Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:11]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH2:8])=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetic acid (0.05 mL) was added to a stirred suspension of tert-butyl 4-(3-amino-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 38) (7.0 mg) in DCM (1 mL) under argon at 25° C. The resulting suspension was stirred at 25° C. for 2 days. The reaction mixture was evaporated to dryness to afford the di-TFA salt of 4-amino-N-(3-amino-1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a partially solid oil (13.0 mg).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].N1CCCC1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30]>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:31][C:29]1[N:30]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:6][C:5]=2[N:28]=1
Reactant: N=C(N)N
Reactant: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: O=C(O)O
Solvent: ClC(Cl)Cl
Solvent: C1CCNC1
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 25 °C

Procedure:
To a stirred solution of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (200 mg, 0.80 mmol) from stage 1, in chloroform was added pyrrolidine (68 mg, 0.96 mmol). The reaction mixture was stirred at ambient temperature and monitored by TLC until complete disappearance of 2-acetyl-5-(4-fluoro-phenyl)cyclohexane-1,3-dione. The reaction mixture was washed with water (10 ml) and the solvent was removed under reduced pressure to give a solid m=229 mg, mass spectrum (ES-MS (+ve)) 302 [MH]+, Retention time 1.44 min, 100% UV. To a stirred solution of this solid (229 mg, 0.76 mmol) in dioxane (2.5 ml) was added guanidine carbonate (504 mg, 2.8 mmol) and the mixture heated at 100° C. and stirred for 16 h. 1,4-Dioxane was removed by evaporation under reduced pressure, water (5 ml) was added and the resulting precipitate was filtered, washed with water and heptane and air dried.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][S:12][CH:13]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][S:12][CH:13]=1)=[N+:15]=[N-:16]
Reactant: BrCc1ccccc1-c1csnn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccccc1-c1csnn1

Procedure:
A solution of 4-(2-bromomethyl-phenyl)-[1,2,3]thiadiazole (7.0 g, 0.027 mol) and sodium azide (5.3 g, 0.081 mol) in N,N-dimethylformamide (200 ml) was stirred at room temperature overnight. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave an oil; flash chromatography (silica gel, hexane-ethyl acetate, 96:4) gave 4-(2-azidomethyl-phenyl)-[1,2,3]thiadiazole; 1H NMR (CDCl3, 300 MHz) δ 8.74 (s, 1H), 7.76 (m, 1H), 7.53 (m, 3H), 4.54 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[C:7]2[S:28][CH:27]=[CH:26][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1.C([O-])(O)=O.[Na+].[O:37]1C[CH2:40][CH2:39][CH2:38]1.C(Cl)(=O)C=C>O>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]3[N:11]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:38](=[O:37])[CH:39]=[CH2:40])[CH:31]=[CH:30][CH:29]=4)[C:7]4[S:28][CH:27]=[CH:26][C:8]=4[N:9]=3)=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: C1CCOC1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3ccsc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
The compound (3.69 mmol) obtained in Step 5 and NaHCO3 (11.07 mmol) were distilled with tetrahydrofuran (40 mL) and distilled water (6 mL), and acryloyl chloride (3.69 mmol) was added thereto slowly at 0° C. with stirring for 15 min. After the reaction was complete, the reaction mixture was distilled with dichloromethane and then washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure, and the residue was separated by column chromatography (chloroform:methanol=20:1 (volume ratio)) to obtain the title compound (yield: 68.2%).
