Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[C:18]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH3:27][O:28]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18]([OH:26])=[C:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH:27]=[O:28])[C:22]=2[CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c(O)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c(C=O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoic acid (7.5 g) and dichloromethyl methyl ether (5.7 ml) in dichloromethane (80 ml) was added a solution of titanium tetrachloride (6.9 ml) in dichloromethane (40 ml) over about 2 hours with ice-sodium chloride cooling. The reaction mixture was added to ice-water and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystals were recrystallized from acetonitrile to obtain 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (7.8 g) (Compound 27). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16]C)=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([OH:16])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)[N:3]=1
Reactant: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
To a solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5,6-dimethoxy-phenyl)-methanone (30 mg, 0.0636 mmol, Example 261) in methylene chloride (20 mL) cooled to 5° C. was added aluminum chloride (129 mg, 0.954 mmol, Fluka). The reaction mixture was stirred at room temperature for 24 hours and quenched with water. Tetrahydrofuran (40 mL) was added and the layers were separated. The organic layer was washed with water (1×5 mL), brine (1×5 mL) and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 A silica gel, eluting with ethyl acetate) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-hydroxy-5-methoxy-phenyl)-methanone as yellow solids (15 mg, 52%). HR-MS (ES, m/z) calculated for C18H22N5O5SF2 [(M+H)+]458.1307, observed 458.1304.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[N:28]=[C:29]([CH2:34][O:35][CH2:36][CH3:37])[N:30]([CH2:31][CH2:32][CH3:33])[C:26]=2[C:25]2[CH:24]=[C:23]([OH:38])[CH:22]=[CH:21][C:20]=2[N:19]=1.CN(C=O)C>O>[CH2:36]([O:35][CH2:34][C:29]1[N:30]([CH2:31][CH2:32][CH3:33])[C:26]2[C:25]3[CH:24]=[C:23]([O:38][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:17])[C:27]=2[N:28]=1)[CH3:37]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of 2-bromo-1-morpholin-4-yl-ethanone (414 mg, 1.99 mmol), 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol), and anhydrous DMF (20 mL). The reaction mixture was heated at 75° C. overnight, allowed to cool, and poured into deionized water (300 mL). The resulting mixture was stirred for 30 minutes and then extracted with chloroform (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-35% methanol/dichloromethane (10:90) in dichloromethane). The resulting solid was recrystallized from acetonitrile to yield 333 mg of 2-(ethoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 196-197° C. Anal. calcd for C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.72; H, 6.86; N, 16.62.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.Cl.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[CH2:7]([N:9]([CH2:10][CH3:11])[C:3](=[O:5])[CH2:2][Cl:1])[CH3:8]
Reactant: CCNCC
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of chloroacetic acid (10 g, 0.11 mol) in methylene chloride (530 mL) at 0° C. was added diethylamine hydrochloric acid (15.3 g, 0.14 mol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (26.4 g, 0.14 mol) and 4-methyl morpholine (29 mL, 0.27 mol). After the reaction stirred one hour at 0° C., the reaction was stirred at room temperature for four hours. The reaction mixture was then washed with water, 1N hydrochloric acid (until the aqueous phase was colorless), and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (9.3 g, 58%) which was used directly in the next step.
