Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:15].O>C1COCC1>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])(=[O:24])=[O:23])=[CH:20][CH:21]=1)#[N:15]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CN)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(CNC(=O)OC(C)(C)C)CNS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl (3-amino-2-methylpropyl)carbamate (200 mg, 1.06 mmol) and TEA (0.444 mL, 3.19 mmol) in THF (5 mL) was added 4-cyanobenzene-1-sulfonyl chloride (214 mg, 1.06 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanophenylsulfonamido)-2-methylpropyl)carbamate (273 mg, 0.772 mmol, 72.7%) as a white powder.
Reaction SMILES: [C@H:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(O)=O)C2(CCCCC2)C1.[NH2:23][CH2:24][C@H:25]([OH:27])[CH3:26].Cl.NCC(N)=O>>[OH:27][C@H:25]([CH3:26])[CH2:24][NH:23][C:9]([C@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: C[C@@H](O)CN
Reactant: O=C(O)[C@@H]1CC12CCCCC2
Agent: Cl
Agent: NCC(N)=O
Agent: O=C(O)C1CC12CCCCC2
Product: C[C@@H](O)CNC(=O)[C@@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 9 for the product from Example 1B and substituting (R)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 173.9, 67.5, 48.0, 38.7, 30.2, 30.0, 28.9, 27.5, 26.9, 26.8, 21.1, 19.4; MS (CI) m/z 212 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[F:29]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: COCc1ccc(F)c(Br)c1
Product: COCc1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromo-1-fluoro-4-(methoxymethyl)benzene (Intermediate 15), the title compound was obtained as a dark yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([O:17][CH3:18])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.[OH-].[Na+]>ClCCl>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[S:3][C:2]([NH:1][C:32]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:33])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc2c1
Reaction time: 6 h
Yield: 14.6 %

Procedure:
2-Amino-5-methoxy-7-phenylbenzothiazol (45 mg, 0.18 mmol) is dissolved in dichloromethane (2 ml) and subsequently treated with triethylamine (0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6 h, further 0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol) are added and the mixture is stirred for additional 18 h at ambient. After addition of 0.1M aqueous sodium hydroxide, the mixture is stirred for additional 16 h. The organic layer is separated, dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1, containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the product as white solid. MS: m/e=380 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)(C)CN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c(NCC(C)(C)C)nc(Cl)nc12
Reaction time: 3 h
Yield: 94 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 179 mg (2.1 mmol) of neopentylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 355 mg (yield: 96.1%) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[C:14]([Li])([CH3:17])([CH3:16])[CH3:15]>>[CH3:11][C:9]1[O:10][C:6]([C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])=[C:7]([CH3:12])[N:8]=1
Reactant: CON(C)C(=O)c1oc(C)nc1C
Reactant: [Li]C(C)(C)C
Product: Cc1nc(C)c(C(=O)C(C)(C)C)o1

Procedure:
Starting with N-methoxy-N-methyl-2,4-dimethyl-5-oxazolecarboxamide and t-butyllithium and following the general method of Preparation 3, the title compound was prepared.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 49% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[CH:18][C:19]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[F:20])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: Fc1ccc(I)cc1F
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)CCc1ccc(Oc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 50-mL RB-flask was added 3-(4-hydroxyphenyl)propionic acid (1.66 g, 10.0 mmol), 3,4-difluoroiodobenzene (2.40 g, 10.0 mmol), copper(I) bromide (0.100 g), potassium carbonate (2.76 g, 20.0 mmol), and n-methyl-2-pyrrolidone (20 mL) as solvent. The mixture was stirred for 5 min at room temperature and then heated to 140° C. (oil bath). After being stirred for 12 hours at 140° C., the reaction mixture was cooled to room temperature and diluted with EtOAC (100 mL). The diluted mixture was washed with citric acid (aq, 30 mL), water (3×50 mL, brine and dried over MgSO4. The removal of solvent in vacuo afforded crude which was purified by chromatography (0.901 g, 32%): 1H NMR (400 MHz, CDCl3) δ 11.44-11.06 (br, 1H), 7.24-7.14 (m, 2H), 7.14-7.00 (m, 1H), 7.00-6.86 (m, 2H), 6.86-6.75 (m, 1H), 6.75-6.61 (m, 1H), 2.94 (t, 2H, J=7.6 Hz), 2.68 (t, 2H, J=7.6 Hz); ESMS m/e: 277.2 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) and TBTU (90 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (217 μL, 1.26 mmol). Then 4-aminotetrahydropyran (28 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (100 mg, 96%) as a white solid. MS: m/e=412.3 [M+H]+.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19](O)[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:27]>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:27])[N:18]2[N:22]=[C:23]([CH3:25])[N:24]=[C:17]2[N:16]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Reactant: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 40 ml of N,N-dimethylaniline, and 35 g of 5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for one hour. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, removing a solvent, an oily product was obtained. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain an oily product. This was allowed to stand to cool and crystallized to obtain 31 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.[Cl:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: CCn1cc(Br)ccc1=O
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 140 °C
Yield: 54.1 %

