Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:13]([C:11]1[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-isopropyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.66) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.125 g, 59%). MS (ISP) 425.3 [(M+H)+]; mp 274.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C@H:3]([NH:8][C:9]([C:11]1[O:15][C:14]([C:16]2[N:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH:2]([CH3:30])[C@H:3]([NH:8][C:9]([C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:20][N:21]=2)=[CH:13][CH:12]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cn2)o1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(-c3ccccc3)cn2)o1)C(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask charged with trifluoromethanesulfonic acid 6-[5-((S)-2-methyl-1-methylcarbamoyl-propylcarbamoyl)-furan-2-yl]-pyridin-3-yl ester (50 mg, 0.11 mmol), phenylboronic acid (27 mg, 0.22 mmol), palladiumtetrakistriphenylphosphine (13 mg, 0.01 mmol), and potassium carbonate (61 mg, 0.44 mmol) is flushed with argon. Toluene (2 mL), ethanol (0.5 mL), and water (1 mL) are added and the reaction is stirred at 100° C. for 2 hours. The reaction is cooled to room temperature, ethyl acetate (10 mL), is added and the mixture washed with water (10 mL), brine (10 mL), and dried over MgSO4. The solution is filtered and evaporated in vacuo to give an oil that is purified by preparative HPLC. 5-(5-Phenyl-pyridin-2-yl)-furan-2-carboxylic acid ((S)-2-methyl-1-methylcarbamoyl-propyl)-amide is obtained as a white solid, 16 mg, 38%, LC/MS ESI m/z (M+H)+=377.43.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12].C(=O)([O-])[OH:27].[Na+].OO>CO>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]1[O:27][C:6]1([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12]
Reactant: COc1cc(C)cc(C(=O)O)c1C1=CC(=O)c2c(O)cccc2C1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc(C(=O)O)c1C12OC1C(=O)c1c(O)cccc1C2=O
Yield: 95.5 %

Procedure:
In methanol (15 ml) was dissolved 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid (100 mg) as obtained in Example 15, followed by addition of sodium hydrogen carbonate (80 mg). The mixture was stirred under ice-cooling. Then, 30% hydrogen peroxide (1.5 ml) was added dropwise and the reaction mixture was allowed to return gradually to room temperature, at which temperature it was further stirred for 5 hours. The solvent was then distilled off under reduced pressure, dilute HCl was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried by addition of magnesium sulfate and the solvent was distilled off to give 2-(5-hydroxy-2,3-epoxy-1,4-dihydronaphthalene-1,4-dion-2-yl)-3-methoxy-5-methylbenzoic acid (100 mg).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Li]>C1COCC1>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5cccs5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/water) solution of 3-cyclobutyl-1-quinolin-7-ylimidazo[1,5-a]pyrazin-8-ylamine (52.7 mg, 0.167 mmol) in THF (5 mL) was added 2-thienyllithium (1 M in THF; 0.6 mL, 0.6 mmol), then the cooling bath was removed, and the solution was stirred overnight at ambient temperature. After 1 d and 2 d, more 2-thienyllithium (0.2 mL, 0.2 mmol) was added, and stirring was continued. The reaction was quenched by adding water and sat. NH4Cl solution, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine and dried over MgSO4. Air was bubbled into the solution for 8 h. The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-6)→1% MeOH in CH2Cl2 (7-21)→2% MeOH in CH2Cl2 (22-43)], yielding a yellow film. Further purification by preparative TLC (20×20 cm silica gel plates, 500 μM thickness, eluting with 3% MeOH in CH2Cl2 four times) yielded the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.01-2.12 (m, 1H), 2.13-2.27 (m, 1H), 2.47-2.58 (m, 2H), 2.62-2.73 (m, 2H), 3.85 (quint, J=8.0 Hz, 1H), 5.40 (brs, 2H), 7.08 (brd, J=4.8 Hz, 1H), 7.14 (d, J=4.8 Hz, 1H), 7.17 (dd, J=3.6, 5.2 Hz, 1H), 7.48 (dd, J=1.2, 5.2 Hz, 1H), 7.76 (dd, J=1.2, 3.6 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.88-7.91 (m, 2H), 8.28 (dd, J=8.8, 0.8 Hz, 1H), 8.34 (d, J=0.8 Hz, 1H); MS (ES+): m/z 398.0 (60) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][N:13]=[C:12]([CH3:15])[C:11]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH:27]([CH3:29])[CH3:28])[N:13]=[C:12]([CH3:15])[C:11]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)I
Reactant: Cc1n[nH]c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Reaction time: 0.03 h

Procedure:
A solution containing 75 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone in 2 ml of dry N,N-dimethylformamide (DMF) at rt under nitrogen was treated with 12 mg of sodium hydride. The mixture was then stirred for 2 min. To the mixture was added 25 μl of 2-iodopropane. The mixture was then stirred for 20 min. To the mixture was added 2 ml of water and then the mixture was extracted with ethyl acetate three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue 7; was purified by flash chromatography on silica gel using diethyl ether hexane (1:7) for the elution to give 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a colourless oil. Mass spectrum (ES) m/z 405[M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]>C(O)(C)C.[H][H].[Pd]>[C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(NC(=NC#N)Oc3ccccc3)cc2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: N#CN=C(Nc1ccc2c(c1)CC[C@@H](N)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The single enantiomer was then BOC-protected, the nitro group reduced by treatment with H2/Pd and the primary aniline treated with diphenyl cyanocarboimidate (slight excess) in 20 mL of isopropanol with stirring at ambient temperature overnight. The solid was filtered, washed with isopropanol and ether and dried to give phenyl (7S)—N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid in high yield (from the single enantiomer via transamination).
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][N:10]=1)C.[CH3:31][NH2:32]>CO>[CH3:31][NH:32][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1
Reactant: CCOC(=O)CCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCCCc1ccc(CCCCN)cn1

Procedure:
A mixture of 11-6 (45 g, 110 mmol) and a saturated solution of methylamine in methanol (300 mL) in a sealed tube was heated at 70° C. for 12 hours. The mixture was cooled and concentrated to an oil. The residue was chromatographed on silica gel (10:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 11-7 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]2[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]3)=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccc(C(C)(C)C)cc2)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.070 g, 19%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 4-tert-butylbenzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.3 Hz, 3H), 1.06-1.30 (m, 4H), 1.15 (s, 9H), 1.48-1.63 (m, 2H), 2.69 (t, J=8.4 Hz, 1H), 5.31 (s, 2H), 5.47 (s, 2H), 6.74 (d, J=8.4 Hz, 2H), 7.05-7.17 (m, 3H), 7.17 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 8.05 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H); mass spectrum [(+) ESI], m/z 593/595 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]P(OC)(OC)=O)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([O:32][C:33]([N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:45]([CH:51]=O)[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:43]=2)[C:38]([CH3:54])([CH3:53])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:45]([CH:51]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:9][CH:8]=3)[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:43]=2)[C:38]([CH3:53])([CH3:54])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Reactant: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: -20 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A solution of 4-(dimethoxyphosphorylmethyl)-benzoic acid methyl ester (0.94 g, 3.6 mmole) in 10 mL of THF at −20° C., was treated with 3.7 mL of 1M lithium bis(trimethylsilyl)amide solution in hexanes. After 20 minutes at −20° C. a solution of 7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.91 g, 2.4 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −20° C. for 30 minutes, at room temperature for 6 hours, quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.98 g of 7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:21])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2CCCCC
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.9 g, 13.3 mmol) in DMF (35 ml) was added cesium carbonate and the mixture stirred for 10 min whereupon iodomethane (0.91 ml, 14.6 mmol) was added and the mixture stirred for 18 h. The reaction was partitioned between ethyl acetate and 2N HCl solution and the organics isolated, dried (MgSO4) and concentrated. Chromatography on silica SPE eluting with cyclohexane/ethyl acetate (5%-20%) provided the product as an oil, 2.78 g, 68%. m/z 311 [MH+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30](O)=[O:31])=[N:25]1)=[O:14].[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:30]([C:26]1[CH:27]=[C:28]([CH3:29])[N:24]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][OH:1])[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:25]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: Cc1cc(C(=O)O)nn1-c1ccc([N+](=O)[O-])cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Reactant: CCCCNCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (5)-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (14.0 g, 32.1 mmol) in DMF (150 mL) were added dibutylamine (8.6 mL, 48.2 mmol), EDC.HCl (9.2 g, 48.2 mmol), HOBT (5.63 g, 41.7 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (300 mL×2) twice. The combined organic layers were washed with water (300 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as and ‘off white’ solid 9 g (51%). Rf=0.47 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.62-8.22 (m, 2H), 8.00-7.80 (m, 1H), 7.30-6.84 (m, 4H), 6.60-6.35 (m, 1H), 5.20-3.80 (m, 3H), 3.79-2.40 (m, 9H), 2.38-2.20 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 548.0 (M+H).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[Na].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>CN(C=O)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(C)Br
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
A 42 g (0.25 mole) portion of methyl 2-bromopropionate was added to 0.25 mole of the sodium salt of p-benzyloxyphenol (prepared from 13.5 g sodium methoxide and 50 g p-benzyloxyphenoxy) in 70 cc of DMF. The reaction mixture was heated at approximately 80° C. for 14.5 hours. The cooled reaction mixture was then poured into 1 liter ice-water. The product was isolated by ether extraction and was crystallized from methanol to give 45.2 g methyl 2-(4-benzyloxyphenoxy)propanoate, m.p. 38°-42°.
Reaction SMILES: ClCCl.[CH2:4]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Yield: 66.4 %

