Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]3[O:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:21][N:22]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1CCc2cc(OCc3nnc(-c4ccccc4)o3)ccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (206 mg, a free form of Reference Example 16) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (231 mg) in DMF (5 ml) was added potassium carbonate (215 mg) and the reaction mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) to obtain the titled compound (307 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]([S:28][CH3:29])[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:11]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]=2[S:28][CH3:29])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)C(SC)C(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1SC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 15.6 g of 2,4-dichlorophenylhydrazine hydrochloride (5) in mL of ethanol was added 22 g of ethyl 4-(4-chlorophenyl)-3-(methylthio)-2,4-dioxobutanoate (4) in 120 mL of ethanol at room temperature. After 2 hours, the mixture was refluxed for 15 hours and then cooled to the room temperature. The mixture was filtered off and the filtrate was evaporated off under the reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc mixture (80/20; v/v) to obtain 25 g of the title compound as pale orange color solid.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(Br)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (80 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (5.0 g) and triethylamine (1.5 ml), and a solution of 3-bromobenzoyl chloride (2.9 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:21]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=C(OCc1ccccc1)N1C[C@H]2CCNC[C@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)OCc4ccccc4)[C@@H]3C2)n1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
To (1S,6R)-benzyl 3,8-diazabicyclo[4.2.0]octane-8-carboxylate (2.5 g, 6.9 mmol) and 2-chloro-4,6-dimethylpyrimidine (980 mg, 6.9 mmol) in DMF (35 mL) was added Cs2CO3 (9.0 g, 27.6 mmol). The reaction flask was heated to 100° C. until starting materials were consumed, cooled to rt, diluted with EtOAc and washed with H2O. The aqueous layer was back-extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na2SO4) to give an oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 1.6 g (63%) of the title compound as a clear oil. MS (ESI) mass calcd. C20H24N4O2, 352.44; m/z found 353.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1nc(Nc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 29.4 %

Procedure:
A mixture of 6.5 g of 6-chloro-3-nitropicolinonitrile (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70° C. for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:13]2[N:12]=[C:11]([C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH:19]=1
Reactant: CCOC(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Yield: 72.2 %

Procedure:
5-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid ethyl ester (76 mg, 0.209 mmol) was saponified by treatment with 4 N LiOH (0.524 mL, 2.09 mmol) in MeOH (1.5 mL) at 40° C. for 15 h. 6 N HCl (2.09 mmol) was added and the mixture was diluted with water. The precipitate was collected by filtration, rinsed with EtOH and dried on vacuum to afford title compound (45 mg, 72%). The crude material was used in the next step.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:28][C:29]1[N:30]=[CH:31][N:32]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 4 h

