Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=3[Cl:24])=[CH:11][C:5]=2[N+:4]=1[O-])#[N:2].P(Cl)(Cl)Cl.O.N>C(Cl)(Cl)Cl>[C:1]([C:3]1[NH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=3[Cl:24])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1[nH]c2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[n+]1[O-]
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: N#Cc1nc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[nH]1
Temperature: 5 °C

Procedure:
2-cyano-5-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-1H-benzimidazole-3-oxide (0.8 g) was suspended in chloroform (5cm3) stirred and cooled to 5° C. in an ice bath. Phosphorus trichloride (0.25cm ) was added dropwise and when addition was complete the mixture was heated under reflux for 5 minutes. The resulting solution was cooled, water (10cm3) added slowly and the mixture made basic with aqueous ammonia. The organic layer was separated and the aqueous layer extracted twice with chloroform. The combined organic phase was washed with water, dried (MgSO4), filtered and the filtrate evaporated under vacuum. A portion of the residue was purified by preparative plate chromatogrpahy (SiO2 ; ether) to give 2-cyano-5-(2-chloro-4-trifluormethyl-6-fluorophenoxy)benzimidazole as a pale yellow solid, recrystallised from ether/hexane. MS (positive FAB) MH+ =356.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCI
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1 g of ethyl 4-nitrophenylacetate dissolved in 20 ml of dimethylformamide was treated with 3.12 g of cesium carbonate and 0.68 ml of iodopentane. The mixture was stirred at room temperature for 18 hours. The mixture was poured onto 50 ml of iced water and the resulting mixture was extracted with two portions of 50 ml ether. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), yielding a pale yellow oil. 1H NMR (CDCl3): 8.18 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 4.25-4.00 (m, 2H), 3.64 (t, J=7.7 Hz, 1H), 2.20-2.00 (m, 1H), 1.85-1.70 (m, 1H), 1.45-1.15 (m, 6H), 1.22 (t, J=7.2 Hz, 3H), 0.90-0.80 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].Cl.CCN(C(C)C)C(C)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:9][N:10]([S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])[CH2:11]1)=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 2 (500 mg, 1.15 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (5.0 mL) and stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 mL) and DIPEA (300 mg, 2.30 mmol) and added 1-propanesulfonyl chloride (164 mg, 1.15 mmol). The reaction was stirred at room temperature for 20 h. The reaction was concentrated under vacuum and the residue was purified by column chromatography (silica gel) using 0 to 35% EtOAc in hexanes to afford 3a as white solid (285 mg, 56%); 1H-nmr (300 MHz, CDCl3) δ 7.69 (d, J=8.5 Hz, 1H), 7.60-7.30 (m, 10H), 7.08 (d, J=8.5 Hz, 1H), 5.68 (dd, J=9.5, 6.5 Hz, 1H), 5.29 (br s, 1H), 3.76-3.71 (m, 2H), 3.55-3.35 (m, 2H), 3.19-3.01 (m, 2H), 2.69 (br s, 1H), 1.98-1.82 (m, 2H), 1.08 (t, J=7 Hz, 9H); LC-MS (214) 98%, 3.30 min, m/z 475 (MMeOH+).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]3[N:17]=[CH:18][CH:19]=[CH:20][C:5]2=3)[CH2:3][CH2:2]1.[BrH:22].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2
Reactant: COc1ccc2c(c1)C(O)(C1CC1)c1cccnc1CO2
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (4.3 g) in acetic acid (30 ml) was added 48% aqueous HBr (25 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5-(3-bromopropylidene)-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepine (5.6 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:14][C:15]([CH3:19])([CH3:18])[CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)CO
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394 mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500 mL) was added concentrated sulfuric acid (3.0 mL). The mixture was stirred at reflux for 4 hours, cooled to room temperature, poured into saturated aqueous sodium carbonate (250 mL) and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate (250 mL), and brine (100 mL), and was concentrated to give 4-trifluoromethyl-benzoic acid, 2,2-dimethyl-propyl ester (102 g, 99% yield) as a yellow liquid: Rf: 0.66 (ethyl acetate/hexanes 25/75); IR 2932, 1727, 1327, 1280, 1133, 1066, 862, 775, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.04 (s, 2H), 1.04 (s, 9); 13C NMR (100 MHz, CDCl3) δ26.51, 31.61, 74.72, 123.63 (q, J=272.7 HZ), 125.4, 129.9, 133.7, 134.35 (q, J=31.7 Hz), 165.35.
Reaction SMILES: Cl.C1(C2C=CC=CC=2)[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:12]([OH:27])[C:11]3[CH2:28][NH:29][CH2:30][C:10]2=3)=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([O-:52])=[O:47].[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH+:29]2[CH2:28][C:11]3[C:12]([OH:27])=[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:14](=[O:15])[N:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:46]([C:48]([F:51])([F:50])[F:49])=[CH:3][CH:4]=4)[C:10]=3[CH2:30]2)=[CH:40][CH:39]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(-c4ccccc4)cc3)c1=O)CNC2
Agent: Cl
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3ccc(C(F)(F)F)cc3)c1=O)C[NH+](Cc1ccc(Cl)cc1)C2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Intermediate 6, compound 6-1, (50 mg, 0.11 mmol) was dissolved in DCM (1 mL) and 4-chlorobenzylbromide (22 mg, 0.11 mmol) and TEA (0.045 mL, 0.32 mmol) were added and the mixture was refluxed for 24 h. The reaction was cooled to rt and TFA (0.5 mL, 6 mmol) was added and the solution was stirred an additional 30 min. The reaction was concentrated and the residue was purified on a C-18 reverse phase chromatography column eluted with 0-90% MeCN in water. The desired fractions were lyophilized overnight affording the title compound, E39-1. 535.8 (M+1); Rt=2.80 min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[CH3:21][C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1>C(#N)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of potassium ethyl malonate (1.62 g, 9.51 mmol, 2.1 eq) in acetonitrile (14 mL) at 10° C. under nitrogen was added triethylamine (1.8 mL) followed by MgCl2 (1.1 g, 11.3 mmol, 2.5 eq). The mixture was allowed to stir at room temperature for 2.5 hours. The mixture was cooled to 0° C. and 4-methylbenzoyl chloride (700 mg, 4.53 mmol, 1 eq) was added dropwise over 15 minutes followed by addition of triethylamine (0.3 mL). The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and cooled to 10° C. The solution was washed (cautiously) with 4N aqueous HCl. The aqueous layer was back extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in aqueous 2N NaOH and extracted 3× with diethyl ether. The ether extracts were combined, washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated. The title compound was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH2:14])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc[nH]c2cc1N
Temperature: 30 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
Raney Nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (15 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30° C. for 3 h. The catalyst was filtered off. The filtrate was dried over Na2SO4 and concentrated. The crude dark brown viscous oil was purified by column chromatography (10-20% ethyl acetate/petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine as a gray solid (11 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(Cl)Cl>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]2[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COc1ncccc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ncccc1Nc1ncnc(Cl)n1

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (265.77 mg, 1.77 mmol) in THF (5 mL) was added DIPEA (0.266 mL, 1.61 mmol) followed by 2-methoxypyridin-3-amine (200 mg, 1.61 mmol). The resultant mixture was stirred at RT for 2 hr, then DCM was added and the organics washed with water (×2) and 0.5M aqueous HCl solution. Combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a beige solid: 1H NMR (250 MHz, DMSO) δ 3.88 (3H, s), 7.05 (1H, dd, J=7.54, 4.95 Hz), 7.86 (1H, dd, J=7.61, 1.68 Hz), 8.07 (1H, dd, J=4.95, 1.75 Hz), 8.56 (1H, s), 10.14 (1H, s); =+238.0/239.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:6]2N=CC=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].Br[CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17].[CH2:20](Br)CCC>>[CH2:16]([CH:15]([CH2:18][CH3:19])[CH2:14][N:1]1[C:6]([CH3:20])=[C:5]([CH3:10])[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH3:17]
Reactant: CCCCBr
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: CCC(CC)CBr
Product: CCC(CC)Cn1c(C)c(C)c(=O)oc1=O

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 123A for the product of Example 1A and substituting 1-bromo-2-ethyl-butane for n-butyl bromide (0.181 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 0.85 (t, J=7.35 Hz, 6 H) 1.29 (m, 4 H) 1.65 (m, 1 H) 1.86 (s, 3 H) 2.25 (s, 3 H) 3.73 (d, J=7.35 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.N1C(C)=CC(C)=CC=1C.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].ClCCl>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: ClCCl
Solvent: Cc1ccccc1C
Solvent: Cc1cc(C)nc(C)c1
Product: O=[N+]([O-])c1ccccc1N1CCc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
5-Bromoindoline (4.0 g, 0.02 mole), collidine (3.6 g, 0.03 mole), and o-fluoronitrobenzene (2.8 g, 0.02 mole) in xylene (25 ml) were heated at 185° C. (oil bath temperature) for 24 hours. The mixture was cooled to room temperature and poured into dichloromethane. The dichloromethane solution was washed with 1N hydrochloric acid (3 times, 150 ml), brine (200 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated. Crystallization of the residue was induced by stirring in ether (15 ml) followed by hexane (200 ml), then chilling in the refrigerator overnight. The solid was filtered and washed with hexane and dried to yield 3.5 g (55%, of product. Recrystallization from 2-propanol yielded the analytical sample, mp 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 68.5 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.2 g) described in Preparation Example 187 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (919 mg) was obtained.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[O:19]([C@@H:27]1[CH2:31][C:30](=[O:32])[CH:29]=[CH:28]1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C([Sn](Cl)(CCCC)CCCC)CCC.I[CH2:48][C:49]#[C:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>O1CCCC1.CCOCC.CN(C)P(=O)(N(C)C)N(C)C>[CH2:14]([C@H:28]1[C@H:27]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:31][C:30](=[O:32])[C@@H:29]1[CH2:48][C:49]#[C:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: [Li]CCCC
Reactant: CCCCCC#CCI
Agent: CCCCP(CCCC)CCCC
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC#CC[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCCC
Temperature: 20 °C
Yield: 49.5 %

Procedure:
Cuprous iodide (99.1 mg; 0.52 mmole) was weighed into a 30 ml reaction tube purged with argon, and the inside of the tube was dried under reduced pressure. Then, the reaction tube was again purged with argon. Dry tetrahydrofuran (2 ml) and tributylphosphine (0.337 ml; 1.35 mmole) were introduced into the reaction tube, and stirred at 20° C. with stirring to form a uniform solution. The solution was cooled to -78° C., and n-butyllithium (1.60M, 0.325 ml, 0.52 mmole) was added, and the mixture was stirred at -78° C. for 10 minutes. Then, a solution of (R)-4-t-butyldimethylsiloxy-2-cyclopentenone (100 mg, 0.471 mmole) in tetrahydrofuran (2 ml) was added dropwise at -78° C. over 10 minutes. The mixture was stirred at -78° C. for 10 minutes. Then, hexamethylphosphoric triamide (1 ml) was added, and the mixture was stirred for 40 minutes at -78° C. Tributyltin chloride (0.14 ml, 0.520 mmole) was added, and the temperature was raised to -40° C. A solution of 1-iodo-2-octyne (184 mg, 0.78 mmole) in tetrahydrofuran (1 ml) was added, and the mixture was stirred for 2 hours. Ether (5 ml) was added to the reaction mixture, and the mixture was successively washed with a saturated aqueous solution of ammonium chloride (5 ml), a saturated aqueous potassium thiocyanate solution (5 ml) and a saturated aqueous sodium chloride solution (5 ml). The separated organic layer was dried over anhydrous sodium sulfate. The dried product was filtered and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (Merck 7734, 6% water, 20 g; hexane:ethyl acetate=30:l) to give (2R,3R,4R)-3-butyl-4-t-butyldimethylsiloxy-2-(2-octynyl)cyclopentanone (88.1 mg, 0.233 