Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1.[CH2:23]([N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH2:27])[CH:24]=[CH2:25]>O.O1CCCC1.C1(C)C=CC=CC=1>[CH2:23]([N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:27][C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1)[CH:24]=[CH2:25]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: C=CCN(N)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=CCN(Nc1cc(Cl)ncc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
7.0 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (70 mL) solution of 4.40 g of ethyl 4,6-dichloronicotinate and 3.44 g of tert-butyl 1-allylhydrazinecarboxylate obtained in Production Example 1-1, and stirred overnight at 70° C. 30 mL of toluene was added to the reaction liquid, and tetrahydrofuran was evaporated away. This was stirred at 120° C. for 6 hours, and then heated overnight under reflux. The reaction liquid was restored to room temperature, water was added thereto, and extracted with ethyl acetate. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=16/1 to 12/1) to obtain 1.29 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30]O>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([O:25][CH3:30])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Solvent: O=S(Cl)Cl
Product: COCCn1c(C)nc2cc(C(=O)OC)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (10.0 g, 29.4 mmol, Step 5) in methanol was added dropwise thionyl chloride (8.57 mL, 118 mmol) at room temperature, and the mixture was refluxed with stirring for 2 hours. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was poured onto saturated sodium hydrogencarbonate aqueous solution, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was suspended in diisopropyl ether (100 mL), and the precipitate was collected by filtration to afford the title compound as a gray solid (9.22 g, 85%).
Reaction SMILES: [Br:1]Br.[F:3][C-:4]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]([F:14])([F:13])[C:5]1([F:16])[F:15].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[Br:1][C:4]1([F:3])[C:5]([F:15])([F:16])[C:6]([F:13])([F:14])[C:7]([F:11])([F:12])[C:8]1([F:10])[F:9]
Reactant: F[C-]1C(F)(F)C(F)(F)C(F)(F)C1(F)F
Reactant: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: FC1(F)C(F)(F)C(F)(F)C(F)(Br)C1(F)F

Procedure:
Bromine was added to a solution of tris(dimethylamino)sulfonium 1,2,2,3,3,4,4,5,5-nonafluorocyclopentanide in benzonitrile, prepared as described in Example 5. Distillation of the reaction mixture gave bromononafluorocyclopentane as a colorless liquid: b.p. 64°-65°; 19F NMR (CCl3F) δ -112.4 ppm (d, J=262 Hz, 2F), -136.2 ppm (d, J=262 Hz, 2F), -141.4 ppm (m, 1F), -125.4 ppm (d, J=255 Hz, 2F) and -127.8 ppm (d, J=255 Hz, 2F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1)[CH2:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1.B(F)(F)F.S(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]([CH3:24])[CH3:25])[CH:16]=1)[CH2:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1
Reactant: COc1ccc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)ccc1O

Procedure:
A reaction mixture of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-benzyltetrazole (60 mg), BF3.Me2S (0.5 ml) and CH2Cl2 (6 ml) was stirred at room temperature over night. The yield after purification was quantitative.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23][C:24]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:41])[CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:37]([O:36][C:34]([NH:33][C:24]([NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:41])[CH:12]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:15]=1)=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCOC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 14.56 q of 4-{[(1S,2R)-2-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazoline-2-carboxylic acid ethyl ester in 350 ml of tetrahydrofuran, 55 ml of a 10% sodium hydroxide solution was added under ice cooling, and then the mixture was stirred at room temperature for 10 hours. The reaction solution was mixed with 170 ml of a 10% potassium hydrogensulfate solution, extracted with chloroform and then dried over magnesium sulfate. The solvent was distilled off to obtain 14.2 g of the desirable compound as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[CH3:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Product: COC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.12 g, 10%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4-methylphthalic anhydride (0.56 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](O)=O>C(O)(=O)C.O>[CH3:11][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:14])[CH:1]=2)[CH:6]=1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
The crude 2,6-naphthalenedicarboxylic acid used for the following Examples was obtained by the liquid phase, air oxidation of 2,6-dimethylnaphthalene in acetic acid/water solvent catalyzed by cobalt II acetate, manganese II acetate and hydrogen bromide as the promoter.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCCO)cc1
Yield: 100 %

