Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1N
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1NC(=O)N(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in pyridine (5 ml) is added N,N-dimethylcarbamic chloride (0.42 ml), and the mixture is stirred at 60-70° C. for two hours. The mixture is made acidic with hydrochloric acid, and then extracted with ethyl acetate. The mixture is washed with a saturated aqueous sodium hydrogen carbonate solution, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:10→1:1→3:1), and recrystallized from ethanol/diethyl ether to give 7-chloro-1-(3-methoxy-4-dimethylaminocarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white plates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:26]([CH3:42])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@H:28]1[C@@H:27]([S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:26]([CH3:42])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:43])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1S(C)(=O)=O
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexylcarbamate in DCM (0.02 M) was added TFA (30.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo; the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 73% yield. LC/MS (m/z)=519.2 (MH+), Rt=0.58 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.52 (s, 1H), 8.51-8.54 (m, 2H), 8.34 (dd, J=8.0, 4.0, 1H), 8.20 (dd, J=8.0, 8.0, 1H), 8.15 (dd, J=16.0, 4.0, 1H), 7.67-7.74 (m, 1H), 7.36 (dd, J=8.0, 8.0, 2H), 7.28 (d, J=4.0, 1H), 3.77-3.79 (m, 1H), 3.18 (s, 3H), 3.02-3.20 (m, 1H), 1.94-2.40 (m, 5H), 1.57-1.62 (m, 1H), 1.24 (d, J=8.0, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (60%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([CH2:19][CH:20]=O)[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([CH2:20][CH2:19][C:12]2[N:13]([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[N:11]=2)[CH2:39][CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: Cn1c(CC=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1c(CCN2CCN(C(=O)c3ccccc3)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step 2 was dissolved in MeOH and treated with sodium acetate (1.6 eq.), 1-benzoylpiperazine (2 eq.), and sodium cyanoborohydride (1.43 eq.). The mixture was left stirring at room temperature for 1 hour. The reaction mixture was concentrated and the title compound was obtained by RP-HPLC purification (C18, eluting with water and acetonitrile containing 0.1% TFA).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[O:4][N:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:3][C:2](=[CH:6][C:5](=[O:4])[CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:1]
Reactant: Cc1cc(CCC(C)C)on1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)CCC(C)C

Procedure:
3-Methyl-5-(3-methylbutyl)isoxazole (3.90 g, 25.5 mmol) [synthesis analogous to C. Kashima et al., Bull. Chem. Soc. Jpn. 46, 310-313 (1973)] is introduced into 80 ml of ethanol, platinum (IV) oxide catalyst (390 mg, 1.72 mmol) is added, and the mixture is then hydrogenated under atmospheric pressure hydrogen for 2 h (slightly exothermic reaction). The catalyst is filtered off, the filtrate is concentrated, and the residue is purified by chromatography on a Biotage 40M cartridge (mobile phase: isohexane/ethyl acetate 3:1). The product fractions are concentrated. The resulting residue is an oil, which crystallizes after a short time. Drying in vacuo results in 3.41 g (86% of theory) of the title compound.
