Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[C:23]1(B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[C:23]1([C:2]2[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(I)c1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
5-Iodo-N-(pyridin-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide (0.05 g, 118 μmol), 2-cyclohexenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 141091-37-4, 22.1 mg, 22.9 μl, 106 mmol) and potassium phosphate (75.2 mg, 355 μmol) were combined in degassed DMF (1.1 ml)/THF (367 μl) to give a yellow solution which was heated to 80° C. and stirred for 2 days. After cooling the mixture was poured into 5 mL saturated NaHCO3 solution and extracted with i-propyl acetate (2×50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give a brown oil that was purified by preparative TLC (silica gel, 2.0 mm, 1:2 n-heptane/1-propyl acetate) to give the title compound (19 mg, 42%) as light yellow solid; MS (ESI) 378.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[S:5])[CH3:2].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH2:1]([N:3]([C:4]1[S:5][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1)[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCN(CC)C(N)=S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(N(CC)CC)n1
Yield: 140.4 %

Procedure:
A solution of 0.972 g (7.36 mmol) of N,N-diethylthiourea and 1.02 ml (8.1 mmol) of ethyl bromopyruvate in 25 ml of acetone was treated with excess solid MgSO4 and heated at reflux for 1 h. The resulting mixture was filtered, and concentrated in vacuo. Silica gel chromatography using CHCl3 provided 2.36 g (38%) of the desired compound as an oil. Mass spectrum: (M+H)+ =229.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[C:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(C)(=O)=O

Procedure:
To a solution of 7.74 ml of methanesulfonyl chloride in 100 ml of dichloromethane were added dropwise, at a temperature of 0° C., 23.12 ml of tert-butylamine. On completion of addition, the precipitate was filtered off and the filtrate was washed with 100 ml of 1 N aqueous hydrochloric acid, the organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The product (14.70 g) was obtained with a molecular weight of 151.2 g/mol (C5H13NO2S).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:20])[CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CNc1ccc(-c2ccc3nonc3c2)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N(C)C)ccc1-c1ccc2nonc2c1
Temperature: 25 °C

Procedure:
200 mg (0.8 mmol) of (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-amine are stirred at 0 to 5° C. in 5 mL of DMF, then over 1 minute treated with 1 mL NaHMDS-solution (1.0 M, 1.25 eq.) and stirred another minute. Then, 0.5 mL (7.8 mmol, 10 eq.) of methyliodide is added and stirred 2 minutes under warming to rt. Then, the mixture is extracted with ethyl acetate/aqueous NaHCO3, the combined organic layers dried with sodium sulfate and concentrated. This yields the desired product as a reddish-yellow solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(C(=O)Oc2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 11.6 g of p-pentylbenzoyl chloride, 11.1 g of p-hydroxyphenyl sulfur pentafluoride and 100 ml of pyridine is stirred it room temperature for 20 hours. Concentrating the mixture and working it up in the customary manner gives 4-(4-pentylbenzoyloxy)-phenylsulfur pentafluoride.
Reaction SMILES: C1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]4[O:20]C[O:22][C:16]=4[CH:15]=3)O)=O)=[CH:4][C:3]=2[O:2]1>CO.[OH-].[OH-].[Pd+2]>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:12][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(CCc2ccc(O)c(O)c2)cc1O
Yield: 74899.8 %

Procedure:
A solution of the tetrahydroxybenzil (see Example 1) (70 mg) in methanol (10 ml) with palladium hydroxide on carbon (20%, 10 mg) was stirred under an atmosphere of hydrogen for 2 hours, The mixture was filtered through Celite, and the solvents removed in vacuo to give an orange gum. Separation by column chromatography over silica gel eluting with 20% ethyl acetate in dichloromethane gave DC-0004 as an off white gum (43 g, 68%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[N:35]([CH2:39][CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[N:34]=2)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[N:35]([CH2:39][CH2:40][C:41]([NH:44][CH2:20][CH:19]([C:16]3[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=3)[OH:25])([CH3:42])[CH3:43])[N:34]=2)=[CH:31][CH:32]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: Cc1nc(-c2ccc(F)cc2)nn1CCC(C)(C)N
Product: Cc1nc(-c2ccc(F)cc2)nn1CCC(C)(C)NCC(O)c1ccc(O)c(CO)c1

