Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])=[O:4].[O:27]1CC[CH2:29][CH2:28]1>CO>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]([OH:20])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:28](=[O:27])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]=2[CH:12]=1)#[N:17]
Reactant: C1CCOC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Solvent: CO
Product: CC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1

Procedure:
To a solution containing (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide (340 mg, 0.97 mmol; isomer A of the title compound of Example 2) in tetrahydrofuran (10 mL, a few drops of methanol were added to obtain a clear solution) at room temperature was slowly added excess acetyl chloride while maintaining the reaction at pH ~8.5 by simultaneous addition of 7% sodium carbonate solution. After the completion of the reaction, it was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide a colorless solid (320 mg, 84.2%) which was recrystallized from hot 2-propanol to give (3S-trans)-N-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl )amino]-2-oxo-1-phenylethyl]acetamide, mp 234°-236° C. Analysis calculated for C22H23N3O4.0.2H2O: C, 66.55; H, 5.94; N, 10.58. Found: C, 66.71; H, 5.58; N, 10.56. [α]D =-91.2° (c =0.5, MeOH).
Reaction SMILES: NC1C2C(C3C=CC(N[C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=C(OC)C=3)=CSC=2C(C#CCCCCN2C(=O)C3C(=CC=CC=3)C2=O)=CN=1.[OH2:49].NN>C(O)C>[CH3:29][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:20]1[C:18]([OH:19])=[O:49]
Reactant: COc1cc(-c2csc3c(C#CCCCCN4C(=O)c5ccccc5C4=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O
Agent: NN
Solvent: CCO
Product: Cn1c(C(=O)O)cc2ccccc21
Temperature: 50 °C
Reaction time: 15 h
Yield: 33.6 %

Procedure:
A solution of N-(4-{4-amino-7-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hex-1-ynyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.078 g, 0.119 mmol) in ethanol (5 mL) was treated with hydrazine monohydrate (0.048 g, 0.955 mmol). The reaction mixture was stirred for 15 hours at 50° C. The solvent was removed under reduced pressure. The compound was purified by preparative HPLC to afford 0.007 g (10%) the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.463 (s, 1H), 8.05-7.98 (m, 1H), 7.94 (s, 1H), 7.65-7.6 (m, 1H), 7.561-7.519 (m, 2H), 7.304-7.265 (m, 2H), 7.124 (s, 1H), 7.104-7.084 (m, 1H), 7.046-7.021 (m, 1H), 5.736 (brs, 2H), 3.99 (s, 3H), 3.867 (s, 3H), 2.7-2.6 (m, 2H), 2.58-2.5 (m, 2H), 1.6 (m, 4H); LCMS (Conditions a) Rt 3.45 min (95%), M+ 524.6.
Reaction SMILES: Br[C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.[N:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[C:8]([C:6]1[N:7]=[C:2]([C:47]2[CH:48]=[CH:49][N:44]=[CH:45][CH:46]=2)[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: OB(O)c1ccncc1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(-c5ccncc5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Under an argon atmosphere, to a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (300 mg), pyridin-4-ylboronic acid (196 mg), and N-methylpyrrolidone (6 mL) were added tetrakistriphenylphosphine palladium (0) (79 mg) and a 2 M aqueous sodium carbonate solution (797 μL), followed by stirring at 100° C. for 4 hours. After leaving to be cooled, ethyl acetate and water were added thereto, followed by stirring, and then the insoluble matter was separated by filtration. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-150:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(pyridin-4-yl)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (222 mg) as a yellow solid.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([OH:45])=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:46][CH:47]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48]2)[CH:27]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH2:2])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:46][CH:47]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48]2)[CH:27]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c12
Temperature: 25 °C

Procedure:
HATU (147 mg) was added at 0° C. to a mixture of 4-(4-fluoro-2-(3-hydroxycyclopentyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxilic acid (130 mg) and DIPEA (67 μl) in DMF (2.0 ml). After 30 min 7 M NH3 in MeOH (1.0 ml) was added and the mixture was allowed to warm to room temperature over weekend. The reaction mixture was concentrated in vacuo. The residue was treated with hot MeOH. The mixture was allowed to cool, then it was filtered to yield the desired product.
