Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2[N:22]=[C:5]([CH:6]=[C:7]3[C:40]([CH:41]=[CH2:42])=[C:39]([CH3:43])[C:9](=[CH:10][C:11]4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:13](=[C:14]([CH2:27][C:28]([OH:30])=[O:29])[C:15]5[NH:19][C:18]([CH:20]=2)=[C:17]([CH3:23])[C:16]=5[C:24]([OH:26])=O)[N:12]=4)[NH:8]3)[C:4]=1[CH3:44].[CH3:45]CC1C(C)=C2NC=1C=C1N=C(C(CC(OC)=O)=C3N=C(C=C4NC(=C2)C(C=C)=C4C)[C@@H](C)[C@@H]3CCC(O)=O)C(C(NCCN)=O)=C1C.CCC1C(C)=C2NC=1C=C1N=C(C(CC(N[C@H](C([O-])=O)CC([O-])=O)=O)=C3N=C(C=C4NC(=C2)C(C=C)=C4C)[C@@H](C)[C@@H]3CCC([O-])=O)C(C([O-])=O)=C1C.[Na+].[Na+].[Na+].[Na+]>>[CH3:1][CH2:2][C:3]1[C:21]2[N:22]=[C:5]([CH:6]=[C:7]3[C:40]([CH:41]=[CH2:42])=[C:39]([CH3:43])[C:9](=[CH:10][C:11]4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:13](=[C:14]5[C@@H:27]([C:28]([O:30][CH3:45])=[O:29])[C:24](=[O:26])[C:16]6[C:17]([CH3:23])=[C:18]([CH:20]=2)[NH:19][C:15]5=6)[N:12]=4)[NH:8]3)[C:4]=1[CH3:44]
Reactant: C=Cc1c(C)c2cc3nc(c(CC(=O)OC)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)NCCN)[C@@H](CCC(=O)O)[C@@H]3C
Reactant: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Agent: C=Cc1c(C)c2cc3nc(c(CC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-])c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)[O-])[C@@H](CCC(=O)[O-])[C@@H]3C
Agent: [Na+]
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)O)[C@@H]3C

Procedure:
merocyanine 540[MC 540]; Vitamin D; 5-amino-laevulinic acid [ALA]; photosan; chlorin e6, chlorin e6 ethylenediamide, and mono-L-aspartyl chlorin e6;
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:30][N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)N>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:31]([CH3:30])[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 480.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56]>>[C:55]([C:42]1[CH:43]=[C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:45]=[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(Br)c(C(C)(C)C)c1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: CC(C)(C)c1cc(C(C)(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)(C)C)c1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 2-bromo-1,3,5-tri-tert-butyl-benzene. MS: 652.2 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B(O)O)cn1
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3cnn(C)c3)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 79 %

Procedure:
Following the general method as outlined in Intermediate 192, starting from tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191) and 1-methyl-1H-pyrazole-4-boronic acid, pinacol ester, the title compound was obtained as a yellow sticky solid in 79% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].CO[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13].O>C1(C)C=CC=CC=1>[CH2:5]([N:7]([CH2:8][CH3:9])[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[N:15]=1)=[O:13])[CH3:6]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc2c(N)cccc2n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A suspension that consists of 1.06 g (7.95 mmol) of aluminum chloride in 35 ml of toluene is mixed with 1.70 ml (15.7 mmol) of diethylamine while being cooled with ice. After one hour at room temperature, 350 mg (1.73 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is added, and the reaction mixture is allowed to stir for 5 hours at 40° C. The reaction is halted by adding water. It is extracted with dichloromethane, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with dichloromethane-methanol (0-10%), 210 mg (50% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23][CH2:31][CH3:32])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:24])=[CH:4][N:3]=1
Reactant: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
Treat a solution of 4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-pyridin-3-ol (100 mg, 0.28 mmol) and cesium carbonate (100 mg, 0.28 mmol) in dimethylformamide (1 mL) with ethyl iodide (44 mg, 0.28 mmol). Stir the mixture at room temperature for 12 hours. Dilute the mixture with ethyl acetate and wash the solution with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 12 g silica gel eluting with a gradient of dichloromethane to ethyl acetate to give the title compound (48 mg, 45%) as a brown solid. MS (ES) m/z 386 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: Cc1ccccc1-c1ccc(C=O)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Cc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Methyl[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:16])[CH2:14][OH:15])[CH:7]=[CH:6]2>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[CH2:14][OH:15])[CH:7]=[CH:6]2
Reactant: C=C(CO)c1ccc2cc(OC)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)CO)ccc2c1
Reaction time: 2.25 h

