Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:29]3[CH2:34][CH2:33][N:32]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[F:16])=[O:13])[CH2:31][CH2:30]3)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=2)[CH2:20][CH2:21]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C2CC2)c1
Yield: 48.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Example 86, the title compound (223 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(N(C)C)=O.O>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][C:4]=2[CH3:10])[CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1cc(I)nc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(I)nc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 20 %

Procedure:
A solution of 6-iodo-2,4-dimethylpyridin-3-ol (5.10 g, 20.48 mmol) in DMA (60 mL) was sparged with Ar, treated with 2,4-dichloropyridine (3.94 g, 26.60 mmol) and K2CO3 (3.40 g, 24.57 mmol) and heated at 105° C. overnight. The mixture was cooled to RT, treated with EtOAc and water, filtered to remove solids, then treated with charcoal, warmed to reflux, cooled to RT and filtered through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2,4-dimethylpyridine (1.476 g, 20%). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=5.8 Hz, 1 H), 7.75 (s, 1 H), 7.05 (d, J=2.3 Hz, 1 H), 6.89 (dd, J=5.8, 2.3 Hz, 1 H), 2.20 (s, 3 H), 2.02 (s, 3 H); MS (ESI) m/z: 361.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
5.3 g (18 mmol) of 4-bromo-N-(2-hydroxyphenyl)benzamide, 8.0 g (46 mmol) of para-toluenesulfonic acid monohydrate, and 200 mL of toluene were put in a 300 mL three-neck flask. The mixture was refluxed for 4 hours under a nitrogen stream. After a certain time, water was added to the mixture, and an organic layer and an aqueous layer was extracted with ethyl acetate. The resulting extract was combined with the organic layer, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then a saturated saline, and dried with magnesium sulfate. The obtained mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethyl acetate/hexane, so that 3.1 g of target white powder was obtained with a yield of 61%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:34]([OH:36])[CH3:35]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:36][CH2:34][CH3:35])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethanol and DBU in DMB. EI-MS rn/e 2%) 284 (M+, 100), 214 (32).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][C:10]([CH3:20])([CH3:19])[CH2:9]2.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:21])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=4)[CH:16]=3)[O:11][C:10]([CH3:19])([CH3:20])[CH2:9]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(N)ccc2O1
Product: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(NC(=O)c3ccc(C#N)cn3)ccc2O1
Yield: 78 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,2-dimethyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.3) and 5-cyanopicolinic acid yielded the title compound (78% yield) as a yellow solid. MS (ISP): m/z=428.3 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]4[C:26]=3[CH3:27])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.O1CCCC1>[NH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([O:25][C:1](=[O:3])[CH3:2])[CH:22]=[CH:21][N:20]4[C:26]=3[CH3:27])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(O)ccn12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetyl chloride (1.2 ml) was added to a mixture of 2-amino-6-[2-(7-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.8 g) and triethylamine (2.4 ml) in dichloromethane (36 ml) under ice-cooling and a mixture was stirred for 15 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and tetrahydrofuran, and the resulting mixture was washed with water. The mixture was dried over magnesium sulfate and evaporated to give 2-amino-6-[2-(7-acetoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.27 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]2[C:9]([CH3:20])=[N:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:3][CH2:2]1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCC1CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid cyclopropylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([F:20])([CH3:19])[CH3:18])[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O.CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([F:20])([CH3:18])[CH3:19])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(C)F)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2 g (6.9 mmol) Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-fluoro-3-methylbutanoate was dissolved in a mixture of 20 ml water and 10 ml methanol and treated with 387 mg (6.9 mmol) potassium hydroxide. After stirring for 4 hours at 50° C., the mixture was added to 50 ml water and extracted with 50 ml ethyl acetate. The aqueous phase was acidified with hydrochloric acid until it was pH 2 and extracted with three lots of 100 ml ethyl acetate. The combined ethyl acetate phase was washed with water, dried over magnesium sulphate, filtered and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C(=O)([O-])[O-:12].[Na+].[Na+].C(OO)(=O)C>>[CH3:9][C:8]([CH:5]1[CH2:6][CH:7]2[O:12][C:2]2([CH3:1])[CH2:3][CH2:4]1)=[CH2:10]
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O=C([O-])[O-]
Agent: CC(=O)OO
Agent: [Na+]
Product: C=C(C)C1CCC2(C)OC2C1
Reaction time: 0.75 h

Procedure:
A mechanically stirred mixture of 1 kg. (7.3 mol.) of d-limonene (7.3 mol.) and sodium carbonate (310.6 g) was cooled to 0°-10° C., and treated with 1.61 kg. (9.1 mol.) 40% peracetic acid by dropwise addition. After the addition was complete, the reaction mixture was stirred for another 45 min., washed with ice water, sodium carbonate, and brine. The oil was dried over magnesium sulfate, and distilled to give recovered limonene (30 g), the cis-epoxide (257 g) and trans-epoxide (296 g), and diepoxide (82 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[NH:9][C:8]=1[C:19]([O:21][CH3:22])=[O:20].F[B-](F)(F)F.[CH3:28][O+](C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:28][O:18][C:10]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:19]([O:21][CH3:22])=[O:20])[N:9]=1
Reactant: C[O+](C)C
Reactant: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCCCc1c(C(=O)OC)nc(OC)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Methyl 5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (2.00 g) was dissolved in dichloromethane (14 ml), trimethyloxonium tetrafluoroborate (2.00 g) was added and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (585 mg).
Reaction SMILES: [CH:1]1([C:4]([CH:6]([C:14]([C:16]2[C:17]([S:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])C(OC(C)(C)C)=O)=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:14]([C:16]2[C:17]([S:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: CSc1ncccc1C(=O)C(C(=O)OC(C)(C)C)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncccc1C(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
A mixture of t-butyl 2-cyclopropanecarbonyl-3-(2-methylsulphenylpyridin-3-yl)-3-oxopropanoate (9.44 g) and 4-toluenesulphonic acid (0.4 g) in dry toluene was stirred at reflux for 5 hours then allowed to stand at room temperature overnight. The mixture was stirred at reflux for a further 5 hours, cooled to room temperature and taken up into ethyl acetate and water. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to give 1-cyclopropyl-3-(2-methylsulphenylpyridin-3-yl)propan-1,3-dione (7.64 g) as a brown oil which was used without further purification.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2C=COC=2)=CC=1.Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccncc1
Agent: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Product: Brc1ccc(-c2ccncc2)cc1
Yield: 100 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromopyridine (700 mg, 3.00 mmol) underwent coupling to 4-bromophenylboronic acid to give 2.38 g (100%) of 4-(4-bromo-phenyl)-pyridine as a yellow solid, which had an NMR that matched literature (Boy, P.; Combellas, C.; Thiebault, A.; Amatore, C.; Jutand, A. Tetrahedron Lett. 1992, 33, 491-494) and was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [187039-57-2] (500 mg, 2.16 mmol) in MeOH (9.0 mL), cooled to 0° C., was added with stirring a solution of Cs2CO3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0° C., followed by addition of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO3 (2×) and water (2×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as a white solid. MS (LC/MS): 665 [2M+Na]+, 266 [MH−tBu]+, 222 [MH−Boc]+; tR (HPLC conditions b): 4.18 min.
Reaction SMILES: C(O[C:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)([CH3:12])[CH3:11])(=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nccc2ccccc12
Reaction time: 24 h
Yield: 68.1 %

Procedure:
(a-2-2) Ten grams of 1-(1-benzoyloxy-1-methylethyl)-isoquinoline was dissolved in 100 ml of ethanol, and 2 g of 10% palladium-carbon was dissolved. The mixture was stirred in a stream of hydrogen at room temperature and atmospheric pressure for 24 hours. The reaction mixture was filtered through Celite, and the solvent was distilled off. Distillation under reduced pressure afforded 4.0 g of 1-isopropylisoquinoline. (b) A mixture of 9.4 g of 1-isopropylisoquinoline and 12 g of N-hydroxymethyl dichloroacetamide was dissolved in 94 g of conc. sulfuric acid and 9.5 g of 20% fuming sulfuric acid, and the solution was heated for 3 hours. The reaction mixture was poured into water, made weakly alkaline with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-benzene to afford 20 g of 1-isopropyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 150.7° to 151.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].BrC1C=C(C=CC(O)=O)C=CC=1O.OC1C=CC(C=O)=CC=1.N1C=CN=C1.[Si:49](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]([O:20][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:12]([CH3:14])([CH3:13])[CH3:15])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)c(Br)c1
Agent: O=C(O)C=Cc1ccc(O)c(Br)c1
Agent: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 43, 3-[3-bromo-4-hydroxylphenyl]acrylic acid (12.01 g) obtainable from 4-hydroxybenzaldehyde (TCI) by a method known from literature (Y. Nagao et al., Tetrahedron Lett., 1980, p. 4931) was reacted with imidazole (16.01 g) and t-butyldimethylsilyl chloride (7.43 g) and treated to obtain the title compound (Intermediate Ac-1, 17.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.Cl.[CH3:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][CH3:28])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to methylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methylterephthalamide. MS (Q1) 401 (M)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[C:10]2[CH:9]=[CH:8][C:7]([O:17][CH2:18][C@@H:19]([N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6][C:5]=2[O:4]1)[CH3:2].NN>C(O)C.C(Cl)Cl>[CH2:1]([CH:3]1[C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[C:10]2[CH:9]=[CH:8][C:7]([O:17][CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CCC1Oc2cc(OC[C@@H](N)CC(C)C)ccc2-c2ccncc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 22.4 %

