Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([N:25]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)C(=O)C(F)(F)F)[CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH2:67]>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O.CO>[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH:67][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH3:8])=[CH:17][C:18]=1[NH:25][CH:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: CN1CCC[C@H]1COc1ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCC[C@H]1COc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid trifluoroacetate (1 mmol, 531 mg) was dissolved in DCM and two drops of anhydrous DMF under nitrogen atmosphere. Oxalyl chloride (0.17 ml, 2 mmol) was added and the mixture was stirred at room temperature for 2 hours. Solvents were evaporated to obtain a yellow powder. The solid was redissolved in THF under an argon atmosphere and cooled at −20° C. DIPEA (0.56 ml, 3.2 mmol) was added. 5-(3,5-Difluorobenzyl)-1H-indazol-3-amine, dissolved in 10 mL of dry THF was then added dropwise in 15′. The reaction mixture was kept at −20° C. for 6 hours then the temperature was allowed to raise at room temperature overnight. The reaction was quenched with 15 mL of NaHCO3 5% and extracted twice with AcOEt (15 ml). Solvents were then evaporated and the residue was redissolved in 20 ml of MeOH. TEA (10 mmol, 1.5 ml) was added and the mixture was heated to 65° C. for 3 hr. Then the reaction was cooled to room temperature and the solvents removed to yield the crude product which was purificated by means of silica gel flash chromatography (AcOEt/MeOH/NH3Aq. 85:15:05) to yield the title compound as a white powder (258 mg, 0.45 mmol, 45%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[OH:18][C:15]1([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:19])[F:20])=[N:4][N:5]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1cccc(Br)c1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Product: N#Cc1cccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 26 %

Procedure:
A mixture of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 3-bromobenzonitrile was allowed to react by the method of Example 315 to give 3-[4-hydroxy-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzonitrile in 26% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1cccc(OC)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(3-methoxyphenyl)indole-3-carboxylic acid ethyl ester (183 mg, 0.46 mmol, see step (b) Example 5) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 170 mg (68%).
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)(C(C)(C)C)(C)C.CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[OH:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH:5]=[O:6])=[C:23]([Cl:28])[CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(Cl)c1
Reactant: N[C@@H](C[SeH])C(=O)O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(O)cc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 42.3 mL, 55 mmol) was added slowly at −78° C. to a solution of intermediate 16, 1-(tert-Butyldimethylsilyl)oxy-3-chloro-5-fluorobenzene (13.1 g, 50 mmol) and TMEDA (8.3 mL, 55 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (4.23 mL, 55 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 12 h. Aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCl was added to attain pH˜3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (7.53 g, 86%, 43 mmol) as a white solid. 1H NMR data (dmso-d6): 11.51 (br.s, 1H, OH), 10.15 (s, 1H, CHO), 6.78-6.83 (m, 1H, H—Ar), 6.68 (dd, 1H, J1=2.2 Hz, J2=12.7 Hz, H—Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Cl)c(N)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 3.6 mmol) in dry CHCl3 (60 mL), NCS (0.411 g, 3.08 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.860 g) as a thick syrup.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) was added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 601.7 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][OH:15])=[O:13])=[CH:4][CH:3]=1.[OH:16]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][OH:15])=[O:13])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(CCCSc1ccc(F)cc1)NO
Reactant: OO
Solvent: CC(=O)O
Product: O=C(CCCS(=O)c1ccc(F)cc1)NO
Reaction time: 1 h

Procedure:
10.5 g (0.046 mol) of 4-(p-fluorophenylthio)-butyrohydroxamic acid dissolved in 45 ml of acetic acid are oxidised with 4.6 ml of hydrogen peroxide of 110 volumes strength. After 1 hour at 50° C, the mixture is left to stand overnight and is then evaporated to dryness in vacuo. The residue is taken up in ethyl acetate and filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Li])[CH:12]([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: [Li]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred solution of 2,4-dichlorobenzaldehyde (2 g, 11.43 mmol) in THF (50 ml) under N2 is added isobutyllithium (7.86 ml, 12.57 mmol) slowly and the reaction is stirred at RT over the weekend. The reaction mixture is added to sat. ammonium chloride (100 ml) and extracted with EtOAc (140 ml). The organic portion is washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica (70 g/150 ml silica-column) eluting with 10% EtOAc/iso-hexane to give (2,4-dichloro-phenyl)-3-methyl-butan-1-ol as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, d, J 8.3), 7.36 (1H, d, J 2.0), 7.29 (1H, dd, J 8.3, 2.0), 5.18 (1H, dd, J 9.2, 3.7), 1.88 (1H, m), 1.61 (1H, ddd, 14.0, 9.2, 4.7), 1.52 (1H, ddd, 14.0, 9.1, 3.7), 1.03 (3H, d, J 6.6), 0.99 (3H, d, J 6.6).
