Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.45 (d, 1H); 7.77 (d, 1H); 7.61 (d, 1H); 7.59 (s, 1H); 7.58 (m, 1H); 7.02 (d, 1H); 4.95 (m, 1H); 3.23 (m, 2H); 3.07 (m, 2H); 2.62 (m, 2H); 2.56 (m, 2H); 1.87 (d, 3H)).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1c(Br)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc(Br)c1N
Temperature: 25 °C

Procedure:
3,5-Dibromo-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dibromo-6-nitroaniline (500 mg, 1.69 mmol) and SnCl2.2H2O (1.90 g, 8.45 mmol) dissolved in 5 mL ethyl acetate and 2 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The thick yellow white emulsion was vacuum filtered and the filtrate extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale yellow oil which crystallized on standing to yield 400 mg (89%). 1H NMR (CDCl3) δ3.62 (br s, 4H, 2(NH2)); 6.78 (d, J=1.8, 1H, H-6); 7.01 (d, J=1.8, 1H, H-4).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH:23]=[CH2:24]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:39])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH:23]=[CH2:24]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: C=CCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.3 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 60 ml of dry methylene chloride, under nitrogen, and tooled to 0° C. is added 22.0 ml of triethylamine followed by a solution of 1.2 equivalents of 4'-(2-propenyloxy)-[1,1'-biphenyl]-4-carbonyl chloride in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 4.8 g of the desired product as a solid. M+H 421.2 M+Na 443.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH:15]([CH:16]=[N:17][O:18][CH3:19])[CH:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH3:19][O:18][N:17]=[CH:16][CH:15]1[C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH:14]1[CH2:13][NH:12][CH2:11]2
Reactant: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CON=CC1C2CNCC12c1ccc(Cl)c(Cl)c1
Yield: 219.5 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.40 g, 6.23 mmol) obtained in step-1 of example 7 in dry DCM (40 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde O-methyl oxime (1.95 g, 97%) as a white solid as a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][C:9]2([CH3:21])C=O)=[O:7])=[CH:4][CH:3]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].N[CH2:36]CC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10](/[CH:36]=[C:30]3/[C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25](=[S:26])[S:24]/3)=[C:9]2[CH3:21])=[O:7])=[CH:22][CH:23]=1
Reactant: NCCC(=O)O
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: COc1ccc2c(c1)CC(C)(C=O)N2C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(/C=C1\SC(=S)N(CC(=O)O)C1=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
To a room temperature solution of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindolecarboxaldehyde (535 mg, 1.63 mmols) and rhodanine 3-acetic acid (345 mg, 1.80 mmols) in 15 mL of acetic acid is added β-alanine (142 mg, 1.59 mmols). The solution is heated at reflux for 1.5 hours, then allowed to cool to room temperature. Filtration, washing with acetic acid, then hexane, provides 458 mg (56%) of (Z)-5-[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methylene]-4-oxo-2-thioxo-3-thiazolidine acetic acid as a yellow solid. An analytical sample is obtained by two recrystallizations from acetonitrile: mp 204-208° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[C:13]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:14]=[CH:15][C:16]([CH:19]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry tetrahydrofuran (64 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol). The yellow reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-biphenylacetic acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture turned dark in color and was allowed to stir at −78° C. for 45 min, at which time, a solution of iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. over a period of 15 h. The reaction mixture was quenched with water (100 mL), and the reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous layer was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a white solid: mp 131-133° C.; FAB-HRMS m/e calcd for C20H22O2 (M+H)+ 294.1620, found 294.1626.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=O.[C:18]1([C:24]2[N:29]=[N:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]([F:17])([C:3]1[N:28]2[N:29]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=[CH:26][C:27]2=[N:30][N:31]=1)[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 150 °C

Procedure:
A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.39 g, 2.1 mmol) and p-toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) in 5 mL of dioxane was heated at 150° C. for 1 hour in a microwave tube in the microwave. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give yellow solid as desired product 6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. MS (ESI pos. ion) m/z: 374.1 (M+H). Calc'd Exact Mass for C21H13F2N5: 373.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>>[NH2:26][C:22]1[O:1][C:2]2[C:10]([CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=3)[C:23]=1[C:24]#[N:25])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: COc1cccc(C=O)c1
Reactant: Cn1ccc2c(O)cccc21
Reactant: N#CCC#N
Product: COc1cccc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)c1

