Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:12]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1)[OH:10]>[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[N:14][CH:15]=1)=[O:10]
Reactant: Cc1cccc(C(O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
Thereafter (2,3-dimethylphenyl)-(3-trityl-3H-imidazol-4-yl)methanol (III) is oxidised with an oxidizing agent, preferably manganese (IV) oxide, to yield (2,3-dimethylphenyl)-(3-trityl-3H-imidazol-4-yl)methanone (IV):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:31][CH:30]=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1

Procedure:
The title compound (D3) was prepared from [1,4]diazepane-1-carboxylic acid tert-butyl ester using the method of Description 1 (D1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][N:27]=[N+:28]=[N-:29])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 75 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a solution of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (2.0 g, 4.99 mmol) in 30 mL of NMP was added sodium azide (1.55 g, 0.024 mol). The reaction mixture was heated to 75° C. with stirring for two hours. The reaction was quenched by addition of water, and the resulting mixture was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc 3:2) to give 1.76 g (quantitative) of C—[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methyl azide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][CH:24]([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:34]=3[N:33]=2)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:22])=[CH:19][C:18]=1[Cl:44])=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[NH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][CH:24]([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:34]=3[N:33]=2)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:22])=[CH:19][C:18]=1[Cl:44])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2ccccn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2ccccn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 17 from 4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)-2-(pyridin-2-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 216 mg (85%, mixture of four stereoisomers); Rf value: 0.27 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C27H26Cl2N6O2 (537.45); mass spectrum: (M−H)−=535/537/539 (chlorine isotope).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].[OH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH2:41][CH2:42]CC2=O.B(F)(F)F>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:28]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:26]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:27][C@H:5]1[O:4][C:1]1[CH:2]=[CH:42][CH:41]=[C:40]2[C:45]=1[CH2:46][CH2:47][CH2:48][C:39]2=[O:38])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: FB(F)F
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](Oc2cccc3c2CCCC3=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (426 mg, 0.84 mmol), 5-hydroxy-1-tetralone (122 mg, 0.75 mmol) and boron trifluoride diethyletherate (120 mg, 0.84 mmol, 106 μl) in dichloromethane (4 ml) was stirred at room temperature, under argon for 19 hours. Work-up as for Stage 1 in Example 1 then flash chromatography on silica gel (eluting with 2% acetone in toluene) gave the title compound as a colourless oil (308 mg of approx. 51% purity).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:14]OCC)[CH:12]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1)(=[NH:21])[NH2:20].C[O-].[Na+]>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[N:20][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=3)=[N:21][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: CCCCc1ccc(C(C=O)=COCC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1

Procedure:
74.2 G. of 2-(4-n-butylphenyl)-3-ethoxy-acrolein, 77.8 g. of the 4-amidinobenzoic acid amide hydrochloride described earlier and 0.546 mol of sodium methylate (obtained by dissolving 12.55 g. of sodium metal in methanol) are suspended in 2500 ml. of methanol and stirred overnight at room temperature under an atmosphere of nitrogen. The yellow suspension is subsequently removed by filtration, washed with a small amount of ethanol and suspended in 4 liters of ether for further purification. The suspension is washed with water and then filtered again. Sparingly soluble 4-[5-(4-n-butylphenyl)-2-pyrimidinyl] benzoic acid amide is obtained.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>CCO>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][C:20]#[N:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC#N
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Solvent: CCO
Product: N#CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a solution of diphenyl-4-piperidylmethane (810 mg, 3.22 mmol, 1.00 equiv) in EtOH (5 mL) was added acrylonitrile (0.53 mL, 8.06 mmol, 2.50 equiv) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-hexane 9:1 to 2:1) to give 480 mg (49%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([O:10]CC)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[N:1]12[CH2:7][C:4]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:10])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Temperature: -30 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A solution of ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (4 g, 23 mmol) in THF (60 mL) was added dropwise to a solution of phenyllithium (1.5 M in 70% cyclohexane/30% diethyl ether, 63.1 mL, 94.6 mmol) pre-cooled to −30° C. under Ar. The reaction was warmed to RT and stirred for 16 h. The reaction was treated with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Trituration (diethyl ether) afforded the title compound (3.595 g, 54%). EI-MS m/z 280 (MH)+ Rt (1.56 min).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:11]([NH:13][C@@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=1)=[O:16])=[O:12].C(N(C(C)C)CC)(C)C>CO.C1(C)C=CC=CC=1.ClCCl>[O:1]=[C:2]1[NH:9][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:11](=[O:12])[N:13]1[C@@H:14]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=1)=[O:16]
Reactant: NC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)NC(c3ccccc3)C2=O)n1
Reaction time: 0.5 h

Procedure:
To a solution of diphosgene (3.7 μL, 0.03 mmol) in a 1:1 v/v mixture of dichloromethane and toluene (0.5 mL total volume) was added dropwise with stirring a solution of 2-[2-(S)-(2-amino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid amide (21.5 mg, 0.051 mmol) and diisopropylethylamine (24 μL, 0.14 mmol) in a 1:1 v/v mixture of dichloromethane and toluene (1 mL total volume). After stirring for 30 minutes, methanol (0.1 mL) was added and the reaction mixture concentrated in vacuo. The residue was purified by reverse phase high performance liquid chromatography using a C-18 stationary phase gradient eluted with a water/acetonitrile mixture containing 0.1% v/v trifluoroacetic acid in both components of the solvent system. After lyophilization 2-[(S)-2-(2,5-dioxo-4-phenyl-imidazolidin-1-yl)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid amide was obtained as an amorphous colorless solid (4.0 mg, 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25]
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Cc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 19.20 min.; purity: 94%; MS (m/e): 360 (M+); 1H NMR (CDCl3): δ 7.93 (1H, d, J=3.1 Hz), 7.54 (1H, d, J=2.6 Hz), 7.30 (1H, t, J=2.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.02 (3H, m), 6.78 (1H, s), 6.61 (1H, dd, J=7.9 Hz, J=2.1 Hz), 2.26 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=O)=[CH:14][CH:15]=3)[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:23][CH2:22]3)=[CH:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][NH:19][CH3:20])=[CH:14][CH:15]=3)[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:25][CH2:26]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc2c(c1)c(C1CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc2c(c1)c(C1CCN(CCN3CCNC3=O)CC1)cn2-c1ccc(F)cc1
Temperature: 0 °C

Procedure:
1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]4-piperidinyl]-N-methyl-1H-indole-5-carboxamide (7a) (2g) and LiAIH4 was refluxed in dry THF (150 mL) for 3 h. After cooling to 0° C., water (100 mL) and aqueous NaOH (1 M, 5 mL) was carefully added. The phases were separated and the aqueous phase was extracted with ethyl acetate. After removal of the solvent, the compound was purified by flash chromatography (EtOAc/MeOH/TEA 80/15/5). Yield 0.3 g (oil). 1H-NMR (DMSO) 1.72 (q, 2H), 1.97 (d, 2H), 2.12 (t, 2H), 2.28 (s, 3H), 2.45 (t, 2H), 2.77 (tt, 1H), 3.00 (d. 2H), 3.10-3.60 (m, 6H) 3.72 (s, 2H), 6.25 (s, 2H), 7.14 (d. 1H), 7.35-7.45 (m, 4H), 7.55-7.65 (m, 3H)
Reaction SMILES: C[C:2]1[C:23](C)=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([OH:20])=[O:19])=[C:12]([CH3:21])[N:11]=3)[NH:8][C:4]=2[CH:3]=1.[K+].[Br-]>CN(C=O)C>[N:6]1[C:5]2[CH:22]=[CH:23][CH:2]=[CH:3][C:4]=2[NH:8][C:7]=1[NH:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]([OH:20])=[O:19])=[C:12]([CH3:21])[N:11]=1
Reactant: Cc1cc2nc(Nc3nc(C)c(CC(=O)O)c(O)n3)[nH]c2cc1C
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2nc3ccccc3[nH]2)nc(O)c1CC(=O)O
Yield: 5 %

Procedure:
was prepared according to procedure used for (2) in Example 1; yield 5%. mp: >300° C. (DMF). IR (KBr): υ=2878, 1748. 1700, 1625, 1557, 1474, 1357, 1219, 744 cm−1. 1H-NMR (CF3CO2D): δ=2.64 (s, 3H, CH3), 3.88 (s, 2H, CH2), 7.52 (m, 2H, 2×Harom), 7.67 (m, 2H, 2×Harom). Accurate mass: calculated: 299.1018. Found 299.1013. Analysis calculated for C14H13N5O3: C, 55.2; H, 4.40; N, 23.40. Found: C. 55.4; H, 4.7; N, 22.5.
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH3:16])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH3:16][C@@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: C[C@@H](N)CCCc1cccnc1

