Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:35][C:36]1[N:40](C(OC(C)(C)C)=O)[C:39]2[CH:48]=[CH:49][CH:50]=[CH:51][C:38]=2[N:37]=1.[I-].[K+]>C(OCC)(=O)C.CN(C)C(=O)C>[NH:37]1[C:38]2[CH:51]=[CH:50][CH:49]=[CH:48][C:39]=2[N:40]=[C:36]1[CH2:35][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2nc3ccccc3[nH]2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 17.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (1.82 g), tert-butyl 2-(chloromethyl)-1H-benzimidazole-1-carboxylate (1.12 g), potassium iodide (0.046 g) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.24 g, 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]2O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCc2c(OCc3ccccc3)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)C1=Cc2cccc(OCc3ccccc3)c2CC1
Temperature: 70 °C
Yield: 49.7 %

Procedure:
To a solution of 5.96 g of 5-(benzyloxy)-1-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene in 23 ml of anhydrous pyridine, 4.37 g of p-toluenesulfonyl chloride was added. After stirring with heating at 70° C. for 3 hours, 0.72 g of p-toluenesulfonyl chloride was further added, followed by stirring for 1.5 hours. The reaction solution was extracted with diethyl ether after adding iced water. The extract was washed in turn with water, 10% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.79 g of the desired compound as a colorless crystal having a melting point of 64 to 67° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCn1ccc2ccccc21
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCn3ccc4ccccc43)CC2)c1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(4-chlorobutyl)-1H-indole and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 418.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][SH:10])=[O:6].Cl.[N:22]([O-])=[O:23].[Na+]>O>[NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][S:10][N:22]=[O:23])=[O:6]
Reactant: O=N[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Reaction time: 1 h

Procedure:
N-(N-L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperature and then the reaction mixture was cooled to 0° C. With rapid stirring, a solution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) was added. Stirring with cooling of the reaction mixture was continued for approximately 1 hour after which time the pink precipitate which formed was collected by vacuum filtration. The filter cake was resuspended in chilled 40% acetone-water (600 ml) and collected by vacuum filtration. The filter cake was washed with acetone (2×200 ml) and ether (100 ml) and then dried under high vacuum at room temperature in the dark to afford the title compound as a pink powder. 1H NMR (D2O) δ 1.98 (m, 2H), 2.32 (t, 2H), 3.67 (t, 1H), 3.82 (s 2H),3.86 (dd, 1H), 3.98 (dd, 1H), 4.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][C:14]([CH3:16])=[CH2:15])=[C:4]([OH:12])[C:5]([CH2:9][CH:10]=[CH2:11])=[C:6]([CH3:8])[CH:7]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:15][C:14]1([CH3:16])[O:12][C:4]2[C:5]([CH2:9][CH:10]=[CH2:11])=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=2[CH2:13]1
Reactant: C=CCc1c(C)cc(C)c(CC(=C)C)c1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: C=CCc1c(C)cc(C)c2c1OC(C)(C)C2
Reaction time: 4 h
Yield: 97 %

