Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][C:29](=[O:31])[CH3:30])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 57.9 %

Procedure:
A solution of 39 (0.06 g, 0.16 mmol), acetic anhydride (0.4 mL, 4.23 mmol) and a catalytic amount of DMAP in CH2Cl2 (30 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 4% MeOH/CH2Cl2) to afford 0.04 g (58%) of 40 as a white solid, mp 222-224° C. (EtOAc/n-hexanes).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[BrH:48].[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(CCCCC1CCNCC1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
In 2 ml of acetic acid is dissolved 0.7 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 2 hours. The reaction solution is diluted with 100 ml of ethyl ether, and after the mixture is allowed to stand, the supernatant layer is removed by decantation. The precipitate is rinsed with 50 ml of ethyl ether and dried to give 3(RS)-[5-(4-piperidyl)-1(RS)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid.hydrobromide. This product is dissolved in 20 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made acidic with 2 ml of acetic acid and purified by XAD-2 column chromatography (methanol:water=1:1). The effluent is concentrated under reduced pressure, and the crystals, which separate out, are rinsed with 50 ml of acetone and collected by filtration to give 0.22 g of 3(RS)-[5-(4-piperidyl)-1(RS)-carboxypentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-acetic acid as colorless prisms. m.p. 240°-260° C. (decomp.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:38])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
In analogy with Example 1i), 1.4 g (2.79 mmol) of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-one in 45 ml of dimethoxyethane and 23 ml of water are hydrolysed with 11 ml of a 1 M lithium hydroxide solution. The reaction mixture, which has been partially evaporated, is poured onto a mixture of ice, 137 ml of sat. NH4Cl solution, 11 ml of 10% citric acid solution and 56 ml of methylene chloride, and methanol is added until the precipitated solid dissolves. The aqueous phase is extracted with 2 portions of methylene chloride/methanol, approximately 10:1, and the organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (I)=24.0 min; FAB-MS (M+H)+ =520.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>CO>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[CH3:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: Cc1ccc(C)c(NN)c1
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CO
Product: Cc1ccc(C)c(-n2ncc(C#N)c2N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2,5-Dimethylphenylhydrazine hydrochloride (CAS no. 56737-78-1) (10 g, 57.92 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (60 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to afford free base of the starting material. The resultant oil was suspended in MeOH (100 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (7.07 g, 57.92 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (11.07 g, 90%) which was used without purification. 1H NMR (400 MHz, DMSO) δ 1.98 (3H, s), 2.31 (3H, s), 6.39 (2H, s), 7.07 (1H, s), 7.21-7.28 (2H, m), 7.72 (1H, s); m/z (ES+) (M+H)+=213; HPLC tR=1.79 min.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[NH2:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:20][C@@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Agent: Cl
Product: O[C@H]1CC[C@@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cis-4-aminocyclohexanol hydrochloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9](SC)=[N:8][C:7]=2[CH:18]=1.O.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]3)=[N:8][C:7]=2[CH:18]=1
Reactant: CSC1=Nc2cc(SC)ccc2Nc2cscc21
Reactant: OCCN1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc2c(c1)N=C(N1CCN(CCO)CC1)c1cscc1N2

Procedure:
A solution of 7,10-bis(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-(2-hydroxyethyl)-piperazine and glacial acetic acid is heated at 140°-160° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: C([N:8]1[C:12]([C:13]([OH:23])([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:10]1[CH:11]=[C:12]([C:13]([OH:23])([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])[N:8]=[CH:9]1
Reactant: CC(O)(CCc1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(O)(CCc1ccccc1)c1c[nH]cn1

