Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)[O:17][C:16]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH:9]=1.[C:27]([O:31][P:32](N(CC)CC)[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:30])([CH3:29])[CH3:28].N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:56])C=1.S(=O)(O)[O-].[Na+]>ClCCl>[P:32]([O:14][CH2:13][C:10]1[CH:9]=[C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:3][C:2]=2[F:1])[O:12][N:11]=1)([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:56]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2cc(CO)no2)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCc1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
(5R)-3-{3-Fluoro-4-[3-(hydroxymethyl)isoxazol-5-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 3, 0.1 g, 0.3 mmol) was suspended in dichloromethane (3 ml), and di-tert-butyl-N,N-diethylphosphoramidite (93 μl, 0.3 mmol) and 1H-tetrazole (35 mg, 0.5 mmol) were added sequentially. The mixture was stirred under nitrogen at room temperature for 1.5 hours. Solution was cooled to 0° C. and m-chloroperbenzoic acid (≈70%, 0.1 g, 0.4 mmol) was added. The reaction was stirred at 0° C. under nitrogen for 2 hours. After warming to room temperature, saturated sodium bisulfite (3 ml) was added and the mixture stirred for 5 minutes followed by dilution with dichloromethane (10 ml). After the layers were separated, the aqueous phase was extracted with dichloromethane (3×10 ml); the combined organics were washed with saturated sodium bicarbonate, and brine, and dried over sodium sulfate. The crude material was purified by chromatography (using a Jones Flashmaster) using 0–5% methanol in dichloromethane as eluent. Relevant fractions were combined giving 91 mg of the desired product as a white solid.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>>[Cl:13][CH2:9][C:2]1[O:3][CH:4]=[C:5]([OH:8])[C:6](=[O:7])[CH:1]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)occ1O
Product: O=c1cc(CCl)occ1O
Reaction time: 3.5 h
Yield: 90 %

Procedure:
Kojic Acid (50.0 g; 352 mmol)—an inhibitor of tyrosinase with an EC50 of 17.0 μM—was carefully added in portions over 30 min to a stirring solution of thionyl chloride (150 mL) containing hexanes (100 mL). After an additional 3.5 hours of stirring, the product was collected by Büchner filtration and washed with hexanes (2×50 mL). The light yellow solid was dried over night under vacuum to afford chloro-kojic acid (50.9 g; 90% yield). Chloro-kojic acid was found to be a more potent inhibitor of tyrosinase than kojic acid with an EC50 of 6.8 μM. 1H NMR (DMSO-d6) δ 9.30 (br s, 1H; 5-OH); 8.12 (s, 1H; 6-H); 6.56 (s, 1H; 3-H); 4.66 (s, 2H; 2-CH2Cl).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:33][CH2:34][CH2:35]Br)=[C:4]2[CH:25]=[C:23]3[N:24]=[C:20]([C:21]([CH3:30])=[C:22]3[CH2:26][CH2:27][CH2:28][Br:29])[CH:19]=[C:17]3[NH:18][C:14]([CH:15]=[C:16]3[CH3:31])=[CH:13][C:11]3=[N:12][C:8]([CH:9]=[C:10]3[CH3:32])=[CH:7][C:6]=1[NH:5]2.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br-:29].[Br-:29].[CH3:1][C:2]1[C:3]([CH2:33][CH2:34][CH2:35][N+:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:4]2[CH:25]=[C:23]3[N:24]=[C:20]([C:21]([CH3:30])=[C:22]3[CH2:26][CH2:27][CH2:28][N+:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:19]=[C:17]3[NH:18][C:14]([CH:15]=[C:16]3[CH3:31])=[CH:13][C:11]3=[N:12][C:8]([CH:9]=[C:10]3[CH3:32])=[CH:7][C:6]=1[NH:5]2
Reactant: c1ccncc1
Reactant: CC1=Cc2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)cc5C)C(C)=C4CCCBr)c(CCCBr)c3C
Product: CC1=Cc2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)cc5C)C(C)=C4CCC[n+]1ccccc1)c(CCC[n+]1ccccc1)c3C
Product: [Br-]
Yield: 92.8 %