Procedure:
A mixture of 5-bromo-1-ethylpyridin-2(1 H)-one (1.9 g, 9.45 mmol), 6-chloropyridin-3-ylboronic acid (1.8 g, 11.46 mmol), Cs2CO3 (9.9 g, 30.37 mmol) and tetrakis(triphenylphosphine)palladium (0) (543 mg, 0.55 mmol) were suspended in dioxane:water (15:1, 20 ml). After degassing, the mixture was heated in a microwave at 140° C. for 30 min. The reaction was then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was purified by LCMS to provide the title compound, 5-(6-chloropyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 51% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH:11]([NH:16][C:17]2[N:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=2)[CH2:10][CH:9]1[CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])C.C(=O)([O-])[O-].[K+].[K+].[CH2:32](N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[CH:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH:11]([NH:16][C:17]2[N:18]=[CH:19][C:20]([O:23][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][N:22]=2)[CH2:10][CH:9]1[CH2:24][CH3:25])=[O:7])([CH3:3])[CH3:4]
Reactant: CCC1CC(Nc2ncc(O)cn2)CC(CC)N1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1CC(Nc2ncc(OCc3ccccc3)cn2)CC(CC)N1C(=O)OC(C)C
Reaction time: 2 h
Yield: 171.7 %

Procedure:
To a mixture of 2,6-diethyl-4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.72 mmol, 580 mg) and potassium carbonate (3.23 mmol, 1.12 g) in DMF (12 mL) is added benzylamine (3.53 mmol, 0.42 mL) at room temperature and stirred for 2 hours. Water is added to the mixture, and the precipitate is collected and washed with hexane to give 4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ester (1.26 g, 74%) as a colorless solid. To a solution of 4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ester (2.86 mmol, 1.26 g) in DMF (28 mL) is added sodium hydride (60% oil suspension, 5.72 mmol, 230 mg) at 0° C. and stirred at room temperature for 20 min. To the mixture is added 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (4.29 mmol, 0.79 mL) at 0° C. and stirred at room temperature for 17 hours. To the mixture is added sodium hydride (60% oil suspension, 2.86 mmol, 115 mg) and 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (2.73 mmol, 0.5 mL) at 0° C. and stirred at room temperature for 5 hours. To the mixture is added water, and extracted with EtOAc. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give cis-4-[(5-benzyloxy-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylic acid 4-methoxycarbonyl-cyclohexyl ester (880 mg, 46%); ESI-MS m/z: 667 [M+1]+, Retention time 2.69 min (condition A).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O.O1CCOCC1>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:10]1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(F)cc3)[C@@H](CO)O2)cc1F
Temperature: 35 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
A 7.5 g quantity of potassium hydroxide was dissolved in a mixture of 300 ml of water and 80 ml of dioxane. To the solution were added 2.00 g of 2'-deoxy-5-fluorouridine and 4.9 ml of 4-fluorobenzyl chloride, and the resulting mixture was stirred at 35° C. for 2 days. After the reaction, the same subsequent procedure as in Reference Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.57 g of the title compound in a yield of 20%.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](Cl)=[O:21])=[CH:15][N:14]=1>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][N:14]=1
Reactant: CC(C)N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of isopropylamine (1.28 ml, 15.0 mmol) and triethylamine (2.10 ml, 15.1 mmol) in dry THF (5 ml) was added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (obtained as described in J. Med. Chem., 1972, 15, 200; 3.18 g, 15.0 mmol) in dry THF (8 ml) at −10° C. The solution was stirred 0° C. for 2 hours, filtered and evaporated to dryness to yield the product (0.93 g), which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:38](=[CH:37][CH:36]=[C:35]([O:34][C:33]([F:44])([F:43])[F:32])[CH:40]=4)[NH:41][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O.S(=O)=O.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: Cl
Agent: O=S=O
Product: Cc1cc(C)cc(C(=O)Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Into the same apparatus as used in the method A, were charged 300 g (2 mol) of 3,5-dimethylbenzoic acid and 357.2 g (3 mol) of thionyl chloride. The temperature was raised to 80° C. while stirring in a nitrogen atmosphere to allow the reaction to proceed for 3 h under reflux. During the reaction, sulfur dioxide and hydrogen chloride generated were washed away and captured by an aqueous alkali solution, The result of analysis of the reaction product solution showed the production of 310 g (1.84 mol) of the aimed 3,5-dimethylbenzoyl chloride (yield: 92%). By vacuum distillation, 287-(1.7 mol) of 3,5-dimethylbenzoyl chloride was isolated (yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:17]2[NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=Cc1ccccc1
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(c1ccccc1)NS2(=O)=O

