Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
A round bottom flask was charged with 5-bromo-2-chloropyridin-3-amine (2.50 g, 12.1 mmol) and 24 mL THF and the solution was cooled to −78° C. under nitrogen. 1.0 M LiHMDS (24.1 ml, 24.1 mmol) was added slowly and the solution was stirred for 10 min at −78° C. 4-methoxybenzene-1-sulfonyl chloride (3.49 g, 16.9 mmol) dissolved in a minimum amount of THF (˜5 mL) was added slowly, and the cooling bath was removed after 10 min. The reaction was stirred at room temperature overnight and was quenched with saturated NH4Cl. The layers were separated, and the organic portion was diluted with CH2Cl2, washed with 1 N HCl and brine. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in CH2Cl2 (˜20 mL) and ether was added (˜40 mL) in portions over 15 min. After allowing to stand in the freezer for 1 h, the solids were filtered and washed with ether. N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (3.127 g, 68.7% yield) was isolated as a white crystalline solid. MS (ESI pos. ion) m/z calc'd for C12H10BrClN2O3S: 377.6. found 378.8.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1c(Cl)cccc1Cl
Yield: 39.7 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,6-dichloro aniline (2.0 g, 12.34 mmol), thiophosgene (1.41 g, 12.34 mmol) and N-ethyl di-isopropyl amine (7.42 g, 57.51 mmol) in DCM (20 mL) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.62 (d, J=7.8 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCc1ccc(CCCCCCC(=O)O)cc1
Yield: 90.7 %

Procedure:
This compound was synthesized from 7-(p-butylphenyl)-6-heptenoic acid (1.30 g, 5 mmol) by a hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.19 g, 97%) as white crystals (mp 32-33° C.). IR: 3400-2500, 1718 cm-1 ; 1H-NMR:0.92 (t, 3H), 1.35 (m, 6H), 1.60 (m, 6H), 2.32 (t, 2H), 2.55 (m, 4H), 7.02 (s, 4H), 9.70 (bs, 1H). Anal. Calcd. for C17H26O2 : C, 77.82, H, 9.99%; Found: C, 77.73, H, 10.01%.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:38][C@H:35]4[CH2:36][CH2:37][C@H:32]([OH:31])[CH2:33][CH2:34]4)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N[C@H]4CC[C@H](O)CC4)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(trans-4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.5 g (1.15 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.389 g (3.45 mmol) trans-4-hydroxy-cyclohexylamine. The final product was purified by column chromatography (20:1 dichloromethane/ methanol). This gave 0.320 g (57%) of 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(trans-4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 108° C.–110° C.; MS (APCI) m/z 486.2, 487.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(Cl)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(N3CCOCC3)c21
Temperature: 50 °C