Procedure:
Prepared according to general working method A from 344 mg (1 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 262 mg (1 mmol) of 3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[CH2:4][CH:5]=[CH2:6].[OH-].[K+].O.Cl>CO>[CH2:1]=[CH:2][CH:3]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
9.3 g of the compound (2), 4.0 g of potassium hydroxide and 1 ml of water were dissolved in methanol, and reflux was carried out for one hour. After addition of 50 ml of water, reflux was further carried out for three hours. The reaction mixture was adjusted to pH 2 by adding diluted hydrochloric acid. The precipitate was collected by filtration and was then washed with water, to obtain 8.1 g of the objective compound (3). (Yield: 90%)
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]([CH3:36])[CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:35][CH2:34][CH:33]([C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[CH3:36])=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=11.97 min. MS (ESI−): mass calcd. for C22H17Cl3N4O3S2, 553.98; m/z found, 553/555/557 [M−H]. 1H NMR (400 MHz, CDCl3): 11.51 (s, 1H), 8.36 (dd, J=7.0, 1.1, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.74-7.70 (m, 2H), 7.40 (d, J=8.2, 1H), 7.29 (d, J=2.1, 1H), 7.04 (dd, J=8.3, 2.1, 1H), 7.01-6.99 (m, 1H), 6.89 (dd, J=8.4, 2.0, 1H), 5.81 (s, 1H), 3.74-3.67 (m, 1H), 3.34-3.28 (m, 1H), 3.06-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[C:6]([CH3:14])=[N:5]2.O=P(Cl)(Cl)[Cl:17]>CN(C)C1C=CN=CC=1>[Cl:17][C:7]1[C:6]([CH3:14])=[N:5][C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Cc1nc2cc(F)c(F)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: Cc1nc2cc(F)c(F)cc2nc1Cl

Procedure:
6,7-Difluoro-3-methyl-1H-quinoxalin-2-one (2 g, prepared from 4,5-difluoro-1,2-phenylene-diamine and pyruvic acid according to general procedure (A), step 1) was mixed with POCl3 (20 ml) and 4-dimethylaminopyridine (10 mol %) and the mixture was refluxed for 2 hours. The mixture was allowed to cool and poured onto ice (300 ml), filtered and washed with water to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:33])([CH3:32])[C:30]#[CH:31]>>[F:27][C:3]1[C:2]([C:31]#[C:30][C:29]([OH:33])([CH3:32])[CH3:28])=[CH:26][C:6]2[C:7]3[N:8]([C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1ncsc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: Cc1ncsc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 18 %

Procedure:
9-fluoro-3-(hydroxy(4-methylthiazol-5-yl)methyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 5.4 mg of the titled compound (18% yield). M+1=457.1. 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.01 (br s, 1H), 7.59-7.53 (m, 2H), 7.00 (d, J=10.5 Hz, 1H), 6.94 (d, J=6.3 Hz, 1H), 5.54 (s, 1H), 4.57-4.48 (m, 1H), 4.48-4.36 (m, 2H), 4.31-4.22 (m, 1H), 2.25 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([CH2:17][CH2:16][C:15]([NH:13][N:14]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:28])=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)CCc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1)NN=C1C(=O)Nc2ccc(Br)cc21
Temperature: 100 °C
Yield: 82 %

