Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13].[CH3:14][O-:15].[Na+]>CO>[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][NH:13][CH:14]=[O:15]
Reactant: Cn1ncc(CCCN)c1N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(CCCNC=O)c1N

Procedure:
To a solution of 3-(5-amino-1-methylpyrazol-4-yl)propylamine dihydrochloride (9.3 g, 40 mmol) in methanol (80 ml) was added 28% sodium methoxide solution in methanol (15.9 g). The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. A solution of the oily residue in ethyl formate (60 g) was stirred under reflux for 20 hours. After cooling, to the reaction mixture was added chloroform. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give N-[3-(5-amino-1-methylpyrazol-4-yl)propyl]formamide (6.7 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[N:4][CH:3]=1.C[CH:14](Br)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]2=[O:12])=[N:4][CH:3]=1
Reactant: Oc1nncc2ncc(Br)cc12
Reactant: CC(Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)cnc2cnn1Cc1ccc(F)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,5-diazaisoquinoline (1.00 g, 4.46 mmol) using methyl 4-fluoro-benzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(4-fluorobenzyl)-7-3-phenylprop-1-ynyl-2H-3,5-diazaisoquinolin-1-one
Reaction SMILES: [O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:38]([Si:40](Cl)([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39].O>CN(C)C=O>[O:1]=[C:2]([C@H:16]([CH3:32])[C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC

Procedure:
A solution of tert-butyl (3S,6R,7S,8S)-5-oxo-3-hydroxy-4,4,6,8-tetramethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.8 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (20:1 toluene/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)[C:2]=1[NH2:1]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Cl)c1N
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a mixture of 2-amino-3-chlorobenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous extractions were collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 581 mg of 2-chloro-6-(1H-tetrazol-5-yl)aniline. MS (EI) for C7H6ClN5: 196 (MH+). Step 2: N-[2-Chloro-6-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 2-chloro-6-(1H-tetrazol-5-yl)aniline (300 mg, 1.5 mmol) in 8 mL of DCM, DIPEA (3.1 mmol, 2.0 eq.) was added followed by thiophene-2-carbonyl chloride (2.3 mmol, 1.5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. The material was then washed with acetonitrile, and dried under vacuum to afford 33 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 7.96 (d, 1H), 7.87-7.81 (m, 3H), 7.58 (t, 1H), 7.23 (t, 1H). MS (EI) C12H8ClN5OS: 306 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Br-:21].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.C(Cl)Cl>[Br:21][C:8]1[NH:9][C:10]2[C:6]([C:7]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:5][CH:4]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[C:2]=2[Cl:1]
Reactant: [Br-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a mixture of the methyl 7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (1 g, 3.43 mmol) in a mixture of THF/CH2Cl2 (9 ml/9 ml) at r.t. under N2 was added pyridinium tribromide (1.33 g, 4.16 mmol, recrystallized from AcOH), and the reaction mixture stirred at r.t. for 2 hr. The mixture was then diluted with CH2Cl2 (40 ml), and the organics washed with NaHCO3 (30 ml, sat. aq.), followed by hydrochloric acid (30 ml, 1N) and brine (30 ml). After concentration of the organic layer, the residue was purified by Biotage flash chromatography (gradient elution, 0 to 20% EtOAc/Hexane) to gave methyl 2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (841.8 mg, 66%) and to recover the starting material (201 mg). 1H NMR (500 MHz): (CD3OD) δ 7.67 (b d, J=8.5, 1H), 7.59 (d, J=8.5, 1H), 3.93 (s, 3H), 2.89 (m, 1H), 2.00-1.90 (overlapping m, 4H), 1.83-1.78 (overlapping m, 3H), 1.50-1.40 (m, 3H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=370.02, 372.03, 374.02, HPLC Rt=2.002 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:15]2[CH2:16][CH2:17][C:12]([CH3:11])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]2)=[S:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (U.S. 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].[C-:16]#[N:17].[Na+]>CCO.O>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][C:16]#[N:17])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 258 (0.8 g, 2.8 mmol) and EtOH:water (4:1) was heated to 50° C. was added NaCN (0.20 g, 4.2 mmol) and the reaction stirred at 50° C. overnight. The reaction was then cooled and concentrated to dryness then partitioned between H2O and EtOAc. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 3:1) to afford 0.5 g (77%) of (S)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile (282).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[ClH:1].[C:14]1([CH:13]2[N:7]=[C:6]([NH2:8])[C:5]3[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: N=C(N)c1ccccc1N
Agent: Cl
Solvent: CCO
Product: NC1=NC(c2ccccc2)Nc2ccccc21
Yield: 52.1 %

