Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)[O-])c(OC)c4)C3)nc3scnc23)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)c(OC)c4)C3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a stirred solution of 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoate (80 mg, 0.14 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (5 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The suspension was filtered and dried. The crude was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-methoxybenzoic acid (30 mg, 39%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.66 (s, 1H), 8.83 (s, 1H), 8.74-8.72 (m, 1H), 7.88 (brs, 1H), 7.66 (d, 1H, J=7.8 Hz), 7.50-7.46 (m, 3H), 6.91 (d, 1H, J=8.7 Hz), 4.59 (brs, 1H), 3.87 (s, 4H), 3.76-3.72 (m, 8H), 2.27 (brs, 1H), 2.09 (brs, 1H). LC-MS: 550.8 [M+H]+, tR=1.38 min. HPLC: 98.09% at 214 nm, 96.40% at 254 nm, tR=4.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[CH:17]([N-]C(C)C)(C)[CH3:18].[Li+].C(Br)C.Cl>O1CCCC1>[CH2:17]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])[CH3:18]
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cccc(C2CCCCNC2=O)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC1(c2cccc(OC)c2)CCCCNC1=O
Temperature: 25 °C

Procedure:
Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.19 g) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (from butyllithium 1.4 molar 15.7 ml, and diisopropylamine 3.15 ml) under nitrogen at 0° C. Ethyl bromide (1 ml) was added in one portion and the reaction allowed to warm up to room temperature. After two hours the reaction was poured into 2 M HCl, the organic layer separated and the aqueous layer extracted with chloroform. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to an oil which was crystallised from ethyl acetate giving 1.68 g of the title compound m.p. 85°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](=O)([O-])[O-].[Na+].[Na+]>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.4 g, 1.85 mmol) in formic acid (5.4 mL) and aqueous formaldehyde (40%, 4.8 mL) was heated at 85° C. for 2.5 h. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×70 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 100:0) gave the title compound (0.131 g). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 129-131° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 7), 157 (5), 129 (6), 58 (30), 57 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][C:15]([OH:17])=O)[N:10]3[CH:23]=[CH:24][CH:25]=[C:9]3[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.O[N:31]1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.N.Cl>ClCCl.C(#N)C>[CH2:21]([O:20][C:18]([C:11]1([CH2:14][C:15](=[O:17])[NH2:31])[N:10]2[CH:23]=[CH:24][CH:25]=[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Br:1])=[CH:3][C:4]=2[F:29])[C:12]1=[O:13])=[O:19])[CH3:22]
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(=O)C1(CC(=O)O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C1(CC(N)=O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid (21.4 g), N-hydroxysuccinimide (5.8 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g) in dichloromethane (150 ml) was stirred at 25° C. for 1 hour, and 7.8% (w/w) ammonia in acetonitrile (40 ml) was added. The resulting mixture was stirred at 25° C. for 1 hour, poured into 5% hydrochloric acid, and extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (18.5 g, 86.4%) as colorless crystals, mp 190°-192° C.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:18]=[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:12]3=[N:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[Cl:28][CH2:29][C:30]([N:15]1[CH2:16][CH2:17][C:12]2=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:19])([F:2])[F:20])=[CH:9][N:8]=3)[CH:18]=[C:13]2[CH2:14]1)=[O:31]
Reactant: FC(F)(F)c1ccc(-n2cc3c(n2)CCNC3)nc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2nn(-c3ccc(C(F)(F)F)cn3)cc2C1

Procedure:
1 g of 2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride is suspended in 12 ml of dichloromethane, in a round-bottomed flask equipped with a magnetic stirrer. 0.95 ml of triethylamine is added and the mixture is brought to 0° C. At 0° C., 0.33 ml of chloroacetyl chloride, i.e. the compound of general formula (V) in which Hal=Hal′=Cl and n=1, is run in dropwise. The mixture is left to react for 1 and a half hours and is poured into water. Extraction is carried out with dichloromethane. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. The residue is purified by flash chromatography on a Biotage® column, elution being carried out with 9 cyclohexane/1 ethyl acetate. 1.08 g of the title compound are obtained in the form of a yellow solid.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1[CH:64]=[CH:63][C:54]([CH2:55][O:56][C:57]([NH:59][CH2:60][CH2:61][SH:62])=[O:58])=[CH:53][CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:62][CH2:61][CH2:60][NH:59][C:57]([O:56][CH2:55][C:54]3[CH:63]=[CH:64][C:51]([N+:48]([O-:50])=[O:49])=[CH:52][CH:53]=3)=[O:58])[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 92 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like solid in a yield of 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]=2[C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1.[CH2:21]=O.Cl.[CH3:24][NH:25][CH3:26]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]=2[C:14](=[O:16])[CH2:15][CH2:24][N:25]([CH3:21])[CH3:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3ccccc3c2C(C)=O)cc1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2oc3ccccc3c2C(=O)CCN(C)C)cc1

