Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4noc(N)n4)cc23)n1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
To a solution of 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (220 mg, 0.44 mmol) in 1,4-dioxane (2.2 mL) was added 10% aq NaOH (1.1 mL) and the reaction was heated at 100° C. for 2 h. The mixture was cooled to RT and treated with ice cold water (2.2 mL). The precipitate was collected through filtration and the crude product was purified with preparative HPLC (eluent: 20-100% MeCN in water with 0.01% TFA) to give 3-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (25 mg, 17%). MS (ESI, pos. ion) m/z: 336.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 9.10 (s, 1H), 8.16 (s, 1H), 7.75-7.64 (m, 4H), 7.52 (d, J=8.4 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 5.54-5.52 (m, 1H), 1.44 (d, J=6.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:20]3[N:21]=[CH:22][CH:23]=[N:19]3)=[CH:26][CH:27]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(Cn2nccn2)cc1
Product: C[C@@H](n1ncn(-c2ccc(Cn3nccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2H-1,2,3-triazol-2-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 21).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3]([NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[O:4]
Reactant: O=C(Br)C(Br)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(Br)CCCBr)CC1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
To a solution of crude 2,5-dibromopentanoyl bromide (6.50 g, 20 mmol) and triethylamine (3.06 g, 30.2 mmol) in CH2Cl2 (40 mL) cooled to 0° C. was added tert-butyl-4-aminopiperidine-1-carboxylate (4.23 g, 21.1 mmol) in one portion. The reaction was allowed to stir for 4 hours at which point the reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL). The organic layer was separated and the aqueous layer washed with additional CH2Cl2 (3×15 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude material was purified over silica gel (3:1 hexanes/EtOAc) to give tert-butyl 4-(2,5-dibromopentanamido)piperidine-1-carboxylate (8.00 g, 90%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold and vigorously stirred solution of dibenzylamine (918 g.) in 98% formic acid (105 ml.) is added dropwise, over 45 minutes, acetic anhydride (35 ml.). The resulting mixture is stirred for one hour at room temperature, then diluted with ice water (40 ml.) and kept overnight at 15° C. The solution is evaporated in vacuo to dryness and the residue extracted with ether. The ethereal solution is washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield N-formyl-dibenzylamine (9.9 g.) as a white solid, m.p. 53°-54.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[Cl:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ncc(Cl)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(Cl)s1
Reaction time: 3 h

Procedure:
2-Amino-5-chlorothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled and filtered to recover the desired product 5-chlorothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([S:24][CH2:26][C:27]5[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=5)[C:30]#[N:31])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc23)cc1
Yield: 76 %

Procedure:
In the same manner as in Example 7 and using 5-[3-[4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 76%) was obtained as colorless crystals.
Reaction SMILES: [NH:1]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:2]([C:27]([N:29]1[CH2:59][CH2:58][CH2:57][C@H:30]1[C:31]([NH:33][C@H:34]([C:42]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([CH3:53])=[O:52])=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[O:32])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:70][C:71]1[C:76]2[N:77]=[C:78]([C:80]#[N:81])[S:79][C:75]=2[CH:74]=[CH:73][CH:72]=1.C([SiH](C(C)C)C(C)C)(C)C.C(#N)C.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:2]([C:27]([N:29]1[CH2:59][CH2:58][CH2:57][C@H:30]1[C:31]([NH:33][C@H:34]([C:42]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([CH3:53])=[O:52])=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH3:41])=[O:32])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH2:6].[NH2:70][C:71]1[C:76]2[N:77]=[C:78]([C:80]#[N:81])[S:79][C:75]=2[CH:74]=[CH:73][CH:72]=1
Reactant: CC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCN(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: N#Cc1nc2c(N)cccc2s1
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCN(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
A solution of Cbz-Gln(Trt)ProLys(Me2)Lys(Ac)-aminocyanobenzothiazole (SEQ ID NO:3) (5.26) and triisopropylsilane (4 mL) in TFA/DCM (40 mL, 1/1) was stirred under a N2 atmosphere at −20° C. for 1 hour. After the conversion of starting material to a new species was confirmed by reverse phase HPLC (Agilent 1100 HPLC; column: Phenomonex Synergi, 4 μm 80 Å, 250×4.6 mm. method: 20% ACN to 55% ACN over 15 minutes, 1 mL/min, aqueous buffer contains 0.1% TFA v/v), the reaction mixture was concentrated. The resulting viscous sludge was then flooded with diethyl ether (200 mL), agitated for 5 minutes, and the solids collected via centrifugation and dried under full vacuum to provide crude Cbz-GlnProLys(Me2)Lys(Ac)-aminocyanobenzothiazole (SEQ ID NO:4) (4.4 g).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[F:16][C:17]([F:27])([F:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[F:16][C:17]([F:27])([F:26])[C:18]1[C:20]2[C:25]([C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2]=1[C:3]=34)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2c(C(F)(F)F)c3ccccc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 2,2,2-trifluoroacetophenone:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:6]([N:9]=[C:10](/[CH:12]=[CH:13]/[C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[C:16]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)c(C)n2nc(/C=C/c3nc(N4CCCC4)nn3C)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc12
Reaction time: 5 h
Yield: 67.6 %

