Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Br[CH2:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>O.C(#N)C>[Na+:5].[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([CH2:8][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)[O-])cc2)cc1
Yield: 124.2 %

Procedure:
A solution of sodium sulfite (0.73 g, 7 mmol) dissolved in water (10 mL) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (1.41 g, 5.6 mmol) in acetonitrile (10 mL). The mixture was stirred and heated under reflux for 2 hours. Solvents were evaporated and dried to give the 4-(4-nitrobenzyl)-phenylmethanesulfonic acid sodium salt as a white powder (2.29 g).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])O.[CH2:9]([O:12][CH2:13][CH:14]([SH:17])[CH2:15][SH:16])[CH2:10][CH3:11]>>[CH2:2]([C:3]1[S:16][CH2:15][CH:14]([CH2:13][O:12][CH2:9][CH2:10][CH3:11])[S:17][C:4]=1[CH2:6][CH3:7])[CH3:1]
Reactant: CCCOCC(S)CS
Reactant: CCC(=O)C(O)CC
Product: CCCOCC1CSC(CC)=C(CC)S1
Yield: 42 %

Procedure:
The method of Example 4 was followed, using propioin (4-hydroxy-3-hexanone) (11.6 g) and 3-propoxypropane-1,2-dithiol (16.6 g) to give 5,6-diethyl-2,3-dihydro-2-propoxymethyl-1,4-dithiin as a greenish oil, b.p. 110°-111.5°/0.2 mm, yield 42%. N.M.R. (CDCl3) 0.8-1.25 δ triplets), 1.6-1.95 δ (complex overlapping signals), 2.75-3.65 δ (complex overlapping signals).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH2:11][OH:12])[CH2:25][CH2:24]1
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2CO)CC1

Procedure:
A mixture of (2-fluoro-5-nitrophenyl)methanol (4.500 g, 26.3 mmol), diisopropylethylamine (6.89 mL, 39.4 mmol), and 1-methyl-1,4-diazepane (4.25 mL, 34.2 mmol) in acetonitrile (150 mL) was refluxed for 24 hours. The solvent was evaporated. The residue was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4 and filtered. The title compound was crystallized from the organic layers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([F:27])[F:26])=[CH:4][C:3]=1[F:9]
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1cc(OC(F)F)ccc1Br
Temperature: 80 °C
Yield: 78.3 %

Procedure:
To a solution of 4-bromo-3-fluoro-phenol (962 mg, 5.037 mmol) in acetonitrile (25 mL) was added a solution of potassium carbonate (28.3 g, 181 mmol) dissolved in water (25 mL) all under nitrogen. To the reaction mixture was added 2-chloro-2,2-difluoroacetophenone (5 g, 25 mmol) and the reaction was heated to 80° C. for 4 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The organic layer was dried with sodium sulfate, filtered and concentrated onto silica gel. Silica gel chromotography (5% ethyl acetate 95% heptane to 100% ethyl acetate over 55 minutes) furnished a clear oil (950 mg, 78%). LCMS m/z 531.7 (M−1)1H NMR (400 MHz, METHANOL-d4) δ ppm 6.85 (s, 1H) 6.92 (dd, J=8.88, 2.63 Hz, 1H) 7.05 (t, 1H) 7.38 (t, 1H)
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:15][C@H:14]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Reactant: Clc1ccccn1
Product: C[C@@H](COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1

Procedure:
The resulting (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was reacted with 2-chloropyridine in the same manner as described in Example 1 to give (S)-(+)-2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][C@H:20]([CH2:22][NH2:23])[CH2:19][O:18]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][C@@H:20]3[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC1(C)OC[C@@H](CN)O1
Product: CC1(C)OC[C@@H](CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)O1
Yield: 88.4 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (22.00 g, 76.52 mmol) was treated with (R)-2,2-dimethyl-1,3-dioxolane-4-methanamine (11.61 g, 114.8 mmol) according to the method described in Part A of Examples 152-156. The crude product was triturated with water (200 mL), isolated by filtration, washed with water, dried, and suspended in diethyl ether (100 mL). The suspension was sonicated, and the resulting solid was isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 25.84 g of (R)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid, mp 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].[H-].[Na+].Br[CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: CCC(Br)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Sc1ccc(OC)c(Cl)c1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 4.4 g of 2,3-dichloro-4-methoxythiophenol in 30 ml of anhydrous dimethylformamide is added 1.2 g of sodium hydride in small portions. The mixture is stirred at room temperature until gas evolution subsides (20-30 minutes) and 3.34 g of α-bromobutyric acid in 10 ml of dimethylformamide is added. After stirring at room temperature for 1 hour, the mixture is diluted with water and acidified with conc. hydrochloric acid. The white crystalline solid is filtered, air dried and recrystallized from acetone-hexane to give 5.32 g of α-(2,3-dichloro-4-methoxyphenylthio)butyric acid as granular crystals, mp 143°-145°.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:24])[CH2:14][N:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]1)(C)(C)C>C(Cl)Cl>[F:22][C:20]([F:21])([F:23])[C:18]1[CH:17]=[N:16][N:15]([CH2:14][C:13]([OH:24])=[O:12])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(F)(F)F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Trifluoroacetic acid (10 mL) was added to tert-butyl[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (1.3 g, 5.2 mmol) (see Preparation 84) in dry DCM (10 mL) and the mixture was stirred for 18 hours at 25° C. Then the mixture was evaporated in vacuo and the residue was purified by trituration with diethyl ether:pentane (1:9, 2 mL) to afford the title compound as a white solid in 79% yield, 800 mg.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.[C:20]([NH2:24])(=[O:23])[CH:21]=[CH2:22]>N1C=CC=CC=1.CO.C(=O)(O)[O-].[Na+]>[N:11]1([CH2:10][C:2]2[N:1]([CH2:22][CH2:21][C:20]([NH2:24])=[O:23])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: C=CC(N)=O
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: NC(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Yield: 33.3 %

Procedure:
1-(1H-Benzimidazol-2-ylmethyl)-1H-benzotriazole (300 mg, 1.20 mmol) and acrylamide (86 mg, 1.20 mmol) were dissolved in pyridine (5 mL). Triton B (40% by weight in methanol, 0.010 mL, 0.024 mmol) was added at room temperature. The temperature was slowly raised to reflux. The reaction mixture was stirred at reflux overnight under nitrogen. The solvent was stripped under reduced pressure. The residue was taken up in aqueous saturated sodium bicarbonate solution and extracted with EtOAc (4×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (EtOAc/MeOH 12:1 to 4:1) to give 128 mg (33%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].C([O-])=O.[NH4+]>[Pd].CN(C=O)C>[NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
Trt-Gly-Gly-Phe-Gly-OBzl (670 mg), 10% Pd-C (100 mg), and ammonium formate (200 mg) were added to DMF (5 ml) and stirred for three hours. The reaction mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=8:1 solution) to obtain the title compound (300 mg).
Reaction SMILES: [OH:1][CH:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[CH:4]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[O:3]1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:3][CH:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:2][OH:1])[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(C2OC(O)c3cnccc32)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccc(C(O)c2ccncc2CO)c1
Reaction time: 1 h

Procedure:
3-(3-Hydroxy-1,3-dihydro-furo[3,4-c]pyridin-1-yl)-benzonitrile (110 mg) was dissolved in ethanol (5 mL) and then treated with sodium borohydride (51 mg). The reaction mixture was stirred for 1 hour, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4-yl)-methyl]-benzonitrile as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)[C@H](O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 34.2 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (R)-(−)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at ambient temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL of 1 M HCl. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v) ethyl acetate/hexanes and filtered though a 10 g plug of silica gel. The eluent was concentrated to dryness and triturated with 3×5 mL portions of hexane followed by 3×10 mL portions of 10% (v/v) portions of ethyl acetate/hexanes. The residue was dried to yield 47 mg (34%) of the titled compound as a white solid. ESI-MS m/z 382 (MH+), 380 (M−H−).
Reaction SMILES: [CH2:1]1[NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH:3]=[CH:2]1.[Li].[CH2:10](O)[CH3:11]>C1COCC1.N>[CH:11]1([C@H:2]2[CH2:1][NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3]2)[CH2:10][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: O=C(O)C1C=CCN1
Reactant: CCO
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A solution of 2.0 g (0.0062 moles) of dehydro proline (prepared as described in Example 3) in 10 ml THF was added to a solution of lithium (0.65 g, 0.093 moles) in ammonia (150 ml) at ~-78° C. After the addition, the reaction mixture was stirred for 20 minutes and then absolute ethanol (3.6 ml, 0.062 moles) was added to the reaction mixture. The reaction mixture was stirred at -33° C. for 6 hours and quenched with 2.0 g of ammonium chloride. Ammonia was evaporated and the residue was acidified to pH=1 using 5% HCl and extracted with ethyl acetate (2×100 ml). Palladium hydroxide on carbon (20%, 0.25 g) was added to the aqueous layer and hydrogen gas was bubbled through the solution at room temperature for about 3 hours. It was filtered through a celite pad and the filtrate was concentrated and pH was adjusted to 6.3 by adding 5% NAOH solution. The precipitated product was filtered on the next day, and vacuum dried to obtain 0.52 g of trans-4-cyclohexyl-L-proline as white flaky solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](Cl)[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][OH:18]>>[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([O:18][CH3:17])[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: COC(=O)c1sc2ncc(Cl)cc2c1N
Agent: [Na]
Product: COC(=O)c1sc2ncc(OC)cc2c1N
Yield: 86 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was added to methanol (20 mL) and allowed to react until metallic sodium was consumed. To the solution was added the product from Example 32A (0.485 g, 2.0 mmol) and the reaction was heated to reflux for 2 h. The reaction was quenched in sat. aq. NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to yield 0.410 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.88(s, 3H), 4.02 (s, 3H), 6.74 (d, 1H), 7.77 (d, 1H).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39](Br)[C:40]#[CH:41]>CC(C)=O>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:41][C:40]#[CH:39])[CH2:9]2)=[N:16][CH:17]=1
Reactant: C#CCBr
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in acetone (3 mL) and cesium carbonate (65 mg, 0.200 mmol, 3.0 eq) was added followed by propargyl bromide (80% in toluene) (7.9 μL, 0.0734 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an orange foam (30 mg, 92%). LCMS (m/e) 487 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.66 (d, 1H, J=8.5 Hz), 8.08 (s, 1H), 7.51-7.40 (m, 2H), 7.37 (d, 1H, J=2.2 Hz), 7.30-7.20 (m, 1H), 7.10-7.0 (m, 2H), 6.92 (s, 1H), 6.18 (bs, 1H), 3.37 (d, 2H, J=2.3 Hz), 3.03 (d, 3H, 4.9 Hz), 3.03-2.98 (m, 1H), 2.97-2.87 (m, 3H), 2.52-2.45 (m, 2H), 2.23-2.15 (m, 2H), 2.14 (t, 1H, J=2.3 Hz), 1.70-1.62 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:7][CH:8]=1)=[O:29]
Reactant: CSc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of N-(4-methylthiophenyl)-1-phenyl-1-H-pyrazol-3-amine (1.4 g) in dichloromethane (100 ml) at 0° was added a solution of 3-chloroperbenzoic acid (0.9 g) in dichloromethane (20 ml) and the mixture stirred and allowed to reach room temperature over 1 hour. The solution was washed with dilute sodium hydroxide solution, dried over magnesium sulphate, filtered and evaporated to an oil. The oil was dissolved in hot ether and gradual evaporation to a small volume gave the title compound as a colourless solid (1.2 g), collected by filtration, mp 123°-124°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(#N)C>[N:11]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1CNC1
Solvent: CC#N
Product: O=C(c1ccc(O)cc1)N1CCC1
Temperature: 50 °C
Yield: 0.1 %

