Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11](OCC)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C([BH3-])#N.[Na+].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1sc(Cl)nc1C(F)(F)F
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
To a mixture of 2.6 g (0.01 mol) of ethyl 2-chloro-4-(trifluoromethyl)-5-thiazolecarboxylate and 10 ml of ethanol was added 0.62 g of sodium cyanoborohydride. The reaction mixture was stirred for 5 minutes and 0.40 g of sodium borohydride was added. The temperature of the reaction mixture raised spontaneously to boiling point. The reaction mixture was stirred for 30 minutes and quenched with water. The aqueous mixture was extracted with ether. The ether solution was dried over CaSO4 and concentrated under reduced pressure. The residue was crystallized from petroleum ether to give 1.6 g (74%) of 2-chloro-4-(trifluoromethyl)-5-thiazolemethanol, mp 39°-45° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@@H:57](O)[CH2:56][CH2:55]1)([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.O>[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:55][CH2:56][C@H:57]([O:12][C:7]2[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH2:58][CH2:59]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: Oc1ccnc2c(F)cccc12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Fluoroquinolin-4-ol (948 mg, 5.81 mmol), triphenylphosphine (1.52 g, 5.81 mmol) and DIAD (1.17 g, 5.81 mmol) were dissolved in tetrahydrofuran (140 mL). After adding tert-butyl-N-[(cis-4-hydroxycyclohexyl)methyl]carbamate (1.11 g, 4.84 mmol), the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate. After removal of the solvent residues and chromatographic purification of the residue, the product was obtained at 42% yield (960 mg).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(CC4CNC4)cc3N21
Yield: 100 %

Procedure:
A solution of 3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (0.019 g, 0.042 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-azetidin-3-ylmethyl-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.002 g, 100%). LC/MS (Table 1, Method 5) Rt=2.023 min; MS m/z: 355 [M+H]+.
Reaction SMILES: [C:1]1([C:20]([O-:22])=[O:21])[C:10]2[CH:9]=[C:8]([C:11]([O-:13])=[O:12])[CH:7]=[C:6]([C:14]([O-:16])=[O:15])[C:5]=2[CH:4]=[C:3]([C:17]([O-:19])=[O:18])[CH:2]=1.[K+].[K+].[K+].[K+].Cl>O>[C:1]1([C:20]([OH:22])=[O:21])[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=2[CH:4]=[C:3]([C:17]([OH:19])=[O:18])[CH:2]=1
Reactant: O=C([O-])c1cc(C(=O)[O-])c2cc(C(=O)[O-])cc(C(=O)[O-])c2c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C(=O)O)c2cc(C(=O)O)cc(C(=O)O)c2c1