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3-methoxybenzaldehyde (38 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 64 mg (69%) of white solids. 1H NMR (CDCl3): 7.23-7.18 (m, 1H), 7.05-7.00 (m, 2H), 6.83-6.74 (m, 4H), 6.56 (d, J=3.0 Hz, 1H), 4.81 (s, 1H), 4.64 (brs, 2H), 3.76 (s, 6H).
Reaction SMILES: ClC1C=CC2[N:6]=C(N)N=C(OCC)C=2N=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:6])=[CH:19][CH:18]=1
Reactant: CCOc1nc(N)nc2ccc(Cl)nc12
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine (0.22 g), 4-fluorobenzaldehyde (2.0 mmol), acetic acid 5.0 mmol) and molecular sieves (10 mg) in DCE (3 mL) was stirred at room temperature for 30 minutes. NaBH(OAc)3 was added portion by portion. The mixture was stirred for 16 hours, and then quenched by adding saturated aqueous NaHCO3. The solution was partitioned with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash chromatography using hexane/ethyl acetate as eluting solvent. 0.33 g of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-yl)-(4-fluoro-benzyl)-amine (Example 61) was obtained (yield: 50%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z) 333.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[C:16](OCC)=[O:17])[CH:5]=[CH:4][C:3]1=2.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccccc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC1(C)CCC(C)(C)c2cc(-c3ccccc3CO)ccc21

Procedure:
Employing the same general procedure as used for the preparation of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(Z)-en-1-ol (Compound C), but instead using 420 mgs (1.25 mmols) ethyl 2-[5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2yl]benzoate (Compound H) and 6 mmols of diisobutylaluminiumhydride the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)[CH:24]=1>>[OH:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([NH:1][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)[CH:24]=2)[CH2:35][CH2:34]1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(N)nc23)c1
Product: Cc1nc(Nc2ncc3scc(-c4cccc(NS(C)(=O)=O)c4)c3n2)cc(N2CCN(CCO)CC2)n1
Yield: 53.7 %

Procedure:
N-(3-(2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (18 mg, 53% yield) was prepared in the same manner as Step 10 of Example 1 using N-(3-(2-aminothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (20 mg, 0.062 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (16 mg, 0.062 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:25][N:24]=[C:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:41][CH:42]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 5.5 h

Procedure:
Under stirring at 50° C, to a solution of di-tert-butyl(3-ethinyl pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-1 (2.0 g), 2-(4-(2-nitro-ethyl)-benzyloxy) pyridine described in Preparation Example 1-3-4 (2.44 g), triethylamine (0.086 uL) and tetrahydrofuran (20 mL) was added phenyl isocyanate (2.8 mL) divided into four portions over 5.5 hours. After the additions were finished, stirring was carried out at 50° C for another two hours. NH-silica gel was added to the reaction solution, and the solvent was concentrated under a reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=3:1). The resulting solution was concentrated under a reduced pressure and purified by silica gel chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain the title compound (2.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OC1CCOC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-nitropyrazole (1 g, 8.8 mmol), 3-hydroxy-tetrahydrofuran (779 mg, 8.8 mmol) and triphenylphosphine (2.81 g, 10.56 mmol) in THF (30 mL) at 0° C. was added diisopropylazodicarboxylate (2.27 g, 1 mmol) dropwise and the reaction was allowed to warm to rt overnight. The reaction was concentrated and purified on SiO2 (30% EtOAc/heptane) to give 4-nitro-1-(tetrahydrofuran-3-yl)-1H-pyrazole as a clear oil. The oil was then dissolved in EtOH (30 mL) and hydrogenated via H-cube with 10% Pd/C at 30 psi H2 for 3 hrs. The solvent was removed and the residue was purified on SiO2 (1%-10% EtOH/EtOAc) to give the title compound (1.0 g, 42% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.21 (m, 1H), 2.22-2.35 (m, 1H), 3.72-3.85 (m, 4H), 3.85-3.96 (m, 2H), 4.76-4.85 (m, 1H), 6.93 (s, 1H), 7.05 (s, 1H). m/z (APCI+) for C7H11N3O 154.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[O:5][N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.CCN(CC)CC>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4noc(-c5cccc(F)c5)n4)CC3)ccc2s1
Temperature: 90 °C