Procedure:
To a stirred solution of 2-((2S)-1-(5-ethyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.25 g, 0.548 mmol) in ethanol (15 mL) was added hydrazine (0.172 mL, 5.48 mmol) and the reaction mixture was stirred at 40° C. for 6 h. The reaction was cooled to room temperature then diluted with DCM (20 mL) and filtered through a bed of celite. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (0.1% TFA in water and methanol) to yield (2S)-1-((5-ethyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (40 mg, 21% yield). The diastereomeric mixture was resolved by SFC (0.5% DEA in methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](Br)[CH:8]=1)[CH3:6])[CH3:2].C(O[C:19]([S-:21])=[S:20])C.[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:19](=[S:20])[S:21][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(C)c1ccc(N)c(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=S)sc2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(4-Amino-3-bromo-phenyl)-propionic acid ethyl ester (1.58 g) in DMF was added potassium ethylxanthate (1.86 g) at room temperature. After stirred with reflux for 14 h, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=6:1 to 4:1) to afford the product as yellow oil. (595 mg, 38.3%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1)[CH2:5]2.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[CH3:45][O:44][C:42](=[O:43])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:29])[CH3:30])[CH2:16][CH2:17]1)[CH2:5]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc2c(c1)CC(CN1CCC(n3c(C(C)(C)O)nc4cc(C)ccc43)CC1)C2
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (36 mg, 0.096 mmol), N,N-diisopropylethylamine (37 mg, 0.29 mmol) in THF (3 mL) was added methyl chloroformate (9 mg, 0.11 mmol). After stirring overnight, the reaction mixture was quenched with silica-supported diamine-3 (95 mg, Silicycle) to scavenge the excessive amount of methyl chloroformate. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography eluent to afford (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-ylmethyl}-indan-5-yl)-carbamic acid methyl ester (20 mg, 59%) as white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:10]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 111.3 %

Procedure:
A mixture of 4-fluorobenzaldehyde (0.242 g, 1.95 mmol), 1-isopropylpiperazine (0.335 mL, 2.34 mmol), and K2CO3 (0.323 g, 2.34 mmol) in DMF (2.44 mL) was heated at 120° C. overnight. The mixture was diluted with EtOAc (200 mL), washed with 10% aqueous LiCl (3×75 mL) and brine (75 mL), dried over Na2SO4, and filtered. The volatiles were removed under vacuum to yield 4-(4-Isopropylpiperazin-1-yl)benzaldehyde (0.504 g) as an orange solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[O:13]=[C:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]#[N:24])[CH:20]=2)[NH:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[OH:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:2]1[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=1)=[CH:20][C:19]([C:23]#[N:24])=[CH:18][CH:17]=2
Reactant: O=C1CCCc2nc(Cl)ccc21
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc4c(n3)CCCC4=O)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 20 %

Procedure:
To a suspension of 2-chloro-7,8-dihydroquinolin-5(6H)-one (50 mg, 0.275 mmol) and 2-oxoindoline-5-carbonitrile (45.7 mg, 0.289 mmol) in tetrahydrofuran (1.4 mL) was added a 1.0 M solution of sodium bis(trimethylsilyl)amide (641 μL, 0.641 mmol). The mixture was stirred for 3 min at RT and then heated in a microwave oven to 110° C. for 10 min. After cooling to RT the reaction was quenched by addition of methanol (1 mL). The resulting solution was evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol) yielding an orange solid. Amount 17 mg. Yield 20%.