Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2.OO.[O-:15]S([O-])=O.[Na+].[Na+].[I-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-:15])=[CH:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cnc2ccc(F)cc2c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2cc(F)ccc2[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3-methyl-quinoline (Intermediate 28) (48.0 mg, 0.298 mmol) was dissolved in acetic acid (1 mL) and 30% aqueous H2O2 (0.040 mL, 0.396 mmol) was added. This was stirred at 80° C. for 16 h before cooling. A few mLs of a 10% aq. solution of Na2SO3 was added followed by a spatula tip of sodium iodide. This was stirred for 10 min before partitioning between ethyl acetate and sat. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 6-fluoro-3-methyl-quinoline 1-oxide (29.4 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=9.4, 5.3 Hz, 1 H) 8.38 (s, 1 H) 7.36-7.50 (m, 3 H) 2.46 (s, 3 H); MS (M+1): 178.1.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li+].CC([N-]C(C)C)C.[CH2:19]([C:23]1[C:27]([CH2:28]Cl)=[C:26]([CH3:30])[O:25][N:24]=1)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:23]1[C:27]([CH2:28][CH2:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[C:26]([CH3:30])[O:25][N:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1noc(C)c1CCl
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (157 mg, 1.0 mmol) in THF (3 mL) at −78° C. and under argon was added LDA (1.0 mL of a 2M solution in THF, 2.0 mmol) dropwise. After 1.5 h a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (188 mg, 1.0 mmol) in THF (2 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1 N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (210 mg, 68%) as an off white solid. MS: m/e=307.3 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.CN.[CH2:18]([N:20](CC)CC)C.[BH4-].[Na+].N>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:18][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN(CC)CC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CN
Solvent: CCO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 57.4 %

Procedure:
To tert-butyl 4-oxo-1-piperidinecarboxylate (3.99 g, 20 mmol) was added ethanol (30 ml), and methylamine hydrochloride (2.70 g, 40 mmol), triethylamine (5.6 ml, 40 mmol) and titanium(IV)isopropoxide (11.8 ml, 40 mmol) were added under ice-cooling with stirring, and the mixture was stirred at room temperature for 8 hr. Then, to the reaction mixture was added sodium borohydride (1.14 g, 30 mmol), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 28% aqueous ammonia, and the reaction solution was filtered off through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane-ethanol=5:1 mixed solvent, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (dichloromethane-methanol) to give the title compound (2.46 g, yield 57%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:10]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:21]2[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:29])([F:28])[F:30])[C:23](=[O:24])[N:19]([CH2:18][C:11]3[CH:10]=[C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH:14]=[CH:13][C:12]=3[CH2:15][OH:16])[N:20]=2)=[CH:33][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ccc2CO)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
230 mg (0.39 mmol) of the compound from Example 134 were dissolved in 5 ml of THF, the solution was cooled to 0° C. and 55 μl (0.39 mmol) of triethylamine and also 56 μl (0.43 mmol) of isobutyl chloroformate were added. The mixture was stirred at 0° C. for 1 h. The suspension was then filtered through a Seitz frit into a flask cooled to 0° C., and the residue was rinsed with about 2 ml of THF. With vigorous stirring, this solution was added to a solution, cooled to 0° C., of 44 mg (1.18 mmol) of sodium borohydride in 0.6 ml of water. After 1 h, 5 ml of saturated aqueous sodium bicarbonate solution were added, and the mixture was warmed to RT. The mixture was extracted with 15 ml of ethyl acetate. The organic phase was washed successively with in each case 5 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 13 mg (6% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C#CCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Yield: 94.8 %

Procedure:
Ethoxyacetyl chloride (96%, 4.40 g, 34.3 mmol) was added to a 6° C. solution of 2-chloro-N4-pent-4-ynylquinoline-3,4-diamine (8.10 g, 31.2 mmol) and triethylamine (6.50 mL, 46.8 mmol) in dichloromethane (100 mL). Additional ethoxyacetyl chloride (3.0 g) was added after 45 minutes until all the starting material had been consumed. The solution was diluted with dichloromethane and washed with saturated aqueous potassium carbonate, water, and brine, dried over potassium carbonate, filtered, and concentrated to afford N-[2-chloro-4-(pent-4-ynylamino)quinolin-3-yl]-2-ethoxyacetamide as a pale yellow solid (10.23 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.[BH4-].[Na+]>CC(C)=O>[C:2]1([CH2:1][N:9]2[CH2:10][CH:11]=[C:12]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCC1=CCN(Cc2ccccc2)CC1
Yield: 18.5 %

