Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(C(=O)C(C)C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added isobutyryl chloride (0.013 mL, 0.124 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, warmed to 23° C. and stirred for an additional 15.5 h. The reaction mixture was concentrated via rotary evaporation and partitioned between EtOAc (4 mL) and NH4Cl (2 mL). The layers were separated and the organic phase was washed with brine (2 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.25 g), and purified via medium pressure chromatography using a 50% to 100% gradient of EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (39.3 mg, 66.9%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.99 (d, J=6.8 Hz, 2.7H), 1.03 (d, J=6.8 Hz, 3H), 1.11-1.22 (m, 6H), 2.58 (br s, 3.8H), 2.69 (t, J=5.4 Hz, 1.2H), 2.88-3.13 (m, 5H), 3.58 (s, 2H), 3.75 (dt, J=10.9, 5.6 Hz, 2H), 4.05-4.17 (m, 1H), 4.41 (s, 1.1H), 4.49 (s, 0.9H), 5.29-5.42 (m, 1H), 7.08 (td, J=8.5, 2.4 Hz, 1H), 7.21 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+F]+ 473.0.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 1-acetyl-4-(4-aminophenyl)piperazine (1.0 g, 4.6 mmol) (from Step B above) in N,N-dimethylformamide (10 mL) was added dropwise to a cooled (−15° C.) solution of thiocarbonyidiimidazole (855 mg, 4.8 mmol) in N,N-dimethylformamide (10 mL). After the addition was complete, the mixture was stirred at −15° C. for 30 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether (4×50 mL). The combined ether layers were washed with brine, dried (MgSO4), filtered, and evaporated to give 1-(acetyl)-4-(4-isothiocyanatophenyl)piperazine (1.0 g, 84%).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C.CCOC(C)=O>[C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH3:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of compound 4b (0.15 g, 0.517 mmol) in DMF (2 mL) was added NaH (60% in mineral, 31 mg, 0.775 mmol) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 30 min and then MeI (0.065 mL, 1.034 mmol) was added. The reaction was allowed to warm to room temperature with continuous stirring for 2 h. To the reaction mixture was added water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 35% EtOAc/hexanes) gave compound 4c (0.12 g). MS m/z (M-Boc+) 204.2.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@:9]([CH3:60])([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1[N:45]1[C:49](C2C=CN=CC=2)=[N:48][CH:47]=[N:46]1)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35].CI>CN(C)C=O>[F:5][C:4]([F:7])([F:6])[C:2]([O-:3])=[O:1].[NH2:8][C@:9]([CH3:60])([C:56]([CH3:59])([CH3:57])[CH3:58])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1[N:45]1[C:49]([CH:4]2[CH:2]=[CH2+:19][CH:12]=[CH:13][N:45]2[CH3:49])=[N:48][CH:47]=[N:46]1)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4C4C=[CH2+]C=CN4C)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid-TFA salt (Example 173, 50 mg, 0.059 mmol) and methyl iodide (0.1 mL, 1.6 mmol) in dimethylformamide (0.2 mL) was blanketed with nitrogen and stirred at room temperature for 2.5 hours. The mixture was evaporated and purified by reverse phase HPLC using a 19×150 mm Sunfire Preparative C18 OBD column (elution with MeCN/water+0.05% TFA). Fractions were evaporated and freeze-dried from a mixture of ethanol and benzene to give the title compound as a TFA salt (40.9 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1Cl
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
A solution of 2-bromo-5-[[(4-chloro-3-methylphenyl)thio](2,5-difluorophenyl) methyl]-4-methylpyridine (2.0 g, 4.4 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.4 ml, 5.3 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (409 μl, 5.3 mmol) was added. After stirring for 30 minutes at the same temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (700 mg, 1.7 mmol, 40%) as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]([C:11]1[NH:12][C:13]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:23])=[C:20](O)[CH:21]=2)[N:15]=1)([CH3:10])[CH3:9].[Cl:30]CCl>CO.C(=O)([O-])O.[Na+]>[Cl:30][C:20]1[CH:21]=[C:16]([C:14]2[N:15]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[NH:12][C:13]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[Cl:23]
Reactant: CS(=O)(=O)Cl
Reactant: ClCCl
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(CNS(C)(=O)=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
