Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[NH:16][N:15]=3)=[CH:12][C:8]([C:9]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(-c2cc(C(=O)O)c(C)cc2C2CCC2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)n[nH]1
Temperature: 30 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound 445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and 4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 30° C., and then diluted with 40 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (59.0% CH3CN up to 73.0% in 6 min, up to 100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 150 mg (72%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH:22]([N:25]1[C:29]([CH3:30])=[CH:28][C:27]([CH2:31]O)=[C:26]1[CH3:33])([CH3:24])[CH3:23].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:33][C:26]1[N:25]([CH:22]([CH3:24])[CH3:23])[C:29]([CH3:30])=[CH:28][C:27]=1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: Cc1cc(CO)c(C)n1C(C)C
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c(C)n1C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
To a stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.84 g, 3.0 mmol) and (1-isopropyl-2,5-dimethyl-1H-pyrrol-3-yl)methanol (0.50 g, 3.0 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise tributylphosphine (0.90 g, 1.5 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.78 g, 4.5 mmol) was added. The solution was stirred at ambient temperature for 16 h then quenched with saturated ammonium chloride (50 mL). The aqueous solution was extracted with ethyl acetate (200 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 1′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 24%) as a colorless solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.02-6.95 (m, 2H), 6.49 (s, 1H), 6.09 (s, 1H), 5.85-5.82 (m, 2H), 5.77 (br s, 1H), 4.77 (ABq, 2H), 4.69 (ABq, 2H), 4.37 (sep, J=7.0 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 1.43 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ194.7, 177.2, 155.9, 148.7, 142.9, 142.2, 132.5, 128.7, 127.0, 125.5, 123.6, 122.9, 119.9, 113.0, 109.6, 107.6, 103.2, 101.4, 93.5, 80.5, 58.2, 47.3, 37.0, 22.2, 14.1, 11.5; MS (ES+) m/z 431.20 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:8]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH3:28][N:14]([CH2:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:8][CH2:9]1)[S:15]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless solid, MS: 502 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Br)C1C=CC=CC=1>>[C:1]([O:5][C:6]([C:8]1([CH2:29][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: BrCc1ccccc1
Product: CC(C)(C)OC(=O)C1(Cc2ccccc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 55 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with benzyl bromide afforded 170 mg (55%) of intermediate 21a. MS (ESI) 476.5 (M+H+), 498.5 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.689 g,2.65 mmole), 3-methoxy-5-nitro-4-propoxybenzaldehyde (40) (0.633 g, 2.65 mmole) and 0.266 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane and was purified by flash column chromatography with 9:1 hex/ethyl acetate as eluent. The product mixture contains a 1/1 cis/trans ratio (0.600 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+].ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:12][C:6]1[C:7]2[S:11][N:10]=[CH:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2sncc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)c2sncc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of 4-methoxy-benzo[d]isothiazole (prepared as described above) (1.0 g, 6.05 mmol) in carbon tetrachloride (20 mL) at 0° C. was added bromine (310 μL, 6.05 mmol) in carbon tetrachloride (10 mL). The reaction was allowed to stir at 0° C. for 3 h and was then warmed to rt. Saturated aqueous NaHCO3 and dichloromethane were added and the organic phase was separated. The aqueous phase was extracted with 2×20 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:20] to yield the title compound (980 mg, 66%): δH (300 MHz, CDCl3): 9.09 (1H, s), 7.52 (1H, d, J=8.1 Hz), 6.67 (1H, d, J=8.4 Hz), 4.00 (3H, s).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][NH:6][C:7](=O)[CH:8]=1.C1(P(Cl)([Cl:20])=O)C=CC=CC=1>>[Cl:20][C:7]1[CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:4]=[CH:5][N:6]=1
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: FC(F)(F)c1cc(Cl)ncn1
Temperature: 25 °C

Procedure:
Phenylphosphonic dichloride (107 ml) and 4-trifluoromethylpyrimidin-6-one (103 g) were heated at 130° C. under nitrogen for 30 minutes. The reaction was cooled to room temperature and the reaction flask was equipped with a short path distillation head. The bath temperature was raised to about 200° C. and the product distilled out of the reaction mixture. Fractional distillation of this material gave 80.8 g of 4-chloro-6-trifluoromethylpyrimidine as a colorless liquid (b.p.=134°-136° C. @ 760 mm Hg).
