Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10](C(=O)C)[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44]([OH:46])[CH3:45]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:44]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:30])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:29])(=[O:46])[CH3:45]
Reactant: CCO
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Clc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccccn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (108 mg, 0.259 mmol), 2-chloropyridine (35.3 mg, 0.311 mmol), potassium carbonate (108 mg, 0.778 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.99 mg, 0.013 mmol) in ethanol (2.5 mL) and toluene (2.5 mL) was degassed for 15 min under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (30 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP (reversed phase, water/acetonitrile, modifier: ammonium bicarbonate) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (32.1 mg, 0.087 mmol, 34%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:21]=1>CN(C=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:23]=[C:24]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[CH:25]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 110 °C
Yield: 70.1 %

Procedure:
A mixture containing 5-methyl-1H-pyrazol-3-amine 187 mg, 1.93 mmol), N,N-diisopropylethylamine (503 μl, 2.89 mmol), sodium iodide (289 mg, 1.93 mmol) and DMF (50 mL) was treated with 4,6-dichloro-2-(2-chlorophenyl)pyrimidine (500 mg, 1.93 mmol). The reaction mixture was then heated at 110° C. for 48 h before being cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with MeOH/DCM, 5/95) to give the title compound as a solid (433 mg, 70%). MS (ES+) m/e=320. 1H NMR: (DMSO) 2.18-2.23 (3H, m), 7.40-7.70 (6H, m), 10.32 (1H, s), 12.10 (1H, brs)
Reaction SMILES: CS(O)(=O)=O.[Cl:6]C1C2C(=CC=CC=2)C(CNC(O)C(C)CO)=C2C=1C=CC=C2.[CH3:29][O:30][CH2:31][CH2:32][O:33][C:34]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH:48]=O)=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2.[NH2:50][C:51]([CH3:56])([CH2:54][OH:55])[CH2:52][OH:53]>>[ClH:6].[CH3:29][O:30][CH2:31][CH2:32][O:33][C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]([CH2:48][NH:50][C:51]([CH3:56])([CH2:54][OH:55])[CH2:52][OH:53])=[C:42]2[C:47]=1[CH:46]=[CH:45][CH:44]=[CH:43]2
Reactant: CC(CO)C(O)NCc1c2ccccc2c(Cl)c2ccccc12
Reactant: CC(N)(CO)CO
Reactant: COCCOc1c2ccccc2c(C=O)c2ccccc12
Agent: CS(=O)(=O)O
Product: COCCOc1c2ccccc2c(CNC(C)(CO)CO)c2ccccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 2B, (10-methoxyethoxy)anthracene-9-carbaldehyde (27A) and 2-amino-2-methyl-1,3-propanediol gave 2-(((10-(2-methoxyethoxy)-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride.1/4H2O mp 182°-183° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH2:33][NH:32][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1
Reactant: NCCO
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)NCCO)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminoethanol (8 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration in vacuo, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(2-hydroxyethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (6 mg, 10%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.18 (dd, 1H, J1=6.6 Hz, J2=1.8 Hz), 8.08 (d, 1H, J=2.1 Hz), 8.04-8.01 (m, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.60-7.55 (m, 1H), 6.39 (d, 1H, J=7.5 Hz), 6.29 (d, 1H, J=8.7 Hz), 4.30-4.26 (m, 1H), 3.78-3.69 (m, 3H), 3.58-3.49 (m, 3H), 2.21-2.08 (m, 3H), 1.81-1.78 (m, 1H), 1.19 (d, 3H, J=5.1 Hz). LC-MS: [M+H]+, 458, tR=1.52 min, HPLC: 96.29% at 214 nm, 96.47% at 254 nm, tR=5.332 min.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=[C:7]2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28]/[C:17](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=3)=[CH:30][CH:31]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2nc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(n1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (2.6 g, 7.10 mmol) in DMF (5 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (1.94 g, 7.43 mmol) at RT and the reaction mixture was heated to 110° C. and stirred for 1 h. The reaction mixture was allowed to cool to RT, treated with piperidine (3 mL) and stirred for 30 min. The reaction mixture was evaporated and the resultant residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(O)[CH2:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCCCCC1(O)CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1=CCC(c2ccc(OCC)c(F)c2F)CC1

