ccc(N)cc4)cc3)cc2N)cc1

Procedure:
To a solution of 1-(4-tolyl)-3-(4′-(4-nitrophenyl)sulfonylamino phenyl)-5-aminopyrazole (0.8 g, 1.8 mmol) in EtOAc (30 mL) at room temperature was added 10% Pd-C (0.2 g). The mixture was treated with hydrogen gas at 30 psi for 4 h on a Parr shaker. The mixture was filtered through Celite and the solvent evaporated to yield 1-(4-tolyl)-3-(4′-(4-aminophenyl)sulfonylamino phenyl)-5-aminopyrazole as a solid, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH:18]([N:31]([CH3:41])[CH2:32][CH2:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]([CH3:41])[CH2:32][CH2:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(CCCCN)CCN(C)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(CCCCNC(=O)C=Cc1cccnc1)CCN(C)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 5.5 g (36.8 mmol) 3-(3-pyridyl)-acrylic acid, 12.7 g (100.0 mmol) oxalyl chloride and 10.9 g (33.5 mmol) 4-([2-(benzhydryl-methyl-amino)-ethyl]-methyl-amino)-butylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[O:5])[CH3:2].[CH2:12]([O:14][CH:15](OCC)OCC)[CH3:13]>C(OC(=O)C)(=O)C>[C:9]([C:8](=[CH:15][O:14][CH2:12][CH3:13])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])#[N:10]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)NC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)NC(=O)OCC

Procedure:
A mixture of N-ethoxycarbonylcyanoacetamide (42 g), triethylorthoformate (40 g) and acetic anhydride (100 ml) is heated to reflux for one hour. The reaction is allowed to stand until cool and then is filtered, washing with ether, to yield α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[N:13]1C=CC=CC=1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:13])=[O:11]
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: ClCCl
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Indolyl carboxylic acid amides as starting materials may be produced by reacting an indolyl carboxylic acid chloride in absolute methylene chloride with an amine in the presence of pyridine at -10° to 0°.
Reaction SMILES: [NH:1]([C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]1)=[S:4])[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[S:25][CH:26]=[C:27]([C:30]([CH3:32])=O)[C:28]=2[OH:29])[CH:20]=[CH:21][C:22]=1[Cl:23].CN(C)C=O.Cl>O>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[S:25][CH:26]=[C:27]([C:30](=[N:2][NH:1][C:3]([N:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10]3)=[S:4])[CH3:32])[C:28]=2[OH:29])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: COC(=O)CN1CCN(C(=S)NN)CC1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CCN(C(=S)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)CC1
Yield: 18 %

Procedure:
Methyl 2-[4-hydrazinothiocarbonylpiperazin-1-yl]acetate (356 mg, 1.52 mmol) prepared in Reference Synthetic Example 10 and 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (147 mg, 0.512 mmol) were stirred with dimethylformamide (4 mL) and concentrated hydrochloric acid (42.6 μL, 1.52 mmol) at room temperature to 60° C. for 5 days. After addition of water, the reaction mixture was filtered, and the filter cake was dried. The filter cake was mixed with chloroform and filtered, and the filtrate was concentrated then mixed with chloroform, isopropyl alcohol and n-hexane and filtered. The filter cake was dried to give the crude desired product (yield 18%). The crude product was used directly for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([O:12][CH2:21][CH3:22])=[O:11])=[CH:6][CH:7]=1
Reactant: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1

Procedure:
To a 0° C. solution of (3S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (2.7 g, 13.2 mmol) in ethanol (135 mL) is added sulfuric acid (2.7 mL) and the mixture is heated at reflux for 4 hours, concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yellow oil (2.1 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 4.9 (bs, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.04 (m, 1H), 2.60-2.75 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[C:19]([O-])([O-])=O.[Na+].[Na+].CI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[N:7]([CH3:19])[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCC
Temperature: 35 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
A stirred solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 4.03 mmol) in anhydrous DMF (10 ml) was treated with Na2CO3 (470 mg, 4.43 mmol) followed by Methyliodide (275 ul, 4.43 mmol). The mixture was heated at 35° C. for 17 hours. K2CO3 (500 mg, 3.6 mmol) and Methyliodide (275 ul, 4.43 mmol) were added and then stirred at 50° C. for a further 18 hours. The reaction mixture was allowed to cool then partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated giving a yellow/brown oil (1.24 g). The product was purified by silica SPE (10 g), eluting with EtOAc/cyclohexane mixtures. The product fractions were combined and concentrated to afford the title compound as a pale yellow solid (1.11 g, quant.); m/z 263.3 [MH+].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[N:18]\[O:19][CH3:20])/[C:15]([NH2:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 80 °C