Procedure:
To a solution of 9.3 grams of the 2-(p-methoxyphenyl)-3-acetylbenzofuran that was thus produced in 30 milliliters of isopropanol were added 1.4 grams of paraformaldehyde and 4.1 grams of dimethylamine hydrochloride and the mixture was heated under reflux for a period of 12 hours. The solvent was then evaporated under vacuum and the residue was taken up in a 5% aqueous solution of hydrochloric acid. The acid solution was then extracted with benzene and the aqueous solution that had thus been freed of benzene-soluble substances was then made alkaline by the addition thereto of a 5% aqueous solution of sodium hydroxide, thereby precipitating the oily base. The solution containing the precipitated oily base was then extracted with ethyl ether, the ether extract was dried over anhydrous sodium sulfate, and a solution of hydrogen chloride in ethanol was added thereto, thereby precipitating the hydrochloride of the compound named in the heading of this example, which was separated by suction filtration. After recrystallization from ethanol, 6.5 grams of crystals of the hydrochloride, which had a melting point of 161°-162.5° C, was thus obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:18][CH:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[O:16]1[CH2:18][CH:17]1[CH2:19][N:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: C1CCN(CCCN2CCNCC2)CC1
Product: C1CCN(CCCN2CCN(CC3CO3)CC2)CC1
Yield: 64 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3-piperidin-1-ylpropyl)piperazine and (±)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as an orange oil in a 64% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([CH2:16]Cl)=O.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:22]([C:37]#[N:38])=[C:21]([SH:39])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:22]([C:37]#[N:38])=[C:21]([S:39][CH2:16][C:14]2[N:11]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:10][CH:13]=2)[N:20]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(NCCO)nc1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(NCCO)nc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
18 mg (0.10 mmol) of 4-fluorophenylthiourea and 13 mg (0.10 mmol) of 1,3-dichloroacetone are dissolved in 2 ml of DMF, and the reaction solution is stirred at 80° C. for 3 h. After cooling, 89 mg (0.09 mmol, 33% pure) of the compound from example 4A and 32 mg (0.38 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 20 h. The mixture is then filtered through a paper filter, and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Sat. sodium bicarbonate solution (5 ml) is added to the product fraction obtained, and the mixture is extracted with ethyl acetate (three times, 5 ml each). The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(CC(C)C(=O)N(C)C)c2ccc(C(=O)NCC3CCCC3)cc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)O)ccc1Cn1cc(CC(C)C(=O)N(C)C)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 69 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N,N-dimethylcarbamoyl)propyl]indol-1-ylmethyl]-3-methoxybenzoate (0.53 g) in dioxane (3 ml) was treated with triethylamine (0.31 ml) and trimethylsilyl trifluoromethanesulfonate (0.38 ml). The solution was heated under nitrogen at reflux for thirty minutes, allowed to cool, and then diluted with water to give a precipitate which was collected by filtration and dried under vacuum to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N,N-dimethylcarbamoyl)propyl]indol-1-ylmethyl]-3-methoxybenzoic acid (0.33 g, 66%) as a yellow powder; mp 120°-122°; partial NMR (250 MHz, DMSO-d6): 1.04(d, 3H, CHCH3), 2.07-2.24(m, 1H, CH3CH), 2.71(s, 3H, NCH3), 2.80(s, 3H, NCH3), 3.93(s, 3H, OCH3), 5.42(s, 2H, NCH2), 6.58(d, 1H, Ar), 7.30(s, 1H, H2 -indole), 7.40(d, 1H, H5 -indole), 7.90(br s, 1H, H7 -indole), 8.33(br t, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S-2:24].[Na+].[Na+].O>CS(C)=O>[SH:24][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [S-2]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1cc([N+](=O)[O-])ccc1S)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 44.6 %