Procedure:
3.3 g of 2-(3-benzyl-3H-imidazol-4-yl)-4-phenylbutan-2-ol is dissolved in 100 ml of ethanol. The reaction solution is hydrogenated at 50° C. with 10% palladium on carbon as catalyst for 4.5 hours. Work-up of the reaction mixture gives the crude product, which is recrystallized from ethyl acetate. The yield is 2.0 g.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([F:6])[F:5].[C:14]([O-:17])(=[S:16])[CH3:15].[K+]>CN(C=O)C.O>[F:5][C:4]([F:6])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][CH2:2][S:16][C:14](=[O:17])[CH3:15]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCCC(F)(F)c1ccc(F)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.25 g, 1.2 mmol) in dry DMF (1 ml) is added potassium thioacetate (0.41 g, 3.60 mmol) at RT. The reaction mixture is heated at 60° C. for 1.5 h. After completion of the reaction, the mixture is diluted with water (30 ml) and extracted with EtOAc (3×30 ml). The organic layer is washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 1% EtOAc/hexane) to yield ethanethioic acid S-[3,3-difluoro-3-(4-fluorophenyl)-propyl]ester (0.26 g, 1.05 mmol, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Reactant: COC1=CCCCCCCCCCC1
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCCCCCC1
Yield: 78.9 %

Procedure:
The compound 8 (375 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclododecene (589 mg, 3 mmol) in the same manner as the example 10 to give the compound 13 (426 mg, 79 %) as oil. Rf 0.57 (Al2O3 60, Type E, 10:1 toluene - EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(C#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Nc1ncc(Br)cc1CN1CCCCC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-bromo-3-piperidin-1-ylmethyl-pyridin-2-ylamine (500 mg, 1.85 mmol), tert-butyl acrylate (0.3 mL, 2.0 mmol), (i-Pr)2EtN (0.5 mL, 2.8 mmol) and P(o-tol)3 (114 mg, 0.37 mmol) in EtCN (10 mL) was de-oxygenated with argon for 30 min. Pd(OAc)2 (43 mg, 0.19 mmol) was added, and the mixture was de-oxygenated for 15 min. The mixture was heated to reflux for 18 h and then allowed to cool. The solvent was removed in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and satd NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, CH2Cl2 to 96:4 CH2Cl2/CH3OH) gave the title compound (350 mg, 60%) as a yellow solid: MS (ESI) m/e 318 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][CH:4]=2)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]
Reactant: Cc1nc(CO)co1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: Cc1nc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)co1

Procedure:
Prepared by the method of Example 31b using (2-methyl-4-oxazolyl)methanol (0.08 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.26 g).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25][C:26]([CH3:49])=[CH:27][CH2:28][O:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:46]1[CH2:47][CH2:48][CH:43]([C:41]([C:33]2[N:32]([CH2:31][CH2:30][O:29][CH2:28][CH:27]=[C:26]([CH3:49])[CH3:25])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=2)=[O:42])[CH2:44][CH2:45]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Product: CC(C)=CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccccc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][Si](C(C)(C)C)(C)C)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[C:29]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=5)[N:12]=4)=[N:9][N:10]=3)[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
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: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12
Temperature: 110 °C
Yield: 37.1 %

Procedure:
2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline (0.500 g, 1.10 mmol), phenylboronic acid (0.167 g, 1.37 mmol), Pd(PPh3)4 (0.0634 g, 0.0549 mmol), and 2M aqueous Na2CO3 (2.74 mL, 5.49 mmol) (degassed with nitrogen 30 minutes prior to use) were combined with 7 mL dioxane (degassed with nitrogen 30 minutes prior to use), sonicated, and heated to 110° C. in a reaction block for 18 hours, during which the reaction went dry. The reaction mixture was cooled to ambient temperature, diluted with DMF, and the suspension was vacuum filtered through compressed Celite, rinsed with DMF, and the filtrate was concentrated. The crude material was purified on silica gel (1-20% methanol in dichloromethane gradient) to give the title compound (0.138 g, 0.408 mmol, 37.1% yield) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:22][CH3:23])(=O)=O>O>[CH2:22]([N:4]1[CH:5]=[C:6]([Br:8])[N:7]=[C:2]([Br:1])[C:3]1=[O:9])[CH3:23]
Reactant: O=c1[nH]cc(Br)nc1Br
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(Br)nc(Br)c1=O
Reaction time: 15 h
Yield: 66.8 %

