Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][NH:5][CH2:6][C@:7]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:38])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.O1CCOCC1>>[C:3]([CH2:4][NH:5][CH2:6][C@:7]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:38])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([OH:45])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To the solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-methoxy-2-oxoethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (50 mg, 0.081 mmol) in dioxane (2 ml) sodium hydroxide (0.162 ml, 0.162 mmol) was added. The resulting mixture was stirred at 70° C. for 2 h. The solvent was evaporated and the residue was purified by prep. HPLC to afford the title compound as a white solid (18 mg, 35%). LCMS: m/e 602.4 (MH+), 2.32 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.90 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.18-5.40 (m, 1H), 4.73 (s, 1H), 4.62 (br. s., 1H), 3.96 (d, J=5.0 Hz, 2H), 2.78-2.94 (m, 1H), 2.37-2.60 (m, 1H), 2.10 (s, 2H), 1.78-1.92 (m, 3H), 1.62-1.78 (m, 6H), 1.38-1.61 (m, 8H), 1.16-1.38 (m, 6H), 1.11-1.16 (m, 4H), 1.07 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:17]
Reactant: CC(=O)c1ccc(CC(C)C)c(Br)c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CC(C)C)c(C#N)c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
3′-Bromo-4′-isobutylacetophenone (182 g) and copper cyanide (95.7 g) were stirred in dimethylformamide (520 ml) at 140° C. for 7 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added water and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give 3′-cyano-4′-isobutylacetophenone (70 g), melting point: 71–72° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[NH:13][C:12](=O)[C:11]2=[C:15](C)[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:10]2[N:9]=1.[CH3:29]OCCOC>>[CH3:29][C:8]1([NH2:7])[NH:13][CH2:12][C:11]2=[CH:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:10]2[NH:9]1
Reactant: COCCOC
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)[nH]c(=O)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(N)NCc2cnc(-c3cccc(C(F)(F)F)c3)n2N1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride was added in portions to a stirring solution of 2-amino-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Intermediate 43) (2.0 g, 6.47 mmol) in DME (50 mL) at rt. The resultant mixture was then heated to reflux for 2 h. The reaction mixture was then cooled to 0° C. and carefully quenched with H2O. After extraction into EtOAc., the combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification of the residue by chromatography afforded 2-methyl-7-[3-(trifluoromethyl)phenyl]-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-amine (0.60 g) as a pale yellow solid. 1H NMR (DMSO-d6): δ8.67-8.60 (m, 1H), 8.54 (s, 1H), 7.61-7.54 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 4.35 (s, 2H), 2.06 (s, 3H). MS m/z 294 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:17][CH:16]=[C:15]([NH2:33])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])=[CH:17][CH:16]=[C:15]([NH:33][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
Pivaloyl chloride (0.353 g) was added to a stirred, cooled mixture of methyl 2,6-diamino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]benzoate (Intermediate 36, 1.0 g) and sodium bicarbonate (0.268 g) in ethyl acetate (20 mL) and water (7 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. Further pivaloyl chloride (0.048 g) was added and the mixture was stirred for 1 hour. Ethyl acetate was added and the layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-20% to give methyl 2-amino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (0.744 g) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH2:30](CNC1N=C(C(O)=O)C=C(C)N=1)C>>[CH2:1]([N:3]([CH3:30])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2]
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: CCN(C)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{4-[5-(2-(Ethyl-methylamino)-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-(ethyl-methyl)amino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.96 min*; [M+H]+=414.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:6]1[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: Clc1cccc(CBr)c1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 14 mg of white crystals.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH:12]1[C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[CH:24]=1)=[O:19])=O)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[F:29][C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([CH:18]([CH:12]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][NH:11]3)[OH:19])=[CH:24][C:23]=2[CH:25]=1
Reactant: CN1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCNC(C(O)c2cc3cc(F)ccc3o2)C1
Yield: 90 %