Procedure:
A mixture of trityl chloride (17 g), triethylamine (8.5 ml), 4-methylimidazole (5 g) and toluene (40 ml) was stirred at 80° for 4 h and filtered, and the solid material was washed with toluene. It was then partitioned between water and chloroform, and the chloroform solution was separated, dried and combined with the dried toluene filtrate. The combined organic solutions were evaporated to dryness under reduced pressure, and the residue was triturated with diethyl ether to give 4-methyl-1-tritylimidazole, m.p. 214°-216°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([C:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[O:13][N:12]=2)=[O:16])[CH:32]2[CH2:33][CH2:34]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=1.69 min; Mass spectrum (ESI−): m/z=453 [M−H]−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:47][OH:48]>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH:47][OH:48])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.6 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide was prepared by the procedure of example 8 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 1.3 mmol) and hydroxylamine hydrocloride (0.1 g, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide as white solid (0.25 g, 50% yield): mp 148-150° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.19 (s, 3H, CH3CO), 3.19 (dd, J=5, 15 Hz, 1H, CH2), 3.47 (dd, J=10, 15 Hz, 1H, CH2), 4.02 (q, J=7.0 Hz, 2H, OCH2CH3), 5.75-5.82 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H), 7.02-7.07 (m, 3H, Ar), 7.36 (d, J=7.5 Hz, 1H, Ar), 7.54 (t, J=7.5 Hz, 1H, Ar), 8.64 (d, J=8.8 Hz, 1H, Ar), 9.40 (s, 1H, NHCO). 13CNMR (CDCl3): δ 14.5, 24.8, 34.6, 51.1, 64.7, 111.8, 113.5, 115.1, 115.9, 120.1, 122.6, 124.9, 131.0, 136.0, 136.7, 137.4, 140.0, 150.5, 167.1, 167.7, 169.3, 169.6 Anal Calcd for C22H21F2N3O7+0.3 H2O: C, 54.73; H, 4.51; N, 8.70. Found: C, 54.36; H, 4.25; N, 8.54, 0.1% H2O.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:22][C:23]([OH:25])=O)[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[O:25]=[C:23]1[CH2:22][C:3]2([CH2:4][N:5]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C@H:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:7]2)[CH2:2][NH:1]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(CN)(CC(=O)O)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)C2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of amino acid 2-((5S)-3-(aminomethyl)-1,5-bis(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (D6) (1.45 mmol) in CH2Cl2 (32 ml) was added 1-hydroxybenzotriazole (HOBT, 196 mg, 1.45 mmol, 1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 418 mg, 2.2 mmol, 1.5 eq), and N,N-Diisopropylethylamine (DIEA, 756 μl, 4.4 mmol, 3.0 eq). The reaction was aged at room temp. overnight. The solution was diluted with CH2Cl2 (100 ml) and washed with water (100 ml), 1N sodium hydroxide in water (100 ml) and brine (100 ml). The organics were dried over sodium sulfate, filtered, and concentrated with a second extract, to give crude product. This was purified on silica (1% to 20% MeOH/CH2Cl2 gradient) to give spirolactam (3S)-di-tert-butyl 8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (E6) (295 mg, 868 μmol). 1H NMR (CDCl3) δ1.35 (m, 18H), 1.91 (m, 2H), 2.3 (m, 3H), 3.2 (m, 2H), 3.3-3.5 (m, 2H), 4.10 (m, 1H), 6.21 (m, 1H); LCMS for C17H28N2O5 340.20 [M], found ES+ 341.2 [M+H]+, 285.2 [M+H, minus t-butyl]+, 285.2 [M+H, minus t-butyl, minus BOC]+ at 2.6 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: N
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 366) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0756 g, 16%). mp 167-170° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51-7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22ClN3O3S (0.25H2O): C, 57.79; H, 5.19; N, 9.62. Found: C, 57.78; H, 5.02; N, 9.40.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of piperidine-4-carboxylic acid in a 1:1 mixture of H2O/dioxane (0.4 M), 5 eq of K2CO3 were added before dropwise introduction at 0° C. of 1.1 eq of benzyl chloroformate. The reaction was stirred at RT overnight. The reaction was first washed with Et2O. The aqueous phase was acidified to pH 2 with aqueous HCl (6N) before being extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the product (91%); MS (ES+) m/z 264 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[CH:9])=[O:5].C=O.[CH:20](NC(C)C)(C)C>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[CH:8]=[C:9]=[CH2:20])=[O:5]
Reactant: C#CC(C)N(C(=O)COC)c1c(C)csc1C
Reactant: CC(C)NC(C)C
Agent: C=O
Solvent: C1COCCO1
Product: C=C=CC(C)N(C(=O)COC)c1c(C)csc1C
Temperature: 25 °C