Procedure:
To 120 mg of 3,8,13,17-tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipitated crystals are recovered by filtration, washed with 3 ml of pyridine and dried, whereby 140 mg (yield 92.8%) of brownish black desired compound is obtained.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(F)cn2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C(=O)Nc2ccc(F)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (0.682 g, 17.05 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide (Intermediate AX2) (3.0 g, 8.12 mmol) in anhydrous THF (80 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (2.63 g, 8.93 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane to afford the product (4.29 g, 88%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 3.06-3.10 (2H, m), 3.15-3.19 (1H, m), 3.27-3.31 (1H, m), 3.87-3.90 (2H, m), 4.41-4.48 (1H, m), 5.89-5.92 (1H, m), 7.40-7.55 (4H, m), 7.61-7.63 (1H, m), 8.15 (1H, d), 8.22-8.26 (1H, m), 8.36 (1H, s), 8.59 (1H, s), 9.82 (1H, s); m/z (ES+) (M+H)+=598; HPLC tR=2.82 min.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17]>O>[CH3:14][O:15][C:16]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@@H](C(=O)O)C(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a mixture of L-valine (220 mg, 1.9 mmol) and NaHCO3 (482 mg, 5.6 mmol) in H2O (6 mL) at 0° C. is added dropwise methylchloroformate (0.25 mL, 3.25 mmol). The reaction mixture is stirred for 2 hours at 0-5° C. The mixture is diluted with water and washed with Et2O. The aqueous layer is acidified with 1N HCl to pH 3 and the product is extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue is triturated with hexanes-Et2O to give (R)-2-methoxycarbonylamino-3-methyl-butyric acid (248 mg, 75%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.5 mL TFA was added to a solution of 0.750 g (2.000 mmol) tert-butyl (4′-chloro-biphenyl-4-yloxy)-acetate in 20 mL dichloromethane and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated down i. vac. and diluted with 1 M aqueous NaOH and EtOAc. The precipitate was filtered off and dried at 80° C. i. vac.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH3+:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1.ClCCl>CCCCC>[CH:23]1([NH:26][C:27](=[O:39])[CH:28]([OH:38])[CH:29]([NH:37][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[N:5]2[CH:6]=[C:2]([F:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:24][CH2:25]1
Reactant: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Reactant: [NH3+]C(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCC
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-a minium chloride. The obtained crude product was treated with a mixture of dichloromethane and n-pentane gave 148 mg of the desired product; ESI-MS [M+H]+: 500.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH3:22])[C:5]1[CH:10]=[CH:9][C:8](/[N:11]=[N:12]/[C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Cl.[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[NH2:32].[OH-].[Na+]>C(O)(=O)C.O>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[N:32]=[CH:17][C:16]1[CH:19]=[CH:20][C:13](/[N:12]=[N:11]/[C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][Br:1])[CH2:21][CH3:22])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCN(CCBr)c1ccc(/N=N/c2ccc(C=O)cc2)cc1
Reactant: Cc1cs/c(=N\N)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCBr)c1ccc(/N=N/c2ccc(C=N/N=c3\scc(C)n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.43 g of 4-((E)-{4-[(2-bromoethyl) (ethyl)amino]phenyl}diazenyl)benzaldehyde and 0.21 g of (2Z)-3,4-dimethyl-1,3-thiazol-2(3H)-one hydrazone hydrochloride in 10% acetic acid is stirred at room temperature for 60 minutes. Next, the preparation is diluted with 50 mL of water and cooled with ice. The reaction mixture is made neutral with 2N sodium hydroxide, then the precipitate that formed is suction filtered off, washed with water, and the product obtained is dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1
Yield: 93.2 %

