Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].[Cl-:16].[NH4+]>C(OCC)C>[Cl:16][C:5]1[CH:10]=[CH:9][C:8]([Sn:12]([CH3:14])([CH3:13])[CH3:11])=[CH:7][CH:6]=1
Reactant: Brc1ccccc1
Reactant: C[Sn](C)(C)Cl
Reactant: [Cl-]
Agent: II
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
A small quantity of iodine was put in a vessel containing 280 mg (12 mmol) of metal magnesium and 10 ml of anhydrous diethyl ether, and a solution of 2.0 g (10 mmol) of 4-bromobenzene in 10 ml of anhydrous diethyl ether was gradually added dropwise under stirring. Reaction progressed rapidly, and after the reaction somewhat calmed down, the mixture was heated and stirred at 50° C. for further 3 hours. Thereafter, the reactor was cooled to 0° C., 2.1 g (10 mmol) of trimethyltin chloride was added, and the mixture was heated again to 50° C. and refluxed for 2 hours. After the reaction, the reaction solution was cooled again to 0° C., saturated ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) and vacuum distillation to give 1.9 g of 4-chlorophenyltrimethyltin as a colorless oil (yield 64%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15]1([CH:23]=[C:21](O)[CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>[Cl-].[Cl-].[Zn+2].O=P(Cl)(Cl)Cl>[OH:16][C:15]1[C:23]2[C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[O:1][C:21]=2[CH:20]=[C:18]([OH:19])[CH:17]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Oc1cc(O)cc(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Temperature: 80 °C
Yield: 9.8 %

Procedure:
A mixture of 3-hydroxy-2-naphthoic acid (2.0 g, 10.63 mmol), phloroglucinol (1.34 g, 10.63 mmol), ZnCl2 (3.30 g, 24.24 mmol) and POCl3 (40 mL) was stirred under reflux at 80° C. for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to 1 L of ice water. The resulting solid was allowed to stand (1 d), filtered, washed with water, and then dried under reduced pressure to obtain an ocherous compound. This compound was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (289 mg, 9.8%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[NH:23][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Reactant: CC(C)N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
Combine [4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid (400 mg, 1.5 mmol), isopropylamine (0.14 mL, 1.65 mmol), EDC (345 mg, 1.8 mmol), HOBt (243 mg, 1.8 mmol), triethylamine (0.63 mL, 4.5 mmol) and DMAP (18.3 mg, 0.15 mmol) in anhydrous DCM (15 mL). Stir at room temperature for 1 day under nitrogen. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (426 mg, 92%). MS (ES+) m/z: 324 (M+NH4+)+.
Reaction SMILES: [O-]CC.[Na+].[Na].[Cl:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:10][C:11](=[CH:14]N(C)C)[CH:12]=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C.C(O)(=O)C.O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:10][C:11]1[CH:14]=[N:22][C:23]([OH:24])=[N:25][CH:12]=1
Reactant: NC(N)=O
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of sodium ethoxide, prepared from sodium (0.95 g, 41.4 mmol), 2-(3,4-dichlorophenoxy)-3-dimethylamino-propenal (5.38 g, 20.7 mmol) and urea (2.48 g, 41.4 mmol) in ethanol (25 ml) was heated at 60° C. for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.92 g, 17% yield) as a brown solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].COC[C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.C(Br)C(C)C>>[CH:2]([C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1)=[C:1]([CH3:4])[CH3:3].[C:1]([NH:5][C:6](=[O:7])[O-:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: CC(C)(C)NC(=O)O
Solvent: CC(C)CBr
Product: CC(C)(C)NC(=O)[O-]
Product: CC(C)=CC1(S(N)(=O)=O)CC1

Procedure:
Step 44a) This compound, 1-(2-Methyl-allyl)-cyclopropanesulfonamide-tert-butylcarbamate, was obtained in 95% (1.18 g) from 1.0 g (4.52 mmol) of cyclopropanesulfonamide-tert-butylcarbamate according to the procedure described in the synthesis of 1-methoxymethylcyclo-propylsulfonylamine tert-butylcarbamate (Step 15IId) except 1.1 equivalents of iso-butyl bromide was used as electrophile: 1H NMR (CDCl3) □ ppm 0.93 (m, 2H), 1.49 (s, 9H), 1.73 (m, 2H), 1.78 (d, J=7.93 Hz, 3H), 2.58 (s, 2H), 4.87 (m, 1H), 4.88 (m, 1H), 6.77 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]=[CH2:20])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:22]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]3[CH2:22][CH2:20]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C=COCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: CCOCC
Product: Clc1ccc(Br)cc1Cc1ccc(CCOC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(2-(vinyloxy)ethyl)benzyl)benzene (100 mg, 0.27 mmol) and Et2Zn (0.68 mL, 0.68 mmol, 1.0 M in hexane) in dry ethyl ether (2 mL) was added diiodomethane (0.06 mL, 0.68 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and then with brine (10 mL), and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC (eluent EA:PE=1:25) to obtain intermediate CR (86 mg) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.32˜7.24 (m, 3H), 7.18 (d, 2H), 7.12 (d, 2H), 4.05 (s, 2H), 3.73 (t, J=7.2 Hz, 2H), 3.32˜3.29 (m, 1H), 2.88 (t, J=7.2 Hz, 2H), 0.57˜0.44 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=[O:16])[CH2:5][O:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: CCO
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to the procedure described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90 using (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (D44, 3.13 g, 13.33 mmol) in EtOH (30 mL), cooling in an ice bath before adding Thionyl Chloride (1.46 mL) dropwise, and then stirring at R.T. for 6 hours. Added more thionyl chloride (1 mL) and stirring at R.T. overnight. Added more thionyl chloride (1 mL) and stirred for 4 hours, added further thionyl chloride (0.5 mL) and stirred overnight again. Added thionyl chloride (0.2 mL) and left stirring for 5 hours. Solvent evaporated to afford the title compound as an orange oil in quantitative yield.
Reaction SMILES: [CH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][CH2:11][C:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCC1=CC2(CCCCC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: BrCC1=CC2(CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained in Step 5 in chloroform (1 mL) were added triphenylphosphine (87 mg) and N-bromo-succinimide (87 mg) under ice-cooling, followed by stirring the reaction mixture at room temperature for 1 hour. Then, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (hexane) to give 2-bromomethyl-spiro[4.5]dec-1-ene (55 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][Si:12]([CH3:15])(Cl)Cl.O>O1CCCC1.C([Li])CCC.CCCCCC>[CH3:11][Si:12]([CH3:15])([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH3:1])[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1[Si](C)(C)C1C(C)=Cc2ccccc21
Reaction time: 1 h
Yield: 68 %

Procedure:
In a 500 ml glass reactor, 4.3 g (33 mmole) of 2-methylindene was dissolved in 80 ml of tetrahydrofuran, to which 21 ml of 1.6M n-butyllithium in hexane was slowly added under cooling. After the mixture was stirred at room tempearture for 1 hour, it was cooled again, and 2.1 g of dimethyldichlorosilane was added dropwise. After the mixture was stirred at room temperature for 12 hours, 50 ml of water was added, and the organic phase was separated and dried to give 3.5 g of dimethylbis(2-methylindenyl)silane.
Reaction SMILES: [P:1]([O:39]CC1C=CC=CC=1)([O:31]CC1C=CC=CC=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[O:18])=[N:12]2)=[C:6]([C:27]([F:30])([F:29])[F:28])[CH:5]=1)=[O:2]>C(O)C.CO.CS(C)=O.[Pd]>[P:1]([OH:39])([OH:31])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[O:18])=[N:12]2)=[C:6]([C:27]([F:30])([F:29])[F:28])[CH:5]=1)=[O:2]
Reactant: O=C(Nc1ccn(Cc2ccc(OP(=O)(OCc3ccccc3)OCc3ccccc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccn(Cc2ccc(OP(=O)(O)O)cc2C(F)(F)F)n1)c1c(F)cccc1F

Procedure:
A solution of 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl bis(phenylmethyl) phosphate (for a preparation see Intermediate 58)(15.85 g, 24.1 mmol) in ethanol (200 ml) was hydrogenated using the H-cube midi (settings: 25° C., 15 bar, 10 ml/min flow rate) and 10% Pd/C CatCart as the catalyst. The solvent was evaporated in vacuo to give a white foam. The sample was loaded in methanol/DMSO and purified on reverse phase (C18) 1900 g using a 0-50% acetonitrile (+0.1% TFA)-water(+0.1% TFA) over 7 column volumes. The appropriate fractions were combined and the acetonitrile was removed in vacuo. The resulting suspension was filtered to give 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl dihydrogen phosphate (5.02 g). The filtrate was extracted using ethyl acetate (600 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo to give a further amount of 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl dihydrogen phosphate as a white solid (2.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH:27]([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)Br
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(C)C)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available 2-bromopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.77 min.; [M+H]+: 384.28 g/mol.
Reaction SMILES: [C:1]1(=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]1(=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
tert-Butyl (2E)-3-{4-[cyclooctylidene(4-hydroxyphenyl)methyl]phenyl}prop-2-enoate (50) (0.0586 g, 0.140 mmole) was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was recrystallized from EtOAc to provide compound 51 (0.013 g, 25%) as a white solid. 1H NMR (DMSO-d6): δ 12.32 (s, 1H), 9.27 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.51 (d, J=16.1 Hz, 1H), 7.14 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.43 (d, J=16.1 Hz, 1H), 2.18 (m, 4H), 1.59 (m, 2H), 1.45 (m, 8H). LRMS (ESI): m/z 361 (M−H)−.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:10]1[CH2:11][CH2:12][CH:8]([C:7]2[C:2]([O:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:14]4[S:13][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[N:15]=4)=[CH:28][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Fc1ncccc1C1CCOC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOC2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydrofuran-3-yl)pyridine (1.00 g, 5.98 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (1.56 g, 6.44 mmol) and cesium carbonate (4.88 g, 14.98 mmol) in DMSO (10 mL). The reaction mixture was sealed under argon and was heated thermally at 100° C. for 24 h. The reaction was cooled to rt and diluted with water. The product turned into a gum and the aqueous solution was decanted. The gum was stirred over MeOH for 1 h resulting in a precipitate that was filtered, washed with MeOH and dried in vacuo to give the title compound as a white crystalline solid. MS (ESI, pos. ion) m/z: 389.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Br:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[OH-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:45][N:46](C)[OH:47].C(N(CC)CC)C>O1CCCC1>[Br:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:46]([O:47][CH3:32])[CH3:45])=[O:29])[C:12]([CH3:28])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Reactant: CN(C)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 3-[5-bromo-2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (148 mg, 0.31 mmol) in tetrahydrofuran (2 mL) was added 1N sodium hydroxide (1 mL) and the solution stirred at ambient temperature for three hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to provide a yellow oil used without any additional purification. To a solution of the crude acid in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (75 mg, 0.46 mmol). After stifling at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (45 mg, 0.46 mmol) and triethylamine (0.09 mL, 0.62 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a yellow oil (60 mg, 40%). MS (M, M+2): 487, 489
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]=[O:14])[CH:12]=1)[O:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]2([CH3:18])[CH3:17])#[CH:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)(=O)C>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>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([CH:13]=[O:14])[CH:12]=2)[O:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]3([CH3:18])[CH3:17])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(C=O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure J and using 6-ethynyl-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Compound 44, 0.39 g, 1.61 mmol), 4-iodo phenyl acetic acid methyl ester (0.444 g, 1.61 mmol), triethyl amine (10 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.090 g, 0.13 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent the title compound was obtained as an oil (0.5 g, 80%).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:10](=O)[CH2:11][CH3:12])\[C:6]([O:8][CH3:9])=[O:7])C.[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:11]([C:10]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:2]=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:12]
Reactant: NNc1ccccc1
Reactant: CCC(=O)/C(=C/N(C)C)C(=O)OC
Solvent: CCO
Product: CCc1c(C(=O)OC)cnn1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Methyl (2Z)-2-[(dimethylamino)methylene]-3-oxopentanoate (383 mg, 2.07 mmol) and phenylhydrazine (0.308 ml, 3.10 mmol) were added to ethanol (4 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford methyl 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: C(NC(=O)O)C1C=CC=CC=1.N[CH:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([N:24]([CH:31]([CH3:33])[CH3:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[C:15]([CH3:38])=[N:14]1>CO.[Pd]>[CH:31]([N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](=[O:23])[CH2:21][N:18]1[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH:15]([CH3:38])[NH:14][CH2:13][C:19]1=[O:20])([CH3:32])[CH3:33]
Reactant: CC1=NC(N)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Agent: [Pd]
Agent: O=C(O)NCc1ccccc1
Solvent: CO
Product: CC1NCC(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Reaction time: 15 h
Yield: 108.7 %

Procedure:
To 2-(3-amino-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide benzyl carbamate (783 mg, 1.60 mmol) in methanol (16 mL) was added 10% palladium on carbon (320 mg). The resulting mixture was stirred under a hydrogen atmosphere for 15 h. The solids were removed by filtration through a pad of celite. The celite pad was washed with methanol and the filtrate concentrated in vacuo to give the titled compound (611 mg, 100%). Rf =0.04 (2/3 ethyl acetate/hexane); 1HNMR (300 MHz, CD3OD) d 1.06 (d, J=6.9 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H), 1.47 (d, J=6.3 Hz, 3H), 3.18 (s, 2H), 4.07 (d, J=16.6 Hz, 1H), 4.20 (d, J=16.6 Hz, 1H), 4.43 (m, 1H), 7.21 (m, 1H), 7.34 (m, 6H), 7.51 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[CH:25][O:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1nocc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=1.[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:29]=[C:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[S:24][C:19]([C:17]2[N:18]=[C:13]([CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[CH:14]=[CH:15][CH:16]=2)=[N:20]1
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 78.8 %

Procedure:
6-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-pyridinecarbonitrile (1.25 g, 4.7 mmol) and methyl thiosalicylate (1.59 g, 9.4 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The reaction mixture was refluxed for 15 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-chloroform to give the titled compound (1.48 g, 78%) as white crystals.