Procedure:
6.2 g of 3,5-dibromo-pyrazin-2-one are suspended in a mixture of 38 ml of water, 11.1 ml of 2N sodium hydroxide solution and 0.5 g of sodium carbonate. 4.3 g of diethyl sulfate are then added dropwise at 20°-25° C. and the mixture is subsequently stirred at the same temperature for 15 hours. The product is filtered off at 0° C., washed with ice-water and dried to give 4.6 g of 1-ethyl-3,5-dibromo-pyrazin-2-one.
Reaction SMILES: CC(OC(N[C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)=O)(C)C.Cl.[O:23]1CCOCC1>>[F:18][C:13]1[CH:12]=[C:11]([CH2:10][C@@H:9]([OH:23])[C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)c(F)c1)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Product: O=C(O)[C@H](O)Cc1ccc(F)c(F)c1
Temperature: 23 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
Boc-D-3,4-Difluorophenylalanine (3.05 g, 11.0 mmol, 1 equiv) was dissolved in 1,4-dioxane (10 mL), and a solution of HCl in 1,4-dioxane (4.0 M, 10 mL) was added. The reaction was stirred at 23° C. for 5 h, then the solvent was removed under reduced pressure. The residue was dissolved in 1 M H2SO4 (22 mL), cooled to 0° C. and 2 N NaNO2 (22 mL) was added via addition funnel under argon. The reaction mixture was stirred at 0° C. for 3 h and warmed to room temperature overnight. The resulting mixture was extracted with MTBE (3×40 mL), dried over Na2SO4 and concentrated. The residue was recrystallized from ether/petroleum ether to afford the title intermediate (1.29 g, 58%) as off-white solid. 1H NMR (DMSO-d6) δ 0.82-0.86 (m, 2H), 1.10-1.27 (m, 4H), 1.40-1.48 (m, 2H), 1.63-1.78 (m, 5H), 3.95-4.00 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.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>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 3 g (8.06 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.3., 4.59 g (24.17 mmol) of 3-(trifluoromethyl)phenylboronic acid, 6.84 g (32.23 mmol) of hydrated potassium phosphate and 0.93 g (0.806 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.22 g of product are obtained in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:15])([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:11]([C:10]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)[CH2:12][CH3:13]
Reactant: CCCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCCc1nc(C(=O)OCC)cs1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (6.32 mL) was added to a solution of butanethioamide (example 87, step a) (5.2 g) in ethanol (100 mL) and the resulting mixture heated at reflux overnight. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with brine (100 mL) dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 10:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 5.24 g.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[F-:13].[K+]>>[F:13][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: [F-]
Agent: [K+]
Product: O=C1OC(=O)c2c(F)cccc21
Temperature: 235 °C
Yield: 69 %

Procedure:
A mixture of 20 parts of 3-chlorophthalic anhydride, and 20 parts of anhydrous potassium fluoride was heated and maintained at about 235° C. for about 9 hours. The reaction mixture was then cooled and the crude product was removed by vacuum distillation and recrystallized from chloroform to yield 12.65 parts of purified 3-fluorophthalic anhydride (69% yield).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=1)C>C1COCC1.C1CCCCC1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12](=[O:27])[CH2:2][C:1]#[N:3])=[CH:19][CH:18]=1
Reactant: CC#N
Reactant: CCOC(=O)Cc1ccc(OCCCN(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(CC(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-Dimethylamino-propxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.627 mL) in 20 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 6 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 2.45 gms. of [4-(3-dimethylamino-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture is then vacuum filtered affording the desired nitrile, 4-[4-(3-dimethylamino-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (20–28% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]([CH3:20])[CH:12]=1)=[C:5]2[CH3:21].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:19][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:21])=[CH:3][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:10][CH:9]=3)=[CH:12][C:13]=1[CH3:20]
Reactant: COc1c(C)cc(-c2[nH]c3ccc(N)cc3c2C)cc1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(C)cc(-c2[nH]c3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.85 g of 5-amino-2-(4-methoxy-3,5-dimethylphenyl)-3-methylindole was dissolved in 20 ml of pyridine, and 1.51 g of p-toluenesulfonyl chloride was added. The mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% hydrochloric acid and water, and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 2-(4-methoxy-3,5-dimethylphenyl)-3-methyl-5-p-toluenesulfonylaminoindole.