Reaction SMILES: CN(C=O)C.[SH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[F:21][C:22](I)([F:45])[C:23]([F:44])([F:43])[C:24]([F:42])([F:41])[C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]>O>[F:45][C:22]([F:21])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:23]([F:43])([F:44])[C:24]([F:41])([F:42])[C:25]([F:39])([F:40])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30]
Reactant: Sc1ccccc1-c1ccccc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Yield: 63.5 %

Procedure:
To a solution composed of 40 ml of DMF and 4.66 g (25 mmol) of 2-mercaptobiphenyl was added 1.00 g (25 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 13.6 g (25 mmol) of perfluorooctyl iodide was added. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 hours. Water was addd to the reaction mixture, and the mixture was extracted with hexane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography using hexane as an eluent to give 9.60 g (64%) of 2-(perfluorooctylthio)biphenyl as a colorless oil. The properties of the product were as shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.[C:17](#[N:21])[CH:18]([CH3:20])[CH3:19].C(#N)C.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([C:18]([CH3:20])([CH3:19])[C:17]#[N:21])=[CH:7][C:2]=2[F:1])=[N:14]1
Reactant: Cc1cc(F)cc(F)c1C1=NC(C)(C)CO1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C#N)cc(F)c1C1=NC(C)(C)CO1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A flask containing a solution of 2-(2,4-difluoro-6-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole (14.84 g, 65.9 mmol) and isobutyronitrile (9.11 g, 132 mmol) in dry tetrahydrofuran (130 ml) was cooled to −15 to −20° C. (acetonitrile/dry ice bath) under an argon atmosphere. A solution of potassium bis(trimethylsilyl) amide (171 ml, 0.5M in toluene) was added via slow drop-wise addition. The mixture was stirred for 30 minutes at −15° C. and then gradually warmed to 15° C. over about 1.5 hours. The material was quenched via the addition of a saturated solution of aqueous ammonium chloride (100 ml). Water (80 ml) and diethyl ether (50 ml) were added and the material was transferred to a reparatory funnel and the organic phase was collected. This was washed with an equal volume of water and the organic phase was collected. The aqueous phases were back extracted with ether (2×100 ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by chromatography on silica gel eluting with 60% ethyl acetate/hexane to provide semi-pure product as a golden yellow oil (18 g, 75% pure). This material was used “as is” in subsequent steps. (M+H)+=275 m/e.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: Fc1ccc(OCCBr)cn1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2CCOc2ccc(F)nc2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 5-[(2-bromoethyl)oxy]-2-fluoropyridine: MS (ESI) m/z 366 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CO[C@H]1C(=O)N(CCN(C)CCc2ccc(OC)cc2)c2ccccc2S[C@H]1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCN(C)CCN2C(=O)[C@H](OCC(=O)O)[C@H](c3ccc(OC)cc3)Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of (+)-cis-2-(4-methoxyphenyl)-3-(ethoxycarbonylmethyl)oxy-5-{2-[N-methyl-N-(4-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (5.4 g), sodium hydroxide (423 mg), water (50 ml) and methanol (50 ml) is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and water is added to the resulting residue. The mixture is washed with ether, and the pH value thereof is adjusted to 4 with 10% hydrochloric acid, and then extracted with a mixture of chloroform and isopropyl alcohol. The extract is washed, dried, and the solvent is distilled off to give (+)-cis- 2-(4-methoxyphenyl)-3-(carboxymethyl)oxy-5-{2-[N-methyl-N-(4-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one (4.57 g) as oily product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[CH2:22]([S:25](Cl)(=[O:27])=[O:26])[CH2:23][CH3:24]>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:1]([S:25]([CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26])[S:25]([CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26]
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl) methanone (50 mg, 0.176 mmol, 1 eq.) in DCM (5 mL) were added TEA (89 mg, 0.88 mmol, 5 eq.) and propane-1-sulfonyl chloride (55 mg, 0.387 mmol, 2.2 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (30 mg, 34.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH3:21])=O.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reaction time: 3.5 h