A solution of methanesulfonyl chloride (33 mg, 0.3 mmol) in dichloromethane (4 ml) was treated with a solution of Example 3 (103 mg, 0.3 mmol) in methanol (1 ml). The mixture was stirred at room temperature for 2 hours then diluted with dichloromethane and sodium hydrogen carbonate solution. The aqueous layer was then separated and extracted with additional dichloromethane. The combined organic layers were then washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (10:1:0.1) to give the title compound (16 mg, 13%) as a pale yellow solid; MS(ES+) m/e 421/423 [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[N:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:42][C:43]=1[CH3:44])[CH2:12][N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30](O)=[O:31])[C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>ClCCCl.CN(C)C=O>[CH3:44][C:43]1[O:42][C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:40][C:39]=1[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30]([Cl:4])=[O:31])[C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)Cl)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 mL of oxalyl chloride was added to the solution of 10.0 g of (±)-4-{9-[3-methoxy-4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-butyric acid prepared by the example 27 in 1,2-dichloroethane (100 mL), and then 5 drops of N,N-dimethylformamide was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was vacuum concentrated, and (±)-4-(9-(4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxybenzyl)-9H-carbazole-4-yloxy)-2-methylbutanoyl chloride was prepared.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14](F)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].C(N(CC)CC)C>CS(C)=O>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.83 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution (3S)-3-(dimethylamino)pyrrolidine (75 μl, 594 μmol) was added at 150° C. to a dimethyl sulfoxide (8 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (160 mg, 495 μmol) and triethylamine (90 μl, 644 μmol), followed by stirring at the same temperature for 50 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]acetate from Step H (150 mg, 0.46 mmol) in THF (3 mL) and H2O (3 mL) was added 1 N aqueous LiOH (0.55 mL, 0.55 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=300 (M+1).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:39][C:31]1[CH:30]=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:24][CH:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=4)(=[O:8])=[O:9])=[CH:15][CH:14]=3)[CH2:17][CH2:18]2)=[CH:33][C:32]=1[NH:34][S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25, 1-[4-(Toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.12 g (0.5 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.18 g of a white solid; m.p. 115-118° C.; MS (ES) m/z 560.0 (MH+); HRMS (FAB) Calcd. for C27H34N3O6S2 (MH+): 560.1889, Found: 560.1886.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].N.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH2:37])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1nc(-c2cccc(C(N)=O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 25.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added ammonia (2.0 M soln. in isopropanol, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (6 mg, 26%). LC-MS m/z 468 (M+H)+; 1H-NMR (MeOD) δ 2.16 (s, 6H), 2.36 (m, 2H), 3.20 (m, 2H), 4.46 (s, 2H), 7.14 (m, 2H), 7.49 (m, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 8.00 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2C=1N[C:8](=O)[CH2:7]2.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.[CH3:20][N:21]([CH:23]=[O:24])[CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:20]=1[N:21]([CH3:22])[C:23](=[O:24])[C:7]2([CH3:8])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cccc(Br)c2N1
Agent: [Cs+]
Solvent: CI
Product: CN1C(=O)C(C)(C)c2cccc(Br)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-bromo-1,3-dihydro-2H-indol-2-one (200 mg, 0.94 mmol) in DMF (5 mL) were added cesium carbonate (676 mg, 2.07 mmol) and iodomethane (294 mg, 2.07 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then partitioned between H2O (50 mL) and EtOAc (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 85:15, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:26]([C:34]#[N:35])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:14]([NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:32])=[O:31])=[C:26]([C:34]#[N:35])[CH:25]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: N#Cc1cc(Cl)ccc1S(N)(=O)=O
