Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:36][N:2]([CH3:1])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:34][CH3:35])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 87 %

Procedure:
A mixture of N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 149, 230 mg, 0.47 mmol), iron (158 mg, 2.83 mmol), NH4Cl (17.7 mg, 0.33 mmol), ethanol (9 mL) and water (3 mL) was heated at reflux for 50 minutes. The reaction was judged to be incomplete so further iron (158 mg, 2.83 mmol) and NH4Cl (17.7 mg, 0.33 mmol) was added and the mixture was heated at reflux for a further 0.5 h. After cooling, the mixture was filtered and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7M methanolic ammonia in CH2Cl2 gave the title compound (187 mg, 87%) as a grey foam; 1H NMR: 1.78 (1H, m), 2.06 (1H, m), 2.20 (6H, s), 2.86 (1H, d), 2.90-3.01 (2H, m), 3.12 (1H, m), 3.15-3.23 (1H, m), 3.76 (3H, s), 3.88 (3H, s), 4.27 (2H, s), 6.72 (1H, s), 7.14 (1H, d), 7.15-7.21 (1H, m), 7.22-7.34 (1H, m), 7.50 (1H, s), 7.52 (1H, d), 7.74 (1H, s), 8.26 (1H, s), 8.28 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.75.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O>N1CCCCC1.C(O)C>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C
Yield: 39.5 %

Procedure:
A mixture of 5-carboxy-2-oxindole (88.5 mg) (prepared as described in Compound IN-05), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was filtered and acidified with 2N hydrochloric acid. The resulting darker solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 60 mg (40% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a mustard-colored solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[CH2:14]C(C)(C)N[C:17](=O)[C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:40])=[N:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH2:49]>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>[CH3:5][C:6]1([CH3:23])[NH:7][C:14](=[O:49])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([C:28]5[C:27]([CH3:40])=[N:26][N:25]([CH3:24])[C:29]=5[CH3:30])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2sc(N3CCOc4ccc(Br)cc43)nc2C(=O)N1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Yield: 34 %

Procedure:
A stirred solution of Example 39 (0.055 g, 0.14 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.066 g, 0.28 mmol), potassium phosphate (0.089 g, 0.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.004 mmol) in DME (4 mL) and water (1 mL) was heated to 140° C. under microwave irradiation in a sealed tube for 30 minutes, and then concentrated in vacuo. Purification by preparative HPLC (Method 7) gave the title compound (0.020 g, 34%) as an off-white solid. δH (CDCl3) 7.84 (1H, d, J 1.9 Hz), 7.08-6.99 (2H, m), 5.45 (1H, s), 4.43-4.35 (2H, m), 4.22-4.16 (2H, m), 3.79 (3H, s), 2.87 (2H, s), 2.29 (6H, s), 1.40 (6H, s). LCMS (ES+) 424.0 (M+H)+, RT 3.17 minutes (Method 2).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16](Cl)=[N:17][C:5]1=2)[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:25])=[CH:22][C:21]=3[O:36][CH3:37])=[N:17][C:5]1=2)[CH:2]=[CH2:3]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: C=CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: C=CCN1CC(C)C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Yield: 50.1 %

Procedure:
A solution of 0.050 g (0.00019 mole) of (rac)-9-allyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-65), 0.049 g (0.00019 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00025 mole) of p-toluene-sulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.047 g of (rac)-4-(9-allyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-65) as white solid. HRMS (ES+) m/z Calcd for C26H35N7O3+H [(M+H)+]: 494.2874. Found: 494.2878.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:17][OH:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:24][O:25][C:26]([C:28]1([C:31](OC)=[O:32])[CH2:30][CH2:29]1)=[O:27].C(O)(=O)C>O1CCCC1.O>[CH3:24][O:25][C:26]([C:28]1([C:31]2([OH:32])[O:18][N:17]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:10]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
1-(4-Methoxy-phenyl)-2-phenyl-ethanone oxime, which may be produced as in Example 137 (110 g, 456 mmol, 1 equiv) is dissolved in tetrahydrofuran (825 mL), and the solution is cooled to about 0 □C in an ice/isopropyl alcohol bath. Butyllithium (2.5 M in hexane, 383 mL, 957 mmol, 2.1 equiv) is added at a rate to keep the temperature below 10 □C (about 1 hour addition time). The solution is allowed to stir for about 15 minutes. Cyclopropane-1,1-dicarboxylic acid dimethyl ester (86.5 g, 547 mmol, 1.2 equiv.) is added rapidly, and the reaction is allowed to stir for about 15 minutes. The reaction is quenched by the addition of acetic acid (65.3 mL, 1140 mmol, 2.5 equiv), and water (200 mL) is added. The mixture is allowed to sit overnight. The water layer is removed, and the organic layer is washed with water (300 mL). Toluene (100 mL) is added, and the organic layer is concentrated to give crude title compound, 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester, which may be used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[C:20]([C:22](OC)=[O:23])[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCN(C(=O)OCc3ccccc3)CC2)oc1-c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(c2nc(CO)c(-c3ccc(F)cc3F)o2)CC1

Procedure:
To a 0.5 liter round bottom flask fitted with a condenser, nitrogen inlet, and mechanical stirrer is added 30.25 g, 66.3 mmoles of 4-[5-(2,4-Difluoro-phenyl)-4-methoxycarbonyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, and a mixture of methanol and ether (4 mL to 200 mL). Lithium borohydride 2.17 g (0.1 mol) is added in three portions and then the mixture is stirred and heated to reflux for 30 minutes. The reaction is allowed to cool and carefully quenched with 400 mL of 0.5 N hydrochloric acid. The resulting mixture is extracted with 3×200 mL of methylene chloride. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O.[NH2:21][CH2:22][C:23]([NH:25][CH:26]1[CH:31]2[CH:27]1[CH2:28][N:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30]2)=[O:24].C(OC(C(N)C(O)=O)=O)(C)(C)C.C(N1CC2C(C2N)C1)C1C=CC=CC=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:32]([N:29]1[CH2:28][CH:27]2[CH:31]([CH:26]2[NH:25][C:23]([CH2:22][NH:21][C:12](=[O:14])[CH2:11][CH:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:30]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Reactant: NCC(=O)NC1C2CN(Cc3ccccc3)CC21
Agent: CC(C)(C)OC(=O)C(N)C(=O)O
Agent: NC1C2CN(Cc3ccccc3)CC12
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C)cc1C(CC(=O)NCC(=O)NC1C2CN(Cc3ccccc3)CC21)c1ccccc1

Procedure:
The compound, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (209 mg, 0.77 mmole, 1 eq) and 2-amino-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-acetamide, 0.77 mmole, 1 eq (prepared by reacting t-butoxy carbonyl amino-acetic acid with 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett 1996, 1100) were dissolved in dimethylformamide (5 ml). The reaction mixture was cooled to 0° C. with subsequent addition of N-methyl morpholine (0.13 ml) and 1-hydroxy benzotriazole, HOBT (105 mg). The resulting mixture was diluted with water and extracted the organic compound with ethyl acetate. The solvent was removed under reduced pressure. The crude organic compound thus obtained was purified by column chromatography using 80% ethyl acetate in hexane. Yield=367 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:32][C:33](=[O:34])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(O)cc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
a mixture of 4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (100 mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) and α-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambient temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (30 mL), dried (MgSO4) and condensed to give the desired product (129 mg, 96%) as a yellow oil: NMR δH(400 MHz; d6-DMSO) 1.40 (9H, s), 3.30–3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s), 5.54 (2H, s), 6.86–6.91 (2H, m), 7.20–7.26 (2H, m), 7.54–7.60 (2H, m) and 7.66–7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56 min).
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(N(CC)CC)C.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:15]1([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]2[C:4](=[O:6])[CH2:5][O:1][C:2]2=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1COC(=O)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1COC(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 600 mg of 2,4-oxazolidinedione and 601 mg of triethylamine in 7.0 ml of chloroform was added 1.66 g of triphenyl chloromethane and the reaction mixture stirred at room temperature for 30 minutes. The resulting mixture was dissolved in 250 ml of ethyl acetate and washed with water (3×50 ml) and brine (2×20 ml) and dried over sodium sulfate. Removal of the solvent gave 1.8 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S-:11][C:12]#[N:13].[NH4+].[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:16]>S(Cl)(Cl)=O>[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[S:11][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:13]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Yield: 81.3 %

Procedure:
The reaction procedure of Example 6 was followed except that 3.60 g (30.64 mmol) of 2-chloronicotinic acid, 20 ml of thionyl chloride, 2.33 g of ammonium thiocyanate and 3.55 g of 4-cyanoaniline were used. As a result, 6.85 g of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[CH3:14])=[O:4].[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1>>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=2[CH3:14])=[O:4])[CH2:21]1
Reactant: COc1cccc(NC(=O)CCl)c1C
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C

Procedure:
The subtitle compound was prepared from 2-chloro-N-(3-methoxy-2-methylphenyl)acetamide (10.72 g) and cis-2,6-dimethylpiperazine (6.29 g) by the method of Example 58 step (i) as a tan solid. Yield: 13.13 g
Reaction SMILES: [OH:1][N:2]=[C:3]([N:10]1[C:14]([CH3:15])=[N:13][N:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]Br)[N:27]=1>CC#N>[Br:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][O:1][N:2]=[C:3]([N:10]2[C:14]([CH3:15])=[N:13][N:12]=[N:11]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:27]=1
Reactant: BrCc1csc(Br)n1
Reactant: Cc1nnnn1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nnnn1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a stirred solution of N-hydroxy-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (2.0 g, 9.84 mmol, 1.0 eq.) in 50 ml of MeCN was added Cs2CO3 (3.52 g, 10.82 mmol, 1.2 eq.) followed by KI (0.163 g, 0.984 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-bromo-4-(bromomethyl)-1,3-thiazole (2.52 g, 9.84 mmol, 1 eq.) in one portion. The reaction was stirred for 24 hrs at room temperature. The solvent was evaporated then the residue was dissolved in EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (3.3 g, 88% yield) as a yellow viscous oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)([Cl:27])=O>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2[N:4]=[C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]3=[C:1]([Cl:27])[C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccccc13)CCN(Cc1ccccc1)C2
Yield: 60.1 %