Procedure:
A solution of 128.0 g of 4-(4-ethoxy-2,3-difluorophenyl)-1-pentylcyclohexanol in 1 l of toluene was refluxed in a water separator with addition of 5.0 g of toluene-4-sulphonic acid monohydrate. When all the water had been removed, the mixture was subjected to conventional work-up, giving 1-ethoxy-2,3-difluoro-4-(4-pentylcyclohex-3-enyl)benzene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:17]1[C:18]([O:19][CH3:20])=[CH:2][C:3]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])=[C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH:16]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C=C2C(=O)Nc3ccccc32)c(-c2ccccc2OC)cc1OC
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.20 g, 0.56 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.1 ml, 2.2 mmol). To this mixture was added 2-methoxyphenylboronic acid (0.09 g, 0.62 mmol), and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. Chromatography (silica, 30-40% ethyl acetate/hexanes) afforded 0.14 g (64%) of 3-(4,5,2′-trimethoxy-biphenyl-2-ylmethylene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[C:21]1([C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(C)[C:28]([OH:30])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=C[C:42]=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:2]([C:4]1[N:5]=[C:6]([CH:9]([NH:20][C:28](=[O:30])[C@H:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:26]2[CH:42]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: On1nnc2ccccc21
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1csc(C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@@H](Cc2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and 1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF (10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.502 g, 2.62 mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.903 g (70% yield) of the desired product which is used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 13.6 g (100.0 mmol) of 4-hydroxyacetophenone in 100 mL of DMF was added 20 g (144 mmol) of K2CO3, then 12 mL (101 mmol) of benzyl bromide. The reaction was stirred for 1.5 h at ambient temperature, then poured into 300 mL of H2O to give a white precipitate. This was filtered and washed with 50 mL of H2O. The product was taken up in 100 mL of CH2Cl2, and the H2O that separated was drained. The organic layer was extracted with H2O (1×25 mL) and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to 22.1 g (98%) of a white solid as the titled compound. MS (ESI) m/e 226.9, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 3H) 5.21 (s, 2H) 7.11 (m, 2H) 7.41 (m, 5H) 7.92 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]2)[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5][O:4]1)[CH3:2].C1(OC([Cl:35])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[ClH:35].[ClH:35].[CH2:1]([C:3]1([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC1(CCN2CCN(C)CC2)OCCc2cc(OC)c(OC)cc21
Solvent: Cc1ccccc1
Product: CCC1(CCN2CCNCC2)OCCc2cc(OC)c(OC)cc21
Product: Cl
Yield: 209.1 %

Procedure:
A mixture of 20 g of crude 1-[2-(1-ethyl-3,4-dihydro -6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-methylpiperazine and 7.5 g of phenylchloroformate in 150 ml of toluene was refluxed for 4 h. The toluene was evaporated, and the residue dissolved in a mixture of 150 ml of ethanol and 150 ml of 50% aqueous sodium hydroxide and refluxed for 2 h. The ethanol was evaporated and the residue dissolved in diethyl ether. The solution was washed, dried and concentrated and the residue was dissolved in acetone with anhydrous hydrochloric acid to yield 20.4 g (87.9%) of crude 1-[2-(1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]piperazine dihydrochloride.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH:16][CH:17]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19][CH:18]1[CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Cl)(Cl)Cl.CCOC(C)=O>CC(C)=O>[CH3:25][C:21]1([CH3:24])[O:20][CH:19]([CH:18]([CH2:17][OH:16])[CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:23][O:22]1
Reactant: CC1(C)OCC(O)C(CNC(=O)OCc2ccccc2)CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OCC(C(CO)CNC(=O)OCc2ccccc2)O1
Temperature: 25 °C
Yield: 47 %

Procedure:
Camphorsulfonic acid (0.069 g, 0.296 mmol) was added to a solution of benzyl ((5R/S,6R/S)-6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)methylcarbamate (1.83 g, 5.92 mmol) in acetone (50 mL) and the solution was stirred at RT. After 40 mins chloroform was added and the solution was washed with aq NaHCO3 and then processed normally. Chromatography (EtOAc/Hex 1:1, and then 3:1) gave firstly benzyl (RS)-2-((RS)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropylcarbamate (0.86 g, 2.78 mmol, 47.0% yield) and then benzyl ((4RS,5RS)-4-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methylcarbamate (0.942 g, 3.05 mmol, 51.5% yield) as syrups; compound 10.3 13C NMR (CDCl3) δ 157.6, 136.8, 128.9, 128.6, 128.5, 109.3, 76.4, 68.0, 67.3, 61.3, 44.3, 39.9, 26.9, 25.7; compound 10.4 13C NMR (CDCl3) δ 157.1, 136.8, 128.9, 128.6, 128.5, 99.0, 72.5, 69.1, 67.3, 64.2, 62.3, 40.3, 36.7, 29.1, 20.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1COCC1>[CH2:21]([O:20][C:18]([NH:17][C@H:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:16][C@H:13]1[CH:14]([OH:15])[N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To a cooled (0° C.) solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (4.6 g, 12.3 mmol) in CH2Cl2 (100 mL) was added DIBAL-H (37 mL of a 1.0 M solution in THF). The mixture was stirred for 105 min at 0° C. The reaction was quenched with 1N HCl and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,2S,5R,7R/S)-2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a mixture of diastereomers. MS found: (M−H2O+H)+=359.2. This material was dissolved in THF (20 mL) and added by cannula (6 mL THF rinse) to a pre-mixed (15 min), pre-cooled (0° C.) solution of ethyltriphenylphosphonium iodide (6.4 g, 14.8 mmol) and KHMDS (31 mL of a 0.5 M solution in toluene). The reaction was stirred for 25 min at 0° C. before being quenched with the addition of sat. NH4Cl. The biphasic mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1R,3R,4S)-(4-benzyloxycarbonyl-amino-3-propenyl-cyclohexyl)-carbamic acid tert-butyl ester as a colorless oil (3.44 g, 72% yield). MS found: (M+H)+=389.3.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])[CH2:18][CH2:17]1>>[ClH:15].[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:31])[F:32])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Product: CCCCCNC(=O)c1ccc(N2CCC(Nc3ccccc3C(F)(F)F)CC2)nn1
Product: Cl
Yield: 37 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to react with piperidin-4-yl-(2-trifluoromethylphenyl)amine, the title compound was obtained as a white powder in 37% yield. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J=5.4 Hz, 1H), 7.94 (d, J=9.9 Hz, 1H), 7.66 (d, J=9.6 Hz, 1H), 7.50-7.40 (m, 2H), 7.05-7.02 (m, 1H), 6.72 (t, J=7.5 Hz, 1H), 4.48 (d, J=13.2 Hz, 2H), 3.83 (br., s, 1H), 3.34-3.26 (m, 4H), 2.02 (d, J=10.8 Hz, 2H), 1.65-1.50 (m, 4H), 1.37-1.16 (m, 4H), 0.86 (t, J=6.3 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) δ 162.0, 157.3, 144.4, 144.1, 133.6, 127.9, 126.8, 126.5, 123.2, 116.5, 115.7, 113.0, 112.2, 48.9, 44.5, 30.6, 28.8, 28.6, 21.8, 13.9. MS (ES+) m/z 436.2 (M+1-HCl).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:18]([O:22][C:23]([NH:24][NH:25][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-oxopiperidine-1-carboxylate (4.08 g, 17.5 mmol) in 50 mL of methanol was added tert-butylcarbazate (2.31 g, 17.5 mmol). The mixture was stirred at room temperature for 3 h and then was concentrated in vacuo to afford a white foam. This residue was taken up in 50 mL of 50% glacial acetic acid. To the resulting suspension was added sodium cyanoborohydride (1.1 g, 17.5 mmol) portionwise with vigorous stirring at room temperature. After the addition was complete the mixture was stirred for 3 h at room temperature. The mixture was neutralized with 1N NaOH/solid NaOH and then extracted twice with methylene chloride. The combined organics were washed with sat'd aq sodium bicarbonate and brine, dried (Na2SO4), filtered through a pad of silica gel and concentrated in vacuo to afford Example 12A, benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate, as a solid (6.0 g) which was pure enough to be used without purification. LRMS (ESI): 350.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([CH3:7])[CH3:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.CCN(CC)CC>C1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:27](=[S:28])[NH:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(C(C)(C)C(=O)CN)cc1OC
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Yield: 90.7 %

Procedure:
A mixture of 1-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride (210 mg, 0.77 mmol), 4-fluorophenyl isothiocyanate (141 mg, 0.92 mmol), and Et3N (0.16 mL, 1.15 mmol) in benzene (7 mL, anhyd) was refluxed for 8 h. The volatiles were removed under reduced pressure. The residue was combined with acetic acid (5 mL) and heated at reflux 4 h. After concentration, the crude product was purified by flash chromatography to provide 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (260 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 6.87 (t, 2H), 6.80 (d, 1H), 6.67 (d, 1H), 6.62-6.59 (m, 2H), 6.48 (d, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H), 1.44 (s, 6H).