Procedure:
1,1-Carbonyldiimidazole (95.57 mmol; 16.57 g) was charged to a 250 mL round bottomed flask purged with nitrogen, acetonitrile (72 mL) was added, to form a mobile white slurry. 4-Hydroxybenzoic acid (86.88 mol; 12.00 g) was added in portions over 30 minutes to give clear yellow solution, which then became a slurry after approximately 15 minutes. The slurry was heated to 50° C. and azetidine (104.25 mol; 5.95 g) in acetonitrile (10 mL) was added drop wise over 10 minutes. Further azetidine (17.38 mmol; 992.08 mg) was added in acetonitrile (12 mL) and the reaction mixture was heated to 50° C. for a further hour. The precipitated product (10 g, 65% yield) was isolated by filtration and washed with acetonitrile (15 mL) and then dried in a vacuum oven at 40° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:22][C@H:23]([OH:39])[C@@H:24]([NH:32]C(=O)C(F)(F)F)[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CO>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:22][C@H:23]([OH:39])[C@@H:24]([NH2:32])[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc(CN(C[C@H](O)[C@H](Cc3ccccc3)NC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCN(c2ccc(CN(C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 15 h

Procedure:
100 ml of a 1N solution of K2CO3 are added dropwise to a solution of 5.8 g (10.0 mmol) of 1-[p-(4-methylpiperazin-1-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 100 ml of methanol and the whole is heated to boiling for 15 h. The mixture is partially concentrated by evaporation, after which methylene chloride and water are added; the water phase is separated off and extracted twice with methylene chloride, after which the organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated by evaporation. Stirring the residue in hexane yields the title compound:
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1>O>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCC1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Solvent: O
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCC(CCO)CC1

Procedure:
Ethyl 2-phenylquinazoline-4-carboxylate (1.7 g) and piperidine-4-ethanol (8 g) are heated at 150° C. for 4 hours. After cooling, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with ethyl acetate as the eluant, and the product recovered is recrystallised from isopropyl ether. This gives 1-[(2-phenylquinazoline-4-yl)carbonyl]-piperidine-4-ethanol (0.5 g), melting at 146° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:19]([OH:21])(=[O:20])[CH3:18].[NH:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]1
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)COC1CCNCC1
Yield: 192.1 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (2.3 g), ethanol (200 ml), glacial acetic acid (0.6 ml), 10% Pd on C (200 mg) and hydrogen gas were reacted to give ethyl piperidin-4-yloxyacetate, acetate salt (1.7 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.41 (2H, m), 1.82 (3H, s), 1.86 (2H, m), 2.58 (2H, m), 2.95 (2H, m), 3.46 (1H, m), 4.11 (4H, m); Mass Spectrum m/Z 188 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31](I)[CH2:32][CH3:33]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Reactant: CCCI
Product: CCCn1cc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and propyl iodide (0.01 mL) as starting materials, N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.