Procedure:
Crude tetrapotassium 1,3,5,7-naphthalenetetracarboxylate obtained in Example 13 was again dissolved in water, and the solution was acidified with hydrochloric acid to an acidity lower than pH 1 to form free crude 1,3,5,7-naphthalenetetracarboxylic acid. The product was separated and dried to form crude 1,3,5,7-naphthalenetetracarboxylic acid as shown in Table 7.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1)[CH2:6][CH3:7])[CH3:4].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O1CCCC1>[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[O:16][C:10]=2[CH:9]=1)[CH2:6][CH3:7])[CH3:4]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc2cc(C(=O)OC)oc2c1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a 250 mL three necked, round bottom flask equipped with a mechanical stirrer, reflux condenser, and Y-tube with a rubber septum and nitrogen inlet was added 1.8 gm (45 mmol) of 60% sodium hydride in mineral oil. After washing twice with 20 mL of hexanes, 150 mL of THF was added, followed by the rapid dropwise addition via transfer syringe of 3.86 gm (20 mmol) of 4-(N,N-diethylamino)-2-hydroxy benzaldehyde, dissolved in 50 mL of tetrahydrofuran (THF). The flask was placed in an 80° C. oil bath and stirred vigorously for 5 minutes, at which time 2.08 mL (20 mmol) of methyl bromoacetate was added in one portion. Sodium bromide precipitated from solution and vigorous stirring had to be maintained throughout. The suspension was refluxed for 80 minutes, allowed to cool to room temperature, and diluted with 75 mL of diethyl ether. The reaction was quenched by the slow dropwise addition of 50 mL of dilute aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with 100 mL of diethyl ether (Et2O). The combined organic phases were washed with 20 mL 1 N NaOH and 20 mL water. After drying (MgSO4), the solvent was removed by rotary evaporation and the residual oil purified by flash chromatography (CH2Cl2 ; SiO2, 11/2×15") to yield 2.23 gm (45.3%) of the product as a colorless oil. Field desorption mass spectrum: m/e 247 (M+). Anal. Calcd. for C14H17NO3C,: 68.0; H, 6.9; N, 5.7. Found: C, 67.9; H, 6.8., N, 5.8. 1H 270 NMR (CDCl3): δ6.7 (m, 2H, ArHa,b), 7.4 (m, 2H, ArHc,d).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CSc1ncc2ncnc(O)c2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
This compound may be obtained in the following way: a mixture of 10 g 4-hydroxy-6-methylthio-pyrimido[5,4-d]pyrimidine, 16 ml hexamethyldisilazane, 32.5 g 3-chloro-4-fluoro-aniline and 1 g p-toluenesulphonic acid hydrate are heated at boiling point for 12 hours. Then 500 ml methanol is added and the mixture heated at boiling point for a further hour. The solvents are distilled off in a rotary evaporator, the residue is dissolved in methylene chloride, the solution is extracted with 100 ml 2N sodium hydroxide and dried over magnesium sulfate. After distilling off the solvent in a rotary evaporator the residue is triturated with 200 ml ether, filtered off and washed several times with ether.
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].Cl.[NH2:12][NH:13][C:14]([NH2:16])=[O:15].C(#N)C=C>C(O)C.C(O)C.O>[NH:13]([N:12]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1])[C:14]([NH2:16])=[O:15]
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Reactant: NNC(N)=O
Agent: Cl
Solvent: C=CC#N
Solvent: O
Solvent: CCO
Product: N#CC=CC(=O)C=NNC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-azido-2-furaldehyde (92 mg, 0.67 mmole) in 4 ml of ethanol was added dropwise to a solution of semicarbazide hydrochloride (75 mg, 0.67 mmole) in 10 ml of ethanol:water (5:1) mixture. The reaction mix was stirred at room temperature overnight and evaporated to dryness. The residue was dissolved in 1.2 ml of acetone and streaked on one preparative silica gel TLC plates (EM-5717-7), developed with ethyl acetate:petroleum ether (9:1). Two well-separated major bands (upper band with Rf of 0.56 and lower band with Rf of 0.20) were detected under UV lights and were separately stripped and eluted with excess of ethyl acetate. The ethyl acetate eluents were evaporated to give pale yellow residues (45 mg and 35 mg, respectively). On silica gel TLC, both residues showed identical pattern of two distinctly separated spots with Rf of 0.56 and 0.33 when the TLC was developed with ethyl acetate:petroleum ether (6:1). The TLC analysis suggested that both residues contained interconvertible cis and trans isomers and were, therefore, combined (total yield 0.48, 72%). 1H NMR analysis of 2 confirmed that it is a mixture of two isomers with the acrylonitrile moiety in cis (Z) and trans (E)-configurations (coupling constant J=11.6 and 16.5 Hz, respectively).
Reaction SMILES: [Br:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[O:4][CH2:5][C@H:6]([OH:37])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35]C)[CH2:31][CH2:30]3)[CH2:21][C:20]=1[CH:19]=2.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].Cl.Cl.ClC1C=CNC(=O)C=1C1NC2C(N=1)=CC1C(=O)N(C3CCN(CC)CC3)C(=O)C=1C=2.NC[C@@H](O)COC1C=CC=CC=1Br>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[Br:1][C:2]1[CH:41]=[C:40]([F:45])[CH:39]=[CH:38][C:3]=1[O:4][CH2:5][C@H:6]([OH:37])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH2:21][C:20]=1[CH:19]=2
Reactant: CCN1CCC(N2Cc3cc4[nH]c(-c5c(NC[C@@H](O)COc6ccccc6Br)cc[nH]c5=O)nc4cc3C2=O)CC1
Agent: CCN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Agent: Cl
Agent: NC[C@@H](O)COc1ccccc1Br
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(N2Cc3cc4[nH]c(-c5c(NC[C@@H](O)COc6ccc(F)cc6Br)cc[nH]c5=O)nc4cc3C2=O)CC1

Procedure:
2-{4-[(R)-3-(2-bromo-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-ethyl-piperidin-4-yl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one as TFA salt (5c) was prepared from 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-ethyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione dihydrochloride and (R)-1-amino-3-(2-bromo-phenoxy)-propan-2-ol. ESI-MS m/z 623.0 (M++2).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]([OH:39])=O)[C:32]3[C:27](=[CH:28][C:29]([CH3:40])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH2:65]([NH:67][C:68]([C@@H:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)=[O:69])[CH3:66]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]([N:71]3[CH2:72][CH2:73][CH2:74][C@H:70]3[C:68](=[O:69])[NH:67][CH2:65][CH3:66])=[O:39])[C:32]3[C:27](=[CH:28][C:29]([CH3:40])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Reactant: CCNC(=O)[C@@H]1CCCN1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@@H]1CCCN1C(=O)COc1cc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc2cc(C)ccc12
Reaction time: 2 h

Procedure:
To a solution of 80 mg of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester in 8 ml of DMF, 33 mg of EDC, 32 mg of pentafluorophenol and 24 mg of NEM was added and the reaction mixture was stirred for 2 h. Then, 39 mg of (S)-Pyrrolidine-2-carboxylic acid ethylamide trifluoroacetate and 20 mg of NEM in 5 ml of DMF was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][C:24]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:13][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(Nc2nccc(-c3ccccc3)n2)c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A mixture of 4-phenylpyrimidin-2-amine (100 mg, 0.58 mmol) and methyl 3-bromo-4-methylbenzoate (111 mg, 0.48 mmol), Cs2CO3 (221 mg, 0.68 mmol), Pd2(dba)3 (22 mg, 0.024 mmol) and Xantphos (22 mg, 0.039 mmol) in a microwave reaction vessel was suspended in 5 mL of toluene. The reaction mixture was heated in a microwave at 130° C. for 30 min, and then at 180° C. for 30 min. After cooling, the mixture was purified by ISCO system to give 80 mg of product (yield: 43%). MS (ESI+) m/z 320.1 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:25]=[C:24]([C:26](=[O:28])[CH3:27])[CH:23]=[C:22]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:21]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[Cl-].[NH4+]>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:25]=[C:24]([C:26]([OH:28])([CH2:1][CH3:2])[CH3:27])[CH:23]=[C:22]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:34])[F:35])[N:21]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reaction time: 0.08 h

Procedure:
Ethylmagnesium bromide (0.86 mL, 2.57 mmol, 3M in THF) was dissolved in THF (5 mL). 1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (140 mg, 0.32 mmol) was dissolved in THF (5 mL) and was added slowly to the solution of ethylmagnesium bromide. The mixture was cooled on ice, ammonium chloride (sat, aq, 5 mL) was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as an oil, 63 mg (42%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11](O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[NH2:36]>C(O)CCCCC>[OH:14][C:9]1[C:10]2[C:29](=[O:28])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=3[NH:36][C:11]=2[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1
Reactant: COC(=O)c1cccnc1N
Reactant: Oc1cc(O)cc(N2CCOCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCCO
Product: O=c1c2cccnc2[nH]c2cc(N3CCOCC3)cc(O)c12
Yield: 2.1 %

Procedure:
5-Morpholin-4-yl-benzene-1,3-diol (345 mg 1.77 mmol), TsOH.H2O (30 mg, 0.20 mmol), and 2-aminonicotinic acid methyl ester (269 mg, 1.77 mmol) were heated at 160° C. in hexanol (5 mL) for 12 hours. Upon cooling, the mixture was purified via flash chromatography CH2Cl2/MeOH (95:5), followed by a second flash column eluting with Et2OAc/hexanes (7:3) to provide 11 mg (2%) of the product. 1H NMR (CDCl3, 400 MHz) δ: 13.5 (s, 1H), 8.80 (br s, 1H), 8.62 (d, 1H), 7.25 (dd, 1H), 6.22 (d, 1H), 6.04 (s, 1H), 5:97 (s, 1H), 3.86-3.83 (m, 4H), 3.40-3.35 (m, 4H). LRMS (APCI, positive): Da/e 296.4 (m−1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl.[NH2:16][CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([NH:31][C:32]3[N:37]=[C:36]([CH:38]([F:40])[F:39])[CH:35]=[CH:34][N:33]=3)[CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH:21]=[N:20]1>ClCCl>[F:40][CH:38]([F:39])[C:36]1[CH:35]=[CH:34][N:33]=[C:32]([NH:31][C:26]2[CH:25]=[C:24]([C:22]3[CH:21]=[N:20][N:19]([CH2:18][CH2:17][NH:16][S:11]([CH3:10])(=[O:13])=[O:12])[CH:23]=3)[CH:29]=[C:28]([CH3:30])[CH:27]=2)[N:37]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCN)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCNS(C)(=O)=O)c2)c1
Reaction time: 2 h

