Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(=O)C(Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25.6 g, 145.28 mmol) in THF (300 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (300 ml; prepared from 22.6 ml of diisopropylamine (160 mmol) and 100 ml of 1.6 M n-BuLi in hexane (160 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (30.5 g, 159.8 mmol) in THF (300 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 3:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.32-2.52 (m, 2H), 2.82-2.90 (m, 2H), 3.10-3.18 (m, 2H), 3.78 (s, 1H), 4.52-4.58 (m, 1H), 7.01-7.05 (m, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.47-7.48 (m, 1H). ES+−MS: 211.3, 213.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20](C)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4)(=[O:3])[CH3:2].Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>C1C=CC=CC=1.CCOCC.C(=O)([O-])[O-].[K+].[K+]>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([N:20]1[CH2:19][CH2:18][C@@:15]23[C:16]4[CH:17]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C)CC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCC(Cl)(Cl)Cl)CC3
Yield: 66.1 %

Procedure:
To a mixture of 2.7 g of (-)-3-acetyl-N-methylmorphinan, 50 ml of benzene and 20 mg of potassium carbonate, was added dropwise 2.11 g of 2,2,2-trichloroethyl chloroformate in 10 ml of benzene. The reaction mixture was stirred at reflux temperature for 48 hours and after cooling it was diluted with 100 ml ether. The ether solution was extracted with 1 N hydrochloric acid (2×30 ml) and dried over magnesium sulfate. Removal of the solvent gave 2.8 g (66%) of crude (-)-3-acetylmorphinan-17-carboxylic acid (trichloroethyl)ester. For analysis, a sample of this compound was distilled, bp 230°-240° (0.1 mm), [α]25D-127.21° (c 1.11, MeOH).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:23]=[CH:22][C:15]2[CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1.C(O)C>[CH2:1]([NH:8][CH:18]1[CH2:17][CH2:16][C:15]2[CH:22]=[CH:23][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][C:14]=2[C:20](=[O:21])[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Solvent: c1ccccc1
Product: O=C1CC(NCc2ccccc2)CCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
A solution of benzylamine (8.18 g) in benzene (100 ml) was added dropwise to a suspension of 8,9-dihydro-3-nitro-5H-benzocyclohepten-5-one (15.51 g) in ethanol (155 ml) at ambient temperature over 20 minutes. The resulting mixture was stirred at the same temperature for 3 hours 30 minutes, allowed to stand at the same temperature overnight, and filtered. The filtrate was evaporated in vacuo to afford 7-benzylamino-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (25.41 g) as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.7 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 986 mg (8.4 mmol) 3-ethynyl-phenol using 106 mg (0.56 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 8 mL (55 mmol) triethylamine in 12 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel (DCM/MeOH gradient) and subsequently RP-HPLC (ACN/H2O gradient). Yield: 419 mg (29%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]([O:12][CH2:13][O:14][CH3:15])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1ccc(Cl)cc1C(=O)OC
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)OC

Procedure:
To a solution of methyl 5-chloro-2-methoxymethoxybenzoate (1.45 g, 6.29 mmol) and 1-benzylpiperazine (1.66 g, 9.43 mmol) in toluene (50 mL) were added palladium acetate (28 mg, 0.126 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol) and cesium carbonate (3.07 g, 9.43 mmol), and the resulting solution was refluxed for 3 hours. Water was added to the resulting solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 400 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:4].[OH-].[K+].O>C(O)C>[CH3:10][C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:7]=1
Reactant: COC(=O)c1sc(C)nc1-c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(C)sc2C(=O)O)cc1

Procedure:
2-Methyl-4-p-tolyl-thiazole-5-carboxylic acid methyl ester (2.67 mmol) and solid KOH (5.35 mmol) were dissolved in ethanol (1.04 mL) and water (0.26 mL) and heated under reflux for 3 hours. After cooling, the solvent was evaporated under reduced pressure and ice water was added to the residue, followed by washing with hexane. The aqueous layer was acidified with 1N aq. HCl and the crystals thus precipitated were collected by filtration, washed with water and then dried to provide 2-methyl-4-p-tolyl-thiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)-5-(methoxycarbonyl)pyrazole (4.0 g, 13.2 mmol) in 40 mL of tetrahydrofuran and 20 mL of water was added an aqueous solution of lithium hydroxide monohydrate (0.55 g, 13.2 mmol). The reaction was allowed to stir at ambient temperature for 1 h. The tetrahydrofuran was removed in vacuo and the aqueous was extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 3.2 g (84%) of the title compound, which was used without further purification. LRMS (ES-): 289.0 (M-H)-.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[N:12]=[CH:11]3)[N:5]([CH3:7])[CH:6]=1.[Li+].[Cl-].Br[C:21]1[S:22][C:23]2[C:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:28]([C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:27]([CH3:48])=[CH:26][C:24]=2[N:25]=1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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>[C:44]([O:43][C@@H:37]([C:28]1[C:27]([CH3:48])=[CH:26][C:24]2[N:25]=[C:21]([C:2]3[N:3]=[C:4]([C:8]4[CH:9]=[C:10]5[C:14](=[CH:15][CH:16]=4)[N:13]([CH3:17])[N:12]=[CH:11]5)[N:5]([CH3:7])[CH:6]=3)[S:22][C:23]=2[C:29]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:45])([CH3:46])[CH3:47]
Reactant: Cn1cc(Br)nc1-c1ccc2c(cnn2C)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cn(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In a 10 mL reaction vial, 5-(4-bromo-1-methyl-1H-imidazol-2-yl)-1-methyl-1H-indazole (50 mg, 0.172 mmol) was dissolved in dioxane (3 mL) at rt. The solution was bubbled with argon for 5 min. Then Sn2(n-Bu)6 (0.136 mL, 0.259 mmol), LiCl (60 mg, 1.4 mmol), Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) and Pd(PPh3)4 (40 mg, 0.0344 mmol) were added sequentially. The resulting reaction mixture was sealed and heated to 90° C. in oil bath. To this mixture, a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (128 mg, 0.259 mmol) in dioxane (1.5 mmol) was added slowly through syringe pump over 1.5 h. The resulting reaction mixture was stirred at 100° C. in oil bath for 16 h. The reaction was then diluted with EtOAc (20 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-20% EtOAc/Hex to afford product. LCMS-ESI+: calc'd for: C34H34ClN5O3S: 628.2, 629.2, 630.2 (M+H+); found: 628.1, 629.1, 630.1 (M+H+)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1([CH3:24])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:20]C(=O)C)=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)C.B(F)(F)F.[CH3:30][CH2:31][O:32]CC>C(O)(=O)C.CCOCC>[C:31]([C:14]1[C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]2[O:8][C:7]([CH3:24])([CH2:6][CH2:5][C:4]([OH:3])=[O:25])[CH2:12][CH2:11][C:10]=2[CH:13]=1)(=[O:32])[CH3:30]
Reactant: CCOCC
Reactant: CCCc1c(OC(C)=O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Agent: FB(F)F
Solvent: CC(=O)O
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)O)CC2
Temperature: 105 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a stirred solution of 276 mg of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 2 ml of glacial acetic acid was added 0.21 ml of boron trifluoride etherate, at room temperature. The mixture was stirred at 105° C. for 24 hours then cooled and diluted with ether. The ether solution was washed with water and brine and processed in the usual manner given 298 mg of a yellow-brown oil. This material was chromatographed on 30 g of silica gel. Elution with 4:1 toluene-ethyl acetate afforded 183 mg (72.1%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as an off-white solid, mp 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:13]([OH:15])=[O:14])=[CH:19][C:18]=1[F:26]
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 324.0456 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C@H:13]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CN(C=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH:9]([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)F)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stream of nitrogen was passed through a suspension of the aryl bromide from Step 5 (65 mg), 4-(methylthio)phenylboronic acid (40 mg), 2 M Na2CO3 (0.22 mL) and DMF (1.0 mL) for 5 minutes. PdCl2 dppf was then added and the reaction was warmed to 80° C. and stirred under nitrogen for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and poured into a saturated solution of sodium bicarbonate. The ethyl acetate layer was separated and the aqueous further extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 50:50) to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cc2ccccc2)ccc2ccccc12
