Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C([OH:24])C>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([OH:24])(=[O:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CCO
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phytanol (19.5 g) was dissolved in acetic acid (250 ml) and cooled in an ice bath. Chromium trioxide (21.0 g) dissolved in a minimum amount of water was added to the above solution and stirred at room temperature for 18 hours. Ethanol (50 ml) was slowly added to the reaction mixture and stirred for a further 3 hours. Most of solvent was removed and water (250 ml) was added. This solution was extracted with ether (2×200 ml) and the combined ether extract was dried (MgSO4), decolourized with activated charcoal and filtered through a thin flash silica bed. The solvent was removed and the crude product chromatographed on flash silica (1-4% methanol in dichloromethane) to give phytanoic acid as a pale yellow liquid. Yield 7.03 g, 34%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])[C:10]=2[C:11]([NH2:13])=[O:12])[CH:5]=[N:6][CH:7]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[CH:3]=2)[C:10]([C:11]([NH2:13])=[O:12])=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH:15]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cncc(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)S(=O)(=O)Nc1cncc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In analogy to GP 6b, 100 mg of 2-(5-Amino-pyridin-3-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 3.1; 0.21 mmol, 1 eq.) were dissolved in 1.5 mL pyridine and treated with 37 mg iso-propylsulfonyl chloride (0.26 mmol, 1.25 eq., dissolved in 0.5 mL pyridine). The reaction mixture was stirred at rt overnight, treated with another 1.25 eq. sulfonylchloride (in 0.2 mL pyridine) and stirring was continued at rt overnight. After addition of further 1.25 eq. sulfonylchloride (in 0.2 mL pyridine) and further stirring at rt for 3 days, the resulting mixture diluted with ethyl acetate, washed with water and the organic layers dried. Concentration in vacuo was followed by prepurification by chromatography and subsequent HPLC purification to provide the desired compound.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]=[C:14]1[C:22]1[C:26]([NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[F:1])=[CH:25][NH:24][N:23]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)O)c1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(=O)Nc2c[nH]nc2-c2nc3ccccc3[nH]2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 8 %

Procedure:
A mixture of 2-fluoro-3-methoxybenzoic acid (47 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 h. The reaction mixture was poured into water (30 ml) and the resultant solid collected by filtration and purified by re-crystallisation from MeOH/petrol to yield N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-fluoro-3-methoxy-benzamide (7 mg, 8%) as a gray solid. (LC/MS: Rt 3.63, [M+H]+ 352.00).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[C:28]([NH:39][CH:40]([CH3:42])[CH3:41])[CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.O.[Pd].C(Cl)(Cl)Cl>[OH:43][C@H:8]([C:5]1[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=1)[CH2:9][N:10]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[O:33])=[C:28]([NH:39][CH:40]([CH3:42])[CH3:41])[CH:27]=2)=[CH:24][CH:25]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)Nc1cc(-c2ccc(CCN(C[C@H](O)c3ccc(Cl)nc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)Nc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (132 mg) in methanol (3.0 ml) and water (0.30 ml) were added ammonium formate (66 mg) and palladium on carbon (66 mg) at room temperature. The mixture was stirred under reflux for 1 hour. The suspension was cooled to room temperature, diluted with chloroform and filtrated. The filtrate was concentrated in vacuo and the residue was dissolved with chloroform, methanol and water. The organic layer was separated, and the aqueous layer was extracted with chloroform and methanol twice. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3′-(isopropylamino)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (123 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A dichloromethane (40 ml) solution of 16.58 ml (233.6 mmol) of dimethyl sulfoxide was added dropwise to a dichloromethane (200 ml) solution of 10.19 ml (116.8 mmol) of oxalyl chloride at −78° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction solution was added dropwise a solution of 23.50 g of literary known 1-benzyloxycarbonyl-3-hydroxypyrrolidine in 200 ml of dichloromethane at −78° C., followed by 60 minutes of stirring at the same temperature. This solution was mixed with 74.02 ml (531.1 mmol) of triethylamine at −78° C., and stirred for 60 minutes at the same temperature and then at room temperature for 60 minutes. After completion of the reaction, 500 ml of water was added dropwise to the reaction solution, and the organic layer was separated. The aqueous layer was washed with dichloromethane (100 ml×2), and combined organic layer was washed with saturated brine (300 ml×1). After drying the organic layer over sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 20.1 g (86%) of the title compound as an oily product from the eluate of n-hexane:ethyl acetate=1:1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4.36 g of 4-methyl-phenol in 70 ml of dry dimethylsulfoxide under nitrogen with stirring is added 9.0 g of potassium t-butoxide. After stirring for 15 minutes, 0.1 g of copper metal is added followed by 10.0 g of 4-iodobenzoic acid. The reactants are stirred under nitrogen while heating at 210° C. for 18 hours. The cooled reaction mixture is extracted with chloroform (2×900 ml) and the remaining water acidified with 2N HCl (pH=3) with ice bath cooling, to give 8.1 g of the desired product. MS(M+H=229.0).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2nc(Sc3ccc(Cl)cc3)sc2c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Sc2nc3ccc(OCCCCBr)cc3s2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.74 g (2.5 mmol) of 6-hydroxy-2-(4-chlorophenylmercapto)-benzothiazole are dissolved in 20 ml of dimethylformamide and after the addition of 2.16 g (10 mmol) of 1.4-dibromobutane and 2.07 g (15 mmol) of potassium carbonate the resulting mixture is stirred for 20 hours at ambient temperature. The mixture is then added to water and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is purified by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate=4:1). Yield: 0.85 g (79.3% of theory), oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[C:14]([NH:20][C:21]4[C:26]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][N:28]=5)=[CH:25][CH:24]=[CH:23][N:22]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(N(CC)CC)C.[CH3:45][Si:46]([C:49]#[CH:50])([CH3:48])[CH3:47]>O.ClCCl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:19][C:15]1[CH:16]=[CH:17][C:18]2[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:50]#[C:49][Si:46]([CH3:48])([CH3:47])[CH3:45])[CH:3]=3)=[N:10][CH:11]=[CH:12][C:13]=2[C:14]=1[NH:20][C:21]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc2c(Nc3cccc(Br)c3)nccc2c1Nc1ncccc1-c1ccncn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cccc(C#C[Si](C)(C)C)c3)nccc2c1Nc1ncccc1-c1ccncn1
Reaction time: 48 h

