Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])(O)=O.[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: CNc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reaction time: 1 h
Yield: 56.3 %

Procedure:
3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile (300 mL) was added dropwise over 30 minutes to a vigorously stirring solution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO3 (18.0 g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixture was stirred for additional 1 h and then concentrated to remove acetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) and water (500 mL), and dried. The solid was dissolved in dichloromethane (500 mL) and n-butylamine (20 mL) was added. The mixture was stirred at rt for 16 hrs and concentrated. The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) and then crystallized from hexane/ethyl acetate (75/25) to give 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g) as a white solid. MS [M+H]+: 339.7/341.8; tR=2.19 min. (method 1)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3[C:39]=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:39][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H) 8.06 (m, 1H) 8.01 (m, 2H) 7.87 (t, J=8.0 Hz, 1H) 7.63 (s, 1H) 7.23 (d, J=8.32 Hz, 1H) 7.16 (d, J=8.32 Hz, 1H) 4.34 (t, J=6.32 Hz, 2H) 3.72 (t, J=6.32 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 2.02 (m, 2H) 1.18 (t, J=7.32 Hz, 3H). [M+H] calc'd for C22H22ClN2O4S, 445; found, 445.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH2:5].F[C:8]1[C:25](F)=[CH:24][C:23]([I:27])=[CH:22][C:9]=1[C:10]([C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11].[H-].[Na+]>CN1C(=O)CCC1>[I:27][C:23]1[CH:22]=[C:9]2[C:10](=[O:11])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][N:5]3[CH2:4][C:3](=[O:6])[N:2]([CH3:1])[C:25]([CH:24]=1)=[C:8]23
Reactant: CNC(=O)CN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)N(C)C(=O)C2
Temperature: 100 °C
Yield: 60.7 %

Procedure:
Glycine methylamide (1.0 g) is added at room temperature to a solution of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation 21, 2.0 g) in NMP (20 mL). Sodium hydride (400 mg, 60% dispersion in mineral oil) is added in two portions to the solution, and the solution is heated at 100° C. for 30 min. The product is partitioned between chloroform and water, the chloroform phase is concentrated and applied to a silica gel column with 1-2% methanol chloroform as the eluant. The purified fractions are triturated with ether to give 1.22 g of the title compound. Physical characteristics: M.p. 278-283° C.; 1H NMR (DMSO-d6) δ1.29, 3.63, 4.23, 5.10, 7.65, 8.09, 8.55. Anal. Found: C, 43.49; H, 3.18; N, 6.75.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CO)cc3)nc2)CC1
Yield: 77.3 %

Procedure:
1-Methylethyl 4-[({6-[4-(hydroxymethyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (208 mg, 77%) was prepared as a white solid from 4-(hydroxy methyl)phenylboronic acid (130 mg, 0.84 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 250 mg, 0.70 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (4 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.37 (bs, 1H), 7.94 (d, 2H, J=7.9 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.46 (d, 2H, J=8.1 Hz), 7.45-7.30 (bs, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.74 (s, 2H), 4.21 (bs, 2H), 3.90 (d, 2H, J=6.2 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 385 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:28])=[O:27].CCN(CC)CC.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:25])[S:44]([C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
To secondary amine 30 (150 mg, 0.35 mmol, 1 eq.) in dry DCM (15 mL) at 0° C. was added Et3N (3 mL) followed by dropwise addition of a DCM solution of 4-fluorobenzenesulfonyl chloride (90 mg, 0.42 mmol, 1.2 eq). After stirring at 0° C. for 20 min, the mixture was stirred at room temperature for 2 h. The reaction was extracted between DCM and water and the organic layer was washed with 1N HCl, saturated NaHCO3 solution, and brine, dried (Na2SO4), and concentrated in vacuo to give 150 mg (72%) of t-butyl 2-((4-fluoro-3-(methylsulfonyl)phenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (31) as oil which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26])C.[OH-].[Na+]>C(O)C.CO.O1CCCC1>[F:26][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)c(F)c3)cc21
Temperature: 70 °C
Yield: 27.1 %

Procedure:
A solution of 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)benzoic acid ethyl ester (Compound 9, 0.1 g, 0.274 mmol) in ethanol(4 mL), methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 1M aqueous sodium hydroxide solution and heated at 70° C. for 1 h. The volatiles were distilled off in vacuo and the residue was diluted with water and dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot aqueous acetonitrile to afford the title compound (0.025 g, 27%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[OH-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19].C(=O)=O>O1CCOCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([F:15])[CH:17]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(N)cc1F
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2ccccc2N)cc1F
Temperature: 25 °C
Yield: 38.4 %