Procedure:
A solution of 2-aminobenzamidine dihydrochloride (Example A) (1.0 g, 4.8 mmol) and benzaldehyde (0.48 ml, 5.8 mmol) in ethanol (30 ml) was heated at reflux for 2 hours. The solution was cooled and the solvent evaporated to give an oil which was purified by flash chromatography on aluminium oxide (Brockman 1, activated neutral) using dichloromethane/methanol as eluant to give a solid which was recrystallised from isopropyl alcohol to afford the title compound as a solid (0.65 g), m.p. 212°-214° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[CH2:16]([C:17]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1)[CH3:15]
Reactant: NNc1nccc(-c2ccccc2)n1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2nc(-c3ccccc3)ccn12

Procedure:
A mixture of 1.55 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthopropionate is refluxed for 6 hours. On cooling the desired compound is obtained by filtration, m.p. 246°-247° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10](=[O:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Li].CO>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10]([OH:12])([CH3:25])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc([C@@H](CC(C)=O)NC(=O)OC(C)(C)C)ccc1OC
Reactant: [Li]C
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(C)(C)O)NC(=O)OC(C)(C)C)ccc1OC
Yield: 14.1 %

Procedure:
To a solution of (1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-oxo-butyl]-carbamic acid tert-butyl ester (1 g, 3 mmol) in THF (10 mL) was added a solution of methyl lithium (4 mL, 3M, 12 mmol) at 0° C. To the mixture was added methanol (5 mL). The residue was extracted with ethyl acetate (50 mL) and NH4Cl (sat, 25 mL). The organic layer was washed with brine (100 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with preparative HPLC to give (R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester (150 mg, 14% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10])=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(O)cc(C)c1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1c(C)cc(O)cc1C

Procedure:
4-Amino-3,5-dimethylphenol (1.8 g, 1.3 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.6 g, 10 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to a yellow solid which on recrystallisation from ethanol, followed by methanol, afforded 3-butyryl-4-(4-hydroxy-2,6-dimethylphenylamino)-8-methoxyquinoline as yellow crystals, m.p. 247°-8°.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([C:14]([O:16]C)=O)=[CH:11][C:10](=[O:18])[C:9]=2[CH:19]=1.[CH3:20][C@@H:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[CH3:20][C@@H:21]([NH:28][C:14]([C:12]1[O:13][C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:19][C:9]=2[C:10](=[O:18])[CH:11]=1)=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cc(=O)c2cc(F)ccc2o1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C[C@@H](NC(=O)c1cc(=O)c2cc(F)ccc2o1)c1ccccc1

Procedure:
Sodium methoxide (540 mg, 10.0 mmol) was added to a solution of methyl 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylate (2.22 g, 10.0 mmol, obtained in Example 3 or 4) and (R)-α-methylbenzylamine (1.21 g, 10.0 mmol) in dry benzene (20 ml) and the mixture was refluxed for 2 hours.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[CH2:12]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=C2)[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([O:15][C:16]1[CH:24]=[C:23]2[C:22](=[CH:18][CH:17]=1)[NH:21][CH:20]=[C:2]2[CH:1]=[O:5])[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]cc(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.22 mL, 14.1 mmol) in dry CH2Cl2 (20 mL) was added at 0° C. under nitrogen a solution of dry DMF (1.3 mL) in dry CH2Cl2 (20 mL). The mixture was stirred at 0° C. for 30 min and a solution of 5-allyloxy-1H-indole (1.25 g, 7.22 mmol) in CH2Cl2 (10 mL) was added. The resulting solution was allowed to reach RT and stirred for 4 h. The solvent was concentrated and the residue dissolved in THF (35 mL) and 20% aqueous ammonium acetate (48 mL) and heated at reflux for 30 min, cooled, treated with an aqueous saturated solution of NaHCO3, and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude solid was taken up in CH2Cl2 and filtered-off to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:2)=0.56; MS (LC/MS): 202.0 [M+H]+, 224.1 [M+Na]+, 200.1 [M−H]−, 159.1 [M−H-allyl]−; tR (HPLC conditions a): 2.89 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:28]2[CH:36]=[CH:37][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:35][CH2:34]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](CI)NC(=O)OCc1ccccc1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H](CN1CCC(Oc2ccc(F)cc2)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester (0.61 g, 1.2 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.24 g, 1.23 mmol) in dichloromethane (5 ml) is treated with triethylamine (0.335 ml, 2.46 mmol). The reaction mixture is stirred at ambient temperature for 5 days, the solvent evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 4:1 hexane/ethylacetate) to afford {(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester [MH]+ 502.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1.[OH-].[K+]>C(O)C>[NH2:1][CH:2]([CH:14]([OH:15])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(C=O)cc1
Reactant: NCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(O)C(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A solution of glycine (45 g, 0.60 mol) and anisaldehyde (122 g, 0.900 mol) in ethanol (1.5 L) was stirred at ambient temperature and KOH (82.7 g, 1.47 mol) was added. The reaction mixture was stirred overnight at ambient temperature. The mixture was concentrated under vacuum the majority of ethanol. The residue was dissolved in water (800 mL) and the solution was adjusted to pH=5 with 4 N aqueous HCl. The resulting mixture was washed with EtOAc (200 mL×2) to remove any impurities. The aqueous layer was concentrated to a volume of ˜400 mL. The mixture was filtered and the filtration cake was washed thoroughly with water (100 mL×2) and dried to afford 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (29 g, 23% yield, threo-) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cccc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A solution of 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 5.45 mmol) in carbon tetrachloride (30 mL) was treated with N-bromosuccinimide (1.07 g, 6.01 mmol) and benzoyl peroxide (0.15 g). The reaction was then warmed to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 86%) as a white solid. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[C:18]([OH:20])=[O:19]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-chloro-1-fluorobenzene (4.31 g, 20 mmol) was added dropwise to a −78° C. solution of LDA in THF (prepared from diisopropylamine (3.38 ml, 24 mmol) and n-BuLi (1.6 M, 13.1 ml, 21 mmol)). The mixture was stirred at −78° C. for 1 h, and then was transferred slowly (˜30-60 min) via cannula to a stirred −78° C. mixture of dry ice and THF (40 ml). The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to rt (gas evolution). The mixture was concentrated, and was then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with 1N hydrochloric acid, and then was extracted with chloroform (3×400 ml). The chloroform extract was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound. The product was contaminated with a small amount of the isomeric product 2-bromo-6-chloro-3-fluorobenzoic acid. 1H NMR for title compound 3-Bromo-5-chloro-2-fluorobenzoic acid: (400 MHz, CDCl3) δ 7.93 (dd, 1H, J=2.8, 5.6 Hz), 7.79 (dd, 1H, J=2.8, 5.6 Hz) ppm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27](CCO)[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:33])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([C:41](=[O:42])[CH2:40][Cl:39])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:33])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(CCO)C2
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)CCl)C2
Reaction time: 1.5 h
Yield: 112.9 %

Procedure:
4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (100 mg, 0.23 mmol) was stirred in a mixture of CH2Cl2 (2 mL) and saturated NaHCO3 solution (2 mL) and chloroacetyl chloride (32 mg, 0.28 mmol) was added. After 1.5 h, the organic layer was removed and concentrated to provide the title compound (120 mg, 100%) as a yellow oil: ESI MS m/z 462 [M+H]+.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:37])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:35][CH3:36])[CH:10]=1)=[O:8])=O)C>ClCCl.CO>[CH3:34][C:30]1[CH:29]=[C:28]([NH:27][C:21]2[C:20]3[C:25](=[CH:26][C:17]([O:16][CH2:15][C:11]4[CH:10]=[C:9]([S:7]([CH3:37])(=[NH:6])=[O:8])[CH:14]=[CH:13][CH:12]=4)=[C:18]([O:35][CH3:36])[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccnc(C)c4)c3cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccnc(C)c3)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Yield: 79 %

Procedure:
According to GWP 6, conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-4-pyridylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (20 mg, 0.038 mmol) and chromatography (silica gel, dichloromethane/methanol 4/1) gives the desired product in 79% yield (14 mg).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])C.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1>C(O)(=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]2[C:27](=[CH:28][CH:29]=1)[NH:30][CH:4]=[C:5]2[CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Reaction time: 1 h
Yield: 64.6 %

Procedure:
4-[1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl]butanal diethyl acetal (11.6 g) was added with vigorous stirring to a solution of 4-bromophenylhydrazine hydrochloride (9.0 g) in 50% aqueous acetic acid (370 ml). The mixture was heated on a steam bath for 4 hours and was then diluted with water, while still hot, to 1 l. The mixture was cooled and an orange yellow precipitate was filtered off and dried in vacuo. The solid was boiled in ethanol (250 ml) for 1 hour and residual solid filtered off and dried to afford the title compound as a yellow solid (9.5 g) m.p. 206°-209° C. Crystallisation of a portion of this solid (0.5 g) from ethanol (25 ml) gave a sample (0.25 g) m.p. 208°-212° C.