Procedure:
A mixture of 4-(4-nitro-phenyl)-butan-1-ol (2.0 g, 1.02 mmol), palladium on carbon (100 mg, 10%) and ethanol (25 ml) was treated with hydrogen gas on a Parr shaker (50 psi) for 1 hour. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure to afford 4-(4-amino-phenyl)-butan-1-ol (100% yield).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>CCOC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
A well-dried flask was first charged with 1-bromo-2-methoxybenzene (4.0 g, 21.3 mmol) and piperazine (2.2 g, 25.6 mmol), which was evacuated and backfilled with N2 through a balloon under gentle warming (40° C.). Toluene was charged and the mixture was bubbled with N2 for 10 min, then BINAP (398 mg, 0.64 mmol) and Pd2 dba3 (195 mg, 0.21 mmol) was added to the mixture. After the addition of DBU (3.8 mL), the solution was warmed at 60-70° C. while a fine powder of tBuONa (3.5 g, 31.9 mmol) was added in one portion to start the amination. After the reaction mixture cooled to rt, (Boc)2O (11.6 g, 53.2 mmol) was dissolved in DCM and added dropwise to the reaction mixture, then stirred at rt for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=10:1) to give tert-butyl 4-(2-methoxyphenyl)piperazine-1-carboxylate as a white solid. Excess HCl in EtOAc was added dropwise to a solution of tert-butyl 4-(2-methoxyphenyl)piperazine-1-carboxylate in EtOAc and the reaction mixture was stirred at rt for 1.5 h. Filtration gave 1-(2-methoxyphenyl)piperazine hydrochloride salt (intermediate 55) (2.6 g, 42%) as a white solid. HPLC: 99%, RT 1.586 min. MS (ESI) m/z 193.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([C:25]2([C:30]([OH:32])=O)[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si]([NH:43][OH:44])(C)C>C(Cl)Cl>[OH:44][NH:43][C:30]([C:25]1([CH:14]([S:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:13])=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: C[Si](C)(C)NO
Reactant: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C2(C(=O)O)CCCC2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C2(C(=O)NO)CCCC2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
1-[1-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentyl]cyclopentane carboxylic acid (0.69 g, 1.5 mmol) is dissolved in CH2Cl2 (6 mL), cooled to 0° C. and 2 M oxalyl chloride in CH2Cl2 (2.2 mL, 4.4 mmol) is added. The reaction is warmed and stirred at room temperature 2 hours. The solvent is removed in vacuo and the residue azeotroped with chloroform (2×10 mL). The residue is dissolved in CH2Cl2 (2 mL) and cooled to 0° C. Trimethylsilylhydroxylamine (0.52 mL, 4.5 mmol) is added over 1 minute and this mixture is stirred 5 minutes. Then the ice bath is removed and the reaction stirred at room temperature overnight. The solvent is removed in vacuo and CH2Cl2 (20 mL) added and the solution washed with 1 N HCl (20 mL). The solution is dried over MgSO4 and the solvent removed in vacuo to give 1-[1-(3,4-Dimethoxyphenylsulfonyl)-5-phenylpentyl]cyclopentanecarboxylic acid hydroxyamide (0.48 g, 67%): 1H NMR (300 MHz, CD3OD) δ 7.44 (dd, J=8.3, 2.0 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.22-7.05 (m, 4H), 6.98 (d, J=7.0 Hz, 2H), 3.89 (s, 3H), 3.87 (m, 4H), 2.38 (t, J=7.4 Hz, 2H), 2.35-2.25 (m, 1H), 1.96-1.63 (m, 10H), 1.34-1.27 (m, 2H), 1.21-1.10 (m, 1H), 1.00-0.88 (m, 1H); MS (EI) m/e 476 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (393 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[Cl:21].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([Cl:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Agent: N
Product: Clc1cncc(-c2cc(-c3ccc(Cl)c(Cl)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 51 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J=1.2 Hz, 2H), 7.93 (s, 1H), 8.18 (s, 1H), 8.40-8.44 (m, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 325 (M+H)+, 327 (M+H)+, 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:29])[C:25]=1[CH:26]([OH:28])[CH3:27].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:29])[C:25]=2[CH:26]([OH:28])[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CC(O)c1c(F)cncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(O)c1c(F)cncc1-c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To the solution of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (263 mg, 1.00 mmol), 1-(3-Bromo-5-Fluoro-pyridin-4-yl)-ethanol (220 mg, 1.00 mmol) and PdCl2(dppf). CH2Cl2 adduct (65 mg, 0.08 mmol) in DMF (4 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and sat. NH4Cl solution. After extraction with DCM, the combined extracts were concentrated and purified by ISCO 12 g (0-30% EtOAc/Hep) to give 2-Chloro-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (138 mg, 49%) as a white solid; ESI-MS m/z: 276 [M+1]+, Retention time 1.15 min. 1H-NMR (CDCl3, 400 MHz) δ 1.53 (d, J=6.8 Hz, 3H), 4.76 (q, J=6.8 Hz, 1H), 7.28 (dd, J=8.0, 2.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.46 (d, J=2.0 Hz, 1H). The racemate was separated by chiral HPLC (ChiralPak IA-H, 40% EtOH/Heptane, v/v) and yielded 2-Chloro-4-[5-fluoro-4-((R)-1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile 16-(enantiomer-1) (retention time: 5.24 min) and 2-Chloro-4-[5-fluoro-4-((S)-1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile 16-(enantiomer-2) (retention time: 13.69 min).
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1.C(OCC)(=O)C>O>[Cl:22][C:23]1[CH:28]=[C:27]([N:10]2[CH2:11][CH2:12][N:7]([CH:3]3[CH2:6][CH2:5][CH2:4]3)[CH2:8][CH2:9]2)[N:26]=[CH:25][N:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CC(N2CCNCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.8 g (8.4 mmol) of 1-cyclobutylpiperazine dihydrochloride (Zaragoza et al., J. Med. Chem. 2004, 47, 2833) are initially charged in 18 ml of water, and 2.9 ml (2.1 g, 16.9 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are added. The mixture is stirred at RT for 30 min, and 1.3 g (8.4 mmol) of 4,6-dichloropyrimidine are added. The reaction mixture is stirred at 115° C. for 1 h and cooled to RT, 25 ml of ethyl acetate are added and the mixture is extracted with 25 ml of a saturated aqueous sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 100/3). Yield: 1.9 g (89% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(Cl)Cl>[Si:26]([O:10][CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]2[N:5]([N:12]=[CH:13][CH:14]=2)[C:6]=1[Cl:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: OCCc1c(Cl)nc2ccnn2c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1c(Cl)nc2ccnn2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.4 %