Procedure:
To a stirred suspension of isatoic anhydride (1.63 g, 10 mmol) in 15 mL dioxane at room temperature under nitrogen was added powdered sodium hydroxide followed by 3-fluoro-4-methoxyaniline (1.41 g, 10 mmol). The mixture was immersed in a room temperature oil bath and slowly heated to reflux. Carbon dioxide gas evolution was evident. After stirring at reflux for 2 hours, the reaction mixture was cooled to room temperature and inorganics were filtered off with dioxane. The filtrate was concentrated to dryness to a brown solid. The crude product was dissolved in a minimum of hot 95% EtOH and crystals formed upon cooling. The crystals were filtered off and rinsed with a minimum of ice cold 95% EtOH to give a tan solid (1.0 g, 39%). 1H-NMR (400 MHz, CDCl3) δ 7.66 (br s, 1H), 7.50 (dd, 1H), 7.44 (dd, 1H), 7.26 (m, 1H), 7.17 (m, 1H), 6.95 (m, 1H), 6.71 (m, 2H), 5.50 (br s, 2H), 3.89 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.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:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCn1ccc2ccc(Br)cc21
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Yield: 55.8 %

Procedure:
Following the procedure described in Step 2 of Example 2, 6-bromo-1-ethyl-1H-indole (0.410 g , 1.83 mmol) was reacted with 4-trifluoromethoxybenzene boronic acid (0.422 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium (0.0651 g, 0.0563 mmol), and sodium carbonate (0.792 g, 7.47 mmol) in water (3.7 mL), ethanol (1.4 mL), and toluene (8 mL). Purification by flash chromatography using hexane as an eluant yielded the title compound as a yellow oil (0.312 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ 7.85 (d, 2H, J=6.3 Hz), 7.8 (s, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.4-7.5 (m, 3H), 7.35 (d, 1H, J=6.2 Hz), 6.45 (d, 1H, J=2.3 Hz), 4.3 (q, 2H, J=7.0 Hz), and 1.4 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3]1>C1C=CC=CC=1.O.C(OCC)(=O)C.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]([CH3:20])([CH3:1])[CH:3]=[C:4]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)C=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C=C(c2ccccc2)c2cc(N)ccc21
Yield: 98.7 %

Procedure:
To a mixture of 1,1-dimethyl-5-nitro-3-phenyl-1H-indene (0.56 g, 2.11 mmol) in 5 mL of benzene was added 33% ferric chloride (1 mL) and 4 mL of water. The mixture was stirred at reflux and iron powder 1.00 g, 5.28 mmol) was added in four portions during 2 hours. The resulting mixture was stirred at reflux for additional 18 hours. The mixture was diluted with 20 mL of water and 20 mL of ethyl acetate, and filtered through a pad of celite. The filtrate was extracted with ethyl acetate (20 mL×3). The combined extracts were dried over magnesium sulfate to give 0.49 g (98% yield) of the crude title compound which was not further purified and used in the next reaction; 1H-NMR (CDCl3) δ1.37 (s, 6H), 6.40 (s, 1H), 6.71 (dd, J=2.0, 7.9 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.36-7.58 (m, 5H); MS m/e 236 (MH+).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](OC)=[O:15])([O-])=O.O>C(OCC)(=O)C.CO>[O:15]=[C:14]1[CH:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1Cc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Sodium borohydride (1.10 g) was added to the mixed solution of dimethyl 2-[(2-nitrophenyl)methylidene]malonate (15.2 g) in ethyl acetate (50 ml) and methanol (200 ml) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. Water was added to the mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. 5% Palladium-carbon (6.26 g) was added to the mixed solution of the residue in THF (100 ml) and methanol (100 ml), and catalytic hydrogenation was conducted at room temperature under atmospheric pressure for 3 days. The catalyst was removed by filtration, and the filtrate was concentrated. The obtained crude crystals were washed with a mixed solution of ethyl acetate/hexane=1/4 to give the entitled compound (9.487 g).
Reaction SMILES: [Cl:1][CH2:2][S:3]([N:6]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:5])=[O:4].C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[Cl:1][CH2:2][S:3]([N:6]([CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:4])=[O:5]
Reactant: CN(C)CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)CCl
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCN(C1CCNCC1)S(=O)(=O)CCl
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of the above carbamate (940 mg, 2.36 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 1 hr. After being diluted with CH2Cl2 (10 mL) and H2O (10 mL), the mixture was made alkaline with aqueous NH3. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×15 mL). The combined organic fractions were washed with H2O (2×20 mL) and dried (Na2SO4). Evaporation of the solvent gave chloro-N-[3-(dimethylamino)propyl]-N-(4-piperidinyl)methanesulfonamide (571 mg, 81%): 1H NMR (CDCl3) δ 4.46 (s, 2H), 3.76-3.68 (m, 1H), 3.35-3.31 (m, 2H), 3.16-3.14 (m, 2H), 2.70-2.63 (m, 2H), 2.28 (t, J=6.9 Hz, 2H), 2.22 (s, 6H), 1.88-1.68 (m, 7H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>CC1C=CC=CC=1C.C(OCC)(=O)C>[CH2:21]([O:23][P:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])([O:25][CH2:26][CH3:27])=[O:28])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Temperature: 25 °C
Yield: 58 %