Procedure:
To a partially dissolved mixture of 6A (7.00 g, 20.91 mmol) in DMSO (40 mL), was added sodium sulfide (3.26 g, 41.8 mmol). The mixture was stirred at 50° C. for 45 min. The reaction mixture was cooled to rt, poured into water (500 mL). The mixture was extracted with EtOAc (3×). The combined organic phase was washed with water and brine, filtered though a pad of SiO2 and concentrated to a red oil. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 100% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give 6B (3.10 g, 9.33 mmol, 44.6% yield) as an orange solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (d, J=7.15 Hz, 2H) 7.27-7.48 (m, 6H) 5.20 (br. s., 2H) 4.56 (br. s., 2H) 2.96 (br. s., 3H); MS (ESI) m/z: 333.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([Cl:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[NH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:34])=[C:18]([Cl:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCC4)c(Cl)c3)c2cc1OC
Yield: 55 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-chloroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (38 mg, yield 55%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[NH:10]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.CO.C(Cl)Cl>Cl.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[NH2:10])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C1CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.4 %

Procedure:
Tert-butyl 4-cyclopropylpyridin-3-ylcarbamate (393 mg, 1.677 mmol) was dissolved in 4 M HCl in dioxane (30 mL), and stirred at room temperature for 1 hour, the reaction rapidly becoming a white heterogeneous mixture. TLC (SiO2, 5% methanol/CH2Cl2) showed reaction complete after 1 hour. The solvent was removed by rotary evaporation, the residue was triturated with diethyl ether and vacuum filtered to collect the solid, and the solid was dried in a vacuum oven at 50° C. for 1 hour to afford the product as a beige solid (325 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:30]([F:33])([F:32])[F:31])=[N:20][N:21]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:30]([F:32])([F:31])[F:33])=[N:20][N:21]([C:24]([CH3:29])([CH3:28])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-2-methyl-propanoic acid (0.037 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.053 mmol, 39%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=0.6 Hz, 1H), 7.33-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.61 (s, 1H), 2.92 (m, 1H), 2.37 (s, 3H), 1.97 (s, 6H), 1.03 (d, J=7.1 Hz, 6H); MS: (ES) m/z calculated for C21H22ClF4N5O [M+H]+ 472.1, found 471.9.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C[S:28](Cl)(=[O:30])=[O:29].[O:32]1[CH2:36]CCC1>O>[O:15]=[C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:9]([C:7]2[N:8]=[C:3]([CH2:2][S:28]([O:32][CH3:36])(=[O:30])=[O:29])[CH:4]=[CH:5][CH:6]=2)=[N:14]1
Reactant: O=c1nc(-c2cccc(CO)n2)sc2ccccc12
Reactant: CS(=O)(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COS(=O)(=O)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 92 %

Procedure:
2-(6-Hydroxymethyl-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.54 g, 2.0 mmol) and triethylamine (0.31 ml, 2.2 mmol) were dissolved in tetrahydrofuran (30 ml). Methanesulfonyl chloride (0.16 ml, 2.1 mmol) was added to the mixture while the mixture was stirred under ice cooling condition. The reaction mixture was stirred at room temperature for 3 hrs, diluted with water and extracted with chloroform. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol to give the titled compound (0.64 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:6]2=[O:11].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:44]=[O:45])C>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH:44]=[O:45])=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:13])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:20])[C:6]2=[O:11]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Cl)c2C1O
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2c(C=O)ccc(Cl)c2C1O
Reaction time: 2 h
Yield: 91 %

Procedure:
4-Chloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (1.00 g, 3.31 mmol) was dissolved in THF (40 mL), and the solution was added with TMEDA (1.10 mL, 7.28 mmol), and added with sec-butyllithium-hexane solution (0.99 mol/L, 7.36 mL, 7.28 mmol) by drops at −78° C. for 5 minutes under argon atmosphere, and the mixture was stirred for 2 hours at the same temperature. Then, the mixture was added with DMF (0.384 mL, 4.97 mmol) and warmed from −78° C. to room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=95/5, 60/40) and preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain 4-chloro-3-hydroxy-7-formyl-2-(1-methyl-1-phenylethyl)isoindolinone (993 mg, yield 91%).