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:30][CH:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:30][CH:29]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3ccccn3)cc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-2-oxo-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (3.00 g, 5.33 mmol) in methanol (20 ml) was added a solution (12.8 ml, 6.4 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (2.67 g, 93%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH3:16][N:17]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Reactant: CNc1ccccc1
Solvent: CCO
Product: CN(c1ccccc1)c1ncnc2cc(C(F)(F)F)ccc12
Yield: 42.9 %

Procedure:
2.5 g of 4-chloro-7-trifluoromethylquinazoline and 1.2 g of N-methylaniline were added, in turn, to 5 ml of ethanol, and then the mixture was heated until it became a homogeneous solution. At the end of this time, the ethanol was distilled off and the residual crystals were recrystallized from a 9:1 by volume mixture of ethanol and water, to give 1.4 g (yield 46%) of the desired Compound No. 73 in the form of colourless granules melting at 135°-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28]CC)=[O:27])=[C:24]([CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[N:23]=[C:22]2[CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[N:23]=[C:22]2[CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Example 4, 0.78 g of ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxylate [prepared as described in step (d) above] was hydrolyzed, using 209 mg of lithium hydroxide monohydrate, to afford 0.62 g of the title compound as crystals, melting at 207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:23][CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (830 mg) in DMF (10 mL) was added sodium azide (178 mg), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (723 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.ClC1C([Pd-](Cl)Cl)=NC=CC=1.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[CH:3]=[C:2]([CH3:38])[N:7]=[CH:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CN1CCN(C)C1=O
Agent: Clc1cccnc1[Pd-](Cl)Cl
Agent: C[Zn+]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(6-chloro-4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 0.193 mmol, example 201) in THF (2 mL) were added methylzinc chloride (0.145 mL, 0.29 mmol, 2M solution in THF, CAS RN 5158-46-3), 1,3-dimethyl-2-imidazolidinone (0.4 mL, CAS RN 80-73-9) and (1,3-bis(2,6-diisopropyl-phenyl)imidazolidene) (3-chloropyridyl) palladium(II) dichloride (PEPPSI-IPr, 2.63 mg, 3.87 μmol, Aldrich). The reaction mixture was stirred at 50° C. for 30 min. and then poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography, using preparative HPLC (Gemini NX column) eluting with a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.073 g; 76%). MS (ESI): m/z=497.11 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A solution of 0.65 g (5.4 mmol) 4-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2-quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 4-(2-quinolinylmethyloxy)benzaldehyde.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]#[N:22]>[Cl-].C[N+](CCCC)(CCCC)CCCC.O.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:21]#[N:22]
Reactant: ClCCN1CCCCC1
Reactant: N#CCc1ccccc1Cl
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(CCN1CCCCC1)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
A reaction vessel under a nitrogen atmosphere containing 74.0 kg of 1-(2-chloroethyl)piperidine, monohydrochloride at 10° C. was charged with 255.4 kg of sodium hydroxide solution (50% w/w). The reaction was warmed to 30° to 35° C. and 67.0 kg of 2-chlorobenzeneacetonitrile and 1.4 kg of methyltributylammonium chloride (75% w/w in water) were added. The reaction was stirred at 40° C. for 6 h and then heated to 60° C. for at least 6 h. When the reaction was completed as indicated by gas chromatographic analysis, the reaction mixture was cooled to 25° C. The reaction mixture was diluted with 335 L of water and 134 L of toluene and stirred for 30 min. After separation of the layers, the organic phase was extracted with 275 L of hydrochloric acid (2N). The acidic extract was washed twice with 50 L of toluene, basified with 30 L of sodium hydroxide solution (50% w/w) to a pH>12 and extracted twice with a total of 368 L of heptane. The combined organic phase was washed with 50 L of water and filtered through a layer of diatomaceous earth. The filtrate was dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 104.5 kg (90.0%) of the title product α-(2-chlorophenyl)-1-piperidinebutanenitrile as an oil. Analysis calcd for C15H19ClN2 : C,68.56; H,7.29; Cl,13.49; N,10.66. Found: C,69.64; H,7.53; Cl,12.45; N,9.75. The crude product (oil) was carried forward to the next step without purification. The purity of the title compound was estimated to be 98% based on GC Method B.