Procedure:
(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl]-4-methyl-piperazine-1-carboxylic acid benzyl ester, D50 (0.65 g, 1.6 mmol) in ethyl acetate (20 ml) and methanol (20 ml) was hydrogenated at NTP over 10% Pd—C (0.47 g, 50% w/w paste in water) for 3.5 h. The reaction mixture was filtered through Kieselguhr, washing well with methanol and the filtrate evaporated to afford the title product (0.41 g, 90%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, off-white solid (87 mg, 81%), MS (ISP) m/z=433.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][N:36]([CH3:46])[CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[CH:45])[CH2:39][CH2:38]1>>[CH3:35][N:36]([CH3:46])[CH:37]1[CH2:38][CH2:39][N:40]([CH2:43][C:44]#[C:45][C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([N:19]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:41][CH2:42]1
Reactant: C#CCN1CCC(N(C)C)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CN(C)C1CCN(CC#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 7.5 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and N,N-dimethyl-1-(prop-2-ynyl)piperidin-4-amine (Example 20, Step A, 35.1 mg, 0.211 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.32), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was further purified by trituration with 3:1 pentane/DCM (5 mL) and filtered. The product was obtained as a waxy solid (4 mg, 7%). HPLC: 100% purity (220 nm); LCMS (APCI+): 100% purity, 220 nm, m/z 630 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.49 (m, 1H), 8.17 (br s, 1H), 7.77 (m, 1H), 7.59 (s, 1H), 7.45 (m, 2H), 7.26 (m, 2H, overlaps chloroform), 7.07 (m, 2H), 6.51 (m, 1H), 3.59 (s, 2H), 3.02 (m, 2H), 2.30 (m, 9H), 1.82 (m, 4H), 1.62 (m, 4H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccncc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g, 0.0052 mol) was suspended in 20 ml of toluene. Isonicotinoyl chloride hydrochloride (0.93 g, 0.0052 mol) was added and then a solution of sodium hydroxide (1.25 g of 50% aqueous NaOH) in 5 ml of water was added dropwise. After stirring at 23° C. for 2 hours, the solids were removed by filtration, washed with water and dried in air. The crude product was chromatographed on silica gel using 5% methanol/methylene chloride as eluant to afford pure N'-t-butyl-N-benzoyl-N'-isonicotinoylhydrazine: m.p. >210° C.
Reaction SMILES: [N+:1]([CH:4]1[CH:8]([CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])[S:7][CH2:6][CH:5]1O)([O-:3])=[O:2].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[N+:1]([C:4]1[CH:8]([CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])[S:7][CH2:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC(C)C1SCC(O)C1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(C)C1SCC=C1[N+](=O)[O-]
Reaction time: 3.5 h
Yield: 56.7 %

Procedure:
After dissolving 150 mg of 4-nitro-5-(pentan-2-yl)tetrahydrothiophen-3-ol in 4 ml of dichloromethane, 86 mg of mesyl chloride and 138 mg of triethylamine were gradually dropped thereto at 4° C. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 3.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 78 mg of 3-nitro-2-(pentan-2-yl)-2,5-dihydrothiophene (yield: 57.3%).
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.C(O)C#C.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH2:13]([N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[N:2])[C:8]#[CH:9]
Reactant: N#Cc1ccc[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Agent: CCOC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Product: C#CCn1cccc1C#N
Yield: 46.7 %

Procedure:
51.57 g of 2-cyano-pyrrol[prepared by the process of Can. J. Chem. Vol. 59, p. 2763 (1981)], 146.9 g of triphenylphosphine, and 43.95 g of propargyl alcohol were mixed together and 420 ml of tetrahydrofuran were added. The mixture was cooled at +5° C., and over half an hour at 0° to 5° C., 97.5 g of ethyl azodicarboxylate were introduced. The temperature was allowed to return to ambient, and stirring was maintained for 18 hours. The solvent was evaporated under reduced pressure, and the crystallized residue was taken up in ethyl ether and filtered. After concentrating the filtrate, an oil was obtained which was chromatographed over silica. Elution with a hexane-ethyl acetate (7-3) mixture yielded 34 g of 1-(2-propynyl)-1H-pyrrole-2-carbonitrile.
Reaction SMILES: C[O-].[Na+].[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[I-].[K+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C1C=CC=CC=1.O>[CH:4]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)=[CH:27][CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.19 g of sodium methoxide and 4.4 g of p-cyclohexylphenol in 40 ml of methanol is added 50 mg of potassium iodide and 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The solution is refluxed overnight, cooled to room temperature and poured into 100 ml of water. The mixture is extracted with two 60 ml portions of ether and the combined extracts washed with two 50 ml portions of 5% sodium hydroxide, 50 ml of water and 50 ml of saturated NaCl. The extract is dried (MgSO4) and the solvent removed under vacuum. The residue is triturated with petroleum ether to give the product as white crystals, mp 122°-123.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@H:15]([CH2:20][OH:21])[C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@H:15]([CH2:20][OH:21])[C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Reaction time: 0.83 h

