Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([N:33](CC)C(C)C)(C)C.[Cl-].[NH4+].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH2:33])=[O:28])[CH2:22]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(=O)O)C2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(N)=O)C2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
The compound (50 mg) obtained in Example 56 was dissolved in DMF (1.0 mL), then N,N-diisopropylethylamine (0.030 mL), ammonium chloride (8 mg), 1-hydroxybenzotriazole hydrate (22 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (27 mg) were added thereto in that order, and stirred at room temperature for 3 days. Water was added to the reaction liquid, and extracted four times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the entitled compound (37 mg, 74%) as a colorless solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[CH:23]([O:26][C:27]([NH:29][CH:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][NH2:32])=[O:28])([CH3:25])[CH3:24]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:32][CH2:31][CH:30]([NH:29][C:27]([O:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:20])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)NC(CN)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)NC(CNC(=O)c1ccc(Cl)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
0.21 g of 1,1′-carbonylbis-1H-imidazole was added to a solution of 0.19 g of 4-chlorobenzoic acid in tetrahydrofuran and stirred for 1 hour at room temperature. Then 5 ml of a solution of 0.25 g of 2-(i-propoxycarbonylamino)-3-phenylpropylamine in tetrahydrofuran was added to the above solution and stirred at room temperature for 4 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.26 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[NH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:15][CH:16]1[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:26])=[O:13])=[CH:5]2
Reactant: NC1Cc2ccccc2NC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
5-Chloroindole-2-carboxylic acid (196 mg, 1 mmol) was dissolved in DMF (5 mL) containing 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem. 28, 1985, 1511–16; 162 mg, 1 mmol), EDCI (192 mg, 1 mmol) and HOBT (135 mg, 1 mmol). The mixture was stirred at ambient temperature for approximately 18 h before being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous NaHCO3, saturated brine and dried over MgSO4; then filtered and evaporated to afford the title compound (212 mg, 66%) as an amorphous white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([CH3:15])[NH:7]2.FC1C=CC(N)=C2C=1C=CC(C)=N2>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:15])[NH:7]2
Reactant: CC1C=Cc2c(F)ccc([N+](=O)[O-])c2N1
Agent: [Pd]
Agent: Cc1ccc2c(F)ccc(N)c2n1
Solvent: CCOC(C)=O
Product: CC1CCc2c(F)ccc(N)c2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 10% Pd/C (30 mg) in a mixture of IMS (3 mL) and EtOAc (5 mL) was stirred under an atmosphere of hydrogen for 15 min before a solution of 5-fluoro-2-methyl-8-nitro-1,2-dihydroquinoline (76.8 mg, 0.369 mmol) in EtOAc (15 mL) was added. The reaction mixture was stirred at RT under a hydrogen atmosphere for 20 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording a mixture of the title compound and 5-fluoro-2-methylquinolin-8-ylamine as a purple oil. LCMS (Method J): RT 1.90 min (28%) [M+H]+ 181 and 2.26 min (42%) [M+H]+ 177
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:36][C:35]1[CH:34]=[CH:33][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:38][CH:37]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2cc1OC
Yield: 71.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 222.3 mg (1.2 mmol) of 4-phenoxyaniline to give 283.0 mg (71.3%) of the product as a light yellow solid, m.p. 239-241° C., mass (electrospray, m/e): M+H 397.9.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CC1(C)[O:33][CH:32]([CH2:34][NH2:35])[CH2:31][O:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCC(O)CO)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.31 ml; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (3650 mg; 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1CCC[C@H]1C(O)=O.[OH-].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(N3CCOCC3)c1)N2
Temperature: 120 °C
Yield: 44.1 %

Procedure:
A mixture of 2-(3-bromo-5-chloro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.56 g, 3.7 mmol), morpholine (1.60 g, 18.5 mmol), copper (I) iodide (0.42 g, 2.2 mmol), L-proline (0.25 g, 2.2 mmol) and potassium hydroxide (0.12, 2.2 mmol) in DMSO (20 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.70 g, 44%) as a white solid: LC/MS m/e calcd for C24H29ClN2O3 (M+H)+: 430.0, observed: 429.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH:22]([O:14][C:13](=[O:15])[CH:9]([CH2:10][CH2:11][OH:12])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCO)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 81.5 %