Procedure:
2-Bromobenzene (80 mg, 0.51 mmol) reacted with 2-methylphenylboronic acid (90 mg, 0.66 mmol) using 1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.55 mmol) in THF solvent at room temperature to give the title compound (80 mg, 95%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.51-7.47 (m, 2H), 7.44-7.40 (m, 3H), 7.36-7.32 (m, 4H), 2.36 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 141.91, 141.89, 135.30, 130.27, 129.76, 129.16, 128.03, 127.22, 126.72, 125.73, 20.46. GC/MS(EI): m/z 168 (M+), 153.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([N:16]([CH:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])[C:17](=[O:19])[OH:18])(C)C.O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:20]([NH:16][C:17](=[O:19])[O:18][C:2]([CH3:7])([CH3:3])[CH3:1])[CH:21]([CH3:22])[CH3:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(CO)N(C(=O)O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 123.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamic acid (ester) (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g (68%) of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2-methylpropyl]carbamate; mp. 85° C. (interm. 32).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH:14][C:15]([CH2:17][Cl:18])=[O:16]>>[Cl:18][CH2:17][C:15]([NH:14][C:8]1[C:7]([CH3:6])=[C:12]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:11]=[CH:10][C:9]=1[CH3:13])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: Cc1ccc(S(=O)(=O)Cl)c(C)c1NC(=O)CCl
Reaction time: 1.5 h

Procedure:
To chlorosulfonic acid (75 mL, 1.15 mol) was added with stirring solid 2-chloro-2',6'-acetoxylidide over a 30 minute period at 25°-30° C. and the reaction mixture was stirred at 60°-65° C. for 1.5 hours. The reaction was cooled, added to ice and extracted with ethyl acetate/methyl ethyl ketone. The combined extracts were washed with water and brine; dried, and the solvent was removed in vacuo; the residual product (61.4 g, 69%) was a white solid, m.p. 147.5°-149° C.
Reaction SMILES: [O-]CC.[Na+].C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12]2)(=O)C>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (1.86 g) was added to a stirred solution of ethyl 5-acetoxy-N-(3,4-dichlorobenzyl)indole-2-carboxylate (5.55 g) in ethanol (50 ml) under an atmosphere of argon. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue acidified with aqueous hydrochloric acid (2.0 M) and extracted with dichloromethane. Combined organic extracts were washed with water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo and the residue was triturated with hexane/diethyl ether to give the product as a white solid (3.17 g, 92%); NMR δ(CD3SOCD3) 1.26 (t, 3H), 4.25 (q, 2H), 5.75 (s, 2H), 6.81-6.91 (m, 2H), 6.98 (d, 1H), 7.19 (s, 1H), 7.29 (d, 1H), 7.38 (d, 1H), 7.50 (d, 1H), 9.06 (s, 1H); M/z (+) 364 (MH+).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[F-:14].[K+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CN1CCCC1=O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([F:14])[NH:7][C:6]=2[CH:8]=1
Reactant: [F-]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.02 g, 3.95 mmol), potassium fluoride (688 mg, 11.9 mmol) and hexadecyltrimethylammonium bromide (43 mg, 0.12 mmol) in dry 1-methyl-2-pyrrolidinone (4 ml) was stirred for 20 h at 130° C. under nitrogen to form 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide. The mixture was allowed to cool to room temperature and then reacted directly with 1-ethylcyclohexylamine hydrochloride (0.8 g, 5.93 mmol) and triethylamine (1.65 ml, 11.9 mmol) for 30 h at 75° C. in the sealed flask. The cooled mixture was poured into water, acidified to pH <2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated to dryness to give the pure title compound; mp 244-246° C.; 1H-NMR (DMSO-d6): δ0.79 (t, 3H), 1.70-1.93 (m, 8H), 1.96-2.08 (m, 2H), 2.13-2.25 (m, 2H), 7.09 (s, 1H), 7.24 (br s, 1 H), 10.57 (br s, 1 H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.Cl.[N:17]1([C:24]([C:26]2[CH:27]=[C:28]3[NH:37][C:36](=[O:38])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]3[CH:39]=2)=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C>[CH:10]1([C:13]([N:20]2[CH2:21][CH2:22][CH2:23][N:17]([C:24]([C:26]3[CH:27]=[C:28]4[NH:37][C:36](=[O:38])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]4[CH:39]=3)=[O:25])[CH2:18][CH2:19]2)=[O:14])[CH2:12][CH2:11]1
Reactant: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCCNCC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Diisopropylethylamine (0.11 mL, 0.63 mmol) and cyclopropane carbonyl chloride (30 μL, 0.33 mmol) were sequentially added to a solution of 2-(homopiperazine-1-carbonyl)pyrrolo[1,2-a]quinazolin-5(4H)-one hydrochloride (Compound 5-1, 70.0 mg, 0.20 mmol) in anhydrous N,N-dimethylformamide (0.50 mL), and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (20 mL), and washed sequentially with 0.1M sodium hydroxide aqueous solution (20 mL) and brine (20 mL). The aqueous layer was extracted twice with chloroform (20 mL), and combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate), to obtain the title compound (25.8 mg, yield: 34%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]3)=[N:31][CH:32]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[ClH:1].[ClH:1].[ClH:1].[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=4)[N:16]=[CH:15][C:14]=3[C:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:21])=[CH:28][CH:29]=2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 286.4 %