Procedure:
2.44 g (11.3 mmol) of 3,5-dimethyl-2-(2-methyl-2-propen-1-yl)-6-(2-propen-1-yl)phenol (Compound No. 1) was dissolved in 20 ml of 1,2-dichloroethane, and 0.42 ml (3.39 mmol) of boron trifluoride etherate was added thereto at 0° C. The above mixture was then stirred in an atmosphere of argon gas for 4 hours, poured into an aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The thus obtained extract layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated, whereby 2.37 g of a crude 2,3-dihydro-2,2,4,6-tetramethyl-7-(2-propen-1-yl)benzo[b]furan (Compound No. 2) was obtained as a yellow oily material.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:12][C:13](OC)=[O:14])=[CH:8][C:7]([Br:26])=[CH:6][N:5]=1.O>CS(C)=O>[Br:26][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:13](=[O:14])[CH2:12][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:10][C:9]=2[CH:8]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Sodium hydride (60% in oil, 140 mg, 3.40 mmol) was added to a solution of methyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(4-methoxybenzyl)amino)acetate (1.05 g, 2.66 mmol) in DMSO (17 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of water (45 mL). After 2 hours stirring at room temperature, the reaction mixture was filtered. The resulting solid was dried under high vacuum to give the title compound as a yellow solid (600 mg, 63%)
Reaction SMILES: C(OC(=O)O[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C.[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=[N:39]3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[C:26](NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:25]=1.[NH2:62][CH2:63][CH:64]([C:72]1[CH:77]=[CH:76][C:75]([OH:78])=[CH:74][CH:73]=1)[C:65]1[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=1>>[OH:78][C:75]1[CH:76]=[CH:77][C:72]([CH:64]([C:65]2[CH:66]=[CH:67][C:68]([OH:71])=[CH:69][CH:70]=2)[CH2:63][NH:62][C:26]2[N:25]=[C:24]([Cl:23])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=[N:39]3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[CH:73][CH:74]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BA6) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bis-phenol (second step b). MS (ES+) m/e 578.34 (MH+)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: ClC[C@H]1CO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Method D, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (R)-(−)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:3 EtOAc-heptane); Rt=5.55.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[NH:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=2)[NH2:39])[CH:33]=[N:32]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1.O>[NH:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[C:38]([NH:39][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([C:6]4[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]5[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=5)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[CH:21][C:22]=3[F:30])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=2)[CH:33]=[N:32]1
Reactant: Nc1cc(-c2cn[nH]c2)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cn[nH]c4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (15 mg, 0.036 mmol) in pyridine (3 mL) were added 3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)aniline (8.28 mg, 0.036 mmol) and T3P® (EA solvate) (0.5 mL, 0.036 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was added to water and concentrated to afford N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.024 mmol, 66.3% yield). TLC (DCM/MeOH=15:1, Rf=0.5): 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.37 (s, 2H), 7.32-7.30 (m, 4H), 7.25-7.23 (m, 2H), 6.89-6.86 (m, 3H), 5.36 (s, 2H), 4.15-4.09 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.46 (t, J=6.8 Hz, 3H). ES-LCMS m/z 621.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][C:17]=1[S:28](=[O:31])(=[O:30])[NH2:29].C([Li])(C)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:18][C:17]=1[S:28]([NH2:29])(=[O:31])=[O:30]
Reactant: CC1CCCN(c2ccc(Br)cc2)C1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1CCCN(c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc2)C1
Reaction time: 0.17 h

Procedure:
A solution of 0.821 g of 1-(4-bromo-phenyl)-3-methyl-piperidine in tetrahydrofuran is cooled to −78° C. and treated with 0.3 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide. The mixture is stirred for 10 min and treated slowly with 4.31 mL of a solution of tert-butyl lithium (1.5 M) in tetrahydrofuran (3 mL). The orange solution is stirred at −78° C. for 15 min then at 0° C. for 1 hour. The reaction mixture is quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (2×50 mL). The organics are washed with water, a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a light yellow syrup. MS (m/z): 393 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH3CN in 5 min) room temperature=5.40 minutes.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][OH:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH2:28][OH:29])[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: OCCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCO)C3)c2n1

Procedure:
Prepared similarly to Example 1 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (for example, as prepared for Intermediate 18) and 2-bromoethanol (commercially available, for example, from Aldrich).
Reaction SMILES: [NH:1]([C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:7]=2[CH:6]=1)=[O:4])[NH2:2].C(O)C.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>Cl.O1CCCC1>[CH:32](=[N:2][NH:1][C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:7]=2[CH:6]=1)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN)cc34)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN=Cc5ccccc5)cc34)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
N-(5-Hydrazinocarbonyl-1H-thieno[2,3-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)-benzamide (0.150 g, 0.318 mmol, 1 eq.), ethanol (1 mL) and, by syringe, benzaldehyde (0.048 mL, 0.47 mmol, 1.3 eq.) are placed in a dry 5 mL round-bottomed flask under argon. Two drops of 5 N hydrochloric acid are added to the suspension. The reaction mixture is stirred at a temperature in the region of 50° C. for 3 hours, the solvent is then evaporated off and the residue is placed directly on a column of neutralized silica gel. Elution is performed with a methanol/dichloromethane mixture (10/90 by volume). The product obtained is directly added to a mixture of 1 mL of tetrahydrofuran and 0.5 mL of 5 N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. N-[5-(Benzylidenehydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide is obtained in the form of a white solid (0.029 g, 16%). MS: ES m/z=488 MH+ base peak. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 2.53 (partially masked s, 3H); 2.87 (m, 4H); 3.47 (m, 4H); 7.03 (d, J=9.0 Hz, 2H); from 7.39 to 7.49 (m, 3H); 7.79 (d, J=7.5 Hz, 2H); 8.01 (d, J=9.0 Hz, 2H); 8.28 (s, 1H); 8.39 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([CH3:23])[C:21]#[N:22].CO>CCCCCCC>[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH3:23])#[N:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(N)C#N
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CC(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-propanenitrile monohydrochloride (CAN 2134-48-7) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 286.1552 (M+H)+, αD20 (MeOH)=−9.6°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][F:36])[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:26]2[CH:27]=[CH:22][N:23]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH:30]3[CH2:35][F:36])[N:25]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: FCC1COCCN1Cc1nccc(Cl)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOCC4CF)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (26 mg, 0.09 mmol) and 4-[(4-chloropyrimidin-2-yl)methyl]-3-(fluoromethyl)morpholine (21.70 mg, 0.09 mmol) as starting materials.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][C:6]=2[C:7](=[O:10])[C:8]=1[CH3:9])[CH3:2].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][C:6]=2[C:7](=[O:10])[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1oc2ccc(C(C)C(=O)OC)cc2c(=O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1oc2ccc(C(C)C(=O)O)cc2c(=O)c1C
Yield: 42.2 %