Procedure:
6 g of the obtained N-t-butoxycarbonyl DL-homoserine was dissolved in 100 ml of methylene chloride, and 50 ml of a methylene chloride solution containing 6 g of diphenyldiazomethane was added dropwise thereto over an hour. After completion of the reaction, the reaction mixture was concentrated to a small volume, and petroleum ether was added thereto. The formed crystals were filtered off to obtain 8.6 g of N-t-butoxycarbonyl DL-homoserine benzhydryl ester.
Reaction SMILES: [OH-:1].[Na+:2].C([O:13][C:14]1[C:27]2=[C:28]3[C:29]4[C:24]([CH:25]=[CH:26]2)=[C:23]([S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:21]([S:34]([O-:37])(=[O:36])=[O:35])[C:20]=4[CH:19]=[CH:18][C:17]3=[C:16](S([O-])(=O)=O)[CH:15]=1)CCCCCCCCC.Cl>O>[Na+:2].[Na+:2].[CH2:26]([O:1][C:16]1[C:17]2=[C:28]3[C:29]4[C:20]([CH:19]=[CH:18]2)=[C:21]([S:34]([O-:37])(=[O:35])=[O:36])[CH:22]=[C:23]([S:30]([O-:33])(=[O:32])=[O:31])[C:24]=4[CH:25]=[CH:26][C:27]3=[C:14]([OH:13])[CH:15]=1)[CH2:27][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:29]
Reactant: CCCCCCCCCCOc1cc(S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c43
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCOc1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34

Procedure:
14.5 g Sodium hydroxide and 9.0 g water are heated to ca. 130° C. and 8.53 g 1-decyloxypyrene-3,6,8-trisulfonate (structure IV, R=decyl, M=Na) are added to the melt in small portions under stirring. The temperature is raised within 30 min to 190° C. The mixture is cooled, cautiously acidified with concentrated hydrochloric acid, and the resulting precipitate is filtered and recrystallized from a saturated aqueous salt solution. For further purification it is recrystallized from aqueous ethanol. Yield is 2.6 g of yellow crystals that decompose at above 232° C. and which have a green fluorescence that is strongly pH-dependent in the pH 6-8 range.
Reaction SMILES: C([O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)CC.C(OC1C=C(C=CC=1OCCC)C(OCCC)=O)CC>>[N+:16]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:19])=[O:4])([O-:18])=[O:17]
Reactant: CCCOC(=O)c1ccc(OCCC)c([N+](=O)[O-])c1
Agent: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Product: CCCOc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
When the product of Step A was substituted for propyl 3,4-dipropoxybenzoate in Example 43 Step B, the identical process afforded the title compound in 97%, as creamy solid. 1H-NMR (CDCl3) 1.05-1.09 (m, 3H); 1.83-1.96 (m, 2H); 4.12-4.17 (m, 2H); 7.13 (d, 1H, J=9 Hz); 8.23 (dd, 1H, J=3, 9 Hz); 8.53 (d, 1H, J=3 Hz).
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[C:7]([C:21]#[N:22])=[C:6]([C:23]#[N:24])[C:5]=1[S:25][C:26]([F:29])([F:28])[F:27].C(Cl)Cl.O>FC(F)(F)C(O)=O>[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Cl:20])[C:7]([C:21]#[N:22])=[C:6]([C:23]#[N:24])[C:5]=1[S:25]([C:26]([F:29])([F:28])[F:27])=[O:1]
Reactant: OO
Reactant: N#Cc1c(SC(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(S(=O)C(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
Hydrogen peroxide (278 mg, 35%, 2.9 mmol) was added to solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,3-dicyano-4-trifluoromethylthiopyrrole (850 mg, 1.9 mmol) in trifluoroacetic acid (10 ml). The resulting solution was stirred at 20° C. for 0.75 hour. Another portion of hydrogen peroxide ( 0.97 mmol) was added and the mixture stirred at 20° C. for a further hour. The reaction mixture was poured into methylene chloride (60 ml) and water (60 ml) and the organic layer washed with water (2×), dried (sodium sulfate), concentrated and purified by chromatography on silica gel, eluting with heptane/ethyl acetate (4:1) to give the title compound as a yellow solid (293 mg, 0.64 mmol); 19F-NMR: −64.35, −75.59.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+].Cl>O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Yield: 99 %

Procedure:
A solution of Raltegravir potassium (˜3.4 g) in water was acidified with 2N HCl until pH 2 was obtained. The acidified solution was extracted with mixture of methyl tert-butyl ether (MTBE)/isopropyl alcohol (IPA) (400 ml/100 ml). The organic extract was evaporated to dryness. Raltegravir free hydroxy (3.1 g) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:18]3[CH:19]=[N:20][C:15]([CH3:14])=[CH:16][CH:17]=3)[CH:3]=2)[C:8]1=[O:12]
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Reactant: Cc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Yield: 199.8 %