Procedure:
To a solution of 10.0 g (0.04 mol) 2-methoxy-N-(2,4-dimethylthien-3-yl)-N-(1-butin-3-yl)acetamide in 80 ml dioxan are added 1.92 g (0.064 mol) paraformaldehyde, 4.85 g (0.048 mol) diisopropylamine and 1.89 g cuprous bromide and the mixture heated to reflux for 6 hours. The mixture is cooled to room temperature, filtered, evaporated in vacuo, the residue partitioned between ethylacetate and 1 M aqueous citric acid solution, the organic phase separated, washed subsequently with a saturated aqueous NaHCO3 -solution, water, is dried over MgSO4 and the solvent evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][CH2:24][CH2:25]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:24][F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCCF
Product: FCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIl was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-fluoroethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCCCCC(=O)c1cc(Cl)ccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture containing 15 g of 4-chloro-2-hexanoylaniline and 10.5 g of tosyl chloride is heated in 100 ml of pyridine at 100° C. overnight. The solvent is evaporated off, the residue is taken up with hydrochloric water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product crystallizes from isopropyl ether to give 14.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH:18]1([C:22]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:24][O:23]2)[CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][C:22]([CH:18]3[CH2:21][CH2:20][CH2:19]3)([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:23])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: Fc1ccc(C2(C3CCC3)CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CCC2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.5 g, 6 mmol) was dissolved in DMF (15 mL) and stirred for 5 min. Sodium hydride (720 mg, 10 mmol) was then added to it portionwise under nitrogen. This was followed by addition of 2-cyclobutyl-2-(4-fluorophenyl)oxirane (1.906 g, 18 mmol) at RT, and the reaction mixture was stirred for 18 h. After completion of reaction, the reaction mixture was poured into ice water and the product extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by silica gel (#100-200 mesh) column chromatography using 1% MeOH in DCM as eluent. The pure compound was converted into the oxalate salt. 1HNMR (CDCl3, Oxalate salt) d (ppm): 7.30 (d, 1H), 7.20 (m, 2H), 6.95 (m, 4H), 4.20 (m, 1H), 4.0 (m, 1H), 3.80 (m, 2H), 3.10 (m, 1H), 2.70 (m, 4H), 2.50 (s, 3H), 2.20 (m, 2H), 2.0 (d, 1H), 1.80 (t, 2H), 1.70 (m, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](Cl)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:16]1([CH3:18])[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[N+:21]=[N-:22]
Reactant: CC1(Cl)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(N=[N+]=[N-])CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
A mixture of 1-benzhydryl-3-chloro-3-methyl-azetidine (2 g, 7.39 mmol) and NaN3 (0.8 g, 12.31 mmol) was dissolved in DMF (30 mL) and the mixture was stirred at 100° C. overnight. The mixture was cooled to ambient temperature and partitioned between water (150 mL) and DCM (50 mL). The organic phase was washed with brine (3×30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give 3-azido-1-benzhydryl-3-methyl-azetidine as a yellow oil (2.1 g, 100%), which was used directly in the next step. LC/MS (Table 1, Method 2) Rt=0.915 min; MS m/z: 279 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([N:28]=[C:29]=[O:30])=[N:25][N:24]=2)[CH3:22])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCCC>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:30])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:25][N:24]=2)[CH3:22])=[CH:31][CH:32]=1
Reactant: CNCC(OC)OC
Reactant: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(C)cc2)s1)OC
Reaction time: 8 h

Procedure:
Methylaminoacetaldehyde dimethylacetal (1.8 grams, 0.015 mole) was added to a benzene solution containing 4.0 grams (0.015 mole) of the 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, topped on a roto-vac at 70° C. to form a viscous red-orange oil, which was redissolved in benzene-hexane mixture and left to stand overnight. Crystals formed which were removed by suction filtration, and dried in a vacuum oven at 70° C. to 3.2 grams of tan crystals of [5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl-1-methyl-1-(2,2-dimethoxyethyl)urea, (melting point 94°-100° C.).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[CH3:3][CH:2]([O:18][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: COc1cccc(O)c1
Product: COc1cccc(OC(C)CCCC(C)C)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with m-methoxy-phenol to obtain m-[(1,5-dimethyl-hexyl)-oxy]-anisole (boiling point =210°-212° C/12 mmHg);
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13]([OH:26])[C@@H:14]2[NH:24][CH3:25])[CH2:6]1)(=O)C.O>CO.[OH-].[K+]>[Cl:28][C@:7]12[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21][C@:20]1([CH3:23])[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C@@H:14]([NH:24][CH3:25])[C@H:13]([OH:26])[CH2:12]3)[CH2:9][C@H:8]2[Cl:27]
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3C[C@@H](Cl)[C@@]4(Cl)C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3C[C@@H](Cl)[C@@]4(Cl)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A stirred suspension of 5α,6β-dichloro-17β-methylamino-5α-androstane-3β,16α-diol 3-acetate (13 g) in methanol (105 ml) and aqueous potassium hydroxide solution (3.9 ml; 10 N) was heated under reflux for 1 hr., cooled and water was added to precipitate the product as a white solid, which was filtered off, and washed with water (wt. 11 g). Recrystallisation of a sample from methanol gave 5α,6β-dichloro-17β-methylamino-5α-androstane-3β,16α-diol as prisms, m.p. 194°-195° C. (decomp.).
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.C(N(CC)CC)C.Cl[C:16](=[CH2:19])[C:17]#[N:18]>C(O)C>[CH:3]1([C:4]2[N:6]=[C:17]([NH2:18])[CH:16]=[CH:19][N:5]=2)[CH2:2][CH2:1]1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccnc(C2CC2)n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
Cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) was dissolved in ethanol (25 mL) and triethylamine (1.26 g, 12.5 mmol), followed by the addition of 2-chloroacrylo-nitrile (870 mg, 10 mmol). The resulting orange-yellow solution was refluxed for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase Combiflash to afford 196a (300 mg, 27%) as a light brown solid. MS-ESI: [M+H]+ 136