Yield: 89.6 %

Procedure:
A solution of 3-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (1.993 g, 6.773 mmol) in CH2Cl2 (34 mL) at 0° C. is treated with 1.0 M diisobutylaluminum hydride in toluene (DIBAL, 14.3 mL) dropwise over 3 min. time and stirred for 3.5 h. The reaction mixture is quenched with MeOH (5.0 mL), treated with 1M tartaric acid (50 mL), and stirred overnight. The organic layer is separated. The aqueous layer is extracted with CH2Cl2 (1×50 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide (3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (1.616 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2=[C:7]([CH:11]=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1
Reactant: CC1(C)Cc2c(CO)cccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)Cc2c(C=O)cccc2O1
Yield: 122.8 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-4-methanol (7.35 g, 41 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (8.87 g, 100%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[C:13]3[NH:21][N:20]=[N:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[CH:10][CH:9]=[N:8]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32]C(=O)OC(C)(C)C>CN(C=O)C>[NH2:32][CH2:31][C:30]1[CH:29]=[C:28]([CH:42]=[CH:41][CH:40]=1)[CH2:27][N:19]1[C:14]2[N:15]=[C:16]([NH2:18])[N:17]=[C:12]([C:11]3[CH:10]=[CH:9][NH:8][N:7]=3)[C:13]=2[N:21]=[N:20]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2nn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1cccc(Cn2nnc3c(-c4cc[nH]n4)nc(N)nc32)c1
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
A stirred solution of the 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (330 mg, 1 mmol) in dry DMF (5 mL) was treated with NaH (40 mg, 60% in oil, 1 mmol), stirred for 15 min, treated with tert-butyl N-(3-(bromomethyl)benzyl)carbamate (300 mg, 1 mmol) and stirred for 1 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), the organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:1)]. The resulting yellow syrup was dissolved in MeOH (3 mL), treated with HCl (2 mL, 4-M in dioxane), stirred for 17 h and the resulting solid filtered to give the title compound (258 mg, 80%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.I[CH:18]1[CH2:21][O:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH:18]3[CH2:21][O:20][CH2:19]3)[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: IC1COC1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C1COC1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 115a (200 mg, 0.71 mmol), 3-iodooxetane (647 mg, 3.53 mmol), Cs2CO3 (1150 mg, 3.53 mmol), and acetonitrile (5 mL) was heated at 80° C. in a sealed tube overnight. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford the 312a as a yellow solid (120 mg, 50%). MS-ESI: [M+H]+ 339.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1CCOCC1.ClC(OCC(C)C)=O.CN.C(O)C>C1COCC1>[CH3:14][NH:15][C:11](=[O:13])[CH2:10][O:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)CONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo to yield tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8]3[C:9]([C:14](O)=[O:15])=[CH:10][CH:11]=[CH:12][C:13]=3[C:2]1=2>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][C:8]3[C:9]([CH2:14][OH:15])=[CH:10][CH:11]=[CH:12][C:13]=3[C:2]1=2
Reactant: O=C(O)c1cccc2c1CCc1ccsc1-2
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1CCc1ccsc1-2
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
To a stirred solution of 4,5-dihydronaphtho[1,2-b]thiophen-6-carboxylic acid (3.4 g, 0.015 mole) in 50 ml of tetrahydrofuran under an argon atmosphere was added dropwise borane-tetrahydrofuran complex (2.5 g, 0.030 mole). Upon complete addition, the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was then taken up in water and concentrated under reduced pressure to a residue. The residue was washed into a separatory funnel with aqueous 2N sodium hydroxide and methylene chloride. The aqueous layer was extracted with two 100 ml portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4,5-dihydronaphtho[1,2-b]thiophen-6-methanol; 2.8 g, mp 99°-100°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Nc1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1N
Yield: 37 %

Procedure:
Using 3-amino-4-methoxybenzoic acid and aniline as materials, compound 2621 is synthesized following a similar method as in Example 28. Yield: 37%.