Procedure:
2,4-Dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (20 mg, 0.066 mmol), triethylamine (18.44 μL, 0.132 mmol) and morpholine (5.75 μL, 0.066 mmol) were mixed in dichloromethane at room temperature and stirred over the weekend at 50° C. The solvent was removed in vacuo to give crude 2-chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] Found 354.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1)[CH3:2].O.[NH2:26][NH2:27]>Cl.CC(O)C>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=[N:26][NH2:27])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: NN
Reactant: CCN(CC)c1ccc2c(c1)C(=O)c1cc(N(CC)CC)ccc1-2
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCN(CC)c1ccc2c(c1)C(=NN)c1cc(N(CC)CC)ccc1-2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2,7-Bis(diethylamino)-9-fluorenone (11.5 g, 35.66 mmol), 50 ml of 2-propanol, 98% hydrazine monohydrate (5.2 ml, 0.11 mol, from Aldrich), and 8 drops of concentrated hydrochloric acid (obtained from Aldrich) were added to a 100 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was refluxed with an intensive stirring until 2,7-bis(diethylamino)-9-fluorenone disappeared (1.5 hours). The reaction mixture was cooled to room temperature to form crystals. The crystals were filtered off, washed first with water, and then with a mixture of 2-propanol and n-hexane to yield 9.5 g (79%) of the hydrazone. The melting point was found to be 150–151° C. (recrystallized from 2-propanol). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.50–7.20 (m, 4H, Ar); 6.82–6.50 (m, 2H, Ar); 7.10 (s, br, 2H, NH2); 7.00 (q, 8H, N(CH2CH3)2); and 3.75 (t, J=7.1 Hz, 12H, N(CH2CH3)2). An elemental analysis yielded the following results in weight percent: C, 74.69; H, 8.28; N, 16.52, which compared with the following calculated values for C21H28N4 in weight percent: C, 74.96; H, 8.39; N, 16.65.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH2:10]1[CH2:14]OC[CH2:11]1>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:11]#[C:10][CH3:14])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C1CCOC1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC#Cc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (10.0 g, 39.5 mmol) in THF (200 mL) was added copper (I) iodide (0.377 g, 1.98 mmol), bis(triphenylphosphine)palladium (II) dichloride (1.39 g, 1.98 mmol) and TEA (16.5 mL, 119 mmol). The reaction mixture was cooled to about 0° C. and degassed with Ar. The reaction mixture was stirred for about 5 min and then the reaction mixture was sparged with propyne and a propyne atmosphere was maintained via balloon. The reaction mixture was stirred for about 30 min at about 0° C. and then was allowed to warm to ambient temperature. The reaction mixture was stirred for about 2 h and then EtOAc (100 mL) and water (100 mL) were added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude mixture was purified by chromatography on silica gel (120 g) eluting with 10-60% EtOAc in DCM (dry loaded) to provide 5-bromo-3-(prop-1-ynyl)pyrazin-2-amine (7.05 g, 84%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 212, 214 (1:1) (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)(=[O:3])[NH2:2].C(Cl)(=O)[C:17](Cl)=[O:18]>C(Cl)CCl>[N:2]([C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3])=[C:17]=[O:18]
Reactant: COC(=O)c1ccc(C(N)=O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)N=C=O)cc1OC
Yield: 63.6 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using methyl 4-carbamoyl-2-methoxybenzoate (1.4 g, 6.69 mmol), oxalyl chloride (0.72 mL, 8.03 mmol) and EDC (10 mL) to afford 1.00 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=3)[CH2:15]2)[N:4]=1.[H][H]>[Ni]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:26])([F:27])[F:25])[CH:20]=3)[CH2:15]2)[N:4]=1
Reactant: [H][H]
Reactant: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1[N+](=O)[O-]
Agent: [Ni]
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1N

Procedure:
A suspension of Raney®-Nickel in a methanolic solution of 5b (0.76 g in 50 ml, 1.98 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.69 g, 1.96 mmol, 99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1[CH:36]=[C:37]([C:41](=[O:43])[CH3:42])[CH:38]=[CH:39][CH:40]=1>CS(C)=O>[C:29]([N:27]1[CH2:26][CH2:25][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=[C:7]([NH:34][C:35]3[CH:36]=[C:37]([C:41](=[O:43])[CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:8]=2[CH2:28]1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)c1cccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CN(C(C)=O)CC3)c1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. 1-(3-aminophenyl)ethanone (9.5 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(3-(6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)phenyl)ethanone (17.5 mg, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:20]([S:22][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:18][OH:19])[CH2:10]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (i.e., a substrate) (11.8 g: 40 mmole) and potassium thioacetate (5.94 g: 52 mmole) in dimethylformamide (120 ml) is stirred at 65° C. for 3.75 hours. The reaction mixture is mixed with ethyl acetate (330 ml), ice water (100 ml), and 1N-hydrochloric acid (20 ml) to adjust the aqueous layer at pH 4. The organic layer is taken, successively washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene-ethyl acetate=2:1) to give (2S,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (9.48 g). Yield: 86%. Pale orange colored oil. NMR δ(CDCl3) ppm: 1.47(s, 9H), 2.34(s, 3H), 2.4 to 3.2(m, 2H), 3.58 to 4.1(m, 6H). IR ν (CHCl3) cm-1 : 3380, 1690.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][S:23][CH2:24][CH2:25][OH:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][S:23][CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(2-hydroxyethylthio)propionamide (prepared as described in Example 11) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[C@@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 18 h
Yield: 29.3 %