Reaction SMILES: C([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([CH3:17])=[N:9][CH:8]=1)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[CH3:17][C:10]1[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:12][C:7]([C:6]([OH:18])=[O:5])=[CH:8][N:9]=1
Reactant: Cc1ncc(C(=O)OC(C)(C)C)cc1CC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)O)cc1CC(C)C
Reaction time: 3 h

Procedure:
A solution of 6-methyl-5-isobutyl-nicotinic acid tert.-butyl ester (0.50 g, 2 mmol) is dissolved in dioxane (20 mL) and 4 N HCl in dioxane (30 mL) is added. The mixture is stirred for 3 h. The solvent is evaporated to give 6-methyl-5-isobutyl-nicotinic acid hydrochloride (0.52 g); LC-MS: tR=0.54 min; [M+1]+=194.29; 1H NMR (d6-DMSO) δ 0.91 (d, J=6.5 Hz, 6H), 1.91 (hept, J=6.5 Hz), 2.68 (d, J=7.3 Hz, 2H), 2.73 (s, 3H), 8.47 (d, J=1.8 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(CC)CC.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCCCCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of methyl-9-hydroxy-nonanoate (0.838 g, 4.46 mmol, 1.0 equiv: Aldrich) in CH2Cl2 (15 mL, 0.3 M) was treated successively with Et3N (0.75 mL, 5.38 mmol, 1.2 equiv), t-butylchlorodiphenylsilane (1.28 mL, 4.93 mmol, 1.1 equiv), and DMAP (0.180 g, 1.48 mmol, 0.33 equiv), and the reaction mixture was stirred at 25° C. for 12 h. Saturated aqueous NH4Cl was added to the reaction mixture and the mixture was partitioned between CH2Cl2 (100 mL) and H2O (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, 0-5% EtOAc-hexanes gradient elution) afforded the intermeidate as a clear, colorless oil (1.22 g, 1.831 theoretical, 64.1%): 1H NMR (CDCl3, 250 MHz) δ 7.66 (m, 4H, ArH), 7.38 (m, 6H, ArH), 3.67-3.62 (m, 5H, C(O)OCH3 and CH2OTBDPS), 2.30 (t, 2H, J=7.4 Hz, CH2C(O)OCH3), 1.58 (m, 4H, CH2CH2OTBDPS and CH2CH2C(O)OCH3), 1.28 (b s, 8H, alkyl protons), 1.05 (s, 9H, C(CH3)3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:4]2[CH:3]=1.[OH2:20].[C:21]1(C)C=C[C:24](S(O)(=O)=O)=[CH:23][CH:22]=1>C(O)CCC>[CH2:21]([O:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:4]2[CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccccc32)n1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CCCCOc1cc2nc(C(=O)OCC)cn2c2ccccc12

Procedure:
A mixture of ethyl 5-chloroimidazo[1,2-a]quinoline-2-carboxylate 2.75 g. (0.01 mole) and 40 mg. of p-toluenesulfonic acid monohydrate in 150 ml. of n-butanol is heated at 100° C. for 18 hours. The butanol is then removed under reduced pressure. The residue is dissolved in a small amount of chloroform and chromatographed on a silica gel column. The fractions containing the title compound are combined and evaporated to dryness. The product can be further purified by crystallization.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Li+].[OH-]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The title compound 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29) was prepared by the following procedure: To methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (291) (23 mg, 0.044 mmol) in MeOH (0.55 mL) and water (0.11 mL) was added an aqueous solution of LiOH (0.066 mL of 2.0 M, 0.13 mmol). The reaction mixture was stirred at rt for 15 hours, concentrated under reduced pressure to remove MeOH and diluted with water. The pH was adjusted to ˜4 with 2 M HCl, and the resulting precipitate was isolated by filtration and washed with water. The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 98:2-92:8, to provide the desired product 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29): MS (ESI(+)): m/z 507.1 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2>O1CCCC1.N1CCCCC1>[F:22][C:14]1[CH:15]=[C:16]2[C:20](=[C:12]([NH:11][CH:1]=[O:3])[CH:13]=1)[NH:19][C:18](=[O:21])[CH2:17]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Solvent: O=CO
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: O=CNc1cc(F)cc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A solution of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and added with 7-amino-5-fluoro-1,3-dihydro-indol-2-one (2.0 g, 12 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran and piperidine (0.02 ml). The resulting mixture was stirred for 3 hours at room temperature until a precipitate was formed. The solid was filtered and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide (700 mg, 30.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1.[CH3:24][CH:25]([CH3:27])[O-:26].[Na+]>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH:25]([CH3:27])[CH3:24])[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1