Reaction SMILES: I[C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1.C[Sn](C)C.C[Sn](C)C.[C:45]([N+:49]#[C-])(C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[C:45]([C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:5][C@@H:4]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1)#[N:49]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Cc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](C#N)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
The following preparation should to be performed under a hood and all precautions taken not to inhale any of reagent fumes. A suspension of 3'-deoxy-3'-iodo-5'-O-tritylthymidine (Verheyden, et al., J. Org. Chem. 1970, 35, 2868) (60 g, 0.1 mol), hexamethylditin (36 g, 22.7 ml, 0.11 mol), t-butylisocyanide (166 g, 225 ml, 2 mol), and AIBN (1.6 g, 10 mmol) in toluene (freshly distilled over Na/benzophenone, 2 lt) was thoroughly deoxygenated by bubbling argon through the reaction mixture for 30 min. and then heated at 80° C. for 13 h. The reaction mixture was cooled at 60° C. and AIBN (1.6 g, 10 mmol) was added and heating continued for 24 h. During this period addition of AIBN was repeated for 3 times in an identical manner. The reaction mixture was cooled to room temperature and transferred on the top of a prepacked silica gel column (1.5 kg, in hexanes) and eluted with hexanes: Et2O (100% hexanes→100% Et2O with a 10% gradient change each time using 1 lt of eluent). Most of the impurities were removed during the gradient elution as non-polar compounds. Final elution with Et2O (2 lt), pooling and evaporation of appropriate fractions gave two compounds in the order these were collected. (i) 12.93 g (25%) of 3'-C-Cyano-3'-deoxy-5'-O-tritylthymidine as white powder (crystallized from toluene/Et2O, mp 153°-157° C.); 1H NMR (CDCl3) δ 8.83 (s, 1, NH), 7.04-7.4 (m, 18.5, TrH, C6H, and 0.5 ArH from toluene), 6.10 (dd, 1, H1', J1',2' =4.1 Hz, J1',2" =7.1 Hz), 4.20 (m, 1 , H4', J3',4' =8.4 Hz, J4',5' =2.8 Hz), 3.33-3.60 (m, 3, H5', 5", 3'), 2.68 (m, 1, H2', J2', 2" =13.8 Hz), 2.52 (m, 1, H2"), 2.28 (s, 1.5, 0.5 CH3 from toluene), and 1.50 (s, 3, CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:13]1[O:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=1)CCC.F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[O:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=1
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccccn2)on1
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A 20 mL BIOTAGE® microwave vial and stir bar were oven dried and cooled under a stream of dry nitrogen. The vial was flushed with argon and charged with dichlorobis(triphenylphosphine)-palladium(II) (96 mg, 0.137 mmol) and dioxane (12 mL) followed by sparging with argon for several minutes. 2-Bromopyridine (0.217 mL, 2.28 mmol), ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (980 mg, 2.28 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.047 mL, 0.228 mmol) were added and sparging was continued for several minutes. The vial was sealed and processed in a BIOTAGE® microwave at 150° C. for 60 minutes. The solution was cooled, evaporated, and the residue was loaded onto a 120 g Isco silica gel cartridge, which was pre-equilibrated with hexanes, and then eluted with 0-50% EtOAc/Hexanes. The product fractions were evaporated to give a pale yellow oil, which solidified after being placed under high vacuum to afford ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol, 43% yield). The product had an HPLC retention. time=2.48 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=219.1. 1H NMR (400 MHz, chloroform-d) δ ppm 1.42-1.48 (m, 3H), 4.49 (q, J=7.28 Hz, 2H), 7.31 (s, 1H), 7.39 (ddd, J=7.53, 4.89, 1.13 Hz, 1H), 7.87 (td, J=7.78, 1.76 Hz, 1H), 7.96 (d, J=7.78 Hz, 1H), and 8.73 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1CNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CC(O)C3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 22 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and azetidin-3-ol according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 22%; MS: m/z=387 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:20][NH2:21]>O>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([CH2:2][NH:21][CH3:20])=[N:4][N:5]=3)[N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reactant: CN
Solvent: O
Product: CNCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
(Step 3-ii) 3-(Chloromethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (210 mg, 0.71 mmol) was suspended in 2 mL of 40% methyl amine in water and the suspension microirradiated at 100° C. for 10 min. The reaction mixture was allowed to cool to room temperature and a brown solid was filtered off and dried in vacuo to yield the product, N-(3-chlorophenyl)-3-((methylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (126 mg, 0.43 mmol, 61% yield): MH+=289.02.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([O:15][C:22]3[N:23]([CH3:33])[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=4)=[N:25][N:26]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Product: CC(Oc1nnc(-c2cccnc2)n1C)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
The title compound is prepared from 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol (1 mmol), sodium hydride (1.5 mmol), and 3-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).