Procedure:
A suspension of 5-bromo-1H-indole-2,3-dione (67 mg, 0.30 mmol and) and 4-(3-hydrazino-3-oxopropyl)benzohydrazide (0.03 mg, 0.13 mmol) in acetic acid (2 mL) was heated at 100° C. for 80 min. The reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration, washing with AcOH (3×1 mL) and with AcOH/water (2×1 mL) and water (3×1 mL) and drying in vacuo at 70° C. for 4 hrs gave 68 mg of the title compound in a 79% yield as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][CH3:19])[CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COCc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by C starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxymethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.96 min; [M+H]+=421.17.
Reaction SMILES: Cl.Cl.NCCSSCCN.[OH-].[Na+].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][S:28][S:29][CH2:30][CH2:31][NH:32][C:33](=[O:46])[CH2:34][CH2:35][C:36]([O:38]N2C(=O)CCC2=O)=[O:37])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].C1(=O)OC(=O)CC1.Cl>O>[N:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][S:28][S:29][CH2:30][CH2:31][NH:32][C:33](=[O:46])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCSSCCNC(=O)CCC(=O)ON2C(=O)CCC2=O)cc1
Agent: Cl
Agent: NCCSSCCN
Agent: O=C1CCC(=O)O1
Solvent: O
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCSSCCNC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.2 g of cystamine dihydrochloride were dissolved in 20 ml of water and adjusted to pH 10 with NaOH. 2.1 g of p-azidobenzenesulfochloride were suspended in the solution and the mixture was stirred at room temperature for 5 hours. The precipitated N-(p-azidobenzenesulfonyl)cystamine was reacted with 2 g of succinic anhydride and stirred overnight. The resulting solution was acidified with HCl and the product was subsequently filtered off and washed with water. The residue was dried at room temperature in a high vacuum and gave 1.53 g of N-(p-azidobenzenesulfonyl)-N'-(3-carboxypropionyl)cystamine. The IR showed bands at 3283 (amide NH), 2134 (azide), 1714 (acid carbonyl), 1650 (amide), 1589+1547 (aromatic), 1284 (COOH), 1328+1180 (arylsulfonyl), 839 (p- disubst. benzene); TLC (silica gel: conc. NH3 (EtOH=1%). Rf=0.7; m.p. 163° (dec.).
Reaction SMILES: [CH2:1]([C:3]1[C:14](=[O:15])[N:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:35].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[C:14](=[O:15])[N:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:6]2[N:7]=[C:8]([S:11]([CH3:12])=[O:35])[N:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2cnc(SC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cc2cnc(S(C)=O)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
At 0° C., a suspension of tert-butyl (3-(6-ethyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (55) (720 mg, 1.75 mmol) in DCM (15 mL) was treated with 3-chloroperoxybenzoic acid (70 wt. %, 460 mg, 1.87 mmol) in one portion and stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (15 mL), and treated with ice and a 10% solution of Na2CO3 (ca. 10 mL). The DCM layer was separated and the aqueous layer was extracted with an additional amount of DCM (2×50 mL), dried over sodium sulfate and concentrated to give tert-butyl (3-(6-ethyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6a) (682 mg, 1.59 mmol, 91% yield) as a light yellow amorphous solid. m/z (ESI, +ve ion) 451.0 (M+Na)+. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [ClH:1].C([O:4][CH2:5][CH3:6])C.[NH2:7][C@H:8]1[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1>CO>[ClH:1].[C:5]([NH:7][C@H:8]1[CH2:12][NH:11][C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)(=[O:4])[C:6]1[CH:23]=[CH:10][CH:9]=[CH:8][CH:12]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1
Temperature: 57 °C

Procedure:
To the above methanol concentrate of (2S,4R)-1-benzyl 2-methyl 4-benzamidopyrrolidine-1,2-dicarboxylate, were added a slurry of 10% Pd/C (dry, 4.1 g) in methanol (100 mL) and cyclohexene (80 mL). The mixture was heated at reflux (57° C.) for 7 h. before being cooled to 20-25° C. Palladium catalyst was filtered off through a pad of Celite, and washed with methanol. The filtrate was concentrated, and cyclohexene was removed as a methanol azetrope. To the final methanol solution was added 1 N hydrogen chloride in diethyl ether (110 mL, 0.11 mol) while the temperature was maintained at 20-25° C. The resulting slurry was cooled to 10-15° C. over 20 min. The solid product was filtered and washed with toluene. The wet solid was dried at 60° C. under vacuum to give 22.4 g of (2S,4R)-methyl 4-benzamidopyrrolidine-2-carboxylate hydrochloride as white solid (81.7% overall yield from 1-benzyl 2-methyl (2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate). 1H NMR (CDCl3, δ, ppm): 9.99 (bs, 2H), 8.95 (d, J=6.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.58-7.45 (m, 3H), 4.71 (t, J=8.7 Hz, 1H), 4.68-4.61 (m 1H), 3.78 (s, 3H), 3.58 (dd, J=11.9, 6.6 Hz, 1H), 3.32 (dd, J=11.9, 4.2 Hz, 1H), 2.41 (d, J=8.6 Hz, 1H), 2.39 (d, J=8.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:22]=1)#[N:2]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:20][CH:19]=[CH:18][N:17]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:22]=1)#[N:2]
Reactant: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(-c2ncc[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 120 °C
Yield: 41.6 %

