Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH:11]2[CH2:14][C:15]3[C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[CH:10]2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].O>O1CCCC1>[ClH:26].[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:14][C:15]3[C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)CC1C(=O)N(Cc3ccccc3)C(=O)C21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1OC)CC1CN(Cc3ccccc3)CC21

Procedure:
6.19 g. of the resultant compound of Example 4 suspended in 15 ml. tetrahydrofuran (THF) was treated with 110 ml. 1M BH3 in THF under nitrogen atmosphere. The solution was refluxed 4 hours, then cooled and a solution of 35 ml. concentrated hydrochloric acid and 35 ml. water was added slowly. The solution was refluxed for 20 minutes and then concentrated in vacuum. The residue was made basic with potassium hydroxide solution and extracted with chloroform. The chloroform extracts were dried (K2CO3) and concentrated. The residue was acidified with HCl in isopropyl alochol and this solution was concentrated. Acetonitrile was added to give the product 5.78 g., m.p. 176°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:21][CH3:22])[C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])[C:6]=2[C:19]=1[F:20].[N+:23]([O-])([OH:25])=[O:24].C(OCC)(=O)C>CCCCCC>[F:1][C:2]1[C:3]([N+:23]([O-:25])=[O:24])=[C:4]([O:21][CH3:22])[C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])[C:6]=2[C:19]=1[F:20]
Reactant: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c([N+](=O)[O-])c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
6,7-Difluoro-1-(2-fluoro-4-iodo-phenyl)-4-methoxy-1,3-dihydro-benzoimidazol-2-one (3.0 g, 7.14 mmol) was added portion wise to fuming nitric acid at −78° C. over a period of 1 minute and the resulting mixture was stirred at room temperature for 5 minutes. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was quenched with cold water. The solid formed was collected, washed with water and dried to give the crude product. Purification by column chromatography on silica gel (10-40% ethyl acetate in hexane) afforded 1.6 g of the product (48.2% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc2cccnc2c1
Agent: Cl
Product: COC(=O)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of quinoline-7-carboxylic acid (1.00 g, 5.77 mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in 1,4-dioxane). The reaction was stirred for 18 h at rt (LCMS showed <10% conversion to the desired product). Additional hydrogen chloride (2.00 mL, 8.00 mmol) was added, and the reaction mixture was heated to 50° C. in an oil bath for 36 h. The reaction was cooled to rt, and concentrated in vacuo. The solid was dissolved in DCM, and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried (MgSO4) and concentrated to give the product, which was used without further purification in the next step.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Br)c1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(Br)c2)cc1
Yield: 38.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-bromophenyl) ethanamine (2.16 g) and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound as a solid 1.6 g (benzene-petrol 80-100) m.p. 105°-111° C. as a 42:58 mixture of diastereoisomers. τ(CDCl3) 8.95 (3H, d, J=6 Hz), 6.9-7.7 (7H, m, 2H disappears with D2O), 6.2 (3H, s), 5.5 (1H, m), 3.6 (aH, d, J=16 Hz) 2.55 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(Cl)nc(N[C@@H](C)c2ccccc2)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-chloro-6-methylpyrimidine (11 mg, 0.044 mmol, 1 eq) in DMF (0.2 mL) was added a solution of benzimidazole sodium salt (0.088 mL of a 1M solution, 0.088 mmol, 2 eq). The mixture was warmed to 100° C. for 2 h. The mixture was cooled and the DMF was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (eluted with 2:1 hexanes/acetone to give 9.9 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.23 (3H, d, J=7 Hz), 2.45 (3H, s), 5.2 (1H br s), 5.62 (1H, br s), 6.6 (1H, s), 7.2-7.5 (7H, m), 7.8 (2H, d, J=8 Hz), 8.46 (1H, br s). Mass spectrum (NH3/CI): 330.1 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([N:1]=[N+:2]=[N-:3])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 125 °C
Yield: 56.8 %

Procedure:
Sodium azide (6.96 g, 0.107 mol) and ammonium chloride (2.13 g, 0.0399 mol) were added to a solution of 1-(tert-butoxy carbonyl)3-[(methylsulphonyl)oxy]piperidine (10 g, 0.0358 mol) in DMF (75 ml) and water (12.5 ml). The mixture was heated overnight at 125° C. under stirring, cooled and diluted with water and extracted with chloroform. The organic layer was washed with water, dried over Na2SO4 and concentrated to give 4.6 g of thin reddish brown oil. 1H NMR (CDCl3) δ: 2.80-4.30 (m, 5H), 1.60-2.20 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[C:19]#[N:20]>CCOC(C)=O>[CH2:8]([O:15][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:18]=1[C:19]#[N:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Intermediate B, Step 1: A 250-mL round bottom flask containing a magnetic stir bar and fitted with a condenser and a inert gas inlet was charged successively with sodium hydride (60% dispersion in mineral oil, 1.32 g, 33.0 mmol), THF (46 mL) and a THF (46 mL) solution of benzyl alcohol (2.86 mL, 27.5 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (5.2 g, 27.5 mmol). The resulting solution was warmed to 60° C. for 3 h, then cooled to RT, diluted with EtOAc (200 mL) and washed with water (2×100 mL) and brine (60 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator to give crude 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.32 g, 26.4 mmol, 96% yield) as a colorless oil. LC/MS [M+H]+=278.07. 1H-NMR (400 MHz, CDCl3) δ=7.89 (s, 1H), 7.78 (d, J=12.0 Hz, 1H), 7.5-7.3 (m, 5H), 7.12 (d, J=8.0 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[CH3:14][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[C:9]=2[CH:10]=[C:11]([CH3:12])[C:2]=1[NH:1][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc2c(c(C)c1N)CCCC2=O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCCC2=O