mmole, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([N:70]1[CH2:73][CH:72]([C:74](O)=[O:75])[CH2:71]1)=O)(C)(C)C>CN(C=O)C.CO.Cl>[NH:70]1[CH2:73][CH:72]([C:74]([N:19]2[CH2:18][CH2:17][CH:16]([C:12]3[CH:11]=[C:10]([F:22])[C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:23][C:24]5[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=5)[C:2]([Cl:1])=[CH:7][N:6]=4)=[CH:14][C:13]=3[CH3:15])[CH2:21][CH2:20]2)=[O:75])[CH2:71]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)C5CNC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), di-isopropylethylamine (50 uL, 0.36 mmol) and HATU (55 mg, 0.14 mmol) in DMF (1.5 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (29 mg, 0.14 mmol). After stirring at room temperature for 4 hours, the mixture was diluted with methanol (1 mL) and conc. aqueous HCl (1 mL). The mixture was stirred at 50° C. for 30 min. The mixture was filtered and purified by preparative RP-HPLC to give azetidin-3-yl(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)methanone as white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.68 (d, 2H), 7.04 (d, 2H), 6.26 (s, 1H), 4.74-4.68 (m, 2H), 4.39-4.35 (m, 1H), 4.29-4.24 (m, 2H), 4.11-4.07 (m, 1H), 3.74-3.71 (m, 1H), 3.25-3.24 (m, 1H), 3.07-3.04 (m, 1H), 2.87-2.80 (m, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 1.87-1.84 (m, 2H), 1.66-1.56 (m, 2H); ESMS m/z 499.2 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[CH2:12][O:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.Cl.C([O:30]CC)C>O.CO>[CH3:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:17][CH:22]=[CH:21][C:20]=1[C:19](=[O:30])[CH2:18][C:3]([O:6][CH3:7])=[O:8]
Reactant: CCOCC
Reactant: Cc1ccccc1COCC(=O)c1ccccc1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(=O)c1ccccc1OCc1ccccc1C

Procedure:
14 g (0.6 mol) of 100% pure sodium hydride and 54 g (0.6 mol) of dimethyl carbonate in 225 ml of absolute diethyl ether are initially taken under nitrogen. 72 g (0.3 mol) of 2-(2-methylbenzyloxy)-acetophenone, dissolved in 300 ml of absolute ether, are added dropwise at 20°-35° C. and the mixture is refluxed for 5 h. At 10° C., first 45 ml of methanol and then 100 ml of H2O are slowly added dropwise. The pH is then brought to 7 with dilute hydrochloric acid. The organic phase is washed several times with H2O, dried over sodium sulfate and evaporated down. The product is obtained in quantitative yield as crystals (mp.=38°-42° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13]CCO2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][CH2:26][O:27][CH3:28])[CH2:7][CH2:8][C:9](=[O:13])[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCC(=O)CC1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (39.5 g) in THF (200 mL) was added dropwise over a period of 45 minutes at −5° C. (ice/methanol bath) to a solution of lithiumdiisopropylamide (2M in THF, 184.3 mL) in THF (300 mL). Stirring was continued for 2.5 hours at 0° C. The reaction mixture was cooled to −5° C. and 2-bromoethyl-methylether (34.6 mL) was added dropwise over a period of 30 minutes. Stirring was continued for 12 hours at RT. The reaction mixture was cooled to 0° C. and aqueous HCl (25%, 300 mL) was added dropwise over a period of 45 minutes to reach pH 1. Stirring was continued for 2 hours at RT. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a yellow liquid (25.2 g, 60%). MS (EI)=288.0 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[N:18][C:17]([C@:20]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>C(Cl)Cl>[CH:28]1([C@@:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:17]2[N:18]=[CH:19][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=2)[OH:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O[C@](c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Tert-butyl4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperidine-1-carboxylate (Preparation 3, 5.60 g, 12.3 mmol) was dissolved in DCM (31 ml) and 2M HCl in ether (31 ml, 60 mmol) added. After stirring at room temperature for 5 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a white foam, in 92% yield, 4.03 g (contains 10% of other triazole regio-isomer).