Reactant: CC(C)[O-]
Reactant: COc1cc(-c2nc(N)nc(SC)c2C#N)cc(OC)c1OC
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc(-c2nc(N)nc(OC(C)C)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methylsulfanyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and sodium isopropoxide in isopropanol. ES-MS m/e (%): 367 (M+Na+, 20), 345 (M+H+, 78), 303 ([M+H—C3H6]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)/C=C/c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Under nitrogen, to a solution of (2E)-3-(3-hydroxyphenyl)-2-propenoic acid (330 mg, 2.0 mmol) in THF (20 mL), was added 1-methylpiperazine (400 mg, 4.0 mmol), HOBT (810 mg, 6.0 mmol), HBTU (760 mg, 2 mmol), followed with 4-methylmorpholine (670 μL, 6.0 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→60% MeCN/H2O) to afford the title compound as a white solid (397 mg, 81%). MS (S+) m/e 247 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH:6]=1)=[CH2:2].C(O)C.O>O1CCCC1>[CH:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)=[CH2:2]
Reactant: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.3 %

Procedure:
—Sodium borohydride (8.54 g) was added to a solution of (7α)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (8.72 g) in a mixture of tetrahydrofuran (161 ml), ethanol (161 ml), and water (26.4 ml). The reaction mixture was stirred at room temperature for 50 min. and then poured into water. The product was extracted into ethyl acetate; the combined organic phases were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (7α,17β)-7-ethenyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (8.45 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16][CH2:15]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:26]([O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:19]3)[O:9]2)=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(O)ccc3c(=O)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Yield: 96.4 %

Procedure:
A solution of 7-hydroxy-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (250 mg, 0.73 mmol) obtained in Example 34-1, benzyl bromide (260 μL, 3.64 mmol), and potassium carbonate (503 mg, 3.64 mmol) in dimethylformamide (4 mL) was stirred at room temperature for 26 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue. Then, the supernatant was removed by decantation to obtain 305 mg of the title compound (yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(#N)C>O>[CH2:12]([S:19][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: SCc1ccccc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1cc(SCc2ccccc2)n2nccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (4.1 g, 22 mmol) was added along with benzyl mercaptan (2.8 mL, 22 mmol), triethylamine (3.1 mL, 22 mmol), and acetonitrile (71 mL). The reaction was stirred at room temperature for 3 hours then diluted with water, filtered and washed with water. The product, 7-(benzylthio)-5-chloropyrazolo[1,5-a]pyrimidine, was collected as a solid in 96% yield after drying under vacuum overnight. LCMS (M+1=276)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:17][C:18]1[N:19]=[C:20]([C:26]2S[CH:28]=[CH:29][CH:30]=2)S[C:22]=1[C:23](=O)[CH3:24].[NH3:31]>>[CH3:17][C@@H:18]1[CH2:22][CH2:23][CH2:24][N:19]1[CH2:20][CH2:26][C:30]1[CH:1]=[C:4]2[C:9](=[CH:28][CH:29]=1)[N:31]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]3)=[CH:6][CH:5]=1)[CH:2]=[CH:5]2
Reactant: N
Reactant: CC(=O)c1ccc(-n2ccc(=O)cc2)cc1
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3ccc(-n4ccc(=O)cc4)cc3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-(4-acetyl-phenyl)-1H-pyridin-4-one for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, J=6.10 Hz, 3H), 1.49 (m, 1H), 1.78 (m, 2H), 1.95 (m, 1H), 2.27 (m, 1H), 2.43 (m, 2H), 3.05 (m, 2H), 3.16 (m, 1H), 3.31 (m, 1H), 6.54 (d, J=7.80 Hz, 2H), 7.49 (d, J=8.48 Hz, 2H), 7.66 (m, 4H), 7.87 (d, J=8.81 Hz, 1H), 8.10 (d, J=8.48 Hz, 1H), 8.22 (d, J=8.48 Hz, 1H), 8.33 (d, J=8.48 Hz, 2H); MS (DCI-NH3) [M+H]+ at 410.