Procedure:
Dissolved N1-(3-bromophenyl)-6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine (0.1125 g, 0.233 mmol) in DMF (0.427 ml, 5.84 mmol) and triethylamine (0.162 ml, 1.16 mmol). Added trimethylsilylacetylene (0.0987 ml, 0.698 mmol) followed by copper (I) iodide (0.00887 g, 0.0465 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.0163 g, 0.0233 mmol). Sealed vessel and stirred reaction mixture at 70° C. After 48 hours, the reaction mixture was diluted with 100 mL water and 100 mL dichloromethane. The layers were separated and the organics washed with 2× water and 2× brine. The organics were dried over sodium sulfate, concentrated in vacuo and purified by column chromatography (20-80% EtOAc/hexanes). The combined fractions of the main peak were concentrated in vacuo to afford 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(2-(trimethylsilyl)ethynyl)phenyl)isoquinoline-1,5-diamine as a crystalline solid. MS (M+H)+ 501.2.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](Br)[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.O1CCCC1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CCCCCC.[Cu]I.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.C(OCC)(=O)C>[CH:1]1([N:4]([CH3:5])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(CN(C)C2CC2)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN(C)C2CC2)cc1C#C[Si](C)(C)C
Yield: 94.1 %

Procedure:
Following General Procedure D and using cyclopropyl-(3-bromo-4-methyl-benzyl)-methyl-amine (Intermediate 97, 2.24 g, 8.81 mmol), triethyl amine (10 mL), tetrahydrofuran (5 mL), copper(I)iodide (0.4 g, 2.1 mmol), trimethylsilyl acetylene (5 mL, 35.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.45 g, 2.06 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 6-10% ethyl acetate in hexane as the eluent, the title compound (2.25 g, 94%) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:30]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: Cc1cccc(B(O)O)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 67.1 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (85 mg, 0.197 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). (3-Methylphenyl)boronic acid (40.1 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (22.75 mg, 0.020 mmol) and potassium carbonate (54.4 mg, 0.394 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (58.6 mg). LCMS (A) m/z: 443 [M+1]+, Rt 1.53 min (acidic).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:23]N(C)C=O.CI>O>[CH3:23][O:3][C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimthylformamide which has been cooled to 0° C is added dropwise a solution of 0.01 moles of ethyl 3-hydroxy-4-cyclohexylphenylglyoxylate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 3-methoxy-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C.O>[CH:1]1([CH2:7][CH2:8][NH:17][CH2:16][C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccncc1
Reactant: BrCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1cc(CNCCC2CCCCC2)ccn1