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-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[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]
Reactant: Fc1cccc(CBr)c1F
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,3-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. 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 a colorless solid (0.76 g, 46%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][C@@H:21]([CH2:28][O:29][CH3:30])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@@H:18]1[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[CH:22][C@@H:21]([CH2:28][O:29][CH3:30])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](COC)C=C1C(=O)NC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a mixture of (3R,6S)-3-(N-(allyloxy)-2-nitrophenylsulfonamido)-6-(methoxymethyl)-N-methyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 257, 561 mg, 1.27 mmol) and potassium carbonate (880 mg, 6.37 mmol) in acetonitrile (15 mL) at room temperature was added benzenethiol (0.654 mL, 6.37 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%-20% methanol/dichloromethane) afforded the title compound as an off-white solid (0.26 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[C:34]([O:14][C@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](OC(=O)c1ccccc1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
To an ice-cooled solution of (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (16.1 g) in tetrahydrofuran (320 ml) were added triphenylphosphine (63.3 g), benzoic acid (29.5 g) and diethyl azodicarboxylate (42.0 g). The mixture was stirred at room temperature for 6 hours under an argon atmosphere. After ethyl acetate (800 ml) and water (500 ml) were added thereto, the separated aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with water and a saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=15/1 to 7/1) to give [(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] benzoate (19.2 g) as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C=O)C>[N:3]1([C:9]2[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1-n1ccnc1
Temperature: 100 °C
Yield: 73 %

Procedure:
To a suspension of NaH 60% (0.09 g, 3.97 mmol) in DMF (20 mL) at 0° C. was added in one portion 1H-imidazole (2.5 mol eq, 0.61 g). After 10 min 2-chloro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.61 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction was cooled at room temperature, water was added and the aqueous solution was extracted with EtOAc (3×25 mL). The recombined organic phases were dried over sodium sulfate and evaporated to dryness to give the 2-imidazol-1-yl-4-(trifluoromethyl)benzonitrile as pale yellow oil (0.63 g, 73% Yield) used for the reduction without further purification.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH:11]1[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]2[N:15]3[C:16](=[O:17])[CH:11]([NH:10][C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:12][N:13]([S:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])(=[O:36])=[O:35])[CH:14]3[CH2:21][N:20]([CH:22]([CH3:24])[CH3:23])[C:19]2=[O:25])=[CH:28][CH:29]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclohexanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=668.14 (calculated, monoisotopic); measured value (M+H)+: 669.11
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:25])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: O=C(Cl)N1CCCCC1
Solvent: ClCCl
Product: O=C(C1CN(C(=O)N2CCCCC2)C1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred 0° C. solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (20 mg, 0.084 mmol) in DCM (1 ml) and TEA (0.023 ml, 0.17 mmol) was added dropwise piperidine-1-carbonyl chloride (14.9 mg, 0.013 ml, 0.10 mmol). The reaction was stirred for 1 h and then allowed to warm to RT and the progress monitored by LCMS. After 1 h the reaction was quenched with water (5 ml), extracted with DCM (2×10 ml), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 96:4 gradient of DCM/2M NH3 in MeOH) provided impure title compound (22 mg, 78%) as brown oil. Re-purification by preparative HPLC provided the title compound (3 mg, 10% yield) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:14]#[N:15])[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=2)[C:14]2[N:33]=[N:34][NH:35][N:15]=2)[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of the crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butylester (52 mg, 0.11 mmol), sodium azide (72 mg, 1.11 mmol) ammonium chloride (60 mg, 1.11 mmol) in DMF (2 mL) is stirred at 90° C. for 12 hours. The reaction mixture is diluted with water after letting it cool to room temperature. The product is extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is passed through silica pad (eluent: n-hexane/EtOAc) to give crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:21]#[N:22])=[C:13]([CH:20]=1)[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[C:14]([C:13]1[CH:20]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:23][CH3:24])=[CH:11][C:12]=1[C:21]#[N:22])(=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(C#N)c(C(=O)N(C)OC)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C#N)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a mixture of 5-benzyloxy-2-cyano-4,N-dimethoxy-N-methylbenzamide (reference example 6-2) (203 mg) and tetrahydrofuran (3.1 mL) was added phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.7 mL) under ice-bath cooling. The mixture was stirred for 1.5 hours. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.3 mL) was added to the mixture. After stirring under ice-bath cooling for 50 minutes, the mixture was stirred at room temperature overnight. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.35 mL) was added to the mixture. After stirring at 0° C. for 1.5 hours, to the mixture were added a saturated aqueous solution of ammonium chloride, 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine successively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-30% ethyl acetate/hexane, gradient elution) to give the title compound (112 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([S:15]C(OCC)=S)[CH:5]=1.CO[Na].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([SH:15])[CH:5]=1