Reaction SMILES: [Li].[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:6]=[C:7]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:8]=[N:9][CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([NH:54][NH2:55])[CH:50]=[CH:51][C:52]=1[F:53]>>[Cl:46][C:47]1[CH:48]=[C:49]([N:54]2[C:11]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([O:4][C:3]([F:2])([F:21])[F:22])[CH:6]=3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[N:55]2)[CH:50]=[CH:51][C:52]=1[F:53]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC(F)(F)F)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.13 g (3.25 mmol) of the compound of Example 18A is reacted analogously to the synthesis of the compound of Example 20A with 961 mg (4.88 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 576 mg (44% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)C(OC)=O.[CH3:15][Mg]Br.[Cl-].[NH4+].CC[O:22][CH2:23][CH3:24]>>[F:14][C:9]1[CH:8]=[C:7]([CH:2]([NH2:1])[C:23]([CH3:24])([OH:22])[CH3:15])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CCOCC
Reactant: COC(=O)C(N)c1ccc(F)c(F)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)C(N)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
Into a well-stirred solution of methyl 2-amino-2-(3,4-difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0° C. a solution of methylmagnesium bromide (3 M, 87 mL, 261 mmol) in ether was added over 10 minutes. The reaction mixture was stirred at 0° C. for 2.5 h and allowed to warm to room temperature. After 12 h, the reaction mixture was carefully poured onto a mixture of ice (300 g) and saturated aqueous ammonium chloride (50 g). The ether layer was separated and the aqueous layer was extracted with more ether (4×200 mL). The combined extracts were dried with magnesium sulfate and the solvent evaporated. The crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10, 1000:40:20, 1000:80:40) as the eluent to give the product as an oil (6.5 g, 62% yield) which was used in the next step without further purification.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[CH:9]=O)=[N:3]1.OS(O)(=O)=O.O.[NH2:24]N.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[C:8]2[C:7](=[CH:14][CH:13]=1)[C:4](=[O:5])[NH:3][N:24]=[CH:9]2
Reactant: NN
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A solution of 2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-benzaldehyde (2 g, 8.58 mmoles), prepared as described in example 2, in 30 ml of a mixture of water (5 ml), ethanol (50 ml) and concentrated H2SO4 (4 ml) up to 100 ml with ethanol, was stirred under reflux for 20 hours, then concentrated to small volume, taken up in water, extracted with ethyl ether and the organic phase was washed with water, anhydrified and brought to dryness. The resultant oil was dissolved in acetic acid (14 ml) and dropwise added, under N2, with hydrazine monohydrate (1.25 ml, 25.7 mmoles) dissolved in acetic acid (6 ml). The mixture was stirred for 3.5 hours at room temperature, then at 80° C. for 4 hours, then cooled, brought to almost complete dryness, taken up in water, neutralised with NaHCO3, extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and concentrated. The residue was triturated in CH2Cl2 (10 ml) and filtered to give 1.1 g of the title compound (yield: 73.4%). m.p.: 200-205° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([C:17](=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O1CCCC1>[C:11]1([C:17](=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][C:27]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CCCC(N=C(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N=C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a flask, lithium bis(trimethylsilyl)amide (LHMDS) (1M) in THF (2.83 mL, 2.83 mmol) was added to tetrahydrofuran (10 mL). The reaction mixture was cooled to −78° C., and then a solution of methyl 3-(diphenylmethyleneamino)cyclohexanecarboxylate (700 mg, 2.18 mmol) and tetrahydrofuran (1 mL) was added drop-wise to the reaction mixture at −78° C. The reaction was stirred at −78° C. for 30 minutes. Afterwards, 4-fluorobenzylbromide (0.402 mL, 3.27 mmol) was added, and the reaction was stirred for an additional 24 hours at 0° C. Upon reaction completion, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried with sodium sulfate, and concentrated to yield crude product. The crude product was progressed to the next step without further purification.