Procedure:
Benzyl bromide (4.4 mL, 41 mmol) was added to a solution of 4-pyridineethanol (5 g, 41 mmol) in acetone (100 mL) and the mixture was heated under reflux for 16 hours. The mixture was cooled and the solid was collected, washed with acetone (50 mL) and diethyl ether (2×50 mL) then dissolved in methanol (100 mL) and treated with sodium borohydride (6.2 g 164 mmol). The mixture was heated under reflux for 16 hours, cooled, and the solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) and aqueous sodium hydrogen carbonate (10%, 150 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (92:8:1), to give the title compound as a colorless oil (1.65 g, 18%). m/z (ES+) 218 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[NH:12][C:13](=[O:27])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[C:6]([Br:11])[CH:7]=1)[NH:12][C:13](=[O:27])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1)([CH3:15])[C:3]2=[O:2]
Reactant: COC(=O)c1cc(Br)cc(Br)c1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1[N+](=O)[O-]
Yield: 26.2 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 3,5-dibromo-2-[2-(4-methoxy-3-nitro-phenyl)-propionylamino]-benzoic acid methyl ester (0.65 g, 1.26 mmol) and LiHMDS (3.78 mmol, 1M solution in THF). After normal workup, the objective compound (160 mg, 27%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, DMSO-d6) δ 1.68 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 7.32 (d, J=9.0 Hz, 1H, ArH), 7.43 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.69 (d, J=2.4 Hz, 1H, ArH), 7.84 (d, J=2.6 Hz, 1H, ArH), 8.12 (d, J=2.6 Hz, 1H, ArH); MS(EI) m/e 482 [M+], 277, 207, 102 ; HRMS m/e cacld. for C17H12N2O5Br2 481.9113, found 481.9122.
Reaction SMILES: [CH3:1][C:2]1([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:29](OC)(OC)OC>>[CH3:1][C:2]1([N:15]2[C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=3[N:26]=[CH:29]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1(Nc2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCC(C)(n2cnc3cc(S(C)(=O)=O)ccc32)CC1

Procedure:
Using tert-butyl 4-methyl-4-{[4-(methylsulfonyl)-2-nitrophenyl]amino}piperidine-1-carboxylate as starting material and following the procedure outlined in Method C, Step 2 but replacing trimethyl orthoacetate with trimethyl orthoformate, there is obtained tert-butyl 4-methyl-4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidine-1-carboxylate.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18](O)=[O:19])=[C:13]([F:22])[CH:12]=1.CNC.C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([N:4]([CH3:5])[CH3:1])=[O:19])=[C:13]([F:22])[CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(O)c1ccc(Br)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.8 g, 0.006 mol) was added to a mixture of (4-bromo-2-fluorophenyl)(hydroxy)acetic acid (Oakwood, Cat. No. 019267) (0.5 g, 0.002 mol), dimethylamine in THF (2.4 mmol, 2.0 M, 1.2 mL), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 0.0024 mol) in methylene chloride (10 mL). The mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=276.2/278.2. 1H NMR (300 MHz, DMSO-d6) δ: 9.50 (d, J=1.1 Hz, 1H), 7.97 (dd, J=8.0, 1.5 Hz, 1H), 7.83 (dd, J=11.4, 1.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.01 (s, 1H), 5.70 (s, 1H), 5.65 (s, 1H), 3.96 (s, 6H), 2.94 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:8][C:9]3[C:10]([N:24]=2)=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=2[CH:17]=3)=[N:4][NH:5][CH:6]=1.[CH3:25][C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][C:29]([C:26]5([CH3:25])[CH2:28][CH2:27]5)=[O:30])=[CH:6][NH:5][N:4]=4)=[N:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: CC1(C(=O)O)CC1
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NC(=O)C4(C)CC4)[nH]c3cc21
Yield: 55.9 %

Procedure:
Methyl-cyclopropanecarboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one (300 mg. 0.925 mmol) and 1-methyl-cyclopropanecarboxylic acid (101.8 mg, 1.017 mmol). 210 mg (56%) of the title compound were obtained.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[O:15]C>C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)c(O)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
116 ml (116 mmol) of boron tribromide (1 molar solution in dichloromethane) are added dropwise at −10° C. over a period of 1 h to a solution of 5.00 g (29.2 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene at such a rate that the temperature does not exceed −5° C. The solution is left at 0° C. for 5 h, then added slowly to 600 ml of ice-water and diluted with 100 ml of ethyl acetate. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (10:1 cyclohexane/ethyl acetate). This affords 1.45 g (30% of theory) of the desired compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>ClCCl.C(#N)C>[Br:1][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: BrBr
Reactant: Oc1ccc(-c2cccc(F)c2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: Oc1ccc(-c2cccc(F)c2)cc1Br
Reaction time: 17 h
Yield: 105.2 %

Procedure:
A solution of bromine (887 mg, 5.55 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 4-(3-fluorophenyl)phenol [purchased from Combi-Blocks] (1.044 g, 5.55 mmol) in dichloromethane (10 mL) and acetonitrile (5 mL) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C. to room temperature for 17 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) containing 10% aqueous sodium thiosulfate solution (10 mL). The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 15% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (1.56 g, quant.) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[F:29])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O.C(Cl)Cl>[F:29][C:19]1[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(OC(F)(F)F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(OC(F)(F)F)cc1F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)-piperidine-1-carboxylate (420 mg, 0.96 mmol) (from example 58, step 1) was dissolved in MeOH (4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (40.5 mg, 1.01 mmol) dissolved in water (0.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 62 μL, 1.01 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4.98 mL, 29.91 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. Crude trans-methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (365 mg, 94%) was yielded as a colorless oil. MS m/z 405 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH2:27][C:12]1[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)[CH3:35]
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 61.8 %

Procedure:
Following the procedure of Example 7, 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a pale yellow crystalline powder (yield: 61.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].I[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:13])=[CH:4][C:3]=1[Cl:9]
Reactant: Sc1ccc(Br)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(Br)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
4-Bromo-3-chloro-benzenethiol (0.94 g, 4.21 mmol) was dissolved in tetrahydrofuran (10 ml) and cooled to 0° C. under argon. Sodium hydride (0.19 g, 4.63 mmol) was added and the mixture was stirred for 5 minutes, then iodomethane (0.28 ml, 4.42 mmol) was added. The mixture was allowed to warm, stirring for 30 minutes, then the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane (×2) and the combined organic layers were dried (MgSO4) and concentrated. Purification of the resultant residue by flash chromatography (Si-PCC, pentane) afforded the title compound as a colourless oil (0.65 g, 65%). 1H NMR (CDCl3 400 MHz) 2.47 (3H, s), 6.99 (1H, dd, J=8.45, 2.26 Hz), 7.30 (1H, d, J=2.25 Hz), 7.48 (1H, d, J=8.45 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1NCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCN1
Reaction time: 1 h

Procedure:
A mixture of 1-benzyl-3R-methylpiperazine-2-one (XX, 4.36 g), lithium aluminum hydride (LAH, 2.33 g) and THF (125 ml) is heated at reflux for 16 hr. After cooling to 20°-25°, the mixture is quenched slowly with water (2.3 ml), sodium hydroxide (10%, 3.5 ml) and water (5.7 ml). The residue is diluted with ether (100 ml) and is stirred for 1 hr. The solids are filtered and washed successively with ether, methylene chloride and ether. The combined filtrates are dried over potassium carbonate, filtered and concentrated to give 1-benzyl-(3R)-methylpiperazine (XXI), sufficiently pure to be carried on crude, NMR (CDCl3) 7.2-7.4, 3.49, 2.7-3.0, 1.95-2.1, 166, 1.3-1.7 and 1.01 δ.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12](Cl)[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7].O>CO>[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12]([O:2][CH3:1])[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(OC)nc12
Temperature: 22 °C
Reaction time: 16 h

Procedure:
0.17 g (3 mmol) of sodium methoxide was dissolved in 10 ml of methanol, and 0.79 g (2 mmol) of methyl 7-(1,2-dimethylpropylamino)-5-chloro-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]-pyrimidine-3-carboxylate was added. The mixture was stirred at 22° C. for 16 hours. 10 ml of water were then added, the methanol was distilled off and 10 ml of dichloromethane were added to the residue. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 0.35 g of methyl 7-(1,2-dimethylpropylamino)-5-methoxy-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxylate (logPs=4.60; content according to HPLC: 96%).
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]>>[F:57][C:58]1[CH:59]=[C:60]([C:2]2[C:3](=[O:30])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:5]=3)[CH:61]=[CH:62][C:63]=1[O:64][CH3:65]
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1F
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 112 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (74%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:25][CH:24]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-methylsulfonylmethylaniline according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d, 1H), 11.0 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.1 (d, 1H), 4.45 (s, 2H), 2.9 (s, 3H); APCI−MS m/z 384 (M−H)−.