Procedure:
2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (E/Z=14/86) (0.27 g, 1 mmol) was dissolved in toluene (1 ml). Conc. hydrochloric acid (0.17 ml) was added, and the mixture was heated at 80° C. for 2 hours. A part of the mixture was sampled, and the toluene was evaporated under reduced pressure to give (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide. The E/Z ratio of it was determined (E/Z=98/2).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.CCN(CC)CC.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][N:10]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:24])=[N:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ncc(Br)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Yield: 50.8 %

Procedure:
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et3N (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>C1COCC1.O>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(C(=O)N3CCC(C(=O)N(C)Cc4ccccc4)CC3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in THF (Volume: 1.5 mL). The reaction was stirred for 10 minutes before 1-(bromomethyl)-4-methoxybenzene (0.039 mL, 0.266 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 50%-100% ethyl acetate in hexanes to obtain white solid as a product. (Yield: 42 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.64-7.58, 7.41-7.15, 7.10-7.05, 6.85-6.81, 6.70-6.64, 5.48-5.38, 4.64, 4.56-4.45, 3.70-3.66, 3.01-2.92, 2.78, 1.54
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.O.[OH:31][C:32]1[CH:46]=[CH:45][CH:44]=[CH:43][C:33]=1[CH2:34]P(=O)(OCC)OCC>O1CCCC1>[OH:31][C:32]1[CH:46]=[CH:45][CH:44]=[CH:43][C:33]=1[CH:34]=[CH:26][C:25]1[CH:24]=[CH:23][C:22]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[CH:29][CH:28]=1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h

Procedure:
At first, 14.8 g of potassium tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction vessel having a stirrer, a thermometer and a dropping funnel. Under a nitrogen gas flow, a solution in which 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde were dissolved in tetrahydrofuran was slowly dropped therein at room temperature, and the reaction is further performed for 2 hours at the same temperature. Next, water was added thereto while cooling the reaction product with water, a hydrochloric acid solution with a normal concentration of 2 (i.e., 2N) was added therein to acidize the reaction product, and then tetrahydrofuran was removed by an evaporator. Further, toluene was added thereto to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was then added thereto to dehydrate the toluene phase.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].[NH:56]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C@H:57]([C:60](O)=[O:61])[CH2:58][OH:59]>CN(C=O)C>[C:66]([O:65][C:63]([NH:56][C@@H:57]([CH2:60][OH:61])[C:58]([NH:34][C@@H:35]([C@H:46]([OH:55])[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:59])=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: COc1ccc([C@@H](O)[C@H](N)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Sequentially HATU (645 mg, 1.70 mmol) and DIEA (0.99 mL, 5.7 mmol) were added to a 0° C. solution of (2S,3R)-benzyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 477 mg, 1.41 mmol) and Boc-Ser-OH (290 mg, 1.41 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1) twice to afford (2S,3R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (646 mg, 93% yield) as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]=[O:10])=[CH:3][CH:2]=1
Reactant: OCCCc1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCc1ccncc1
Reaction time: 1 h

Procedure:
4-Pyridinepropanol (0.60 mL, 4.65 mmol) was added to a solution of the Dess-Martin reagent (2.37 g, 5.58 mol) in dichloromethane (30 mL). After 60 min at RT, the solution was quenched with 10% aq. Na2S2O3, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded the title compound. MS 136 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Br:25][CH2:26][C:27](Br)=[O:28].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:25][CH2:26][C:27]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]3[N:11]=2)[CH:6]=1)=[O:28]
Reactant: O=C(Br)CBr
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nn12
Temperature: 25 °C