Reaction SMILES: C(O[C:6](=[O:36])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[C:59]([C:61]1[CH:69]=[C:68]([CH3:70])[C:64](C(O)=O)=[C:63]([CH3:71])[N:62]=1)#[N:60].CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[C:59]([C:61]1[CH:69]=[C:68]([CH3:70])[C:64]([C:6]([NH:7][CH2:8][CH2:9][C@H:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=3)[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)[CH3:11])=[O:36])=[C:63]([CH3:71])[N:62]=1)#[N:60]
Reactant: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1cc(C#N)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C#N)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
(R)-(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.070 g, 0.14 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting brown oil dried in vacuo (high vacuum system) for 2 h. The resulting amine, EDCI (0.030 g, 0.16 mmol) and HOBT (0.021 g, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 6-cyano-2,4-dimethyl-nicotinic acid hydrochloride (0.033 g, 0.16 mmol) followed by DIPEA (163 μL, 0.94 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 6-cyano-N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.041 g, 52%) as a white foam. 1H NMR (CDCl3) δ 0.89 (m, 1H), 0.99 (d, 3H, J=6.0 Hz), 1.08 (m, 1H), 1.53 (m, 1H), 1.74 (m, 3H), 2.11 (br t, 1H), 2.41 (s, 3H), 2.51 (br t, 1H), 2.57 (s, 3H), 2.72 (m, 1H), 2.84 (m, 2H), 3.29-3.38 (m, 2H), 3.73 (s, 3H), 3.84 (m, 1H), 3.97 (s, 2H), 6.65 (d, 2H, J=9.0 Hz), 6.77 (d, 2H, J=9.0 Hz), 7.46 (d, 1H, J=6.0 Hz), 7.52 (s, 1H), 7.53 (d, 1H, J=9.0 Hz), 7.73 (t, 1H, J=9.0 Hz), 8.56 (br s, 1H). ES-MS m/z 552 (M+H), 574 (M+Na). Anal. Calcd. for C32H37N7O2.0.2 CH2Cl2: C, 68.01; H, 6.63; N, 17.24. Found: C, 67.79; H, 6.69; N, 17.11.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]1([O:23][CH2:22]1)[CH3:21]>CN(C=O)C>[OH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:12])=[CH:6][CH:7]=1
Reactant: CC1(C)CO1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Methyl(4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) was dissolved in DMF (3 mL). K2CO3 (829 mg, 6.0 mmol) was added followed by isobutylene oxide (800 μL, 9.0 mmol). The mixture was heated to 150° C. by microwave irradiation for 30 min and concentrated. The residue was dissolved in a 1:1 mixture of methanol and water (20 mL). NaOH (1 g) was added and the mixture was stirred for 30 min. Methanol was removed by rotary evaporation. The aqueous phase was acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were extracted with 2 M NaOH (2×50 mL). The combined aqueous phases were subsequently acidified by 4 M HCl and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to afford [4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid (106MBT52-D, 470 mg, 70%) as a colourless solid. 1H-NMR (CDCl3): δ 7.19 (m, 2H), 6.88 (m, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 1.34 (s. 6H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:32][C:17]3[C:18](=[O:31])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=4)[CH:20]=[CH:21][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.