Procedure:
3-(Chloromethyl)-5-(3-fluorophenyl)-1,2,4-oxadiazole (242 mg, 1.02 mmol) and (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (309 mg, 1.0 mmol) in EtOH (8 mL) were treated with Et3N (0.5 mL, 3.57 mmol) and refluxed at 90° C. on a J-Kem™ block for 48 hours. The reaction product was concentrated and the product purified by flash chromatography (90:10 EtOAc-MeOH) to yield 3-(4-{[5-(3-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16]O)[C:9]=2[F:18])[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:45])C(=O)C1>ClCCl>[Br:45][CH2:16][C:10]1[C:9]([F:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Into a 250 mL round bottom flask was added (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol synthesized above (1.21 g, 4.54 mmol), dichloromethane (20 mL), PPh3 (1.19 g, 4.54 mmol), and the solution was cooled to 0° C. NBS (0.81 g, 4.54 mmol) was added and the reaction stirred for 2 hours at 0° C. The organics were washed with H2O and concentrated. The residue was purified by flash column chromatography eluting with 8% ethyl acetate/hexanes to give 3-bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 956 mg, 64%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].C([N:14]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])(OC(C)(C)C)=O.[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[Cl:34])=[CH:26][C:25]=1[O:35][CH3:36]>CS(C)=O>[ClH:34].[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[O:22][C@H:20]2[CH2:21][NH:14][C@H:15]([C:16]([O:18][CH2:1][CH3:2])=[O:17])[CH2:19]2)=[CH:26][C:25]=1[O:35][CH3:36]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: COc1cc2ccnc(Cl)c2cc1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@@H](Oc2nccc3cc(OC)c(Br)cc23)CN1
Product: Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Potassium t-butoxide (618 mg, 5.5 mmol) was added to a stirred solution of BOC trans-4-hydroxyproline (424 mg, 1.83 mmol) in DMSO (10 mL) at RT. The reaction mixture was stirred for 30 minutes, cooled to 15° C. and the product from Step 3 (500 mg, 1.83 mmol) added. The reaction mixture was stirred overnight and partitioned between ice-cold 10% citric acid and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and the solvent evaporated. The crude product was dissolved in EtOH (100 mL), cooled to 0° C., and HCl was bubbled through until saturated. The reaction mixture was allowed to warm to RT and stirred for 24 hours. The volatiles were evaporated and the residue azeotroped with EtOH (×4) to give the title compound as a tan solid (555 mg). LRMS ESI− (M+H)+395.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][NH2:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1cccnc1
Yield: 97.5 %

Procedure:
To a solution of 47 (104 mg, 0.45 mmol) in CH2Cl2 (1 mL) was added TFA (2 mL, excess) and the resultant solution was stirred at room temperature for 1 h. The solvent and excess TFA were removed under a stream of nitrogen and the residue was partitioned between HCl(aq) (1.0 M, 2 mL) and EtOAc (10 mL). The aqueous fraction was collected and subsequently washed with EtOAc (2×10 mL). To the remaining aqueous fraction was added CH2Cl2 (20 mL) and water (20 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the remaining aqueous fraction was extracted with CH2Cl2 (2×15 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford the title compound 48 (free base, 58 mg, 97% yield) as a brown oil. Due to the high potential of autooxidation, the dihydrochloride salt was made by dissolving the amine free base in Et2O and precipitating with etherial HCl. The solvent and excess HCl were removed in vacuo, the solid dihydrochloride was triturated with Et2O and collected by filtration to afford the title compound 48 (dihydrochloride, 91 mg, 99% yield) as a white solid: 1H NMR (D2O) δ 8.94 (m, 1H), 8.79 (m, 1H), 8.65 (m, 1H), 8.06 (m, 1H), 4.15 (s, 2H); LRMS (ESI) m/z calcd for C8H9N2 [M+H]+ 133. found 133; HRMS (ESI) m/z calcd for C8H9N2 [M+H]+ 133.0766. found 133.0763; HPLC>98% (tR=5.70 min, 60 (A):40 (B): 0.02 (C); tR=3.05 min, 60 (A):40 (B): 0.07 (C)).