Procedure:
A solution, cooled to 0° C., of 1 g (3.1 mmol) of the compound from example 17A in 80 ml of CH2Cl2 was admixed dropwise with 1.2 g (6.1 mmol) of bromoacetyl bromide and a little at a time with 1.2 g (9.1 mmol) of AlCl3. The reaction mixture was warmed to room temperature (30 min.) and then heated at reflux for 2 h and carefully poured into ice-water. Following extraction with CH2Cl2, drying over MgSO4 and concentration under reduced pressure, the residue was triturated with ether. This gave 1.33 g (33% pure according to LC-MS) of the desired product which was reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:34][C:33](=[O:35])[NH:32][N:31]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1-c1n[nH]c(=O)o1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1n[nH]c(=O)o1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 5-(6-chloro-2-methylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (101 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 2-amino-4-chlorobenzoic acid (2.00 g, 11.6 mmol) and urea (2.80 g, 46.6 mmol) was heated to 200° C. for 1 h. The mixture was allowed to cool to room temperature and the resulting mass was triturated well with water. The product was collected by filtration (2.30 g, 100%). The MS and NMR data are in agreement with those that have been previously described: Organic Process Research & Development, 2003, 7, 700-706. 1H NMR (600 MHz, DMSO-d6): 12.00 (br s, 2H), 8.59-8.53 (m, 1H), 7.93-7.80 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].S(O[CH2:22][CH2:23][O:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[N:4]1([CH2:3][CH2:2][S:1][CH2:22][CH2:23][O:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: SCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H](OCCSCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Temperature: 25 °C

Procedure:
To a solution of 0.28 g of 1-(2-mercaptoethyl)pyrrolidine in 20 ml of dimethylformamide, 0.086 g of sodium hydride (60% dispersion in mineral oil) were added under nitrogen atmosphere, and the mixture stirred at room temperature for half an hr; a DMF solution of 1.0 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 7, was added and the mixture was stirred for another 4 hrs; the reaction mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-cromatography (SiO2) using methylene chloride/methanol 95/5 as eluant and 0.90 g of the title compound (I-ai) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].C(O)(=O)C>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][O:9][C:4]2[CH:3]=[C:2]([NH:1][CH:21]([CH3:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Nc1cc(C)cc(OCCc2ccc(C#N)cc2)c1
Yield: 28.9 %

Procedure:
Amino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.252 g; 1.00 mmol; from Example 17(iii) above), ethyl acrylate (130 μL; 1.2 mmol) and acetic acid (9 μL; 0.15 mmol) were refluxed together for 8 hours. After evaporation in vacuo, the resultant black oil was purified by flash chromatography (SiO2; EtOAc:heptane (3:7)) to give 0.102 g (29%) of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([F:27])=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH:12]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.[S-:32][C:33]#[N:34].[K+].BrBr>C(O)(=O)C>[NH2:34][C:33]1[S:32][C:3]2[C:4]([C:30]#[N:31])=[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([F:27])=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=4)[CH:12]=3)[CH:28]=[CH:29][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of N-[5-(4-amino-2-cyanophenoxy)-2-fluorophenyl]-2-[3-(trifluoromethyl)phenyl]acetamide (1.15 g, 2.68 mmol) in acetic acid (40 mL) was added potassium thiocyanate (1.22 g, 12.6 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (652 mg, 4.08 mmol) in acetic acid (6.5 mL) was added dropwise to the obtained solution over 10 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with acetic acid (50 mL), and insoluble material was filtered off and washed with acetic acid, the filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (120 mL)/tetrahydrofuran (12 mL), and the suspension was washed successively with saturated aqueous sodium hydrogen carbonate solution (120 mL) and saturated brine (120 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (1.13 g, 87%) as a beige powder.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10]>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][S:11]([CH:9]([CH3:10])[CH3:8])(=[O:13])=[O:12]
Reactant: NCc1ccco1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a stirred solution of furfurylamine (1.040 g, 10.7 mmol) in pyridine (10 mL) at 0° C. was slowly added 2-propanesulfonyl chloride (1.0 mL, 8.9 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (0.84 g, 46%) as a yellowish thick oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, 1H, J=1.8, 0.9 Hz), 6.35 (dd, 1H, J=3.3, 1.8 Hz), 6.29 (d, 1H, J=3.3 Hz), 4.42 (br s, 1H), 4.33 (d, 2H, J=5.7 Hz), 3.08 (m, 1H), 1.35 (d, 6H, J=6.9 Hz).