[CH3:33][N:34]1[C:39](=[O:40])[CH2:38][O:37][CH2:36][C@H:35]1[CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CC#N>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:32][C:17]3[C:18](=[O:31])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:41][C@@H:35]5[CH2:36][O:37][CH2:38][C:39](=[O:40])[N:34]5[CH3:33])=[C:24]([O:29][CH3:30])[CH:23]=4)[CH:20]=[CH:21][C:16]=3[CH:15]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCC(=O)N2C)cc1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@@H]1COCC(=O)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add Cs2CO3 (339 mg, 1.04 mmol) to a slurry of 2-(4-chloro-phenyl)-6-(4-hydroxy-3-methoxy-phenyl)-6H-thieno[2,3-c]pyridin-7-one, (Preparation 47) (200 mg, 0.522 mmol), in 10 mL CH3CN (10 mL). Stir 1 h and then add toluene-4-sulfonic acid (S)-4-methyl-5-oxo-morpholin-3-ylmethyl ester (172 mg, 0.57 mmol). Warm to reflux overnight. Cool to RT, pour into 1 M NaOH (100 mL) and extract with CH2Cl2 (3×100 mL). Wash the combined organic extracts with brine (100 mL). Purify via silica gel chromatography using 0-5-20% (2 N NH3 in MeOH)/CHCl3 to give 41 mg of product that is 86% pure. Recrystallize from CH2Cl2/hexanes to give 28 mg of the desired product in good purity. MS/ES m/z (35Cl) 511.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:9][CH:8]=[N:7][C:6]=2[N:29]=1>C(O)(=O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([S:21][C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[C:12]([NH:11][C:10]2[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[N:29][C:6]=3[N:7]=[CH:8][N:9]=2)[CH:17]=1
Reactant: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(N)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.3 %

Procedure:
A slurry of the product from Example 86A (0.19 g, 0.469 mmol) and 10% Pd/C (0.025 g) in acetic acid (3 ml) was placed under a hydrogen atmosphere with stirring for 2 hr at room temperature. The slurry was filtered and the solvent removed under vacuum leaving a brown solid as an acetate salt of the title compound (0.21 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])[O:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=O.[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[N+:47]([C:50]1[CH:55]=[C:54]([N+:56]([O-:58])=[O:57])[CH:53]=[CH:52][C:51]=1[NH:59][CH2:60][CH2:61][NH2:62])([O-:49])=[O:48]>CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])[O:5][CH2:6][CH2:7][CH2:8][C:9]([NH:62][CH2:61][CH2:60][NH:59][C:51]1[CH:52]=[CH:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][C:50]=1[N+:47]([O-:49])=[O:48])=[O:11]
Reactant: NCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Nc1cc(OCCCC(=O)[O-])ccc1C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(OCCCC(=O)NCCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium 4-(3-amino-4-formylphenoxy)butanoate (50 mg), HBTU (80 mg) and DMF (2 mL) were combined in a 20 mL glass vial and stirred at ambient temperature. After 30 minutes, N1-(2,4-dinitrophenyl)ethane-1,2-diamine (Oakwood, 45 mg) was added in one portion and the reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc, washed successively with dilute aq. citric acid, water, sat. aq.NaHCO3, water, and