Procedure:
2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide was transformed by Method G (using benzaldehyde). M.p. 235–238° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:33][C:34](Br)([F:36])[F:35].O>CN1C(=O)N(C)CC1>[CH3:25][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:34]([Br:33])([F:36])[F:35])=[CH:7][CH:6]=1)([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=1)[CH3:26]
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: FC(F)(Br)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)Br)cc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 21.6 g of 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether and 13.9 g of potassium t-butoxide in 120 ml of DMI was added dropwise to a mixture of 80 g of dibromodifluoromethane and 50 ml of DMI with stirring for 30 minutes at 50° to 60° C., and the mixture was maintained at this temperature for 3 hours. The reaction mixture was poured into water and extracted with toluene. The toluene solution was washed with dilute hydrochloric acid and water in this order, and dried. Toluene was evaporated under reduced pressure to give 29.4 g of an oily residue. The oily residue was purified by column chromatography [silica gel: 600 g; eluent: toluene/hexane (1:1)] to give 12.4 g of the desired 3-phenoxybenzyl 2-(4-difluorobromomethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[CH3:11].FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:5]2[CH:6]=[N:7][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: Cc1cc(B(O)O)cnc1F
Product: Cc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cnc1F
Yield: 79 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 79% yield, starting from 6-fluoro-5-methylpyridin-3-ylboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate: 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.50 (dd, 1 H), 7.28-7.36 (m, 8 H), 7.17-7.26 (m, 2 H), 7.14 (t, 1 H), 6.84 (d, 1 H), 6.74 (d, 1 H), 4.32-4.42 (m, 1 H), 4.03 (t, 1 H), 3.65-3.76 (m, 4 H), 3.11-3.25 (m, 1 H), 2.73-2.85 (m, 1 H), 2.61 (dd, 1 H), 2.36 (s, 3 H); MS (ESI) m/z 439[M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH:10]=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(C=O)=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(F)cc1)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 113 g (0.69 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-al in 800 ml ethanol at 10° C. was added in portions 13.1 g (0.345 mole) of sodium borohydride. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath while 350 ml of 1 N hydrochloric acid was added dropwise to give a final pH of ~7. The mixture was diluted with 500 ml water and extracted three times with methylene chloride. The organic extracts were dried and concentrated and the residue distilled to give 56.1 g (49%) of colorless liquid, b.p. 68°-70° C. (0.15 mm).