Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:13][CH2:12]2)=[N:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2nsc3ccccc23)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3nsc4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isothiazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]#[N:16].[CH2:17]([O:19][C:20](=[O:26])[CH:21]=[CH:22]OCC)[CH3:18].S(=O)(=O)(O)O>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(O)CO>[O:19]1[CH2:17][CH2:18][O:26][C:20]1=[C:21]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]([C:15]#[N:16])=[CH:22]1
Reactant: CCOC=CC(=O)OCC
Reactant: N#CCc1ccccc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: OCCO
Product: N#CC1=CC(=C2OCCO2)c2ccccc21
Temperature: 0 °C
Yield: 79.7 %

Procedure:
A solution of tricyclohexylphosphine (536 mg, 1.91 mmol) in tetrahydrofuran (25 mL) was charged with palladium (II) acetate (287 mg, 1.27 mmol) under nitrogen. After 1 hour the reaction mixture was cooled to 0° C. and charged with sodium tert-butoxide (31.6 g, 319 mmol). After 5 minutes a solution of 2-bromo-phenylacetonitrile (25.0 g, 128 mmol) and β-ethoxyacrylic acid ethyl ester (18.4 mL, 128 mmol) in tetrahydrofuran (75 mL) was added dropwise over 15 minutes. The reaction was heated to 60° C. After 2 hours 30 minutes the reaction mixture was cooled to room temperature and charged with ethylene glycol (200 mL) over 5 minutes and then charged with sulfuric acid (18.8 M, 36 mL) added dropwise over 15 minutes. After 15 hours the reaction was diluted with water (90 ml) and a solid product was filtered through a glass frit. The solid was dried under vacuum affording 3-[1,3]dioxolan-2-ylidene-3H-indene-1-carbonitrile (21.6 g, 102 mmol, 80%) as a light tan solid. The crude material was slurried in isopropanol (50 mL) for 2 hours, filtered and dried under vacuum affording 3-[1,3]dioxolan-2-ylidene-3H-indene-1-carbonitrile (20.8 g, 98.5 mmol, 77%) as a light tan solid. 1H NMR (400 MHz, d6-DMSO) δ 7.75 (s, 1H), 7.74 (d, 1H, J=7.9), 7.50 (d, 1H, J=7.1), 7.22 (m, 2H), 4.97 (t, 2H, J=7.8), 4.85 (t, 2H, J=7.8); 13C NMR (100 MHz, d6-DMSO) 167.4, 136.7, 135.7, 133.1, 124.7, 123.9, 121.1, 119.4, 118.1, 97.8, 92.7, 71.1, 69.9; mp (decomposition) 228° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([CH2:21][NH2:22])[NH:18]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CCN(C(C)C)C(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[C:17]([CH2:21][NH:22][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[NH:18]2)=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH3:10]
Reactant: CCOC(=O)C(Oc1ccc2cc(CN)[nH]c2c1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(Oc1ccc2cc(CNS(=O)(=O)c3ccccc3)[nH]c2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Aminomethyl-1H-indol-6-yloxy)-malonic acid diethyl ester (80 mg, 0.2 5 mmol) is dissolved in DCM (2 ml). DIEA (87 □l, 0.50 mmol) is added. To the solution, benzenesulfonyl chloride (44 mg, 0.25 mmol) is added. The reaction is stirred at room temperature for two hours. The reaction mixture is concentrated and the residue is purified by chromatography (30% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:13])[CH2:6][CH2:7][O:8]2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1cc2c(cc1Cl)C(=O)CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCOc2cc(CBr)c(Cl)cc21

Procedure:
A mixture of 6-chloro-7-methyl-chroman-4-one (20 g, 101.71 mmol), NBS (19.9 g, 111.88 mmol), and AIBN (4.17 g, 25.43 mmol) in anhydrous CCl4 (300 mL) was heated at reflux in 24 h. The mixture was cooled, filtered the solid. The filtrate was concentrated and used in the next step without purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31]>>[OH:31][CH2:30][C@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)[C@@H](N)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](CO)C(C)C)cn2)CC1
Yield: 73 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-3-methyl-1-butanol. Then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[OH-].[Li+].[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O.CN(C)C=O.C1COCC1>[C:30]([O:33][CH2:34][CH2:35][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)=[CH:17][CH:18]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)Oc1ccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCCOc1ccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of acetic acid 4-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenyl ester (0.33 g; 0.834 mmol), lithium hydroxide (0.04 g; 0.831 mmol) and THF (8 ml) was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure. To the residue were added bromoethyl acetate (0.14 ml; 1.26 mmol), cesium carbonate (0.41 g; 1.26 mmol) and anhydrous N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give 4-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenoxyethyl acetate as colorless oil (0.35 g; 93%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[I:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=2[I:17])=[O:4].[H-].[Na+].Br[CH2:21][C:22]1[CH:26]=[C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[O:24][N:23]=1.BrCC1ON=C(C2SC(Cl)=CC=2)C=1>CN(C=O)C.O>[Cl:32][C:29]1[S:28][C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:6]3[C:7]4[C:12](=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=4[I:17])[C:13]([I:14])=[C:5]3[C:3]([OH:2])=[O:4])[CH:26]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1[nH]c2c(I)ccc(OC)c2c1I