Procedure:
To a methylene chloride (50 mL) solution containing 2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol (640 mg, 2.77 mmol), triethylamine (3.86 mL, 27.7 mmol) and tert-butylchlorodimethylsilane (1.25 g, 8.31 mmol) were added, and this mixture was stirred at room temperature for 16 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (1.04 g).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][C:12]=2[CH3:21])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C)c(-c2ccc(OC)c(Br)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Liquid bromine (1.04 g, 0.36 ml, 6.49 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 1.5 g, 5.41 mmol) in acetic acid (15 ml) at 25° C. The resulting reaction mixture was then stirred at 25° C. for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained after concentration was dissolved in ethyl acetate (100 ml). The mixture obtained was washed with saturated sodium bicarbonate solution (30 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound 8a (1.70 g, 88.5%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:28][CH:29]([F:34])[CH:30]1[CH2:33][NH:32][CH2:31]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:28][CH:29]([F:34])[CH:30]1[CH2:33][N:32]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:17][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:15]3)=[CH:26][CH:25]=2)[CH2:31]1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Reactant: FC(F)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC(C(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.7 %

Procedure:
To a suspension of 68A (0.20 g, 0.57 mmol) in DCM (3 mL) was added 68C (0.25 g, 1.72 mmol) followed by DIPEA (0.30 mL, 1.72 mmol). Sodium triacetoxyborohydride (0.24 g, 1.15 mmol) was added. The mixture was stirred at RT for 5 h and then diluted with DCM. The solution was washed with an aqueous solution of NaHCO3 and then filtered through a phase separator. The solvent was removed by evaporation. The product was purified on a silica gel column using 1-4% methanol in DCM where the methanol contained 2M ammonia. The product was triturated from ether and after drying in the hood there was obtained 47 mg (19%) of 68 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 1H), 3.19 (m, 2H), 3.36 (m, 2H), 3.55 (s, 2H), 4.34 (dd, 1H), 4.64 (dd, 1H), 4.78 (dd, 1H), 5.07 (m, 1H), 5.11 (m, 1H), 5.99 (t, 1H), 6.74 (d, 2H), 7.22 (d, 2H), 7.54 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 441 [M+H]+, LC purity: 90%. A sample of (3-(4-((3-(difluoromethyl)azetidin-1-yl)methyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone was recrystallised from DCM/Et2O had m. p. 147° C. (purity 99%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=4)[NH:17][C:16]3=[O:21])=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccc2c(c1)OCO2
Yield: 74.6 %

Procedure:
With 3.00 g of 5-bromo-1,3-benzodioxol and 1.86 g of 5-chloroisatin as starting materials, 2.32 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[N:7][C:6]=1[CH3:29])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:10]([N:9]1[C:5]([CH2:4][NH2:1])=[C:6]([CH3:29])[N:7]=[CH:8]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-azidomethyl-4-methyl-1-tritylimidazole (3.0 g, 7.9 mmol) in THF (70 ml) was added triphenylphosphine (5.18 g, 19.8 mmol). The resulting solution was refluxed for 1.5 h then water (5 ml) was added. Refluxing was continued for an additional 24 hours. After cooling to room temperature, the solvents were removed in vacuo and the crude reaction mixture was purified by chromatography on silica gel (19:1 chloroform/10% NH4OH in methanol) to give of the title compound. 1H NMR (CDCl3) d 1.40 (s, 3 H), 1.70 (br s, 2 H), 3.70 (s, 2 H), 7.10-7.35 (m, 16 H).