Procedure:
Dichloromethane (1 mL), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) and methanesulfonyl chloride (0.023 g, 0.20 mmol) were added to a vial containing N-(3-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine hydrochloride (0.038 g, 0.10 mmol). The reaction mixture was stirred for two hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% TFA modifier) to afford N-(2-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide. MS ESI calc'd. for C15H21F2N6O2S [M+H]+ 423. found 423. 1H NMR (600 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.02 (s, 1H), 7.78 (d, J=5.5 Hz, 2H), 7.31 (s, 1H), 7.19 (t, J=5.9 Hz, 1H), 7.01 (d, J=6.7 Hz, 2H), 6.81 (t, J=54.5 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.36-3.35 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: C([NH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[NH:18][C:19]([C:21]([O:23]CC)=O)=[O:20])(C(OCC)=O)=O>Cl>[NH:18]1[C:19](=[O:20])[C:21](=[O:23])[NH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]1=2
Reactant: CCOC(=O)C(=O)Nc1sc2ccccc2c1NC(=O)C(=O)OCC
Agent: Cl
Product: O=c1[nH]c2sc3ccccc3c2[nH]c1=O
Yield: 67.2 %

Procedure:
A suspension of 2,3-bis(ethoxalylamino)benzo[b]thiophene (5.47 g, 15 mmol) in 250 ml of 4 N hydrochloric acid was heated to reflux for 2 h. Then the mixture was cooled on an ice bath, and filtered. The crude product was washed with water and recrystallized from a mixture of ethanol, DMF and water with decolorizing charcoal. The recrystallized solid was filtered off, washed with ethanol and ether, and dried for 1 h at 100° C. to give 2.2 g (62%) of the pure title compound as a monohydrate; m.p. 377.6° C. DSC); 1R (KBr): 3200-2500, 1670 cm-1 ; 1H-NMR (DMSO-d6): δ 3.3 (broad s, 2H, H2O); 7.1-7.6 (m, 2H, ArH), 7.8-8.1 (m, 2H, ArH), 11.9-13.6 (broad, 2H, 2NH); MS (m/e): 218 (M+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C)(=O)=O)=[CH:20][CH:19]=2)[N:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:4]2[C:5]([CH3:17])=[C:6]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=3)[C:10]([O:12][CH3:13])=[O:11])[C:2]([CH3:1])=[N:3]2)=[CH:19][CH:20]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCOS(C)(=O)=O)cc3)c2C)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCN=[N+]=[N-])cc3)c2C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 3-[3,5-dimethyl-1-(4-{2-[(methylsulfonyl)oxy]ethyl}phenyl)-1H-pyrazol-4-yl]benzoate (step 2, 2.0 mmol) and KI (330 mg, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (260 mg, 4.0 mmol), and then the resulting mixture was stirred for 1.5 h at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate/toluene (4:1). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to give the title compound as yellow oil (quant.): 1H-NMR (CDCl3) δ 8.01 (2H, s), 7.53-7.34 (6H, m), 3.95 (3H, s), 3.55 (2H, t, J=7.1 Hz), 2.96 (2H, t, J=7.1 Hz), 2.33 (3H, s), 2.30 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH:11]([CH2:45][NH:46][CH2:47][C:48]([O:50]CC)=[O:49])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH:11]([CH2:45][NH:46][CH2:47][C:48]([OH:50])=[O:49])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CNCC1Oc2ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc2-c2cc3c(F)cccc3n21
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNCC(=O)O)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)amino)acetate (35 mg, 0.048 mmol) in 1,4-dioxane/H2O (3.0 mL/0.5 mL) was added LiOH.H2O (20 mg, 0.45 mmol). The mixture was stirred at room temperature overnight. Then it was concentrated in vacuo, neutralized with HCl (aq. 5%), extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide Compound 116 (30 mg, yield: 91%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 8.00˜8.07 (m, 2H), 7.85 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.43 (t, J=8.8 Hz, 2H), 7.20˜7.29 (m, 1H), 7.09 (s, 1H), 6.89˜6.97 (m, 1H), 6.85 (br. s, 1H), 3.19 (s, 3H), 3.07 (m, 2H), 2.88 (s, 3H), 2.83 (s, 3H). MS (M+H)+: 702.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:11](=[O:24])[CH:10]=1)C1C=CC=CC=1>[Pd]>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:24]
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1ccc(Cl)cc1Cl
Agent: [Pd]
Product: O=c1cc(O)ccn1Cc1ccc(Cl)cc1Cl

Procedure:
4-benzyloxy-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one synthesized by the same method as Example 1 was hydrogenated with Pd/C to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22]([NH:17][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:7][C:2]=1[F:1])=[O:23]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1F
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Yield: 47 %

Procedure:
In analogy to example 1, the title compound is prepared from 2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 47%. Brownish solid. MS: m/e=336.1 (M++H).