Procedure:
2-Bromomethyl-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester (Example 44, 2.0 g, 5.46 mmol) was dissolved in 100 mnL of anhydrous o-xylene. To this solution was added triethylphosphite (3.75 mL, 21.84 mmol). A water cooled condenser was attached and the material was heated to exactly 100° C. After six hours the mixture was cooled to room temperature then diluted with with ethyl acetate (400 mL) and washed with brine (2×). After drying over MgSO4 the organic layer was concentrated on a rotovap and then purified by flash column chromatography using 50 to 60% ethyl acetate/hexanes gradient as an eluant to provide 1.34 g of the title compound as a yellow oil.(55%): 1HNMR (CDCl3) δ8.87 (m, 1H), 8.43 (dd, J=9 Hz, 2 Hz, 1H), 8.05 (dd, J=9 Hz, 2 Hz, 1H), 4.12 (m, 4H), 3.81 (s, 2H), 3.77 (d, J=23 Hz, 2H), 1.32 (m, 6H), 0.96 (s, 9H); MS (ES-POS): [M+Na]+ 446; Analytical HPLC determined that this compound was 96.1% pure by C-18 reverse phase.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:31]>CC(=O)CC>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33]2)=[O:31])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C(CCCCBr)N1CCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)=O
Product: O=C(CCCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 45 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (8.0 g) and diisopropylethylamine (15 mL) in butanone (50 mL) was heated to 45° C. followed by the addition of 5-bromo-1-(2,3-dihydro-1H-indol-1-yl)pentan-1-one (5.4 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (3.8 g). Mp 121–123° C. 1H NMR (DMSO-d6): 1.50–1.70 (m, 4H); 2.30–2.65 (m, 8H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 432 (MH+), 315, 202.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:10])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12
Reactant: NC(=O)c1cnc2sccc2c1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1cnc2sccc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A mixture of 4-chlorothieno[2,3-b]pyridine-5-carboxamide (145 mg, 0.68 mmol) and cyanuric chloride (200 mg, 1.08 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 30 minutes. Ice is added to the reaction mixture and the resultant solids are collected by filtration washing with water to provide 84 mg of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 100-103° C.; 1H NMR (DMSO-d6) δ 7.66 (d, J=6 Hz, 1H), 8.26 (d, J=6 Hz, 1H), 9.03 (s, 1H); MS 195.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15](C)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:29](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=CC=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:29])[N:16]=[CH:15][CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)acetic acid (3L) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol (3K) was used instead of compound 1L. 1H-NMR 300 MHz, (CDCl3) δ 8.89-8.86 (m, 1H), 7.98 (s, 1H), 7.75-7.65 (m, 2H), 7.58-7.50 (m, 2H), 7.30-7.20 (m, 2H), 5.30 (s, 1H), 2.66 (s, 3H), 1.02 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClNO3: 384.9. Found:384.1, 386.1.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[NH:15][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[N:15]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:16]=1[CH:17]=[O:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4-Cyanobenzylbromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimidazole-5-carboxaldehyde (1.02 g, 5.39 mmol) in dimethylacetamide (15 mL). The solution was cooled to -10° C. and powdered potassium carbonate (0.745 g, 5.39 mmol) added. The reaction was stirred at -10° C. for 2 h, and a further 4 h at 20° C. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. Solvent evaporation yielded a white solid. 1H NMR (CDCl3, 400 MHz) δ 9.68 (1H, s), 7.64 (2H, d, J=7 Hz), 7.15 (2H, d, J=7 Hz) 5.59 (2H, s), 2.40 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25]OS(C)(=O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:25][CH2:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:17][C:13]=1[CH3:12])[CH:5]=[O:6]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3,5-dimethyl-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride then gave 3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(Z,E)-methoxy-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid as light yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]12([CH2:13][OH:14])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[C:3]12([CH2:13][O:14][C:20]3[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[C:17]=3[C:18]#[N:19])[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 94.4 %

Procedure:
To a cold (ice water) suspension of sodium hydride (206 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 1-adamantane methanol (830 mg; 4.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 40 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (702 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed and the resulting solid is dried under vacuum at 40° C. for 3 hours to give 1.32 grams of 2-(adamantan-1-ylmethoxy)-6-fluorobenzonitrile.