Procedure:
Ethyl acetate was added to (E)-6-chloro-5,8-dimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyridine (15 mg). Palladium (5 wt. %) on barium sulfate (20 mg) was added. The mixture was stirred for 5 h under a hydrogen atmosphere and then filtered over Celite. The mixture was concentrated and purified by preparative HPLC to give the desired product (10.2 mg, 67.8%) as a light yellow powder. MS: m/z=360.5 (M+H+)
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:22][C:23]1([CH3:26])[CH2:25][O:24]1>>[Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:22][C:23]([CH3:26])([OH:24])[CH3:25])[CH:6]=1
Reactant: CC1(C)CO1
Reactant: FC(F)(F)c1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(Br)c(C(F)(F)F)n1
Temperature: 90 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethyl-1H-pyrazole (200.0 mg, 0.9304 mmol), K2CO3 (200.0 mg, 1.447 mmol) and DMF (3 mL, 40 mmol) was added 2,2-dimethyloxirane (0.5 mL, 6 mmol), and the mixture was heated to 90° C. for 2 h in a sealed tube. The material was transferred to a separation funnel, extracting with EtOAc and washing with water (3×). The organic layer was loaded onto silica gel for column chromatography, eluting with 10-30% EtOAc/heptane. The fractions containing the 3-trifluoromethyl product were concentrated in vacuo to afford the title compound as a brown oil. 1H NMR (400 MHz, CD3OD): δ=1.17 (s, 6H), 4.13 (s, 2H), 7.87 (s, 1H). MS (ES+): m/z=287.00/289.00 (100/100) [MH+]. HPLC: tR=1.35 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[C:17]1([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:23]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3 -thiazol-4-yl)phenyl]acetamide and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (8.6 mg) with purity >80%. MS (pos) m/z 450.3.
Reaction SMILES: C(N1CCC(CO)C(O)C1)C1C=CC=CC=1.ClC(OCC1C=CC=CC=1)=O.[OH-].[Na+].[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C@@H:43]([CH2:46][OH:47])[C@H:42]([OH:48])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.O.O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH:42]([OH:48])[CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](CO)[C@H](O)C1
Agent: [Pd+2]
Agent: O=C(Cl)OCc1ccccc1
Agent: OCC1CCN(Cc2ccccc2)CC1O
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CO)C(O)C1
Reaction time: 0.5 h

Procedure:
A solution of the 1-benzyl-4-hydroxymethyl-piperidin-3-ol from Step 1 above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psi over 20% palladium hydroxide on charcoal (10 g) for 48 h in three batches. The combined reaction mixtures were filtered and the filtrate evaporated to give an oil. This was dissolved in water (100 mL) and dioxane (100 mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) was added slowly, with addition of 1M NaOH to maintain a pH of 10–11. After 30 min, the cooling bath was removed and reaction mixture stirred for 30 min. The reaction mixture was concentrated to remove dioxane and the residue extracted with EtOAc (×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give a mixture of cis and trans 3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester products. Purification by flash column chromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cis isomer (major) and the lower Rf trans isomer (minor).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].[H-].[Na+].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH:18]([CH3:19])[CH3:20])[O:21][C:22](=[O:27])[CH:23]=1
Reactant: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 40 g (142 mmol) of 1-(4-benzyloxyphenyl)-4-methyl-pentan-3-one (prepared in Example F), 41.2 g (355 mmol) of methyl acetoacetate, 14.2 g (355 mmol) of 60% NaH dispersion in mineral oil, 216 mL (1.64M, 355 mmol) of n-butyllithium and 700 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4), and the solvents were evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[O:9]2)[CH:7]=1.[Cu][C:22]#[N:23].C(Cl)Cl.[OH-].[NH4+]>CN(C=O)C>[CH3:20][O:19][C:5]1[CH:4]=[CH:3][C:2]([C:22]#[N:23])=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: N#C[Cu]
Reactant: COc1ccc(Br)cc1C1Oc2ccccc2NC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1C1Oc2ccccc2NC1=O
Temperature: 160 °C
Yield: 88.5 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-2H-1,4-benzoxazin-3(4H)-one (I11) (0.90 g, 2.70 mmoles) in DMF (10 mL) was added copper (I) cyanide (1.3 g, 5 equiv.) and the mixture heated at 160° C. for 12 hours. The mixture was cooled and methylene chloride (100 mL) and aqueous ammonium hydroxide (10 mL) were added. The methylene chloride layer was separated and dried over MgSO4 which afforded the required product (I12) (0.67 g, 89%) upon evaporation in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(=O)[nH]cnc2c1
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Pd/C (100 mg) was added as a single portion to a degassed and flushed (3×Ar) suspension of 7-nitroquinazolin-4-one (1.15 g, 6.02 mmol) in methanol (150 mL). The resulting black mixture was degassed, flushed with hydrogen and allowed to stir for 4 hours. The mixture was filtered through celite, washed well with methanol, and the filtrate concentrated to give a tanned solid. This was purified by column chromatography (silica) using 10% methanol/ethyl acetate as the eluent. Combined fractions gave a beige solid (949 mg, 98% yield).
Reaction SMILES: [Cl:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([Br:13])[CH:3]([C@H:5]1[C@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])[Br:4].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([Br:13])[CH:3]([C@H:5]1[C@H:7]([C:8]([Cl:23])=[O:9])[C:6]1([CH3:12])[CH3:11])[Br:4]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Yield: 94 %