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(Cl)cc1C#N

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-chloro-2-cyanobenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(4-chloro-2-cyanobenzenesulfonyl)-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.04 g (2.35 mmol) of N-(4-chloro-2-cyanobenzenesulfonyl)-N'-(2-carboxy-5-chlorophenyl)urea 31 mg of the above-identified compound (yield 3.3%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):7.32-7.36 (2H,m), 7.99 (1H,d), 8.05 (1H,d), 8.38 (1H,d), 8.54 (1H,s), 12.16 (1H,br).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][C:15](O)=[O:16].C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][CH2:15][OH:16]
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a mixture of NaBH4 (3.60 g, 95.4 mmol) in THF (12 mL) cooled below 10° C. was added a solution of 2-(2,3-difluoro-6-nitrophenyl)acetic acid (10.9 g, 50.2 mmol), as prepared in the preceding step, in THF (4 mL) over a period of 1 hour. To this mixture was added a solution of boron trifluoride diethyl etherate complex (16.5 mL, 131 mmol) in THF (24 mL) over a period of 1 hour, keeping the reaction temperature below 10° C. After the addition the reaction was continued to stir on ice for 15 minutes, and then at ambient temperature for 20 minutes. To a mixture of DCM (180 mL) and H2O (140 mL) was added NaHCO3 (15 g, 179 mmol). The reaction mixture was slowly added to the above NaHCO3 solution and stirred overnight. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound (10.1 g, 99% yield) as light brown oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=9.1, 4.4 Hz, 1H), 7.27-7.18 (m, 1H), 3.95 (t, J=6.3 Hz, 2H), 3.30-3.27 (m, 2H), 1.82 (s, 1H).
Reaction SMILES: P(O)(O)(O)=O.[CH3:6][C@@H:7]1[CH2:19][NH:18][CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].[OH-].[Na+]>O.ClCCl>[CH3:6][C@@H:7]1[CH2:19][N:18]([C:23](=[O:25])[CH3:24])[CH2:17][C@@H:16]2[N:8]1[C:9]1[N:10]=[C:11]3[CH2:22][O:21][CH2:20][C:12]3=[CH:13][C:14]=1[CH2:15]2
Reactant: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COC4
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C[C@H]2Cc3cc4c(nc3N2[C@H](C)C1)COC4
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.33 (5R,8aR)-5-Methyl-1,3,5,6,7,8,8a,9-octahydro-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene dihydrogenphosphate in 4 ml water was added a solution of 1.3 ml acetic acid anhydride in 4 ml dichloromethane and the pH of the mixture was adjusted to 12.00 by addition of 1N aqueous sodium hydroxide. The mixture was stirred at room temperature for 15 minutes. The phases were separated and the organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated to dryness to yield 0.25 g of the title compound as slightly yellow oil (MS: 274.1 (M+H+)).
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1.[CH2:33](N)[CH2:34][NH2:35]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:35][CH2:34][CH2:33][N:32]=5)[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1
Reactant: NCCN
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C#N)c3)ccc21
Agent: O=S(=O)(O)O
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C4=NCCN4)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
H2SO4 (454 mg) was added cautiously to a suspension of 4-[2-(4-chlorophenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile (60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at room temperature for 72 hrs, then poured onto ice/NaHCO3. The solid product was collected, washed (H2O) air-dried 59.8 mg. M/z=419 (M+1).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([SH:10])[N:4]=1.[CH3:11]I>CO>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([S:10][CH3:11])[N:4]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of sodium (1.25 g, 54 mmol, 1.1 equivalents) dissolved in anhydrous methanol (100 mL) was added 4-hydroxy-6-methyl-pyrimidine-2-thiol (7.00 g, 49.2 mmol). The mixture was warmed to ~40° C. and methyl iodide (13.06 mL, 49.2 mmol) was added. The mixture was heated under reflux for 3 hours and then cooled to ambient temperature and allowed to stand overnight. The crystals were filtered, washed with methanol and dried to give 7.10 g (75%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 2.17 (s, 3H), 2.48 (s, 3H), 5.60 (bs, 1H). MS (DCl/NH3) m/e 157 (M+H)+, 174 (M+H+NH3)+.