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A mixture of 2-phenylmethyl-1-naphthol (40.0 g, 0.17 mole), methyl iodide (36.4 g, 0.26 mole), potassium carbonate (35.9 g, 0.26 mole) and acetone (1000 mL) was heated at reflux With stirring for 17 hours, then cooled and filtered. The acetone was removed under vacuum, and the residue was dissolved in ethyl acetate, washed with water and brine dried over magnesium sulfate and concentrated. The residual oil was distilled in a short-path distillation apparatus at approximately 160°-180°/0.2 torr to provide the title compound (41.5 g, 98%) as an off-white solid, mp 56°-59°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]2=[O:30])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:31][C:32]([Si](C)(C)C)([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:30])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:2])[C:32]([F:34])([F:33])[F:31])=[CH:9][CH:8]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)(=[O:22])=[O:21]
Reactant: CC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
2-(4-Acetyl-phenyl)-8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.13 g), product of example 151), dissolved in THF (12 ml) under an argon atmosphere was treated at RT with (trifluoromethyl)trimethylsilane (0.062 g) then with tetra-n-butylammonium fluoride (1M solution in THF, 0.29 ml) and the reaction mixture was stirred overnight at RT. The mixture was made acidic with 3M aqueous HCl (a few drops) and stirred further 15 minutes. The solvent was removed in vacuo and the residue adsorbed on silica gel and chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 40%) to give the desired product as white solid (0.091 g). MS (ESI): 517.1 MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23]C=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:31]=2[C:30]([OH:33])=[O:32])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2cc(Nc3c(F)cccc3C#N)c(Cl)cn2)n(C(C)C)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3c(F)cccc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 75 %

Procedure:
A solution of 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzonitrile (4.5 g, 11.69 mmol) in sodium hydroxide—1 M (10 mL, 10.00 mmol) and 1,4-dioxane (10 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). Combined aqueous layers were washed with ethyl acetate, and neutralized with acetic acid. The solid was filtered. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzoic acid (3.2 g, 7.53 mmol, 75% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.24 (d, J=6.57 Hz, 6 H) 2.09 (s, 3 H) 4.34 (quin, J=6.57 Hz, 1 H) 5.86 (s, 1 H) 5.91 (d, J=5.81 Hz, 1 H) 7.35 (td, J=8.02, 4.93 Hz, 1 H) 7.54-7.65 (m, 1 H) 7.81 (d, J=7.58 Hz, 1 H) 7.94 (s, 1 H) 8.45 (s, 1 H) 8.88 (br. s., 1 H) 13.74 (br. s., 1 H); HPLC Rt=2.36 min, MS (ESI): 404.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([NH2:21])[CH:3]=1.Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: OCCO
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
A mixture of 7-bromo-3-(3-chloro-2-methylbenzyl)-2-methyl-3H-benzo[d]imidazol-5-amine (85 g, 233 mmol), 1-bromo-2-(2-bromoethoxy)ethane (108 g, 466 mmol) and DIPEA (60 g, 466 mmol) in ethylene glycol (1 L) was stirred at 100° C. for 18 h. It was cooled to rt, and diluted with water (1 L) and extracted with DCM (500 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (48 g, 47.5%) as a yellow solid; LC/MS: MS (ES+) m/e 434 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.46 (s, 3H), 3.04-3.07 (m, 4H), 3.68-3.72 (m, 4H), 5.47 (s, 2H), 6.04 (d, J=8.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[CH:44]=[N:45][CH:46]=[CH:47][C:42]=2[CH3:41])(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccncc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 53.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (161 mg), 15-crown-5 (132 mg) and a solution of crude 4-methylpyridine-3-sulfonyl chloride (125 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield 127 mg, 53%).
Reaction SMILES: [CH3:1][S:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].Cl[CH2:21][CH2:22][O:23]C1CCCCO1>>[OH:23][CH2:22][CH2:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([S:2][CH3:1])([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]1=[O:12]
Reactant: ClCCOC1CCCCO1
Reactant: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Product: CSC1(Cc2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described in Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[Si:22](OS(C(F)(F)F)(=O)=O)([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)Cc1ccc(CO)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stir. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (MgSO4) filtered and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E133).