Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.ClC1C=CC(C([NH:56][C@@H:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[CH3:58])=O)=C(NS(C2C3N=CC=NC=3C=CC=2)(=O)=O)C=1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:56][C@@H:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride (EXAMPLE 7, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18BrFN4O3S, 528.0; m/z found, 527/529 [M−H]−. HPLC (reverse phase): RT=10.03 min. 1H NMR (500 MHz, CDCl3): 11.34 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=7.4, 1.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.13 (br d, J=6.5 Hz, 1H), 5.25-5.15 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cccc(CBr)c1

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 24, 10 ml acetonitrile, 0.339 g of pyridine and 2.11 g of phosphorus tribromide. The product, 2.27 g, is obtained as colorless needles.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([OH:37])[C:18]2[C:13](=[CH:14][C:15]([C:23](N)=[O:24])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)[C:11]1=[O:36].[BrH:38].C(O)(=[O:41])C>>[BrH:38].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([OH:37])[C:18]2[C:13](=[CH:14][C:15]([C:23]([OH:24])=[O:41])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:28][C@H:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])[CH2:30]2)[C:11]1=[O:36]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Reactant: CC(=O)O
Agent: Br
Agent: Cl
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(=O)O)cc3C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 1-4 (400.0 mg, 0.69 mmol) in acetic acid (2.5 mL) was added 47% hydrobromic acid (7.5 mL), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated, and then recrystallized (methanol-diethyl ether) to give the titled compound (420.5 mg, 98%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:15]1[CH2:19][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][C:16]1=[O:28])[CH2:5][CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:18]1[CH2:19][N:15]([CH:4]([CH2:5][CH:6]([C:11]([F:13])([F:14])[F:12])[C:7]([F:9])([F:8])[F:10])[C:3]([OH:29])=[O:2])[C:16](=[O:28])[CH:17]=1
Reactant: COC(=O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid methyl ester (48 mg, 0.11 mmol) in a 1:1 solution of tetrahydrofuran:water (2 mL) was treated with lithium hydroxide monohydrate (11 mg, 0.22 mmol) and stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water and the pH adjusted to pH=6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid (35 mg, 75%) as an off-white solid: HR-ES-MS m/z calculated for C16H12NO4ClF6 [M+H]+ 432.0432, observed 432.0433.
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH:29]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:31])[CH3:30]>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH:29]([CH3:31])[CH3:30])=[O:28])[S:14][N:13]=1
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CC(C)NCCCCCN
Product: Cc1ccc(COc2nsc(NC(=O)NCCCCCNC(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-isopropyl-pentane-1,5-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 452 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CO>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(Nc2cc(N(C)C)nc(N3CCN(Cc4ccccc4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A mixture of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.10 mmol) and benzaldehyde (11 mg, 0.1 mmol) in a solution of methanol (5 mL) and acetic acid (0.5 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added to the above solution and stirred at room temperature for 16 h. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (8 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([S:13][CH2:14][C:15]([O:17]C)=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([S:13][CH2:14][C:15]([OH:17])=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CSc1c(O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CSc1c(O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 2 h

Procedure:
The 7-chloro-4-hydroxy-3-(methoxycarbonylmethylthio)-2(1H)-quinolone obtained in accordance with Example 7 is dissolved in 2N sodium hydroxide solution and left to stand for 2 hours at room temperature. The reaction mixture is adjusted to pH 2 with 4N hydrochloric acid and the resulting suspension is filtered. The colourless crystals are dried under a high vacuum at 60°. 7-chloro-4-hydroxy-3-(carboxymethylthio)-2(1H)-quinolone is obtained in the form of pure crystals having a melting point of 288° (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:45]([Si:49](Cl)([CH3:51])[CH3:50])([CH3:48])([CH3:47])[CH3:46].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:51])[CH3:50])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (3.15 g, 5.90 mmol) in dichloromethane (22 ml) were added imidazole (0.96 g, 14.17 mmol) and tert-butyl(chloro)dimethylsilane (1.07 g, 7.08 mmol). The reaction mixture was stirred at room temperature for 5 hours, water and dichloromethane were then added. The aqueous layer was separated and the organic layer was washed with water, brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of EtOAc (0-30%) in cyclohexane to yield the title compound as a yellow foam (2.05 g, 53%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([OH:22])=[O:21])=[CH:3]1.FC(F)(F)C(O[C:28]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38])=O.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([O:22][C:28]2[C:29]([F:38])=[C:30]([F:37])[C:31]([F:36])=[C:32]([F:35])[C:33]=2[F:34])=[O:21])=[CH:3]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cn1cc(C(=O)O)c(Nc2ccc3ccccc3c2)cc1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc3ccccc3c2)cc1=O
Yield: 97 %

Procedure:
1-Methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (97%). 1H NMR [400 MHz, (CD3)2SO]δ 9.06 (s, 1H), 8.97 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.92 (t, J=9.0 Hz, 2H), 7.85 (d, J=1.9 Hz, 1H), 7.56-7.46 (m, 3H), 5.73 (s, 1H), 3.51 (s, 3H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][C:18]1[N:17]=[C:16]([N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[O:20][N:19]=1
Reactant: Cc1ccc(CNc2nc(C)no2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN(C(=O)C2CC2)c2nc(C)no2)cc1