Procedure:
In a dry flask (3S,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (43 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL) and then triethylamine (19 μL, 0.14 mmol) and 3-acetylphenylisocyanate (17 μL, 0.12 mmol) were added. After stirring for 18 hours, removed half of the reaction mixture for purification. The remainder of the reaction mixture was taken onto the next reaction without purification. The aliquot was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (17 mg, 57%). 1H NMR (400 MHz, DMSO-d6, 120° C.), δ: 8.64 (s, 1H), 7.94 (m, 1H), 7.57 (d, J=8, 1H), 7.46 (d, J=8, 1H), 7.33 (t, J=8, 1H), 7.17 (m, 2H), 7.00 (t, J=9, 2H), 6.13 (d, J=8, 1H), 4.07 (m, 1H), 3.87 (m, 1H), 3.61 (m, 1H), 3.42 (dd, J=14, J′=4, 1H), 3.32 (m, 1H), 2.98 (m, 2H), 2.70 (m, 1H), 2.50 (m, 1H), 2.49 (s, 3H), 2.02 (m, 1H), 1.73 (m, 3H), 1.53 (m, 1H), 1.39 (s, 9H), 1.22 (m, 2H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3149.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[F:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 17.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-fluorobenzenesulfonyl chloride (0.0280 mL, 0.195 mmol) to obtain 4-(3-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.00740 g, yield 17%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: Oc1ccc(OCCCCCBr)cc1
Reactant: CNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Compound 13a (0.15 g, 0.58 mmol) and compound N-methylaniline (0.07 mL, 0.64 mmol) were stirred in acetonitrile (5 mL) for 30 mins and then diisopropylethylamine (0.24 mL, 1.74 mmol) was added dropwise. The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 13 as a colorless oil (0.05 g, 0.36 mmol, 30% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 285.95. 1H NMR (CDCl3, 400 MHz) δ 7.25 (t, J=8.8 Hz, 2H), 6.70-6.85 (m, 7H), 4.72 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.36 (t, J=7.6 Hz, 2H), 2.95 (s, 3H), 1.85-1.78 (m, 2H), 1.63-1.71 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline(4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 1 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material). Similar results were obtained when the 2,6-lutidine was replaced by 2,4-lutidine (2.15 parts) and 2,4,6-collidine (2.4 parts).
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=C)=[CH:7][N:6]=1)([F:4])[CH3:3].N1C(C)=CC=CC=1C.C1C[O:24]CC1>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:24])=[CH:7][N:6]=1)([F:4])[CH3:3]
Reactant: C=Cc1cnc(C(C)(F)F)nc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(F)(F)c1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
2-(1,1-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) was dissolved in THF (5 ml) and water (2 ml). NaIO4 (571 mg, 2.67 mmol), 2,6-lutidine (143 mg, 0,155 ml, 1.3 mmol) and osmium tetraoxide (138 mg, 0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. 1H NMR showed a mixture of aldehyde and lutidine, which was used directly in the next reaction, (166 mg, 42% yield, 28% pure). 1H NMR (CDCl3 500 MHz): δ 10.24 (s, 1H), 9.30 (s, 2H), 2.12 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27]>>[CH2:32]([O:31][C:29](=[O:30])[CH:28]([C:26]#[N:27])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:3]=1)[CH3:33]
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)c1cccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)c1

Procedure:
In analogy to example 80, step 1, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and ethyl cyanoacetate was prepared the title compound as a light yellow oil, MS (ESI+): m/z=427.2 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([CH2:14][CH:15]=[CH2:16])[CH:10]([OH:13])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O>[I:22][CH2:16][C@H:15]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: C=CCC(OCc1ccccc1)C(O)CO
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: OC[C@H]1O[C@H](CI)C[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A 0° C. solution of 4.5 g of product from Example 333 in 77.8 ml of diethyl ether and 25.5 ml of water is treated with 2.58 g of solid sodium bicarbonate followed by 7.6 g of iodine. The reaction is stirred for 3 hours at 0° C. then at room temperature overnight. The mixture is cooled to 0° C. and sodium sulfite is added until the reaction is colorless. The solution is extracted with diethyl ether, dried and concentrated in vacuo to give 7.0 g of an oil. The oil is purified by chromatography (Silica gel: 5% diethyl ether/hexane) to give 2.8 g of Isomer A and 1.86 g of Isomer B. Isomer A:
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[CH:4]=1)[CH3:2].S(OC)(O[CH3:27])(=O)=O>>[CH2:1]([C:3]1[N:8]([CH3:27])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[CH:4]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Product: CCc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2,4 (1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 72°-74° C.;