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 6-amino-5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1 g, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in anhydrous dichloromethane (20 ml) was added dropwise tert-butylacetyl chloride (0.78 g, 5.8 mmol) at room temperature. The reaction mixture was stirred an additional 3 hours at this temperature. The solvent was removed under reduced pressure, and the residue was purified by Biotage (hexane/EtOAc, 0-40%, 40 min) to give a white solid (1.4 g, 92%). 1H-NMR δ (CDCl3, 300 MHz): 7.82 (s, 1H), 6.73 (brs, 1H, exchangeable with D2O), 2.85 (t, J=6.0 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 2.33 (s, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 2.15 (m, J=6.0 Hz, 2H), 1.16 (s, 9H). MS: 288 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])[N:3]=1.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2[S:6][N:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)=[O:10])[N:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(Cc1nsc(N)n1)C(=O)[C@H]1CCCO1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1nsc(NC(=O)Oc2ccccc2)n1)C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step 2, (R)-tetrahydro-furan-2-carboxylic acid (5-amino-[1,2,4]thiadiazol-3-ylmethyl)-methyl-amide (3.0 g, 12.4 mmol), and pyridine (1.08 g, 13.6 mmol) in DCM (120 mL) was added phenyl chloroformate (1.95 g, 12.4 mmol) by syringe at 0 C under N2. The reaction mixture was stirred at room temperature overnight, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford Intermediate 39: (3-{[methyl-((R)-tetrahydro-furan-2-carbonyl)-amino]-methyl}-[1,2,4]thiadiazol-5-yl)-carbamic acid phenyl ester (3.0 g, yield: 67%) as a pale solid. LC-MS (m/z): 363.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=O)[CH2:7][C:6]=2[CH:11]=1.[Br-].[C:13]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C(C)=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:18][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2c(c1)CC(=O)O2
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc2cc(C)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of the product of Step 2, above (56) (10.81 mmol) and (carbethoxymethyl)triphenylphosphonium bromide (12.0 mmol) in 50 ml of xylene was heated to 155° C. for 20 hours. The reaction was cooled to ambient temperature and concentrated to dryness. The crude residue was chromatographed on silica gel with gradient elution with 5% EtOAc in hexanes to 10% EtOAc in hexanes to obtain the title compound (57).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.Cl.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([CH3:28])=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCN3CCC(c4ccc(C)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
A solution of 8.8 g of 3-(2-bromoethyl)-5-methoxy indole in 100 ml of dimethylformamide is added to a stirring mixture of 4-(4-toluyl)piperidine hydrochloride [Example 5(a)] and 10.1 g of potassium carbonate in 400 ml of dimethylformamide and the reaction mixture is stirred at ambient temperature for 80 hours and then at 50° C. for 10 additional hours. It is cooled to ambient temperature, filtered, and 2 liters of water are added dropwise to produce a precipitate. The precipitate is triturated with ether and eluted with a 5% methanol in benzene solution through a silica gel column. The precipitate is recrystallized from an ethanol-water mixture to give off-white crystals, mp 131°-133° C., 5-methoxy-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-:43].[K+].[K+].OO.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:24][CH2:25][CH:26]([O:29][Si:30]([CH:34]([CH3:35])[CH3:36])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:28]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:43])=[CH:8][CH:7]=1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C(N)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
Cool a solution of (R)-4-{3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.295 g, 0.48 mmol) in DMSO (5 mL) on an ice bath. Add to the solution potassium carbonate (0.331 g, 2.4 mmol) and hydrogen peroxide (30% in water, 1 mL) and stir the reaction at 0° C. for 1.5 hours and then at room temperature for 12 hours. Dilute the reaction with ethyl acetate, and wash three times with water and then one time with brine. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 40% ethyl acetate in hexanes to 100% ethyl acetate gradient to afford 0.210 g (69%) of the title compound. MS (m/z): 633 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([O:5][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:6]1[CH2:8][CH2:7]1
Reactant: COC(=O)C(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a solution of cyclopropyl-hydroxy-acetic acid methyl ester (1.00 g, 7.68 mmol) in DCM (9 mL) was added tert-butyldimethylsilyl chloride (1.27 g, 8.45 mmol) and imidazole (628 mg, 9.22 mmol). The reaction mixture was stirred at RT for 65 hours before being quenched with water (10 mL) and 1M HCl (5 mL). The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic phases were washed with 1M HCl (10 mL), brine (10 mL), dried (Na2SO4) then concentrated in vacuo. This gave (tert-Butyl-dimethyl-silanyloxy)-cyclopropyl-acetic acid methyl ester as an amber oil (1.66 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.81 (1H, d, J=6.33 Hz), 3.74 (3H, s), 1.23-1.13 (1H, m), 0.89 (9H, s), 0.52-0.0.38 (4H, m), 0.06 (3H, s), 0.04 (3H, s).