Procedure:
Cyclopropane carboxylic acid chloride (3.45 g, 0.033 mole) was added dropwise to a solution of 5-(4-methylphenyl)methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mole) and triethylamine (3.45 g, 0.035 mole) in dry benzene keeping the temperature below 10° C. After the addition the temperature was allowed to reach room temperature and then refluxed overnight. On cooling the reaction mixture was washed twice with 2 N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO4 and charcoaled. The product was purified by column chromatography--silica gel (110 g) eluting with petroleum ether 40°-60° C. increasing polarity to 10% ether in petroleum ether. The title compound was recrystallised from petroleum ether 60°-80° C. as white needles. m.p. 49.5°-50.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:19]([C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[Cl:9])[CH:16]=2)=[O:20])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 4-aminomethyl pyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 304/306 (MH+); HPLC Rf: 4.08 min.; HPLC purity: 78%.
Reaction SMILES: N1([O:10][C:11]2[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]4[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]4)[N:23]=3)=[O:20])[C:15](=[O:17])[CH:16]=2)C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1O>>[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:10][C:11]1[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]3[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]3)[N:23]=2)=[O:20])[C:15](=[O:17])[CH:16]=1
Reactant: Oc1ccccc1Cl
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(On4nnc5ccccc54)cc3=O)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4Cl)cc3=O)n2)O1

Procedure:
Using the method described in Example 126, Step 1, 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (Example 114, Step 1) and 2-chloro-phenol afforded 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereomers (99.4 mg, 80%); ES+-HRMS m/e calcd for C27H32N5O5Cl [M+H+] 542.2165 found 542.2167. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (br. s., 1H), 1.28 (br. s., 1H), 1.24 (s, 3H), 1.30 (d, J=1.8 Hz, 3H), 1.37-1.76 (m, 7H), 1.85-2.00 (m, 1H), 2.18-2.33 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.19 (m, 2H), 4.27-4.41 (m, 1H), 5.45 (dd, J=10.6, 4.2 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.35-7.47 (m, 1H), 7.51 (m, 2H), 7.59 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 10.85 (br. s., 1H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:15])/[CH:12]=[CH:13]\I>>[C:1]1([C:7]#[C:8]/[CH:13]=[CH:12]\[C:11]([O:10][CH3:9])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)/C=C\I
Product: COC(=O)/C=C\C#Cc1ccccc1

Procedure:
The general procedure was used to convert phenylacetylene and (Z)-methyl-3-iodoacrylate to the title product. Purification by flash chromatography (15% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a light yellow oil (336 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.35 (m, 3H), 6.36 (d, J=11.39, 1H), 6.14 (d, J=11.41, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.25, 132.16, 129.28, 128.42, 127.79, 123.22, 122.63, 101.45, 86.37, 51.55. Anal. Calc'd. for C12H10O2: C, 77.40; H, 5.41; Found C, 77.41; H, 5.35.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.C(=O)([O-])O.[Na+]>[CH:26]1([N:25]([CH3:24])[C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N(C)C2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol) and N-methylcyclohexanamine (0.158 mL; 1.202 mmol) in THF (1 mL) was placed in a sealed tube and heated at 100° C. for 18 h. The reaction mixture was diluted with a saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 61 mg (49%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:5]2C.[CH2:28]([NH2:31])[C:29]#[CH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])=[C:5]2[NH:31][CH2:28][C:29]#[CH:30]
Reactant: Cc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Reactant: C#CCN
Product: C#CCNc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 71.9 %

Procedure:
6-Chloro-3-cyclopropanecarbonyl-4-methylsulfoxy-8-trifluormethyl-2-quinolinone (377 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (265 mg, yield: 72%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])[C:4]([CH3:29])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (307 mg, 0.642 mmol), (3-fluorophenyl)boronic acid (117 mg, 0.834 mmol), potassium carbonate (266 mg, 1.926 mmol), and Pd(PPh3)4 (37.1 mg, 0.032 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2407 μl) and water (802 μl) were added. The vial was sealed and heated to 90° C. for 19 h. The reaction was cooled down to rt. The whole was extracted with EtOAc (3×25-mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated to afford colorless residue. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(2,3′-difluoro-5-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (179 mg, 56.5% yield) as off-white solid. m/z (ESI) [M+H]+=493.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3 H) 6.44 (d, J=1.87 Hz, 1 H) 6.80 (d, J=9.02 Hz, 1 H) 6.85 (d, J=9.64 Hz, 1 H) 7.26-7.37 (m, 1 H) 7.44-7.54 (m, 3 H) 7.54-7.64 (m, 1 H) 7.75 (d, J=8.40 Hz, 1 H) 7.88 (dd, J=8.97, 2.23 Hz, 1 H) 8.28 (d, J=9.64 Hz, 1 H) 8.41 (d, J=2.18 Hz, 1 H) 8.71 (d, J=1.76 Hz, 1 H) 11.68 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][NH:24][CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][N:24]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCNC4)ccc2N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)ccc2N1

Procedure:
Step 3—Synthesis of compound ud: 5-(4-Morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)indolin-2-one (0.083 g, 0.24 mmol), 2-Chloropyrimidine (0.0406 g, 0.354 mmol), N,N-Dimethylformamide (4.00 mL, 51.6 mmol) and N,N-Diisopropylethylamine (0.164 mL, 0.945 mmol) were combined and reaction mixture was microwaved on 300 watts, 120° C. for 30 minutes on a CEM microwave, and vacuum filtered. 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 8.44 (d, J=4.7, 2H), 8.24 (d, J=8.2, 1H), 8.20 (s, 1H), 6.92 (t, J=10.8, 1H), 6.70 (t, J=4.7, 1H), 4.82 (s, 2H), 3.98 (t, J=5.2, 2H), 3.77-3.69 (m, 4H), 3.57 (s, 2H), 3.47 (d, J=4.4, 4H), 2.75 (dd, J=8.8, 3.8, 2H). LC/MS-m/z+430.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccccc2)nc(N2CCOCC2)cc1=O
Yield: 39.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 134 mg of aniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 95 mg of 2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of a purple solid, the characteristics of which are the following: