Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[N:4]([CH2:23][CH2:24][CH3:25])[N:3]=1.[OH-].[Na+]>O.C(O)C>[CH3:1][C:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[N:4]([CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CCCOc1ccccc1C(=O)Nc1c(C(N)=O)c(C)nn1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 3-methyl-5-(2-n-propoxybenzamido)-1-n-propylpyrazole-4-carboxamide (Preparation 7; 5.456 g, 0.0016 mol) and sodium hydroxide (3.16 g, 0.079 mol) in a mixture of water (150 ml) and ethanol (30 ml), by the method of Example 13, and was obtained as a white solid (4.863 g, 94%) after column chromatography. A sample crystallised from ethyl acetate-hexane as colourless needles, m.p. 112-114° C. Found: C,66.35; H,6.79; N,17.12. C18H22N4O2 requires C,66.24; H,6.79; N,17.17%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1([C:29]([OH:31])=O)[CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N:41]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:46][CH2:45][CH:44]([N:47]2[C@H:51]3[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]3[NH:49][C:48]2=[O:56])[CH2:43][CH2:42]1>CC(N(C)C)=O>[CH3:25][C:26]1([C:29]([N:60]2[CH2:61][CH2:62][CH:57]([N:41]3[CH2:42][CH2:43][CH:44]([N:47]4[C@H:51]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]5[NH:49][C:48]4=[O:56])[CH2:45][CH2:46]3)[CH2:58][CH2:59]2)=[O:31])[CH2:28][CH2:27]1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CCC(N3CCC(N4C(=O)N[C@H]5CCCC[C@@H]54)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
HBTU (284 mg, 0.75 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid (75 mg, 0.75 mmol), N,N-diisopropylethyl amine (194 mg, 1.50 mmol) and (3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one (153.22 mg, 0.50 mmol) in DMA (10 mL) and stirred at room temperature for overnight. Concentrated in vacuo, diluted in dichloromethane (50 ml) and washed with sat. NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by high pH Prep LCMS to give the titled compound (40 mg, 20.6%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 0.51-0.59 (m, 2H) 0.86-0.94 (m, 2H) 1.30 (s, 3H) 1.33-1.45 (m, 6H) 1.68 (s, 1H) 1.74-1.84 (m, 7H) 1.96 (d, J=10.16 Hz, 1H) 2.21-2.32 (m, 3H) 2.48 (t, J=11.13 Hz, 1H) 2.76 (s, 1H) 2.92-3.03 (m, 4H) 3.71-3.81 (m, 1H) 4.49 (s, 3H). MS (M+1): 389.2
Reaction SMILES: [CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])O[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[N:21]([OH:22])[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 21 (200 mg, 0.75 mmol), hydroxylamine hydrochloride (1.05 g, 15.2 mmol), sodium acetate (1.24 g, 15.2 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude was concentrated under diminished pressure to afford a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-decyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-7) as a light yellow oil: yield 0.08 g (40%); silica gel TLC Rf 0.4 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.84-0.88 (m, 3H), 1.24-1.44 (m, 16H), 2.27 (s, 3H), 2.48 (s, 3H), 2.57-2.61 (m, 2H) and 6.65 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>>[C:17]1([C:15]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)co2)cc1
Yield: 20 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with phenacyl bromide to obtain methyl 4-(4-phenyl-2-oxazolyl)benzoate. The product was recrystallized from ethanol. Yield: 20%. Pale yellow prisms. Melting Point: 175 to 176° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:10][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (5 g, 22.8 mmol) in DMF (100 ml) is added benzyl bromide (5.7 ml, 48 mmol) and cesium carbonate (11.9 g, 37 mmol). The reaction mixture is stirred at room temperature for 20 hours then diluted with water (150 ml) and extracted with EtOAc (2×150 ml), the organic portions are combined, washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give a waxy off-white solid. The solid is stirred in iso-hexanes (30 ml) for 30 minutes, filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([C:22](=O)/[CH:23]=[CH:24]/N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(O)(O)(=O)=O.[NH2:34][C:35]([NH2:37])=[NH:36]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([C:22]3[CH:23]=[CH:24][N:34]=[C:35]([NH2:37])[N:36]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1c(-c2cccc(Br)c2)nn2c(N3CCCC3)cccc12
Reactant: N=C(N)N
Agent: O=S(=O)(O)O
Product: Nc1nccc(-c2c(-c3cccc(Br)c3)nn3c(N4CCCC4)cccc23)n1
Yield: 61 %

Procedure:
In a similar manner as described in Example 1 from (2E)-1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (500 mg, 1.1 mmol) and guanidine sulfate, 4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (300 mg, 61%) was obtained as a yellow solid. 1H NMR (d6-DMSO): δ 8.03 (d, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.70–7.62 (m, 2H), 7.46 (t, 1H), 7.35 (t, 1H), 6.58 (broad s, 2H), 6.26 (d, 1H), 6.22 (d, 1H), 3.75 (m, 4H), 1.98 (m, 4H); MS m/z 435 (M+1); Anal. Caled. for C21H19N6Br: C, 57.94; H, 4.40; N. 19.31. Found: C, 57.91; H, 4.51; N, 19.07.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.ClCCl>C1COCC1>[CH2:50]([NH:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4nnc(N)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C)c3cc(-c4nnc(NCc5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-amino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 111 (0.04 g, 0.0755 mmol) in anhydrous THF (2 mL), cooled at −78° C., was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (0.083 mL) and benzyl bromide (0.001 mL dissolved in 0.1 mL THF). The reaction mixture was allowed to warm to room temperature. The reaction mixture was heated at 70° C. for 3 hours. Dichloromethane (50 mL) was added. The organic layer was washed with 1% citric acid, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 6-benzylamino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 114 (0.027 g, 0.0435 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3cc(C#N)ccc3o2)CC1

Procedure:
The same method as in Example 18 was employed. That is, 5-cyano-2-benzofurancarboxylic acid (749 mg, 4.00 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (917 mg, 4.00 mmol) were condensed to give 1.24 g of t-butyl trans-[4-[(5-cyano-2-benzofuranyl)carbonylamino]cyclohexyloxy]acetate as a colorless solid (78%).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[C:36]([NH:35][C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:29]=1)(=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 96 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.37–7.23 (m, 13H), 7.08 (d, 1H, J=8.8 Hz), 6.14 (t, 1H, J=5.6 Hz), 3.37 (dd, 2H, J=6.4, 12.0 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.63 (m, 1H), 2.49 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.27 (s, 3H), 2.02 (s, 3H), 1.99–1.94 (m, 2H), 1.71–1.59 (m, 6H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH:30]([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][CH:30]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1)[CH3:32]
Reactant: CC(C)I
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), 2-iodopropane (0.130 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at 50° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt followed by separation by preparative HPLC to give the title compounds.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCn1c(C(=O)OCC)cc2ccccc21
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of dimethylformamide was added to a suspension of 2.64 g of sodium hydride in 50 ml of dimethylformamide. After 1 hour, a solution of 20.9 g of ethyl 5-bromovalerate in 100 ml of dimethylformamide was added dropwise. After 48 hours, the mixture was poured into water, extracted with dichloromethane and the combined dichloromethane extracts were washed with water, dried and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C@H:11]([OH:14])[CH2:12]Cl.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C@H:11]1[CH2:12][O:14]1
Reactant: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc(F)c(C[C@H]2CO2)cc1F
Reaction time: 1 h
Yield: 80 %

Procedure:
(2S)-3-(2,4,5-trifluorophenyl)-1-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml), and NaOH (2.3 g) was added dropwise thereto. The resulting mixture was stirred for 1 hour and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (6.8 g; yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 102 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.42 (s, 1H), 7.34–7.24 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.57 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.53–2.43 (m, 3H), 2.37–2.29 (m, 4H), 1.99–1.91 (m, 4H), 1.83–1.58 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([CH2:9][NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH2:34])[N:28]=[C:27]2[C:35]([N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])=[O:13])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:9][NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH2:34])[N:28]=[C:27]2[C:35]([N:37]1[CH2:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:45]1)=[O:36])=[O:13]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 ml of 4N HCl in dioxane are added to 1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl (tert-butoxycarbonylmethylamino)acetate in 20 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off and rinsed with 3 ml of dichloromethane.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[F:11][C:7]1[CH:8]=[C:9]([F:10])[C:2]2[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(F)cc(F)c1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(F)cc(F)c2s1

Procedure:
Using 3.94 g (24.6 mmol) of 2,3,5-trifluorobenzaldehyde, 1.48 g (36.9 mmol) of sodium hydride (60% pure) and 2.88 g (27.1 mmol) of methyl mercaptoacetate, 3.58 g (56% of theory) of the title compound are obtained in a purity of 89%. Recrystallization from methanol gives the product in a purity of 97%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH:17]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(-c2csc(N)n2)c(C(C)C)c1
Yield: 25.5 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.9 g, 42.7 mmol) and thiourea (3.24 g, 42.6 mmol) in 95% EtOH (60.9 mL) was heated at reflux overnight. The solution was concentrated and added with water (100 mL), saturated aqueous Na2CO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure, which was purified by column chromatography on silica gel (33% EtOAc in hexanes as eluant) to give 4-(2,4,6-triisopropylphenyl)thiazol-2-amine (3.28 g) as white solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (s, 2 H), 6.22 (s, 1 H), 4.75 (bs, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27-1.14 (m, 18 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][N:27]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:24][CH:25]=[N:26]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (1 g, 4.83 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h and additional tetrakistriphenylphosphine Pd(0) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 6.27 mmol) were added. After 12 h, the reaction was partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜1 g, quant.): LCMS (ES) m/z=209 (M+H)+.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C=CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCOCc1ccc(OC)cc1
Temperature: 0 °C
Yield: 48.8 %

Procedure:
A 250 mL round-bottom flask equipped with stir bar was charged with 7-octen-1-ol (1.20 mL, 7.80 mmol). Anhydrous DMF (60 mL) was added, and the solution was allowed to cool to 0° C. (ice-bath). Sodium hydride (2.40 g, 40.0 mmol) was added in portions, and the mixture was allowed to stir until gas evolution ceased. p-Methoxybenzyl chloride (2.1 mL, 16 mmol) was added by a syringe and the mixture was allowed to stir for 24 h. The reaction was quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL), and washed with ethyl acetate (5×100 mL). The combined organic layers were washed with water (3×100 mL) to remove dmf, further washed in brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography (96:4 hexanes:EtOAc), delivering 1-methoxy-4-((oct-7-en1-yloxy)methyl)benzene (946 mg, 3.81 mmol, 49.0% yield) as a colorless oil. IR (neat): 3074 (w), 2998 (m), 2929 (m), 2854 (w), 1640 (m), 1613 (w), 1586 (w), 1511 (m), 1463 (m), 1441 (w), 1361 (w), 1301 (m), 1245 (s), 1208 (w), 1172 (m), 1095 (s), 1036 (s), 995 (w), 909 (m), 819 (s), 755 (w), 727 (w), 707 (w), 637 (w), 571 (w), 513 (w), 418 (w); 1H NMR (400 MHz, CDCl3): δ 7.25 (2H, d, J=8.8 Hz), 6.87 (2H, d, J=8.4 Hz), 5.80 (1H, m), 4.98 (1H, dd, J=17.2, 2.0 Hz), 4.92 (1H, dd, J=10.0, 2.4 Hz), 4.42 (2H, s), 3.79 (3H, s), 3.43 (2H, t, J=6.6 Hz), 2.03 (2H, app q, J=6.9 Hz), 1.63-1.56 (2H, m), 1.41-1.27 (6H, m); 13C NMR (100 MHz, CDCl3): δ 159.2, 139.2, 130.9, 129.3, 114.3, 113.8, 72.6, 70.3, 55.3, 33.8, 29.8, 29.1, 29.0, 26.2; HRMS (ESI+) [M+NH4]+ calcd for C16H28NO2: 266.2120, found: 266.2130.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.N1(C[C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)C=CC=C1>>[CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc[nH]1
Reactant: Ic1ccc(Cn2cccc2)cc1
Product: Cc1cccn1-c1ccc(I)cc1

Procedure:
The titled compound was prepared from 2-methylpyrrole (J. Org. Chem. 1956, 21, 918.) in an analogous manner to that of 4-(pyrrol-1-ylmethyl)phenyl iodide (EP 488 602 A1).