Procedure:
14 g of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethyl-cyclopropane-1-(R,S)-carboxylic acid were dissolved in 100 ml of carbon tetrachloride, 75 g of thionyl chloride were added and the mixture was heated to the reflux temperature for 4 hours. The solvent and excess thionyl chloride were then stripped off in vacuo. 13.7 g (77.8% of theory) of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethyl-cyclopropane-1-(R,S)-carboxylic acid chloride were obtained as a viscous oil. ##STR14##
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH3:29])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7]1)C.CC[O:18]C(C)=O>O1CCOCC1.O.C(O)CCC.O=[Os](=O)(=O)=O>[O:15]=[C:12]1[N:11]2[CH:6]([CH2:4][CH2:3][CH2:2][CH:1]=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: CCCC(C)C1CCCc2noc(=O)n21
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CCCCO
Solvent: O
Solvent: C1COCCO1
Product: O=CCCCC1CCCc2noc(=O)n21

Procedure:
The product of Example 27 (0.42 g; 2 mmol) and NaIO4 (0.86 g; 4 mmol) were dissolved in a mixture of 12 mL of dioxane and 8 mL of H2O. Two drops of a 2% solution of OsO4 in n-butanol was added to the mixture. The reaction mixture was stirred until tlc (100% EtOAc) indicated that the starting material was consumed. A precipitate had formed and was filtered. This solid was washed with dioxane. The filtrate was concentrated and the residue was partitioned between H2O/CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford the title compound as an oil. 1H NMR (CDCl3) d 1.4-2.2 (m, 7H); 2.3-2.7 (m, 4H); 3.7-3.9 (m, 2H); 9.7 (s, 1H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.O1CCCC1.[CH2:18]([NH2:21])[C:19]#[CH:20]>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:18][C:19]#[CH:20])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC(=O)c1ccccc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
Isatoic Anhydride (4.00 g, 24.5 mmol) was dissolved in tetrahydrofuran (100 mL, 1.230 mol) at 0° C. Prop-2-ynylamine (2.52 mL, 36.8 mmol) was added and the reaction was stirred for 2 hours and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-amino-N-prop-2-ynyl-benzamide as a white solid (4.27 g, 100%). m.p.=75° C.; LCMS (m/e) 120 (M-NHCH2CCH); 1H-NMR (CDCl3, 400 MHz) δ 7.35 (d, 1H, J=7.9 Hz), 7.24 (dd, 1H, J=7.3 and 8.2 Hz), 6.73-6.64 (m, 2H), 6.19 (bs, 1H), 5.56 (bs, 2H), 4.26-4.20 (m, 2H), 2.29 (t, 1H, J=1.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:22][CH:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[OH:20])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cncc(C2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.6 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) was dissolved in DMF (3 ml), sodium hydride (106 mg, 2.65 mmol) was added and the mixture was stirred at RT for 15 min. 3-Oxiranyl-pyridine (214 mg, 1.76 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 3 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (2×60 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-3-yl-ethanol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.7 (d, 1H), 8.53 (s, 1H), 8.4 (d, 1H), 7.85 (t, 1H), 7.25 (s, 1H), 7.08 (t, 1H), 6.9 (d, 1H), 5.28 (t, 1H), 5.03 (t, 1H), 4.42 (s, 2H), 3.76 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.2 (m, 2H), 2.7 (m, 1H), 2.38 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC provides diastereomers II-131a-d.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC(O)=O>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
To a mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (887.5 mg, 2.067 mmol) and K3PO4 (1494 mg, 7.038 mmol), 1,4-dioxane (10.0 mL) was added, followed by water (10.0 mL). The mixture was heated at 100° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). AcOH (1313 mg, 21.86 mmol) was added to adjust the pH to 5. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-15% MeOH in DCM) to give the sub-title compound as a yellow solid (632.0 mg, 76%). LCMS calc. for C18H14BrN2O4(M+H)+: m/z=401.0. found 401.0.