Procedure:
Following general procedure IV-2, (S)-tert-butyl [1-(5-{[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclobutanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (0.20 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (94 mg, 72% over two steps) as a orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.10 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 7.74 (dd, J=9.3, 3.0 Hz, 1H), 7.63-7.23 (m, 2H), 7.10 (d, J=9.3 Hz, 1H), 4.40 (d, J=10.5 Hz, 1H), 4.38-4.23 (m, 1H), 4.03-3.92 (m, 1H), 3.45-3.36 (m, 2H), 2.60-2.36 (m, 4H), 2.26-2.13 (m, 2H), 2.03-1.90 (m, 2H), 1.81-1.70 (m, 2H); ESI MS m/z 547 [M+H]+; HPLC 98.2% (AUC), tR=10.33 min.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:14])=[O:13])=[C:8]([F:21])[CH:7]=1.C([N:25](CC)C(C)C)(C)C.O1CCCC1.[NH4+].[OH-]>>[F:21][C:8]1[CH:7]=[C:6]([NH:5][C:1]([NH2:25])=[S:2])[CH:11]=[CH:10][C:9]=1[S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13]
Reactant: S=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reaction time: 0.67 h
Yield: 35.5 %

Procedure:
Carbonothioic dichloride (25 uL, 0.00032 mol) was added to a mixture of the 4-amino-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (105 mg, 0.000271 mol) and N,N-diisopropylethylamine (0.14 mL, 0.00081 mol) in tetrahydrofuran (1.5 mL, 0.018 mol) at 0° C. and stirred for 40 min. Sat'd NH4OH solution was added to the reaction mixture and stirred for a few min. The reaction mixture was rotovaped to remove THF. The aq phase was acidified with 1.0 N HCl (pH 6), extracted with EtOAc (3×), dried, and was concentrated to give the crude product, which was purified via automated flash chromatography (silica gel, 25% EtOAc in hexanes to 100% EtOAc). 32 mg (36%) of the product was obtained as a yellow solid.
Reaction SMILES: C(OC(=O)[N:5]([CH2:29][CH:30](OC)OC)[CH:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:18]([O:27][CH3:28])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)C.Cl.[C:37]([O:40][CH2:41][CH3:42])(=[O:39])C.CCCCCC>CC(C)=O.O>[CH2:41]([O:40][C:37]([N:5]1[CH:29]=[CH:30][C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=2)[CH:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:39])[CH3:42]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1cccc(OC)c1)c1ccc(OCCCO)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
To a stirred solution of crude (2,2-dimethoxy-ethyl)-[1-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-2-(3-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester in acetone (30 mL) was added 6N hydrochloric acid (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with water. The solvent was evaporated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (130, 32% yield in two steps) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(OC([N:42]1[CH2:47][CH2:46][N:45]([C:48]2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:44][CH:43]1[CH2:79][OH:80])=O)(C)(C)C>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C@@H:43]4[CH2:79][OH:80])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.C[NH2:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CN
Product: NCCc1cccc(Cl)c1

Procedure:
Synthesized according to typical procedures C and D from 3-chlorophenylacetic acid and methylamine.