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([OH:30])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:31]O>>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(O)c1
Reactant: CO
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(OC)c1
Yield: 91.6 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-hydroxyphenyl]propanoic acid, methyl ester (500 mg, 1.18 mmol) and methanol (0.096 ml, 2.37 mmol) were reacted under Mitsunobu conditions as described in example 1 and afforded the title compound (471 mg, 81%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:2].CN(C)C[CH2:30][CH2:31][NH:32][C:33]1N=[C:41](NC2CCNCC2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.N1(C2C=CC=CC=2C=O)C=CN=C1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[N:34]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[CH2:41][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[N:17]=3)[CH2:20][CH2:21]2)[CH:30]=[CH:31][N:32]=[CH:33]1
Reactant: CCN(CC)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Reactant: CN(C)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Agent: O=Cc1ccccc1-n1ccnc1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CCN(CC)CCCNc1nc(NC2CCN(Cc3ccccc3-n3ccnc3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 57 mg (0.160 mmol) N2-(3-(diethylamino)propyl)-N4-(piperidin-4-yl)quinazoline-2,4-diamine (prepared analogously to Compound 129) and 2-(1H-imidazol-1-yl)benzaldehyde (28 mg, 0.160 mmol) in MeOH (1 ml) was added NaCNBH3 (10 mg, 0.160 mmol) and ZnCl2 (11 mg, 0.08 mmol), The solution was stirred at room temperature overnight. Solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography using 5% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to produce the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[CH3:30][C:31]1([NH2:42])[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[C:38]([O:37][C:35]([N:33]1[CH2:34][C:31]([CH3:30])([NH:42][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[CH2:32]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Reactant: CC1(N)CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 2.0 g, 4.05 mmol), tert-butyl 3-amino azetidine-1-carboxylate (0.904 g, 4.85 mmol), diacetoxypalladium (0.091 g, 0.405 mmol), Cs2CO3 (2.64 g, 8.10 mmol) and BINAP (0.252 g, 0.405 mmol) in toluene (10 mL) was heated at reflux for 10 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.2 g, 91%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.16 (s, 1H), 5.96 (brs, 1H), 5.13 (q, J=9.2 Hz, 2H), 4.61 (m, 1H), 4.56 (q, J=13.2 Hz, 2H), 4.41 (brs, 1H), 4.04 (m, 2H), 3.95 (d, J=12.4 Hz, 2H), 3.68 (m, 2H), 1.66 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.46 (s, 9H), 0.99 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][NH:25][CH3:26]>C(O)(C)C.O>[CH3:24][N:25]([CH3:26])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(-c3ccco3)nc(Cl)nc21
Reactant: CNC
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Yield: 86 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (488 mg, 1.4 mmol) in isopropanol (5 mL) was treated with 40% dimethylamine in water (1 mL), refluxed for 2 h, concentrated in vacuo and purified by chromatography [SiO2; EtOAc Heptane, (1:1)] to give the title compound (431 mg, 86%) as a white solid.