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[CH:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[C:28]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:29])=[CH:33][C:34]=1[F:39]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Reactant: C[C@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (31 mg, 0.097 mmol) in CH2Cl2 (5 mL) and triethylamine (1 mL) was added HBTU (37 mg, 0.097 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL) and washed with water (5×50 mL). The organic phase was dried and concentrated. The residue was subject to silica gel chromatography, eluting with CH2Cl2/MeOH (50:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (44 mg, 85%). MS (APCI+) [M+H]+ 536.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([C:25]1[C:24]([CH3:31])=[N:1][C:2]2[C:3]([C:21]=1[NH2:22])=[C:4]([O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9])[CH:18]=[CH:19][CH:20]=2)=[O:27])[CH3:30]
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide (Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H), 1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H), 4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d, J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 8.09 (brs, 2H). MS 414 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:15]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:15]=[N:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2ccc(N)cc2)c1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(NS(C)(=O)=O)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
Methanesulfonyl chloride (80 mg) was added to a mixture of ethyl 1-(4-aminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), triethylamine (76 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Thereafter, the same treatment of Example 2 was carried out to give ethyl 1-(4-methanesulfonylaminophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylate (29 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:20])=O.N>C(Cl)(Cl)Cl>[Cl:20][CH2:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Temperature: 0 °C

Procedure:
38 g of 4,5-Dimethyl-2-(4-(2-propyl)-phenyl)-oxazole 3-oxide are dissolved in 200 ml of chloroform, 16.4 ml of phosphorus oxychloride are added and the mixture is heated under reflux for 30 minutes. The reaction mixture is cooled to 0° C., a slightly alkaline pH is established using ammonia and the mixture is extracted three times with in each case 500 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 10.3 g of 4-chloromethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole as a colorless solid. C14H16CINO (249.74), MS(ESI): 250 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)([C:4]#[CH:5])[CH3:3].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:3][C:2]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)([C:4]#[C:5][CH2:18][CH2:19][CH2:20][Cl:21])[CH3:1]
Reactant: C#CC(C)(C)OC1CCCO1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C#CCCCCl)OC1CCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a dried flask (500 ml volume), the inside of which had been flushed with nitrogen, were charged 15.4 g (0.10 mol.) of 2-methyl-2-tetrahydrofuranoxy-3-butyne, 150 ml of tetrahydrofuran and 20 ml of hexamethylphosphoric triamide, and the resulting mixture was cooled to −70° C. Subsequently, 65 ml of n-butyllithium (1.55 mol./l n-hexane solution, 0.10 mol.) was added to the mixture and the resulting mixture was stirred at 70° C. for 30 minutes. After adding 15.8 g (0.10 mol.) of 1-bromo-3-chloropropane, the reaction solution was warmed to 0° C. over 2 hours and further stirred at 0° C. for 2 hours to complete the reaction. After the completion of the reaction, the reaction mixture was added to 500 ml of an aqueous saturated ammonium chloride solution, cooled by ice, and then subjected to extraction with two 200 ml portions of ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated by distillation of the solvent through a rotary evaporator to give 22.8 g of a crude product. The crude product was purified by distillation under reduced pressure to give 2-methyl-2-tetrahydrofuranoxy-7-chloro-3-heptyne (19.2 g, purity 97.0%, yield 80.8%) having the following physical data:
Reaction SMILES: [O:1]=[C:2]1[NH:15][C:5]2=[N:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH2:3]1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17].C(OCC)C>C(O)(=O)C>[CH2:16]([O:19]/[CH:20]=[C:3]1\[C:2](=[O:1])[NH:15][C:5]2[C:4]\1=[CH:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=2)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Reactant: CCOC(OCC)OC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCO/C=C1\C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.040 g, 0.19 mmol) and diethoxymethyl acetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature, and diethyl ether was added to precipitate the title compound as a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 MHz (DMSO-d6): δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).