Reactant: CCCc1cc(C(=O)OC)cc(SC(=S)OCC)c1OC
Agent: CO[Na]
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)cc(S)c1OC
Temperature: 25 °C
Yield: 104 %

Procedure:
To a stirred solution of 3-ethoxythiocarbonylthio-4-methoxy-5-propylbenzoic acid methyl ester (720 mg, 2.20 mmol) in THF (13 mL) at room temperature was added MeONa (0.5 M in MeOH, 13 mL, 6.5 mmol, 3 eq.). The reaction mixture was refluxed for 75 min, then cooled to room temperature and added to 1 N HCl aqueous solution (100 mL). The resulting mixture was extracted with EtOAc/hexanes (1:1, 100 mL). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to give 3-mercapto-4-methoxy-5-propylbenzoic acid methyl ester (0.55 g). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1ccc2ccccc2n1
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(C#CCCc2ccc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 29.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-methyl-pyridine (209 mg, 1.21 mmol) and 2-but-3-ynyl-quinoline (220 mg, 1.21 mmol Example 118(B)). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 98 mg (0.36 mmol, 30%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33](=[O:49])[NH:34][CH2:35][CH2:36][N:37](C(OCC1C=CC=CC=1)=O)[CH3:38])[CH2:9][CH2:10][CH2:11][NH:12]/[C:13](/[NH2:32])=[N:14]/[S:15]([C:18]1[C:19]([CH3:31])=[C:20]([CH3:30])[C:21]2[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=2[C:28]=1[CH3:29])(=[O:17])=[O:16])(C)(C)C.CC(O)=O>CO.O.[Pd]>[CH3:38][NH:37][CH2:36][CH2:35][NH:34][C:33](=[O:49])[C@@H:8]([NH2:7])[CH2:9][CH2:10][CH2:11][NH:12]/[C:13](/[NH2:32])=[N:14]/[S:15]([C:18]1[C:19]([CH3:31])=[C:20]([CH3:30])[C:21]2[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=2[C:28]=1[CH3:29])(=[O:17])=[O:16]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCN(C)C(=O)OCc2ccccc2)c(C)c2c1OC(C)(C)C2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CNCCNC(=O)[C@@H](N)CCCN/C(N)=N/S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 2.5 h
Yield: 55.5 %

Procedure:
Compound D (4.14 g, 5.77 mmol) and AcOH (330 μl, 5.77 mmol) was dissolved in methanol (40 ml) followed by the addition of Pd/C (5% wt, 880 mg) suspension in water (5 ml). The reaction mixture was subjected to hydrogenation (Parr apparatus, 75 psi) at room temperature for 2.5 h. The catalyst was filtered over a pad of Celite on sintered glass funnel and washed with methanol. Filtrate was evaporated in vacuo to provide compound E (1.96 g, 3.2 mmol) as yellowish amorphous solid. LC-MS [M+H] 483.2 (C22H38N6O4S+H, calc: 483.2).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:26](I)[CH:27]([CH3:29])[CH3:28].OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:26]([CH:5]1[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2](=[O:1])[CH2:7][C:6]1=[O:8])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Reactant: CC(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CC1CN(C(=O)OC(C)(C)C)C(=O)CC1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (Ark Pharm, Inc., Libertyville, Ill.; 2.0 g, 9.389 mmol) in THF (1 L) at 20° C. was added LHMDS (1.0M in THF; 23.47 mL, 23.47 mmol) (dropwise), and the resulting mixture was stirred at 20° C. for 30 min. Isobutyl iodide (6.9 g, 37.55 mmol) was added, and the resulting mixture was stirred at 20° C. for 1 h. The mixture was neutralized with 10M aq. KHSO4 solution and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to provide crude rac-tert-butyl 5-isobutyl-2,4-dioxopiperidine-1-carboxylate (0.75 g) (used without further purification in subsequent transformations): m/z (ESI, +ve) 170.0 [(M+H)-100]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[O:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[NH4+].[Cl-]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]2[CH:21]([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[O:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step 3 (700 mg, 2.4 mmol) in 5 ml MeOH and 1 ml THF at r.t. was added NaBH4 (80 mg, 2.4 mmol). The solution was stirred at r.t. for 0.5 hr. The mixture was poured into cold NH4Cl solution, extracted with HOAc, and chromatographed on silica gel (eluted with 40% EtOAc/hexane) to give 441 mg (58%) of the cis isomer and 279 mg (37%) of the trans isomer of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[CH:9]1[C:22]2[C:13](=[CH:14][C:15]3[C:20]([C:21]=2B(O)O)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1>>[CH:9]1[C:22]2[C:13](=[CH:14][C:15]3[C:20]([C:21]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:14]2[C:15]4[C:20]([CH:21]=[C:22]5[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]5)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1c2ccccc2cc2ccccc12
Reactant: Brc1ccccc1Br
Product: c1ccc(-c2c3ccccc3cc3ccccc23)c(-c2c3ccccc3cc3ccccc23)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Procedure analogous to Example 3a. Instead of 149.0 ml (1.2 mol) of 1,2-dibromobenzene and 98.0 g (308 mmol) of 9,10-anthracenediboronic acid ethylene glycol ester, 12.1 ml (100 mmol) of dibromobenzene and 68.0 g (306 mmol) of 9-anthraceneboronic acid are used. After cooling, the solid is filtered off with suction, washed three times with 100 ml of ethanol each time and then washed twice by stirring with 1000 ml of refluxing acetic acid each time (1 h) and each time filtered off with suction after cooling to 90° C. The mother liquor is discarded in each case. The solid is finally washed once with boiling ethanol. Yield: 33.0 g (76 mmol), 76.6% of theory; purity: 98% according to 1H-NMR.