Procedure:
A standard hydrogenation bottle was charged with 3-nitro-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide (0.50 g, 1.48 mmol), 10% palladium on carbon (0.05 g), methanol (25 mL) and hydrogen gas. It was shaken on a Parr hydrogenation apparatus for 50 minutes. The reaction mixture was filtered and the solvent evaporated to produce a crude oil that was flash chromatographed (eluant: ethyl acetate-hexane, 3-2) to afford the product as a solid, mp 89-92° C. (0.12 g, 26%). MS (+APCI) 307.03 ([M+H]+). Anal. Calc'd for C12H19ClN2O3S: C, 46.98; H, 6.24; N, 9.13. Found: C, 47.44; H, 6.32; N, 8.88.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:27][C:26](=[O:28])[C:25]3[C:16](=[CH:17][C:18]4[C:23]([CH:24]=3)=[N:22][C:21]([C:29]([F:32])([F:31])[F:30])=[CH:20][CH:19]=4)[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:33][NH2:34]>C1COCC1>[CH3:33][NH:34][C:26]([C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([C:29]([F:32])([F:31])[F:30])=[N:22]2)=[CH:17][C:16]=1[NH:15][C:14]([C:4]1[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=[C:2]([Br:1])[CH:3]=1)=[O:27])=[O:28]
Reactant: CN
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2cc3ccc(C(F)(F)F)nc3cc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2cc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
2-[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one is reacted with methylamine in THF analogously to the procedure given in step i) of example H-18. The title product is obtained as pale yellow crystals after flash column chromatography. LC/MS: 553/555/557 (M+1)+; m.p.: 127-129° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[C:11]([CH3:14])[CH:12]=O.C(O)C>C(O)(=O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:12]=[C:11]([CH3:14])[CH:10]=[N:1][C:2]=12
Reactant: CC(C=O)=CN(C)C
Reactant: Nc1n[nH]cc1Br
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cnc2c(Br)cnn2c1
Yield: 71.6 %

Procedure:
3-Amino-4-bromopyrazole (0.331 g, 2.04 mmol) and 3-(dimethylamino)-2-methyl-2-propenal (0.220 g, 1.94 mmol) were dissolved in acetic acid (6.48 mL) and ethanol (9.72 mL) and the reaction stirred at room temperature for 16 h. Solvents were removed under reduced pressure. The remaining residue was taken up in dichloromethane and purified by column chromatography (20-80% EtOAc/Hex) to give the title compound (0.294 g, 1.39 mmol). LRMS (APCI) calc'd for (C7H6BrN3) [M+H]+, 212.0; found 211.9. 1H NMR (500 MHz, cdcl3) δ 8.44 (s, 2H), 8.04 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Reaction time: 0.5 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bias(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5 h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions. The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil. PMR (CDCl3): δ1.38 (6H, s), 1.42 (3H, t, J~7.0 Hz), 1.98 (2H, m), 3.07 (2H, m), 4.39 (2H, q, J~7.0 Hz), 7.20 (1H, d, J~9.0 Hz), 7.28 (2H, d, J~8.1 Hz), 7.82 (1H, dd, J~9.0, 1.8 Hz), 8.12 (2H, d, J~8.1 Hz), 8.17 (1H, d, J~1.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Br)cc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 4-(6-bromobenzo[d]thiazol-2-yl)piperazine-1-carboxylate (300 mg, 0.753 mmol) in CH2Cl2 (6 mL) was added TFA (0.87 mL, 11.30 mmol). Upon completion of addition, the reaction mixture was stirred at rt for 3 hrs. After this time, the reaction mixture was diluted with CH2Cl2 and washed with aqueous NaOH (1 N, 5 mL) and brine (5 mL), and then dried (Na2SO4). The reaction mixture was filtered and then concentrated under reduced pressure to obtain Compound 13B as a light yellow solid (223 mg, 0.748 mmol, 99% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.72 (s, 1H), 7.41 (s, 2H), 3.58-3.66 (m, 4H), 2.98-3.07 (m, 4H). LC/MS (m/z)=299 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][O:14][CH:13]=1)=O)C>O1CCCC1>[C:17]1([C:16]2[C:12]([CH2:10][OH:9])=[CH:13][O:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cocc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cocc1-c1ccccc1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0 M solution in hexane 1.14 ml, 1.14 mmol) was added dropwise to a solution of ethyl-4-phenyl-3-furoate, (246 mg, assumed 1.28 mmol) in tetrahydrofuran (20 Nil) at 0 degrees under argon. The solution was stirred and was allowed to warm to room temperature gradually over 1/2 hour. The mixture was quenched with saturated ammonium chloride and the organics were extracted into ethyl ether, and washed with H2O. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 20% ethyl acetate/hexanes. This was further purified by recrystallation (hexane/ethyl ether) to give the title compound as pale yellow crystals.