Reaction SMILES: C([O-])(=O)C.[Na+].S(O)(O)(=O)=O.[CH3:11][S:12][C:13](=[NH:15])[NH2:14].[CH2:16]([O:18][C:19](=[O:34])[C:20]([C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Br:32])=[CH:21]N(C)C)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][C:19]([C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Br:32])=[N:15][C:13]([S:12][CH3:11])=[N:14][CH:21]=1)=[O:34])[CH3:17]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Br
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1-c1ccccc1Br
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a suspension of 3.81 g (46.54 mmol) sodiumacetate and 6.47 g (23.27 mmol) S-methylisothiourea sulfate in 100 ml N,N-dimethylformamide a solution of 6.90 g (21.15 mmol) 2-(2-bromo-benzoyl)-3-dimethylamino-acrylic acid ethyl ester in 20 ml N,N-dimethylformamide was added at once and the resulting reaction mixture was stirred for 16 hrs. at 90°. The solvent was evaporated and the residue distributed between 100 ml CH2Cl2 and 100 ml H2O. The aqueous phase was extracted twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2) to give 5.20 g (69%) 4-(2-bromo-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a pale green oil.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[NH:13][C:12]1=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:35])[CH3:32].O>CN(C=O)C>[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:4](=[C:11]2\[C:12](=[O:30])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:42][CH:43]=1)=[O:35])[CH3:32]
Reactant: CCOC(=C1C(=O)Nc2ccc(NS(=O)(=O)c3ccccc3)cc21)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
0.84 g (2 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone and 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in 10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then water is added while the mixture is cooled with ice and stirred for 1 hour at ambient temperature. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(O)(C)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: [K+]
Solvent: CI
Solvent: CC(C)O
Product: COc1ccc2c(c1)NC(=O)CC2
Yield: 89.5 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3) (16.317 g, 100 mmol) in anhydrous isopropanol (200 mL) was added potassium carbonate (16.585 g, 120.0 mmol) with stirring under an atmosphere of dry N2. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (10.0 mL, 161.3 mmol) was added slowly. The reaction was heated to reflux with stirring for 60 hours, cooled, and the solvent evaporated under reduced pressure. To this residue water (200 mL) was added, and the mixture stirred and sonicated, filtered, and the pale yellow solid was washed with water (1000 mL), and dried under reduced pressure. To the crude dry solid was added 15% ethyl acetate in n-hexane (150 mL), and the mixture sonicated, filtered, washed with n-hexane (50 mL), and dried under reduced pressure, to afford 7-methoxy-3,4-dihydroquinolin-2(1H)-one (15.865 g, 89.5 mmol, 90%), the compound of formula (4). LCMS mz 178.0 (M+H), 200.0 (M+Na), anal HPLC >95% in purity, 1H NMR (400 MHz; dmso-D6) δ 7.09 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.2 and 2.7 Hz, 1H); 6.48 (d, J=2.7 Hz, 1H); 3.78 (s, 2H); 2.90 (t, J=7.0 Hz, 2H); 2.57 (t, J=7.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[C:33]([C:34]([O-:36])=O)=[CH:32][N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[K+].C1C=CC2N(O)N=[N:44][C:42]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:10]([F:20])=[CH:11][C:12]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:13][C:14]=2[F:15])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[C:33]([C:34]([NH:44][CH3:42])=[O:36])=[CH:32][N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4nncc4C(=O)[O-])n3)s2)c(F)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cnnn1Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium 1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazole-5-carboxylate (131 mg, 0.24 mmol), HOBT (72.6 mg, 0.47 mmol), EDC (91 mg, 0.47 mmol), and methylamine hydrochloride (48 mg, 0.71 mmol) were combined in DMF (5.0 mL), and DIEA (124 μL, 0.71 mmol) was added. The reaction was stirred at room temperature overnight. The solution was diluted with water. The precipitate was collected by filtration, washed with water and CH2Cl2, and dried to provide the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:30]([F:29])=[CH:37][C:36]([F:38])=[CH:35][C:34]=3[F:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1c(F)cc(F)cc1F
Product: Fc1cc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4,6 trifluorobenzaldehyde. MS (ESI) m/z 523.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][N:35]([CH3:39])[C:36]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:37]
Reactant: CN(C)C(=O)Cl
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.46 g, 3.3 mmol) and acetonitrile (20 ml) was stirred at room temperature for 20 minutes. Successively N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (20:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.31 g, 77%) as white crystals.