Procedure:
To dichloromethane (50 ml) was added 1-benzylpiperazine (10.0 g, 56.73 mmol), methanesulfonyl chloride (4.4 ml, 56.85 mmol) was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with 10% aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (9.58 g, yield 66%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: c1cn[nH]c1
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1Cn1cccn1
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (0.268 g, 1.0 mmol), 1H-pyrazole (0.0681 g, 1.0 mmol) and cesium carbonate (0.489 g, 1.5 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 90° C. for 3 h. After cooling to RT, the mixture was diluted with EtOAc, and filtered. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (210 mg, 82.3%) was directly used in next step without further purification. LCMS: (M+H)=256.9/254.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:19]2[NH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:22][N:23]=2)[CH2:5]1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:56])[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:51]([O:50][C:49]([NH:48][CH2:47][C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:27]2[CH:28]=[CH:29][C:24]([C:21]3[NH:20][C:19]([C@@H:6]4[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]4[C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:10])=[N:23][CH:22]=3)=[CH:25][CH:26]=2)=[CH:45][CH:44]=1)=[O:56])=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OCc2ccccc2)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: COCCOC
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Temperature: 85 °C
Yield: 58.9 %

Procedure:
(2S,4S)-benzyl 4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 0.97 mmol), tert-butyl 2-(4-bromophenyl)-2-oxoethylcarbamate (364 mg, 1.16 mmol), Pd(PPh3)4 (112 mg, 0.097 mmol), and K2CO3 (2M in H2O, 1.6 mL, 3.2 mmoL) were combined in DME (10 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 18 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford product (357 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:47][N:48]([CH3:52])[C:49](Cl)=[O:50].[H-].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([O:45][C:49](=[O:50])[N:48]([CH3:52])[CH3:47])([CH3:46])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 30a, 335 mg of 1-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2-methyl-propan-2-ol (from example 128a) and 0.5 g of N,N-dimethylcarbamoylchloride in the presence of 137 mg of potassium hydride are used to afford the title compound as a yellow oil. Rt=5.62.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](OCC)=[O:11])=[C:4]([F:16])[CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:11])[NH:19][N:18]=2)=[C:4]([F:16])[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1F
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
428.4 g of ethyl 3-(4-chloro-2-fluorophenyl)-3-oxopropionate were initially charged in 1400 ml of ethanol. Over a period of 15 min, 92 g of hydrazine hydrate were added dropwise, the mixture was stirred at room temperature overnight, the precipitated solid was filtered off and the filtrate was concentrated to ⅓ of its original volume. The mixture was stirred for another two nights, the resulting solid was filtered off with suction and the filtrate was again concentrated to ⅓ of its original volume. This gave a total of 289.1 g (77.7%) of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid. M.p.: 194° C.
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[O:5][CH:6]([CH2:9][NH2:10])[CH2:7][NH2:8])([CH3:3])[CH3:2].[C:17](SC)(=[O:20])SC>CO>[CH:14]([Si:4]([CH:11]([CH3:13])[CH3:12])([CH:1]([CH3:3])[CH3:2])[O:5][CH:6]1[CH2:7][NH:8][C:17](=[O:20])[NH:10][CH2:9]1)([CH3:16])[CH3:15]
Reactant: CSC(=O)SC
Reactant: CC(C)[Si](OC(CN)CN)(C(C)C)C(C)C
Solvent: CO
Product: CC(C)[Si](OC1CNC(=O)NC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a solution of 2-triisopropylsilanyloxy-propane-1,3-diamine (Step P10) (27.8 g, 113 mmol) in MeOH (450 mL) was added S,S-dimethyl carbonodithioate (17.7 mL, 169 mmol) and the mixture was stirred at 60° C. for 20 h. The reaction mixture was concentrated. The residue was purified by flash chromatography(CH2Cl2/MeOH, 100:0→5:1) to afford the title compound. ESI-MS: [M+H]+273.3 (LC-MS 1-flow injection).