Procedure:
A solution of 50 mg of 2-(6-methoxy-2-naphthyl)prop-2-en 1-ol in 25 ml ethyl acetate was charged to a Parr bottle with 80 mg of 5% by weight palladium on alumina. The mixture enated on the Parr shaker at ambient temperature and 275 kPa for 2.25 hours then the catalyst was filtered off and the filtrate was concentrated to give 2-(6-methoxy-2-naphthyl)propan-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[C:11]1([CH2:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:6]=2)=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(C(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from benzyl 4-hydroxyphenyl ketone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (68%, light yellow oil). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:41]O>ClCCl.O1CCCC1>[CH3:41][O:33][C:32](=[O:34])[CH2:31][CH2:30][CH2:29][N:13]1[C:12]2[N:11]=[C:10]([CH2:9][C:8]3[CH:35]=[CH:36][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)[NH:18][C:17]=2[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:14]1=[O:28]
Reactant: CO
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21

Procedure:
Prepared by reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid with thionyl chloride in dichloromethane/tetrahydrofuran at room temperature and then reaction with excess methanol. Crystallization from methanol gave the product as a colorless solid. MS, m/z(M+H)=508.1986.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[O:22][CH:21]=[CH:20][C:19]=3[CH:18]=[C:17]([NH2:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([Cl:35])(=[O:34])=[O:33]>>[ClH:35].[ClH:35].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:24][C:17]1[CH:16]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[CH:18]=1)(=[O:34])=[O:33]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)cc3ccoc23)CC1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2CCNCC2)c2occc2c1
Product: Cl
Yield: 24.2 %

Procedure:
The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in Example 106, Step 2) and 2-methylbenzenesulfonyl chloride (26 μL, 0.18 mmol). The crude product was purified with preparative HPLC (System B; 10-40% MeCN). The title compound (10 mg, 19%) was obtained as a colorless solid. HPLC 99%, RT=1.41 min (System A; 10-97% MeCN over 3 min), 99%, RT=1.26 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.66 (s, 3H) 3.50-3.65 (m, 8H) 4.67 (s, 2H) 6.86 (d, J=2.01 Hz, 1H) 7.22-7.29 (m, 1H) 7.30-7.37 (m, 2H) 7.40-7.48 (m, 2H) 7.81-7.90 (m, 2H). MS (ESI+) for C20H23N3O3S m/z 386 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:36][CH3:37])CC)C.C([O:40][CH2:41][CH3:42])C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:22])=[O:19])[NH:17][C:41](=[O:40])[CH:42]([C:37]1[CH:36]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCOCC
Reactant: CCN(CC)CC
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](N)CCCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@@H](C)NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(S)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide hydrochloride (13.3 g; 30.5 mmol; from step (b) above) 2-nitrophenyl diphenyl acetate (9.8 g; 30.5 mmol; see Example 1(c) above), triethylamine (4.6 g; 45.8 mmol) and CH2Cl2 (600 mL), 60 hours reaction time. The reaction mixture was submitted to aqueous work up, dried, filtered and concentrated to give the crude product as a solid. The product was dissolved in CH2Cl2 and concentrated until solids began to form. Diethyl ether was added to precipitate more solids. The solids were collected and dried to give the sub-title compound as a white solid (13.5 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][N:12]=1>CN(C)C=O.C(OCC)(=O)C>[I:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Fc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccnc(Oc2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenol (0.464 g) in N,N-dimethylformamide (5 mL) was treated with sodium hydride (60% in mineral oil, 0.057 g). After the gas evolution ceased, 2-fluoro-4-iodopyridine (0.22 g) was added slowly to the solution. The mixture was heated at 100° C. overnight under nitrogen atmosphere, cooled, diluted with ethyl acetate and washed with aqueous NaOH. The organic layer was concentrated and purified by preparative TLC, eluting with petroleum ether/ethyl acetate (10/1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2ncco2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncco3)c2)nc1
Reaction time: 16 h

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(1,3-oxazol-2-yl)benzoate (0.96 g, 3.26 mmol) in tetrahydrofuran (20 mL) at 20° C. was added 20 mL of 0.5 N sodium hydroxide solution. After 16 h at 20° C., the reaction was quenched with 4N HCl in dioxane (5 mL). The titled compound was precipitated out as hydrochloride salt. After filtration, washed by 100 mL of ethyl ether twice and died under vacuum, the titled compound was obtained as pure hydrochloride salt (1.2 g). MS 281.0 (M+1).
Reaction SMILES: [CH:1]([NH:4][OH:5])([CH3:3])[CH3:2].[CH:6]([C:8]1[O:12][C:11]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)=O.[Na]>CO>[CH:1]([N+:4]([O-:5])=[CH:6][C:8]1[O:12][C:11]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: CC(C)NO
Agent: [Na]
Solvent: CO
Product: CC(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Reaction time: 24 h
Yield: 75 %