sat. aq.NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound as a yellow solid. Rf: 0.18 (SiO2, EtOAc). MS (ESI+): m/z 432.20 (MH+). H-NMR (400 MHz, DMSO-d6): 1.914 (2H, quint, J=7.0 Hz), 2.224 (2H, t, J=7.0 Hz), 3.349 (2H, q, J=6.0 Hz), 3.538 (2H, q, J=6.0 Hz), 3.928 (2H, t, J=6.4 Hz), 6.165 (1H, s), 6.176 (1H, dd, J=2.4, 10.0 Hz), 7.133 (1H, br.s), 7.268 (1H, d, J=10.0 Hz), 7.371 (1H, d, J=8.4 Hz), 8.167 (1H, t, J=5.8 Hz), 8.250 (1H, dd, J=2.8, 8.8 Hz), 8.835 (1H, d, J=2.8 Hz), 8.913 (1H, t, J=5.6 Hz), 9.599 (1H, s). C-NMR (100 MHz, DMSO-d6): 24.489, 31.436, 37.331, 42.745, 66.782, 98.040, 104.339, 112.751, 115.130, 123.472, 123.564, 129.725, 134.731, 137.484, 148.305, 152.824, 163.873, 172.251, 191.400.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[C:15]3[O:14][C:13]([F:17])([F:16])[O:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N+:18]([O-])=O)=[N:4][NH:5][CH:6]=1.Cl.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:7]2[C:15]3[O:14][C:13]([F:16])([F:17])[O:12][C:11]=3[CH:10]=[CH:9][C:8]=2[NH2:18])=[N:4][NH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1-c1n[nH]cc1Cl)OC(F)(F)O2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc2c(c1-c1n[nH]cc1Cl)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
6.0 g (0.02 mol) of 4-chloro-3-(2,2-difluoro-5-nitrobenzo-1,3-dioxol-4-yl)pyrazole, in solution in 60 ml of ethanol, are run, at room temperature, onto a mixture of 30 ml of 36% HCl and 20.2 g (0.09 mol) of SnCl2 2H2O in 60 ml of ethanol. The reaction mixture is stirred for 2 h at room temperature, neutralised with 10% NaOH and then filtered. The insoluble material is washed with ethanol. The alcohol phase is concentrated under reduced pressure and the residue is taken up in ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 4.6 g of 4-chloro,3-(5-amino,2,2-difluorobenzo-1,3-dioxol-4-yl)pyrazole melting at 195° C. (yield 84%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]1([C:22]([NH:24][NH2:25])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:25]/[NH:24][C:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:23])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)c1cccc2ccccc12
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2cccc3ccccc23)c2ccccc21
Yield: 58 %

Procedure:
The title compound was prepared using isatin 3 and 1-naphthhydrazide according to the synthetic method E. The product was purified by flash chromatography (eluent: AcOEt/Heptane:3/7) to afford a yellow oil which crystallized. Yield: 58%. 1H NMR (DMSO-d6): δ 0.83 (t, J=6.9 Hz, 3H), 1.26 (m, 6H), 1.59-1.62 (m, 2H), 3.73 (t, J=6.9 Hz, 2H), 7.17-7.23 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 7.63-7.70 (m, 3H), 7.90 (d, J=6.6 Hz, 1H), 8.07 (t, J=6.6 Hz, 1H), 8.19 (d, J=8.7 Hz, 1H), 8.35 (br s, 1H), 13.51 (br s, 1H). 13C NMR (DMSO-d6): δ 14.29 (CH3), 22.39 (CH2), 26.32 (CH2), 27.34 (CH2), 31.27 (CH2), 39.50 (CH2), 110.61 (CH), 119.61 (C), 121.22 (C), 123.65 (CH), 125.36 (CH), 125.51 (CH), 126.83 (CH), 127.20 (CH), 128.03 (CH), 129.04 (CH), 130.34 (C), 131.26 (C), 132.26 (CH), 133.82 (C), 143.49 (C═N), 161.34 (C═O). HRMS (ES+) calcd for C25H26N3O2 (M+H+), m/e, 400.2033. found, 400.2020.
Reaction SMILES: C(#N)C.N(OC(C)(C)C)=O.N[C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:16]=1.C(Cl)(Cl)[Cl:24].CCCCCC>[Cu](Cl)Cl>[Cl:24][C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:16]=1
Reactant: CCCCCCc1csc(N)n1
Reactant: ClC(Cl)Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CCCCCC
Solvent: CC#N
Product: CCCCCCc1csc(Cl)n1
Reaction time: 2 h

Procedure:
To 200 mL of acetonitrile was added 9.7 mL (81 mmol) of t-butyl nitrite and 8.75 g (65.1 mmol) of copper(II) chloride, and 10 mL of acetonitrile containing 10.0 g (54.3 mmol) of 2-amino-4-hexylthiazole (Helvetica Chemica Acta XXXII, Fasciculus I, 35 (1949)) dissolved therein was added to this portion-wise while cooling with ice under an argon atmosphere and the temperature thereof was returned to room temperature and the mixture was stirred for 2 hours. Then, the resultant reaction mixed liquid was poured into 100 ml of chloroform/hexane mixed liquid, and the precipitate was removed by filtration. The filtrate was washed with 100 ml of a 20 wt % hydrochloric acid aqueous solution three times, then, extracted with chloroform. The resultant extraction liquid was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, and purified by silica gel column chromatography (development solvent:chloroform/hexane=1/1 (volumetric ratio)), to obtain the intended 2-chloro-4-hexylthiazole.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:32][C:33](=[O:45])[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38](Br)[CH:37]=1)[CH3:35])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:54]([O:61][C:62]([N:64]1[CH2:73][CH2:72][C:71]2[C:66](=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:68]=[CH:69][C:70]=2[F:74])[CH2:65]1)=[O:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:61][C:62]([N:64]1[CH2:73][CH2:72][C:71]2[C:66](=[C:67]([C:38]3[CH:37]=[C:36]([CH:34]([C:33]([O:32][CH2:30][CH3:31])=[O:45])[CH3:35])[CH:41]=[CH:40][C:39]=3[O:42][CH3:43])[CH:68]=[CH:69][C:70]=2[F:74])[CH2:65]1)=[O:63])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture under N2 of palladium(II)acetate (1.2 mg, 5 μmol, 0.02 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.2 mg, 0.01 mmol, 0.04 eq.), (±)-2-(3-bromo-4-methoxy-phenyl)-propionic acid ethyl ester (80 mg, 0.26 mmol, 1 eq.) and potassium phosphate (109 mg, 0.51 mmol, 2 eq.) in toluene (1.9 mL) and water (0.2 mL) was stirred at r.t. during 2 min. 5-Fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (147 mg, 0.26 mmol, 1 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., diluted with Et2O (10 mL), filtered through celite, washed with Et2O, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:32])[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)=[O:20])=[CH:10]2)=[CH:6][CH:5]=1.Cl[C:36]([O:38][CH3:39])=[O:37].CCCCCCC.C(OCC)(=O)C>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:32])[C:19]([N:21]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[CH:27][CH:26]=[CH:25]4)[C:36](=[O:37])[O:38][CH3:39])=[O:20])=[CH:10]2)=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc2ncccc2c1)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12)c1ccc2ncccc2c1
Temperature: 0 °C

Procedure:
930.2 mg (27.3 mMol) of NaH (as a 60% strength dispersion in mineral oil) are added, under nitrogen, to a cooled, stirred solution of 10.0 g (22.7 mMol) of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinolin-6-ylacetamide in 500 ml of dry THF. The solution is stirred at 0° C. until a yellow precipitate separates out and, after that, stirred for a further 15 minutes. After that, 2.58 g (27.3 mMol) of methyl chloroformate are added dropwise at a temperature below +5° C. The reaction is monitored by thin layer chromatography (eluent: n-heptane/ethyl acetate 1/1 RF=0.11). The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate; the organic phase is washed with a saturated solution of sodium chloride and dried over anhydrous MgSO4. Evaporating off the solvent yields a crude product, which is purified by column chromatography (n-heptane/acetone 2/1) in order to give 3. Thin layer chromatography shows that 3 still contains slight impurities, which can be removed by stirring the crude 3 with acetone for 1 h. Filtration yields 3 as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:21][CH3:22])=[C:4]([F:23])[CH:3]=1.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[H-].[Na+]>CN(C)C=O>[C:24]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:21][CH3:22])[C:4]([F:23])=[CH:3][C:2]=1[Cl:1])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(=O)Oc1cc(-n2c(OC)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and acryloyl chloride with sodium hydride in dimethylformamide there is obtained {2-chloro-4-fluoro-5-[5-fluoro-2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-phenyl} acrylate, 1H-NMR (CDCl3, 400 MHz): 7.42 ppm d,1H), 7.21 ppm (d,1H), 6.68 ppm (q,1H), 6.35 ppm (q,1H), 6.12 ppm (q,1H), 4.00 ppm (s,3H);