Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Br.[OH:12][N:13]1C(=O)C2=CC=CC=C2C1=O.C(N(CC)CC)C.C1(=O)NC(=O)C2=CC=CC=C12.O.NN.[ClH:45].O1CCOCC1>CN(C=O)C.C(O)C.CCOCC>[ClH:45].[F:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([CH2:4][O:12][NH2:13])=[C:6]([CH3:11])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: Cl
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(F)cc(C)c1CON
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,6-dimethyl-4-fluorobenzyl bromide (4.89 g, 22.5 mmol) in DMF (100 ml) was added N-hydroxyphthalimide (3.67 g, 22.5 mmol) followed by drop-wise addition of triethylamine (3.5 ml, 25.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M HClaq. and the resulting white precipitate was isolated by filtration, washed with water and dried in vacuo. This phthalimide intermediate (6.51 g, 21.9 mmol) was treated with hydrazine monohydrate (1.06 ml, 21.8 mmol) in ethanol (60 ml) at reflux for 3 hours. The mixture was cooled to room temperature and ether was added. The precipitated material was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was suspended in EtOAc and filtrated. 4M HCl in dioxane (22 mmol) was added to the filtrate and the resulting precipitate was isolated by filtration and dried under vacuum, and gave the title compound (3.92 g) as a white powder. 13C-NMR (DMSO-d6) δ 161.9, 141.8, 126.5, 114.3, 69.3, 19.2. Alternatively, the phthalimide intermediate can be treated with hydrazine monohydrate (1 eq.) in dichloromethane at room temperature for 20 to 24 hours, remove the formed solids by filtration and evaporate the filtrate to obtain the free hydroxylamine.
Reaction SMILES: [CH2:1]([N:3]1CN(C)C[N:5]([C:10]2[S:11][C:12]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2]>[OH-].[Na+].C1COCC1>[CH2:1]([NH:3][C:4]([NH:5][C:10]1[S:11][C:12]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)=[CH:15][C:13]=2[N:14]=1)=[O:39])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(OC)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(OC)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (225 mg, 0.41 mmol) was dissolved in a mixture of NaOH (1M) (1 mL) and THF (3 mL) and the mixture stirred at rt for 3 hrs. A further portion of NaOH (1M) (1 mL) was added and stirring at rt continued for a further 1 hr. The reaction was heated at 60° C. for 16 hrs then at 100 C for 2 hrs and then with a further portion of NaOH (1 M, 1 mL) for 4 hrs. 5 M NaOH solution (1 mL, 5 mmol) was added and stirring continued at rt overnight, followed by 60° C. for 2 hrs. The reaction mixture was concentrated by freeze-drying then purified using reverse-phase chromatography (C18 column), eluting with 20-60% ACN gradient in water (with 0.1% formic acid), to give Compound 200 (60 mg, light yellow solid). 1H NMR (MeOD) δ 8.63 (s, 2H), 7.43 (s, 1H), 6.94 (s, 1H), 4.45-4.35 (m, 2H), 4.05 (s, 3H), 3.46-3.35 (m, 4H, obscured by solvent), 2.23-2.16 (m, 2H), 1.53-1.42 (m, 2H), 1.28 (s, 3H), 1.24 (t, J=7.2 Hz, 3H). [M+H]+471.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])[CH3:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2C=CC=CC=2N=N1.C(N(CC)CC)C.CN.O1CCCC1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13]([NH:34][CH3:38])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@H](Nc1nc(Nc2cnccn2)ccc1C(=O)O)c1ccc(F)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
80 mg of (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinic acid was dissolved in 1 ml of tetrahydrofuran, 86 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate salt (HBTU) and 59 mg of triethylamine were added thereto. The mixture was stirred at room temperature for 30 minutes, and then 119 μl of 2M methylamine/tetrahydrofuran solution was added thereto, and the mixture was stirred for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C=O)C>[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[N:9]=1
Reactant: Cc1n[nH]c(=O)c2ccccc12
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(CCOc2ccc(C=O)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
##STR30## To a stirred suspension of K2CO3 (11.3 g, 82.5 mmol) in dry DMF (50 mL) at 25-30° C. was added a solution of 4-methyl-1(2H)-phthalazinone (6.6 g, 41.25 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441) in dry DMF (100 mL). The reaction mixture was stirred for 30 min at 25° C. and 4-(2-bromoethoxy)benzaldehyde (9.4 g, 41.25 mmol) was added. The reaction mixture was immersed in a pre-heated oil bath at 70° C. and stirred at 65-70° C. for 24 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was recrystallised from methanol to obtain the title compound (9.7 g, 77%). mp: 90° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH:19]1[CH:24]=[C:23]2[C:25]([N:27]([CH2:30][C:31](Cl)=O)[C:28](=[O:29])[C:22]2=[CH:21][CH:20]=1)=[O:26]>ClCCl>[C:25]1(=[O:26])[N:27]([CH2:30][C:31]2[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[N:11]=2)[C:28](=[O:29])[C:22]2=[CH:21][CH:20]=[CH:19][CH:24]=[C:23]12
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (1.0 g) and triethylamine (793 mg) in dichloromethane (3 ml) under nitrogen was added portionwise phthalylglycyl chloride (1.61 g) in ice water bath and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. To the resulting crude product was added polyphosphoric acid (5 ml) and stirred at 130° C. for 3 hours. After the mixture was cooled at ambient temperature, ammonia solution (28%) was added to the reaction mixture in ice water bath. The precipitate was collected by vacuum filtration to give 2-phthalimidomethyl-4-nitro-1H-benzimidazole (1.35 g).
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:17][N:4]1[C:5]2[N:6]=[CH:7][N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:9](=[O:11])[C:10]=2[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccncc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 70 °C
Yield: 34.1 %

Procedure:
A mixture of 5-iodo-7-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (358 mg, 1.00 mmol), pyridin-4-ylboronic acid (148 mg, 1.20 mmol), sodium carbonate (319 mg, 3.01 mmol) and PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.100 mmol) in 1,4-dioxane (8 ml) and water (1.5 ml) was degassed. The resulting mixture was heated at 70° C. for 48 h. The reaction mixture was cooled and partitioned between saturated sodium bicarbonate solution (100 ml) and DCM (100 ml). The organic phase was separated and concentrated in vacuo. The remaining residue was purified by flash chromatography (0-100% ethyl acetate/cyclohexane) to afford the title compound (105 mg, 34%). LCMS RT=0.64 min, M+H+=309.1
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Br:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1cccc(Br)c1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(Br)c1
Yield: 80 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 3-bromophenylhydrazine according to the method described for Example 1 in 80% yield. MS: M=392.8 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])(C)(C)C.Br[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH:36]([O:35][C:33]([NH:32][CH2:31][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:5])=[O:39])=[O:34])([CH3:38])[CH3:37]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reactant: Brc1ccccn1
Product: Cc1oc(-c2ccc(Oc3ccccn3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1

Procedure:
3-[4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxy-carbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (Example 406) was reacted with 2-bromopyridine by the procedure in Example 397 to give the title compound. MS (ES) m/z 560 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O>C1(C)C=CC=CC=1>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([F:16])[CH:18]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C=O)cc1F
Solvent: Cc1ccccc1
Product: COc1ccc(C=Nc2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Yield: 99.6 %

Procedure:
A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
Reaction SMILES: C(OC([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=[CH:7]1)C)C.CN(C)CCN(C)C.C([Li])CCC.[F:40][C:41]([F:53])([F:52])[C:42](=[N:47][Si](C)(C)C)[C:43]([F:46])([F:45])[F:44].C(=O)(O)[O-].[Na+].COC1C=CC(N2C=CN=C2C(C(F)(F)F)(C(F)(F)F)N)=CC=1>C1COCC1.CCCCCC>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:8]=[C:7]([C:42]([C:43]([F:46])([F:45])[F:44])([C:41]([F:53])([F:52])[F:40])[NH2:47])[NH:6][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)N=C(C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: CN(C)CCN(C)C
Agent: COc1ccc(-n2ccnc2C(N)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C(N)(C(F)(F)F)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 10.0 g (28.4 mmoles) of 1-(α-ethoxyethyl)-4,5-bis-(4-methoxyphenyl)-1H-imidazole and 3.9 g of tetramethylethylenediamine in 150 ml THF was cooled to -78° C. with a dry-ice acetone bath, and a solution of 30 ml of of 1.6 M butyl lithium in hexane was then added dropwise. After stirring for 15 minutes, 11.5 g (48.5 mmoles) of [1,1-di(trifluoromethyl)methyleneamino]trimethylsilane [R. F. Swindell et al., Inorganic Chemistry, 11, #2, 242 (1972)] was added dropwise, and the reaction mixture was then allowed to warm to room temperature. A solution of 10% aqueous sodium bicarbonate (100 ml) was added dropwise and the organic layer was separated and concentrated in vacuo. The residue was stirred with a mixture of 200 ml of ethanol and 100 ml 2 M aqueous HCl overnight. The ethanol was evaporated under vacuum and the aqueous phase was extracted with ether. The combined ether extracts were washed with water, dried and concentrated to give 4.6 g (36%) of crude 4,5-bis(4-methoxyphenyl-α,α-di(trifluoromethyl)-1H-imidazole-2-methanamine. The residue was chromatographed on silica gel eluting with chloroform to give, after recrystallization from methylcyclohexane, the product as colorless crystals, m.p. 127°-128.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1>C(O)C.[OH-].[K+].O>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(SCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Temperature: 55 °C

Procedure:
Dissolve 2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]thio]-acetic acid, 1,1-dimethylethyl ester (1.65 g, 3.18 mmol) in a mixture of ethanol (30 mL) and 15% potassium hydroxide (30 mL). Heat at 55° C. and stir for several hours. Cool, acidify and dilute with water (200 mL). Filter the precipitate and dry to give the title compound.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[F:3][C:4]1[CH:12]=[C:11]([NH:2][CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (13.5 mL, 40% in water) is added to an ice-cooled mixture of 2,4-difluoro-5-nitro-benzoic acid (10.0 g, 49 mmol) in water (100 mL) and it is stirred for 30 min at rt. The mixture is acidified with 6N aq. HCl-solution and the precipitate is filtered, washed with water and dried at 60° C. The crude material was recrystallized from MeOH. The final product was slightly contaminated by its regioisomer 4-fluoro-2-methylamino-5-nitro-benzoic acid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C[Mg]Br.Cl.[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[C:19]=1C(Cl)=O>C1COCC1>[Br:14][C:15]1[N:16]=[CH:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[C:19]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1ccc(-n2cnc(Br)c2C(=O)Cl)c(C)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To 1.6 mL (14 mmol) of mono-ethyl malonate in 35 mL of THF at 0° C. was added 9.3 mL (28 mmol) of 3.0 M methyl magnesium bromide (ether solution). The dianion solution was stirred for 30 min before adding 1.2 g (3.5 mmol) of 4-bromo-1-(2,4-dimethylphenyl)-1H-imidazole-5-carbonyl chloride hydrochloride in 50 mL of THF dropwise. The cooling bath was then removed and the mixture was allowed to stir at room temperature for 3 h. The reaction was quenched by pouring onto ice and was extracted with ethyl acetate after neutralizing to pH 7 with saturated ammonium chloride. The combined extracts were washed with brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 1.2 g (94%) of the title compound as a viscous golden oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19]([C:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[O:23][N:22]=1)=O.N1C=CC=CC=1>C(O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:24]1[O:23][N:22]=[C:21]([C:19]2[N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[S:16][CH:18]=2)[CH2:25]1
Reactant: O=C(CCl)C1=NOC(c2ccccc2F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Temperature: 77 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butoxycarbonylpiperidine-4-carbothioamide (1 g, 4.10 mmol) in ethanol (10 mL) was added 2-chloro-1-[4,5-dihydro-5-(2-fluorophenyl)-3-isoxazolyl]ethanone (i.e. the product of Step A) (0.99 g) followed by pyridine (0.34 mL, 4.10 mmol). The reaction mixture was heated at 77° C. for 3 h, and then stirred at room temperature overnight. Ethanol was removed from the reaction mixture, and the remaining residue was diluted with ethyl acetate (50 mL). The organic layer was separated, washed with water, saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel to provide the title compound as a pale yellow sticky oil (1.11 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH2:6]1)=O.O1CCCC1.[BH4-].[Na+].CO>O>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CO)CC4=O)cc3)CC2)c(C)c1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To 1-{4-[4-(2,4-dimethylphenyl)piperazine-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (1.3 g) described in Example 337 were added tetrahydrofuran (5 mL) and sodium borohydride (124 mg), methanol (0.9 mL) was added with heating under reflux, and the mixture was stirred for 1 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.06 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1.O>CN(C=O)C>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCc5ccccn5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 2.2 %

Procedure:
In DMF (3.8 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (380 mg). To the mixture was added potassium carbonate (252 mg), and the mixture was stirred for 30 minutes. To the mixture was added 2-chloromethylpyridinehydrochloride (130 mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-pyridylmethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 108) (10 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccnc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Benzyl alcohol (1.7 ml, 16.326 mmol, 1.2 eq) was added at 0° C. to a suspension of NaH (1.088 g, 27.21 mmol, 2.0 eq) in THF (50 ml) and the mixture was stirred for 30 minutes. A solution of 2,4-dichloropyridine (2.0 g, 13.605 mmol, 1.0 eq) in THF (10 ml) was added dropwise and stirring was carried out for 2 hours at RT. After monitoring by TLC, the reaction mixture was hydrolyzed with ice-water (60 ml) and extracted with ethyl acetate (2×120 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 1% ethyl acetate in hexane). Yield: 27% (800 mg, 3.653 mmol)