Procedure:
N-Isopropylhydroxylamine (from Example A above) and 5-formylfuran-2-sulfonic acid, sodium salt hydrate (5.94 g) were refluxed in methanol (200 mL) for 24 hours. Another portion of N-isopropylhydroxylamine was added and the reaction stirred for 24 hours. The solvent was stripped to provide a pale yellow solid which was recrystallized from ethyl acetate to afford 5.72 g (75% yield) of the title compound, m.p.=230° C. (decomposed). HPLC analysis showed a major product of 88% by area. Depending upon the pH, the title compound was present as the free acid, or, if in the presence of sodium cations and a higher pH, as the sodium salt. Other salt forms can be prepared by changing the cation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]=[C:36]([NH:39]C(=O)C)[S:37][CH:38]=3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[ClH:1].[NH2:39][C:36]1[S:37][CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[Cl:1])[NH:9][C:8](=[O:12])[C:7]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[C:6]4[OH:18])=[CH:29][CH:30]=2)[N:35]=1
Reactant: CC(=O)Nc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Reactant: O=c1[nH]c2cc(Cl)c(I)cc2c(O)c1-n1cccn1
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: [Na+]
Solvent: C1COCCO1
Product: Cl
Product: Nc1nc(-c2ccc(-c3cc4c(O)c(-n5cccn5)c(=O)[nH]c4cc3Cl)cc2)cs1
Temperature: 120 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
7-Chloro-4-hydroxy-6-iodo-3-(1H-pyrazol-1-yl)quinolin-2(1H)-one (Intermediate 112) (300 mg, 0.774 mmol), N-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl) acetamide (Intermediate 31) (264 mg, 1.0 mmol), Pd(Ph3P)4 (8.94 mg, 7.74 μmol), 1M Na2CO3 (2.32 mL, 2.32 mmol) were mixed in 1,4-dioxane (3 mL). The reaction mixture was stirred at 120° C. for 1 h under microwave irradiation then cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product was then diluted with EtOH and concentrated hydrochloric acid and the resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature then filtered. The powder was washed successively with water, EtOH and Et2O to afford the title compound 6-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-7-chloro-4-hydroxy-3-(1H-pyrazol-1-yl)-2(1H)-quinolinone hydrochloride (70 mg, 19.1% yield) as a grey powder. LCMS: (M+H)+=436; Rt=2.14 min. HRMS: calculated for C21H13ClN5O2S (M−H)+: 434.0479. found: 434.0435.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(F)cc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 355 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1N
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1Nc1nc(Cl)nc(Cl)n1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Cyanuric chloride (0.74 g, 4.02 mL) was added to an acetone solution (15 mL) of 3-amino-4-methyl-N-phenethyl-benzamide (1.02 g, 4.02 mmol) at 0EC. The mixture was stirred for 1 h at 0EC. Ice was added to the mixture and stirred for 15 min. The solvent was removed to afford 3-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-4-methyl N-phenethyl-benzamide (1.52 g, 94%) as white solid MS (m/z) calced for C19H17Cl2N5O (MH+), 402; found, 402.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:11][N:10](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[C:27]([OH:30])(=[O:29])[CH3:28]>C(O)C.[Pd]>[C:27]([OH:30])(=[O:29])[CH3:28].[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CNC1

Procedure:
A suspension of 14 (4.6 g, 13.6 mmol) and 10% Pd/C (2.0 g) in 200 ml of 10:2:1 ethanol:water:acetic acid was hydrogenated at 50 psi for 24 hours. The suspension was subsequently filtered through celite and the solvents removed in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:23]C(=O)OCC1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10]>CO.[Pd]>[NH2:23][C@H:11]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1])=[O:10])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1N

Procedure:
A solution of the crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate in methanol (200 ml) was treated with 10% palladium on carbon (1.0 g) under a hydrogen atmosphere at room temperature for 6 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with ether and dried in vacuo to give tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (5.5 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1.Cl.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>C1COCC1>[Cl:14][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)(=[O:36])=[O:37])[CH:17]=[CH:16][CH:15]=2)[C:12]([Cl:13])=[CH:11][N:10]=1
Reactant: Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(CNc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride (0.20 g, 0.58 mmol) and triethylamine (0.32 mL, 2.3 mmol) in THF (3 mL) was added slowly m-nitrobenzenesulfonyl chloride (0.13 g, 0.58 mmol). The resulting mixture was stirred at rt for 2 hours and the solvent was removed under vacuum. The residue was treated with EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to provide the desired product (0.30 g, 95%). LCMS for C17H14Cl2N5O4S (M+H)+: m/z=453.9, 455.9.