Procedure:
Anthranilic acid (9.6 g, 70 mmol) and 1-benzyl-4-piperidone (13.2 g, 70 mmol) were suspended in phosphorus oxychloride (65.2 ml, 700 mmol), and the suspension was heated under reflux for 4 hours. The excess phosphorus oxychloride was removed by distillation and the concentrated residue was carefully added to 28% aqueous ammonia under ice-cooling and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate/methanol=30:10:1) to obtain the desired compound (13 g, 60%) as a light-yellowish-white substance.
Reaction SMILES: [OH2:1].[N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].OO>C(O)(=O)C.O>[N+:2]1([O-:1])[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: O=C(O)c1cc[n+]([O-])c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A suspension of 2,4-pyridinedicarboxylic acid monohydrate (92.6 g, 0.5 mol) in acetic acid (700 ml) was treated with hydrogen peroxide (300 ml of a 35 wt % solution in water) and then heated at reflux for 16 h. The mixture was allowed to cool to 80° C., water (200 ml) was added and the mixture refrigerated at 4° C. for 16 h. The resulting solid was collected by filtration, washed with cold water (3×100 ml) and dried to give 2,4-pyridinedicarboxylic acid N-oxide (91.5 g, 91%) as a white crystalline solid. 1H NMR (360 MHz, d6-DMSO) δH 8.17 (1H, dd, J 3 and 7), 8.51 (1H, d, J 3), 8.76 (1H, d, J 7).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[N:26][CH:25]=1>O1CCCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:32])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)N(C)OC)cn1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cn1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
1,4-Dibromobenzene (6.5 g, 27 mmol) was dissolved in tetrahydrofuran (120 mL), and a solution of n-butyllithium in hexane (2.6 M, 10 mL, 27 mmol) was added at −78° C., followed by stirring at the same temperature for 30 minutes. A solution of N,6-dimethoxy-N-methylnicotinamide (2.7 g, 14 mmol) in tetrahydrofuran (20 mL) was added to the reaction solution, followed by stirring at −78° C. for further 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.8 g, 9.4 mmol) as a white solid (yield 69%).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:23])(=[N:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[O:15])=[CH:10][CH:9]=2)[O:6]C(C)(C)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:4][C@H:3]([CH2:2][F:1])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:23])(=[N:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[O:15])=[CH:12][CH:13]=1)[OH:6]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc2)OC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)oxazolidine-3-carboxylate (500 mg, 1.168 mmol) in DCM (20 mL) is added Trifluoroacetic acid (2.0 mL). Reaction mixture is allowed to stir at room temperature for 2 h. Excess of Trifluoroacetic acid and DCM is evaporated in vacuo, stripped with toluene followed by washing with n-pentane and diethyl ether to afford crude title compound (426 mg, TFA salt) as faint yellow sticky mass which is used as such for next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[Cl:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C=O)C>[ClH:15].[ClH:15].[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: ClCCN1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCN1CCN(Cc2ccccc2)CC1
Product: Cl
Temperature: 70 °C
Yield: 97.1 %

Procedure:
5-Methyl-1H-indole-2,3-dione (12.85 g) in dry DMF (50 ml) at 0° to 5° C. was treated with sodium hydride (80% dispersion in mineral oil, 2.53 g). The mixture was allowed to warm to room temperature and after a further 10 minutes 1-(2-chloroethyl)-4-(phenylmethyl)piperazine (20 g) in dry DMF (70 ml) was added. The mixture was heated at 70° C. for 3 hours and then evaporated under reduced pressure. The residue was subjected to flash chromatography on silica gel to afford the title compound (17.75 g). Treatment with ethanolic HCl then gave 5-methyl-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione dihydrochloride (16.8 g), m.p. 270°-275° C. (dec.).
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20].[Br:21][CH2:22][C:23](Br)=[O:24]>>[Br:21][CH2:22][C:23]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[C:15]([Br:20])[CH:16]=1)=[O:24]
Reactant: Brc1ccccc1Br
Reactant: O=C(Br)CBr
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Product: O=C(CBr)c1ccc(Br)c(Br)c1
Yield: 13 %

Procedure:
General procedure described for compounds 1 and 2 starting from 1,2-dibromobenzene and bromoacetyl bromide. Purified by column chromatography column (hexane:ethyl acetate 6:1), yield 13% m.p. 60-61° C., 1H-NMR (CDCl3): δ8.2 (s, 1H, Ar), 7.8 (d, 2H, Ar), 4.4 (s, 2H, CH2); 13C-NMR (CDCl3): δ189.7 (CO), 134.6 (CH), 134.4 (CH), 134.3 (C—CO), 132.0 (C—Br), 128.8(CH), 126.2 (C—Br), 30.4 (CH2); M/z (EI): 360, 358, 356, 354 (M+, 5, 14, 14, 5%), 265, 263, 261 (M-CH2Br, 62, 100, 65%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=8.73 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.