Procedure:
A mixture of N-{4-[3-cyano-4-(2,4-dichlorophenyl)-5-(4,5-dihydro-1H-imidazol-2-yl)-2-thienyl]pyridin-2-yl}cyclopropanecarboxamide (0.0650 g, 0.135 mmol) and Magtrieve (0.143 g, 1.70 mmol) was taken up in toluene (5 mL) and heated at 120° C. for 4 hours. The mixture was cooled to room temperature, diluted with DCM (10 mL) and filtered through a pad of celite. The solid residue was washed with 1% ammonia, 9% methanol in DCM mixture (10 mL) and solvent from the filtrate was evaporated. The residue was purified using ISCO chromatography on silica gel, elution 10 to 70% ethyl acetate in hexanes to afford the product (0.027 g, 47%). LCMS: (FA) ES+, 480, 482. 1H NMR (400 MHz, d6-DMSO) δ: 11.88 (s, 1H) 11.11 (m, 1H), 8.57-8.55 (m, 1H), 8.53-8.50 (m, 1H), 7.85-7.84 (m, 1H), 7.58-7.56 (m, 2H), 7.54-7.52 (m, 1H), 7.17-7.16 (m, 1H), 7.00-6.98 (m, 1H), 2.08-2.00 (m, 1H), 0.87-0.81 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:23][C:10]2=[CH:11][N:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:9]2[CH:8]=1)=O.[O-2].[Ca+2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[CH:13]=[N:12][CH:11]=[C:10]3[S:23][C:7]([C:5]4[NH:4][CH2:3][CH2:2][N:1]=4)=[CH:8][C:9]=23)=[CH:17][CH:18]=1
Reactant: NCCNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1ccc(Oc2cncc3sc(C4=NCCN4)cc23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 16.2 %

Procedure:
A suspension of Example 154 (0.15 g, 0.43 mmol) and calcium oxide (0.12 g, 2.15 mmol) in phenyl ether (10 mL) was heated to 220-250° C. The reaction was stirred 45 minutes over which reaction volume decreased due to evaporation of solvent. The reaction was cooled to room temperature and diluted with 10% MeOH/dichloromethane (25 mnL) then filtered. The filtrate was concentrated and residue was purified by preparative HPLC using a gradient of 30%-90% acetonitrile/water +0.1% TFA over 40 minutes. The product containing fractions were combined and neutralized with sat NaHCO3. The product crystalized upon standing for 3 days and was collected by filtration, and dried in a desiccator to yield the title compound as a tan needles (23 mg, 16%).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.P(Br)(Br)([Br:17])=O>>[Br:17][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: Oc1nc(-c2ccccc2)ncc1Br
Reactant: O=P(Br)(Br)Br
Product: Brc1cnc(-c2ccccc2)nc1Br
Temperature: 100 °C
Yield: 62.1 %

Procedure:
A mixture of 5-bromo-2-phenylpyrimidin-4-ol (1.67 g, 6.67 mmol, 1.0 equiv.) and POBr3 (100 g) was heated at 100° C. for 8 hours. The solution was cooled down to 55° C. and poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quench. The reaction mixture was extracted with CH2Cl2. The combined organic layer was washed (cold water), dried (Na2SO4), evaporated and the residue was purified by silica gel chromatography (hexane) to afford 4,5-dibromo-2-phenyl pyrimidine (1.3 g, 70.5%). LC-MS (m/z): 315.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.47-7.50 (m, 3H), 8.37-8.40 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5ccccc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 232 mg of 2-naphthoaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 14 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.41 g of 7-methoxy-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil.