Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[O:3]([CH2:10][C:11]1[S:12][C:13]2[C:14](=[O:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][C:19]=2[N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCCc2nc(COc3ccccc3)sc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2sc(COc3ccccc3)nc2CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.014 g, 0.36 mmol) was added to a stirred solution of 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.066 g, 0.24 mmol) in DMF anhydrous (1 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. Then, benzyl bromide (0.043 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.084 g, 96% yield) as a colourless oil. C21H20N2O2S LCMS: Rt 3.02, m/z 365 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:33](Cl)([CH3:36])(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][O:19][S:33]([CH3:36])(=[O:35])=[O:34])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
To a solution of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 37.1) (400 mg, 1.1 mmol) in dry DCM (15 ml) was added Et3N (0.64 ml, 3.32 mmol) at room temperature. Mesyl chloride (0.16 ml, 2.22 mmol) was then added to this reaction mixture dropwise at 0° C.; and the reaction mixture was stirred at room temperature for 2 hours. TLC shows complete consumption of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol. The reaction mixture was diluted with H2O (10 ml) and the aqueous layer was extracted with DCM (3×10 ml). Combined organic layers were washed with ice water (10 ml), 10% NaHCO3 (10 ml), brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get light yellow oil (500 mg), which was purified by column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10/90] to give the title compound (370 mg, 76%) as a light yellow liquid.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:35]3[N:40]=[C:39]([NH2:41])[C:38](N)=[CH:37][CH:36]=3)[CH2:28][CH2:27]2)=[CH:11][CH:10]=1>C(O)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:35]3[N:40]=[C:39]4[N:41]=[C:2]([CH3:3])[NH:7][C:38]4=[CH:37][CH:36]=3)[CH2:28][CH2:27]2)=[CH:13][CH:14]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2nc(NCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 5 parts of ethyl ethanimidate hydrochloride, 9 parts of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3,6-pyridinetriamine and 100 parts of acetic acid was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was dissolved in trichloromethane. Water was added and sodium hydrogen carbonate was added till foaming had ceased. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 4.8 parts (48.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl-1H-imidazo[4,5-b]pyridin-5-amine; mp. 202.0° C. (compound 146).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:27])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[N:29]1([C:38](=N)[NH2:39])C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[Cl:26][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:27])[C:20]=1[S:19][C:13]1[S:12][C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH2:39])=[NH:29])=[CH:7][CH:6]=2)=[O:10])=[CH:15][C:14]=1[N+:16]([O-:18])=[O:17]
Reactant: N=C(N)n1nnc2ccccc21
Reactant: Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N=C(N)Nc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1
Temperature: 60 °C
Yield: 9.2 %

Procedure:
To a solution of N-(4-aminophenyl)-5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamide (0.2 g, 0.45 mmol) and 1H-benzo[d][1,2,3]triazole-1-carboximidamide HCl salt (0.18 g, 0.91 mmol) in acetonitrile (4 mL) was added triethylamine (0.13 mL, 0.91 mmol). After the addition, the resulting reaction mixture was heated at 60° C. for 24 hours. After this time, the reaction mixture was concentrated and purified by reverse phase HPLC to afford the titled product as a solid (20 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.66 (1H, s), 9.68 (1H, m), 9.01 (2H, m), 8.74 (1H, s), 7.73 (2H, m), 7.39 (4H, m), 7.25 (3H, m), 7.12 (2H, dd). MS m/z: 483.06, 485.06 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4](I)[N:3]=1.C([Mg]Cl)(C)C.C1(C)C(S([C:25]#[N:26])(=O)=O)=CC=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(I)nc1Br
Reactant: Cc1ccccc1S(=O)(=O)C#N
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: COc1ccc(C#N)nc1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-6-iodo-3-methoxypryidine (3-1 or 5-3, 2.1 g, 6.69 mmol, 1.0 equiv) in dichloromethane (17 mL) was added isopropylmagnesium chloride (2.0 M, 4.35 mL, 8.70 mmol, 1.3 equiv) slowly at 0° C. and the reaction mixture was stirred for 45 minutes. The reaction mixture was then cooled to −78° C. and a solution of toluenesulfonyl cyanide (1.8 g, 10.03 mmol, 1.5 equiv) in dichloromethane (5 mL) was added slowly. The reaction mixture was allowed to warm to ambient temperature over 4 hours. To quench, 2 N HCl was added until neutral pH was obtained. The reaction mixture was partitioned between water and dichloromethane and the aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic layer was dried over MgSO4, concentrated and the residue was purified by normal phase column chromatography (10-50% EtOAc in hexanes) to afford the product (3-2) as a tan solid. ESI+MS [M+H]+C7H6BrN2O: 212.9 found, 213.0 required.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([NH:14][NH2:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:22]=1>>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:9]4[CH:8]=[CH:7][C:5]5[N:6]=[C:2]([NH2:1])[S:3][C:4]=5[CH:10]=4)=[N:19][N:18]=3)[N:15]=2)[CH:24]=1
Reactant: NNC(=O)Cc1ccc2nc(N)sc2c1
Reactant: Clc1ccc(-c2cccnc2)nn1
Product: Nc1nc2ccc(Cc3nnc4ccc(-c5cccnc5)nn34)cc2s1

Procedure:
The title compound was prepared as described in Example 1 from (2-amino-benzothiazol-6-yl)-acetic acid hydrazide (0.65 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.34 mmol) to afford a yellow solid. 1H NMR (DMSO-d6) δ 9.30 (1H, d, J=1.6 Hz), 8.78 (1H, dd, J=4.8 Hz, 1.7 Hz), 8.50 (1H, m), 8.49 (1H, d, J=9.5 Hz), 8.01 (1H, d, J=9.6 Hz), 7.69 (1H, s), 7.64 (1H, ddd, J=8.1 Hz, 4.8 Hz, 1.0 Hz), 7.42 (2H, s), 7.26 (2H, s), 4.61 (2H, s). ESI-MS (m/z): Calcd for C18H13N7S: 359.1; found 360.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: Nc1cnc2ccc(Sc3ccccn3)cn12
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cnc2ccc(Sc3ccccn3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(2-pyridylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamide-ethane yields pure 3-(methoxycarbonylamino) 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:33]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 85.3 %

Procedure:
A mixture of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-piperidin-3-yl)amine (about 0.77 mmol), iron powder (129 mg, 2.31 mmol) and ammonium chloride (206 mg, 3.85 mmol) in ethanol/water (8 ml, 3:1) was heated to reflux for 4 hours. After cooling the mixture was filtered through CELITE®, thoroughly washing the filter cake with ethanol. The filtrate and washings were combined and concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0 to 10% methanol in DCM) gave a residue, which was purified by column chromatography on silica gel (gradient: 0 to 5% methanol in ethyl acetate) affording 303 mg (84%) of 1-benzenesulfonyl-N*4*-((R)-1-benzyl-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method B, ESI): RT=2.48-2.68 min, m+H=462.6; 1H NMR (400 MHz, CDCl3) δ: 8.12-8.08 (m, 2H), 7.79 (s, 1H), 7.55-7.49 (m, 1H), 7.46-7.38 (m, 3H), 7.37-7.22 (m, 5H), 6.47 (s, 1H), 5.32-5.26 (br m, 1H), 4.00-3.87 (br m, 1H), 3.58-3.46 (br m, 2H), 2.94-2.28 (br m, 6H), 1.82-1.67 (br m, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16].[ClH:17]>>[CH3:15][NH:16][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:17].[CH3:15][NH:16][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN
Reactant: O=CC1(c2ccccc2)CCCCC1
Agent: Cl
Product: CNCC1(c2ccccc2)CCCCC1

Procedure:
The title compound was synthesized from 1-phenylcyclohexane-carbaldehyde (126 mg, 0.67 mmol) and methyl amine (370 μL, 0.73 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH3CN to give pure N-methyl(1-phenylcyclohexyl)methanamine hydrochloride (8 mg, 6%) as colorless crystals. HPLC Rt=7.76 min; 1H NMR (400 mHz, MeOH-d4) 7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 3.11 (s, 2H), 2.50 (s, 3H), 2.25-2.22 (m, 2H), 1.67-1.23 (m, 8H); LC-MS 6.37 min, (M+1)+ 204 @ 6.62 min.
Reaction SMILES: [I:1][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[I:13][CH:14](O)[C:15]#[CH:16].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O1CCOCC1.CN(C)C1C=CN=CC=1>[I:13][CH:14]([O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:1])[C:15]#[CH:16]
Reactant: C#CCOC(=O)N(I)CC(=O)O
Reactant: C#CC(O)I
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#CCOC(=O)N(I)CC(=O)OC(I)C#C
Temperature: 0 °C
Reaction time: 17 h

Procedure:
N-Iodopropargyloxycarbonyl glycine (compound 1, 4.96 g., 17.52 mmole) was dissolved in a mixture of methylene chloride and 1,4-dioxane (450 ml., 20 ml. respectively) and cooled to 0° C. with an ice bath. Iodopropargyl alcohol (3.51 g., 19.29 mmole) was added, followed by 4-dimethylaminopyridine (0.22 g., 1.80 mmole) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.17 g., 21.75 mmole). The reaction mixture was stirred at 4° C. for 17 hours. Upon warming to room temperature, the reaction mixture was diluted with methylene chloride, washed with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl glycine iodopropargyl ester (compound 4) as a white crystalline solid (8.26 g.). m.p. 86°-88° C.; 1H-NMR (200 MHz, CDCl3) δppm =4.05, d, J=5.6 Hz., 2H (NH--CH2 --), 4.89, d, J=10.2 Hz., 4H (C--CH2 --O), 5.32, m, 1H (--NH--).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.F[C:23]1[C:28]([F:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:29][C:28]1[C:23]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[N:17]=[CH:18][CH:19]=[N:20]2)=[N:24][CH:25]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:27]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 65 mg, 0.36 mmol) and DIPEA (42 mg, 0.33 mmol) in dry DMSO (1.1 ml) was subjected to microwave irradiation at 140° C. for 1 hour. The reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:9][C:8](=O)[CH2:7][CH2:6][CH2:5][C:4]([CH3:12])([CH3:11])[P:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:21][C:20]=1[CH:31]([CH3:33])[CH3:32].C(O)COCCO.O.NN.[OH-].[K+]>>[CH3:34][C:2]1([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH3:12])[P:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([CH:31]([CH3:32])[CH3:33])=[CH:21][C:22]([CH:28]([CH3:30])[CH3:29])=[CH:23][C:24]=1[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCC(=O)CC2(C)C)c(C(C)C)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCCCC2(C)C)c(C(C)C)c1
Temperature: 210 °C
Reaction time: 7 h
Yield: 41.1 %

Procedure:
A round bottom flask was charged with 2,2,8,8-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphocan-4-one (1.25 g, 2.61 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Nitrogen-sparged diethylene glycol (13.7 mL, 144 mmol, 55 equiv) was added, and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (1.16 mL, 13.1 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (733 mg, 13.1 mmol, 5 equiv). The mixture was immersed in an oil bath at 160° C. under a nitrogen atmosphere. The temperature of the bath was gradually increased to 210° C. over 30 minutes and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen overnight. The Claisen adapter was washed with ethyl acetate (30 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (3×20 mL), and the combined organic fractions were washed once with water (50 mL) and aqueous saturated sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The purified product was triturated from hot methanol and collected by filtration to afford the title compound as a white solid (499 mg, 92 area % by HPLC, 41% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-7.87 (m, 1H), 7.33-7.26 (m, 2H), 7.23-7.17 (m, 1H), 6.97 (s, 2H), 3.00-2.85 (m, 1H), 2.61-2.44 (m, 2H), 1.91-1.61 (m, 5H), 1.61-1.41 (m, 5H), 1.39 (d, J=2.5 Hz, 6H), 1.31 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.8 Hz, 6H), 0.98 (d, J=6.7 Hz, 6H), 0.74 (d, J=15.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.2 (d, J=35 Hz), 147.1, 145.8, 137.3, 136.8 (d, J=8 Hz), 136.6 (d, J=21 Hz), 132.0 (d, J=7 Hz), 126.9, 124.6, 119.8, 43.8 (d, J=18 Hz), 36.3 (d, J=30 Hz), 34.3, 31.1, 31.0 (d, J=18 Hz), 28.3 (d, J=4 Hz), 26.8 (d, J=11 Hz), 26.7, 24.4, 23.1 (d, J=2 Hz), 22.4 (d, J=6 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm 10.5 (s). HRMS (TOF-ESI+) calcd for [M, C32H49P]+ 464.3572. Found 464.3584.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>>[C:10]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)(=[O:12])[CH3:11]
Reactant: OCC1CCC(O)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCC(O)CC1

Procedure:
The 4-(hydroxymethyl)cylohexan-1-ol obtained above is treated with 1 eq. of acetic anhydride and 2 eq. of pyridine to provide 4-acetoxymethylcylohexan-1-ol.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[CH:18]=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1.O>C(#N)C>[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[C:18]([N+:7]([O-:8])=[O:6])=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1
Reactant: CCc1cc2c(OC)ccc(Br)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
After adding nitronium tetrafluoroborate (176 mg) to a solution of 7-bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (282 mg) in acetonitrile (20 mL) at 0° C., the mixture was stirred for 20 minutes. Upon completion of the reaction, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (159 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([NH2:22])[CH:20]=[CH2:21]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:19][CH:20]=[CH2:21])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: C=CCN
Solvent: CCO
Product: C=CCNc1nc(-c2ccccc2)ncc1C(=O)OCC

Procedure:
A mixture of 5 g. (0.019 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 2.2 g. (0.038 mole) of allylamine in 150 ml. of ethanol was refluxed 3 hours. At this point, the solution was concentrated to 30 ml. and chilled. A yellow crystalline solid formed and was filtered off to give 4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester--m.p. 49°-54° C. This compound was used in the next step directly without further purification.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:4]=[CH:3]1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:11][C:9]([P:12]([OH:15])(=[O:13])[OH:14])([P:12]([OH:15])(=[O:14])[OH:13])[CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: OP(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(CCc1c[nH]cn1)P(=O)(O)O
Reaction time: 4 h

Procedure:
3.53 g. (20 mMol) 3-(4-imidazolyl)-propionic acid hydrochloride are heated with 2.26 g. phosphorous acid in 10 ml. chlorobenzene to 110° C., while stirring. 4.12 g. (30 mMol) phosphorus trichloride are slowly added dropwise thereto and heating continued for 4 hours at 110° C. After cooling, the chlorobenzene is decanted off and the residue boiled under reflux for 5 hours with 15 ml. 6N hydrochloric aci. The reaction mixture is allowed to cool, mixed with active charcoal, filtered and the filtrate evaporated. The residue is taken up in 10 ml. water, the solution is adjusted with an aqueous solution of sodium bicarbonate to a pH value of 5.5 and mixed with methanol until no further precipitate is formed. The precipitate is filtered off with suction, washed with methanol and dried. There are obtained 3.23 g. (48% of theory) of the title compound. The product is obtained as the monosodium salt with 1 mole of water of crystallisation.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CN1CCCC(Oc2ccc(N)cc2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OC2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-methyl-3-piperidyloxy)phenylamine (1 equivalent) was dissolved in CH2Cl2 and a catalytic amount of DMAP was added. Acetic anhydride (1.3 equivalents) was added slowly, and the solution was stirred at room temperature overnight. The reaction was then quenched with water and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo, to yield N-[4-(1-methyl-3-piperidyloxy)phenyl]acetamide as a yellow oil. LC/MS (m/z) 249.3 (MH+), Rt 1.24 minutes.