Procedure:
To a solution of 2-cyclohexylethyl bromide (1.50 g) in ethanol (16 ml) are added 4-picolylamine (1.00 g), anhydrous potassium carbonate (1.32 g) and sodium iodide (3.49 g), and the mixture is refluxed for 17 hours with stirring. Water is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give the titled compound (Reference compound No. 2-1, 0.68 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:28])[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:21](=[O:27])[C:18]1[CH:17]=[CH:16][C:15]([C:14]([Br:28])=[C:11]2[CH2:12][CH2:13][N:8]([CH2:6][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:9][CH2:10]2)=[CH:20][CH:19]=1)[CH3:26]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Compound 6, prepared in Example 1 (v) above (6.122 g, 13.4 mmoL), was treated with TFA (13 mL) in dichloromethane (80 mL) at room temperature. After 2 h, the reaction mixture was washed with 2M sodium hydroxide (25 mL) and the organic layer was separated. The organic layer was dried (MgSO), filtered and concentrated. The residue was dissolved in dichloromethane (120 mL), cooled to 0° C. and benzyl bromide (1.8 mL, 15.1 mmol) and triethylamine (5.7 mL, 41.0 mmol) were added. The reaction was gradually warmed to room temperature and after 20 hours the reaction was washed with water (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 50 to 60% ethyl acetate in hexanes gave 3.80 g of product (64% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=C2CCCCCC2)c2ccc(Br)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(C(=C2CCCCCC2)c2ccc(Br)cc2)c1
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a cold (5° C.) solution of {(4-bromophenyl)[3-(methyloxy)phenyl]methylidene}cycloheptane (192) (0.557 g, 1.5 mmol) in CH2Cl2 (50 mL) was added BBr3 (0.425 mL, 4.5 mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C. for 4 h and then carefully poured into water (100 mL). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×50 mL) and the combined organic layer dried (Na2SO4). Concentration and purification by flash column chromatography gave 0.44 g (82%) of compound 193 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.4 Hz, 2H), 7.17 (dd, J1=7.8 Hz, J2=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.74 (br d, J=7.5 Hz, 1H), 6.69 and 6.67 (dd, J1=2.4 Hz, J2=8.1 Hz, 1H), 6.62 (app t, J=1.8 Hz), 4.71 (s, 1H), 2.32 (br, m, 4H), 1.59 (br s, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:16]([CH3:15])(=[O:18])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To a stirred solution of 3-bromo aniline (6 g, 34.87 mmol) in dry DCM (200 ml) at 10° C. was added pyridine (4.13 mg, 52.31 mmol) followed by methane sulfonyl chloride (5.194 g, 45.34 mmol) and stirred at RT for 15 h. The reaction was monitored by TLC (35% Ethyl acetate in hexane). The reaction mixture was diluted with DCM (50 ml) and washed with 1N HCl (25 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 8.45 g (96.3% yield) of N-(3-bromophenyl) methanesulfonamide. 1H NMR (DMSO-d6, 300 MHz): δ 10.01 (s, 1H), 7.368 (s, 1H), 7.365-7.19 (m, 3H), 3.03 (s, 1H). MS: m/z=251.8 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])=[CH:11][CH:10]=1.[Si:27]([O:34][CH2:35][CH2:36][C:37]1[CH:38]=[C:39]([CH:42]=O)[S:40][CH:41]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Si](OCCC1C=CSC=1C=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O.CC(O)=O>[Si:27]([O:34][CH2:35][CH2:36][C:37]1[CH:38]=[C:39]([CH2:42][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[S:13][C:9]([CH3:8])=[CH:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)[S:40][CH:41]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)[Si](C)(C)OCCc1ccsc1C=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)s1
Reaction time: 0.08 h

Procedure:
(5-Methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.230 g) was added to a stirred solution of a 4:1 mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde and 3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 27, step b) (0.20 g) and AcOH (0.033 mL) in N-methyl-2-pyrrolidinone (3 mL). After 5 min, sodium triacetoxyborohydride (0.35 g) was added. After 16 h water was added and the mixture extracted with ethyl acetate. The ethyl acetate layer was washed three times with water and evaporated in vacuo. Purification by silica gel chromatography eluting with 20:80:5 ethyl acetate:isohexane:triethylamine, separated the two isomeric products and gave the subtitled compound as a gum. Yield 0.21 g.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCCCCN1CCOCC1
Reaction time: 72 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.