Procedure:
A solution of methyl 2-(2-ethyl-3-methyl-4-oxo-4H-1-benzopyran-6-yl)propionate (1 g) in ethanol (120 mls), and sodium bicarbonate (1 g) in water (30 mls) was refluxed for 20 hours. The ethanol was removed on a `Rotavapor` and the residue was washed with ether (3×50 mls). After acidification with dilute hydrochloric acid, the aqueous phase was extracted with ethyl acetate (3×50 mls), which was washed with brine solution (3×30 mls), dried over anhydrous magnesium sulphate and evaporated to yield an off-white solid. This was recrystallised from ethyl acetate to yield the product as a pale yellow solid (0.4 g; 42%), mp 196°-198° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([OH:26])=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:25][C:24]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2)=[O:26]
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (170.00 mg, 0.465 mmol) was mixed with potassium carbonate (193.0 mg, 1.40 mmol) and methyl iodide (199.0 mg, 1.40 mmol) in DMF (2.0 mL) over a weekend. The reaction mixture was diluted with ethyl acetate, and washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:27])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]([CH3:16])=[C:13](I)[CH:14]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[N:41]([C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=3)[N:40]=[CH:39][CH:38]=2)O1.CN(C)C=O>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.C(O)(C)C>[C:46]([C:45]1[CH:44]=[CH:43][C:42]([N:41]2[C:37]([C:13]3[CH:14]=[C:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:28])[CH3:1])=[O:8])[C:10](=[O:27])[N:11]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[C:12]=3[CH3:16])=[CH:38][CH:39]=[N:40]2)=[CH:49][CH:48]=1)#[N:47]
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C#N)cc2)OC1(C)C
Reactant: Cc1c(I)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
A mixture of N-[3-(dimethylamino)propyl]-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (10 g, 19.71 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (8.9 g, 29.55 mmol), water (0.71 g), N,N-dimethylformamide (100 mL) and diispropylethylamine (7.64 g, 59.14 mmol) was purged with nitrogen for 10 minutes. To the above mixture was charged 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (“Pd-118” ex. Johnson Matthey, 642.38 mg, 985.62 moles) and the mixture heated to 40° C. for 12 h. The reaction mixture was cooled to room temperature and was added to a mixture of isopropanol (100 mL) and water (200 mL). The resulting mixture was stirred for 18 h. The precipitate was filtered, washed with water (50 mL) and dried under vacuum at 50° C. for 12 h to afford the title product as a brown solid (6.2 g, 56%); 1H NMR (400 MHz, DMSO-d6) δ 9.33 (t, J=5.77 Hz, 1 H), 8.07 (s, 1 H), 7.92-7.98 (m, 3 H), 7.91 (s, 1 H), 7.82-7.89 (m, 2 H), 7.72 (d, J=8.03 Hz, 1 H), 7.67 (d, J=8.53 Hz, 2 H), 6.73 (d, J=1.51 Hz, 1 H), 3.26 (q, J=6.86 Hz, 2 H), 2.25 (t, J=6.78 Hz, 2 H), 2.13 (s, 6 H), 1.75 (s, 3 H), 1.59 (p, J=7.03 Hz, 2 H); LCMSm/z: 549 [M+]
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)ccc1O
Yield: 63.1 %

Procedure:
Using 5-bromosalicylic acid and 3-chloroaniline as the raw materials, the same operation as the example 16 gave the title compound.