Procedure:
A solution of 145 g of [R-(R*,R*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide in 900 mL of 6N HCl was treated with 80 mL of conc. HCl and then was heated at reflux for 2 days. After most of the solvent was removed under reduced pressure, the residue was made decidedly basic with 10N NaOH in an argon atmosphere, and extracted with dichloromethane (1×1.2L; 2×600 mL). The dried (K2CO3) extracts were evaporated and the crude product was distilled to give 78.5 g of (R)-alpha-methyl-3-pyridinebutanamine, (bp 95° C./0.2 mm).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(S(C)(=O)=O)C5)n4)n3Cc3ccccc3)n12
Reaction time: 0.07 h
Yield: 84.2 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (6.0 mg, 0.014 mmol, from Example 90) was added methanesulfonyl chloride (1.3 μL, 0.017 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (4.0 μL, 0.028 mmol). The reaction was complete in 4 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (5.9 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cccc(Cl)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
158 mg (0.59 mmol) of ethyl 1-(3-chlorophenyl)-piperidine-4-carboxylate were dissolved in 2.30 ml of methanol and 0.3 ml of water, and 99 mg (1.77 mmol) of powdered potassium hydroxide were added. The mixture was stirred at room temperature overnight After evaporation of the solvent, water was added and the mixture was acidified to pH 2-3 with 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate three times, the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 127 mg (90% yield) of 1-(3-chlorophenyl)-piperidine-4-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH3:16])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH3:16])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(c1cc(Cl)ncn1)c1ccccc1F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C)c2ccccc2F)ncn1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
In 1 ml of tetrahydrofuran was suspended 0.02 g of sodium hydride (60% in oil), to which 0.3 ml of a tetrahydrofuran solution containing 0.02 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was then stirred at room temperature for 20 minutes, to which 0.3 ml of a tetrahydrofuran solution containing 0.06 g of 4-chloro-6-(1-(2-fluorophenyl)ethyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.06 g of 4-(2-butynyloxy)-6-(1-(2-fluorophenyl)ethyl)pyrimidine (the present compound (120)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]=O)[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([OH:24])=[O:23])#[N:2].Cl.[NH2:26]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)C>[C:19]([C:13]1[NH:12][C:11]([CH3:21])=[C:10]([C:22]([OH:24])=[O:23])[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])#[N:26]
Reactant: NO
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of isopropyl ester of 4-(2-cyanophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (3.90 g) in acetic acid (20 ml) were added hydroxylamine hydrochloride (0.88 g) and sodium acetate (1.30 g), and the mixture was stirred for an hour at ambient temperature. To the reaction mixture was added acetic anhydride (3.97 g) with stirring, and the stirring was continued for an hour at ambient temperature and for additional 4 hours at 95°~100° C. After the reaction mixture was allowed to stand at ambient temperature, the acetic acid was removed by distillation under reduced pressure. The resultant residue was diluted with water, neutralized with an aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. After the combined extract was washed twice with water and dried, the solvent was removed by distillation under reduced pressure to give an oil, which was allowed to stand overnight and pulverized with a small amount of ethyl ether. The powder was washed with isopropyl ether and recrystallized from methanol to give yellowish-orange crystals of isopropyl ester of 6-cyano-4-(2-cyanophenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (1.99 g), mp 198°~200° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC.[F-].[K+]>O1CCOCC1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:44](=[O:46])[CH3:45])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
4-[5-(3-Bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 65, 0.34 mmol, 0.2 g), tributyl(1-ethoxyvinyl)tin (0.68 mmol, 0.24 g), tetrakis(triphenylphosphine)palladium (0.034 mmol, 0.04 g) in dioxane (5.0 mL) were degassed with nitrogen for 10 min and heated at 90° C. over night under nitrogen. Cooled, KF solution (2.0 M, 10 mL) was added, stirred at room temperature for 30 min. extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10-25% ethyl acetate in hexanes to provide 4-[5-(3-acetyl-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g).