Procedure:
A mixture of 6-bromo-2-methylisoquinolin-1-one (160 mg, 0.67 mmol), (6-methylpyridin-3-yl)boronic acid (166 mg, 0.32 mmol), Pd(dppf)Cl2 (60 mg, 0.08 mmol) and saturated aqueous NaHCO3 (0.6 mL) in dioxane (6.5 mL) was microwaved at 110° C. for 1.5 h. Purification using silica gel chromatography (PE:EA=3:1 to 2:3) gave the title compound (160 mg, 95.2%) as a yellow solid. LCMS: 251.2 (M+H)+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=3[Cl:6])[N:15]=[CH:16][C:17]=12
Reactant: Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-n2ncc3c(Cl)ncnc32)c1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
Phosphorus oxychloride (26.5 ml, 284.60 mmol) was added to 1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AR3) (4 g, 14.23 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. Allowed to cool to Ambient temperature. The reaction mixture was evaporated to near dryness, dissolved in toluene, evaporated, re-dissolved in toluene and evaporated to dryness again. The solid was triturated with EtOH. A solid was filtered off and dried under vacuum to give the product (2.450 g, 57.5%). 1H NMR (400 MHz, DMSO) δ 7.65 (1H, m), 7.73-7.75 (1H, dd), 7.94-7.97 (1H, dd), 8.83 (1H, s), 8.91 (1H, s); m/z (ES+) (M+H)+=518; HPLC tR=1.89 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:38]=[CH:37][C:29]3[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[S:32][C:28]=3[CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([C:5]2[S:6][C:2]([C:26]3[CH:38]=[CH:37][C:29]4[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[S:32][C:28]=4[CH:27]=3)=[CH:3][N:4]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)c2ncc(Br)s2)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)c2ncc(-c3ccc4nc(NC(C)=O)sc4c3)s2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-(4-methoxyphenylsulfonyl)thiazole (134.8 mg, 4.034 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (163.6 mg, 0.5141 mmol), sodium carbonate (0.40 mL, 2.0 M in water, 0.80 mmol), and palladiumtetrakis(triphenyl phosphine) (59.5 mg, 51.5 μmol) were suspended in 1,4-dioxane (3.2 mL) and the reaction mixture was stirred and heated at 80° C. for 1.5 hours. Additional Pd(PPh3)4 (78 mg) was added to the mixture and stirring and heating were continued at 90° C. for another 90 minutes, at which time the reaction was cooled to RT. The organic phase was decanted, and the residual solid was washed with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad. This pad was washed with DCM and MeOH, and the filtrate was combined with the decanted suspension and concentrated. The solid was treated with Et2O and filtered. Solid washed with Et2O and purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 40 minutes) to afford N-(6-(2-(4-methoxyphenylsulfonyl)thiazol-5-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 446. Calculated exact mass for C19H15N3O4S3: 445. 1H NMR (400 MHz, DMSO-d6): 12.51 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.81 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 3.87 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:15])[CH:4]=1)#[N:2].[NH2:16][OH:17]>CO>[NH2:2][C:1](=[N:16][OH:17])[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c(C#N)cc1F
Reactant: NO
Solvent: CO
Product: COC(=O)c1cc(OC)c(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-cyano-2-fluoro-5-methoxybenzoate (64 mg; 0.31 mmol; 1 eq.) was dissolved in MeOH. Hydroxylamine (90.23 μl; 1.53 mmol; 5 eq.) was added and the mixture was stirred at RT overnight. As the reaction was not complete, it was heated at 50° C. for one more day. The solvents were then evaporated, affording the title product as an orange oil, which was used without further purification (74 mg; 100%). LC/MS (Method B): 243.1 (M+H)+. HPLC (Method A) Rt 1.24 min (Purity: 80.3%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate from Step 1 (3.31 g, 14.5 mmol) in Et2O (80 mL) at 0° C. under N2 was added LiAlH4 (1M in THF, 13.66 mL, 13.66 mmol) in 15 min. The resulting mixture was stirred at 0° C. for another 20 min and quenched by addition of saturated aqueous NH4Cl solution, extracted with EtOAc, dried over Na2SO4. Filtration and evaporation to dryness gave the alcohol as white solid (2.76 g, 100%). LC/MC: 187.1 (MH)
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([F:25])[C:22](Br)=[CH:21][C:20]=1[O:27][CH3:28])[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.CCCCCCC>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=3)=[C:23]([F:25])[CH:24]=1)[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 90 °C
Yield: 74.6 %

Procedure:
A vial was charged with 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (0.200 g, 0.425 mmol), (3-fluorophenyl)boronic acid (0.065 g, 0.468 mmol), potassium phosphate, dibasic (0.296 g, 1.701 mmol), and PdCl2(dppf) (0.031 g, 0.043 mmol)). The vial was flushed with Ar (g), then 1,4-dioxane (1.134 ml) and water (0.567 ml) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 90° C. LCMS showed clean desired product. The mixture was extracted with EtOAc (3×), then the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50%, then 50-100% EtOAc/Heptane) to give 6-(benzylthio)-1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (0.154 g, 0.317 mmol, 74.6% yield). m/z (ESI) 486.0 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: C[C@@H]1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 81.9 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (448 mg, 4 mmol) and (R)-2-methylpyrrolidine (511 mg, 6 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (581 mg, 82%) as a light yellow oil. LC-MS: [M+H]+, 178.2, tR=1.049 min.