Agent: Clc1ccc(-c2cc(CBr)on2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(I)c2c1c(I)c(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg 3,7-Diiodo-4-methoxy-1H-indole-2-carboxylic acid methyl ester in 2 ml DMF 20 mg (60% in oil) sodium hydride were added at RT. After stirring for 30 min 121 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, ChristopherJ.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was heated for 1 h at 60° C. After subsequent cooling of the reaction to RT and addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration under reduced pressure the residue was treated with 30 mg lithium hydroxide monohydrate in THF/water 2:1. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid to pH 2 and the precipitate collected by filtration and washed with 3 ml water The product was obtained as a white solid which was dried under reduced pressure. Yield: 200 mg.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH3:4].[Na].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CN(C)C=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[Si:3]([CH3:5])([CH3:4])[CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A mixture of 5.1 g (0.020 mol) of chloromethyl(2,4-dichlorophenyl)dimethylsilane and 2.0 g (0.022 mol) of imidazole sodium salt in 10 ml of dry dimethylformamide was stirred at 80°-90° for 2 hours and worked up as in Example 23 to give 3.9 g (69%) of the title compound as a brown oil: nD23 1.5637; ir (neat) 1560, 1500, 1450, 1355, 1250, 1105, 1095, 1075, 1025, 840, 780, 735 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.9 (2H, s), 6.7 (1H, broad s), 7.0 (1H, broad s) 7.2-7.5 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19](I)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](Cl)(CCCC)CCCC)CCC.Br[C:57]1[S:61][C:60]([C:62]([NH2:64])=[O:63])=[CH:59][CH:58]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:57]5[S:61][C:60]([C:62]([NH2:64])=[O:63])=[CH:59][CH:58]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Reactant: NC(=O)c1ccc(Br)s1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: NC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)s1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 200 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(1,1,1-tributylstannyl)imidazo[1,2-a]-pyridine prepared from 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39) and tributyltin chloride by the same method as in Production Example 48, 51 mg 5-bromo-2-thiophene carboxamide, 14 mg tetrakis (triphenylphosphine)palladium and 3 mL xylene was stirred at 120° C. for 2 hours under nitrogen atmosphere. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/methanol) to give 37 mg of the title compound as a colorless amorphous.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>CN(C)C=O>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3ccccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A suspension of 0.80 g (0.0041 2 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 17 ml of dimethylformamide was treated with 1.7 ml (0.0123 mol) of triethylamine and 0.67 g (5.3 mol) of 1,2,3,4-tetrahydroisoquinoline and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent and recrystallized from ethyl acetate/diethyl ether. 0.72 g (69%) of 5-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as beige crystals; m.p. 150°-153°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[CH:7]=[N:8]O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:7]#[N:8])[CH:10]=1
Reactant: ON=Cc1cc(Cl)ccc1O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Cl)ccc1O
Temperature: 4 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A solution of 5-chloro-2-hydroxybenzaldoxime (4.2 g) in acetic anhydride (15 ml) was heated for 4 hours at reflux, then allowed to stand for 16 hours at ambient temperature. The mixture was added to a vigorously stirred ice-water mixture and after one hour the resulting solid was collected by filtration. 2M Sodium hydroxide solution (120 ml) was added to a stirred solution of this solid in methanol (50 ml) and the mixture stirred for 20 minutes. The pH of the mixture was then adjusted to 4.0 with 2M hydrochloric acid solution. The mixture was cooled to 4° C. and the white precipitate collected by filtration to give 4-chloro-2-cyanophenol (2.6 g), m.p. 166°-168° C.; NMR (CDCl3 /d6 -DMSO): 6.69(1H,d,J=8 Hz), 7.04(1H,dd,J=8,2.5 Hz), 7.11(1H,d,J=2.5 Hz), 10.33(1H,s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Br)cn1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow volatile oil (2.5 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.87 (dd, 1H), 6.81 (d, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18](Br)=[C:17]([CH3:23])[CH:16]=2)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[F-].[K+].[CH:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)=[C:17]([CH3:23])[CH:16]=2)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Yield: 92.5 %

Procedure:
Isomer 1 of 4-[1-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid methyl ester (500 mg, 1.28 mmol), potassium fluoride (223 mg, 3.84 mmol), 4-isopropylphenyl boronic acid (419 mg, 2.56 mmol) and tetrakis-(triphenylphosphine)palladium (148 mg, 0.128 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (510 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[F:16][CH:17]([F:46])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[C:38]([O:44][CH3:45])[CH:37]=4)[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C.[Na]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH:17]([F:46])[F:16])=[CH:23][CH:22]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[CH:37][C:38]=2[O:44][CH3:45])[CH2:8][O:9]1
Reactant: COc1cc(OC2CN(C(=O)c3nnc(-c4ccc(C(F)F)cc4)o3)C2)ccc1C=O
Reactant: C1CNC2(C1)COC2
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC2CN(C(=O)c3nnc(-c4ccc(C(F)F)cc4)o3)C2)ccc1CN1CCCC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.11 g, ca. 70%, 0.34 mmol) and 4-(1-(5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)-2-methoxybenzaldehyde (0.146 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was added, followed by sodium triacetoxyhydroborate (0.145 g, 0.68 mmol). The mixture was stirred at ambient temperature overnight. An LC-MS showed complete consumption of starting materials. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.119 g (67%) of the desired product as a solid. 1H NMR (500 MHz, CDCl3): δ 1H NMR (600 MHz, DMSO) δ 1.56-1.68 (m, 2H), 2.06-2.14 (m, 2H), 2.55-2.58 (m, 2H), 3.81 (s, 3H), 3.88 (s, 2H), 4.11 (dd, 1H), 4.44 (d, 2H), 4.54-4.59 (m, 1H), 4.63-4.68 (m, 1H), 4.79 (d, 2H), 5.09-5.13 (m, 1H), 5.17-5.22 (m, 1H), 6.42 (dd, 1H), 6.54 (d, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.85 (d, 2H), 8.23 (d, 2H). MS (APCI+) m/z 527.2 [M+H]+, LC purity: 97%.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[CH:19]=[N:18][NH:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1>[OH-].[Na+].CO>[CH:1]1([C:5]2[C:14]([C:15]3[CH:19]=[N:18][NH:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2cn[nH]n2)c(C2CCC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2CCC2)c(-c2cn[nH]n2)cc1C(=O)O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of methyl 4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate (compound 446.3, 92 mg, 0.34 M) in 2N NaOH (1.5 ml) and methanol (MeOH) (4 ml) was heated at 50° C. for 16 hours. After cooling to room temperature, the methanol was removed under reduced pressure. The residue was neutralized with 2N HCl to pH 3-4 and extracted with EtOAc. The organic phase was then washed with brine, dried (MgSO4), and concentrated to yield 83 mg of a white solid that was used without further purification. m/z (ES−) 256 (M−H)+.
Reaction SMILES: Cl.Cl[CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1.Cl.[CH3:32][NH2:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:32][NH:33][CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CN
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(Cl)c4ccccc4)CC3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
One gram of 6-[4-(3-chloro-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.hydrochloride, 0.17 g of methylamine.hydrochloride and 1.2 g of potassium carbonate were dispersed in 20 ml of acetonitrile and the dispersion was stirred at 60° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water then extracted with methylene chloride. The extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. Thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =20:1), then the desired product was converted into a citrate, and recrystallized from ethanol-water to yield 0.5 g of 6-[4-(3-methylamino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. dicitrate. White powdery substance. Melting point: 150° C.-156° C. (decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][S:17](=[O:20])(=[O:19])[NH2:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CO.O1CCOCC1>[ClH:21].[ClH:21].[N:11]1([CH2:14][CH2:15][CH2:16][S:17]([NH2:18])(=[O:19])=[O:20])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCS(N)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NS(=O)(=O)CCCN1CCNCC1

Procedure:
4-(3-Sulfamoyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg) in methanol (5 mL) was deprotected with 4 N hydrochloric acid in dioxane (3 mL) to give 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride (229 mg, white solids)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2([NH:19]S(C(C)(C)C)=O)[C:14]([F:18])([F:17])[CH2:15][OH:16].Cl.O1CCOCC1.C([O-])(O)=O.[Na+].O>C1COCC1.CCO.[Cl-].[Na+].O>[NH2:19][C:5]1([C:14]([F:18])([F:17])[CH2:15][OH:16])[C:6]2([CH2:8][CH2:7]2)[CH2:9][O:10][C:11]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:13][CH:12]=2
Reactant: CC(C)(C)S(=O)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Under ice cooling, to a solution of N-[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]-2-methylpropane-2-sulfinamide (4.60 g, 10.5 mmol) in THF-EtOH (50% v/v, 46 mL) was added 4M HCl/dioxane (13.1 mL, 52.5 mmol), and the mixture was stirred for 3 hours at room temperature. Under ice cooling, saturated aqueous NaHCO3, H2O and brine were added to the mixture, and then the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane=50:50-100:0) to give 2-(4-amino-6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-yl)-2,2-difluoroethanol (2.28 g).