Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[C:4]([F:22])[C:3]=1[F:23].[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1.CN(C)P(N(C)C)(N(C)C)=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:13]1([N:9]2[C:10]3[C:5](=[C:4]([F:22])[C:3]([F:23])=[C:2]([C:30]4[C:25]([CH3:24])=[N:26][C:27]([CH3:35])=[CH:28][CH:29]=4)[C:11]=3[F:12])[C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Br)c(F)c(F)c2c1=O
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)c(C)n1
Yield: 57.4 %

Procedure:
A mixture of 2.8 g ethyl 7-bromo-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.2 g 2,6-dimethyl-4-(trimethylstannyl)pyridine (Example 1, part g), 2 ml hexamethylphosphoramide, 320 mg dichlorobis(triphenylphosphine)palladium and 50 ml dioxane was stirred and heated under reflux in an argon atmosphere for 24 hours. The reaction mixture was concentrated to dryness and the residue was treated with 100 ml of 1N hydrochloric acid and heated at reflux for 2 hours. The latter mixture was filtered and the filtrate concentrated to dryness. The residue was dissolved in 50 ml 5% aqueous potassium carbonate, decolorized with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid, sodium acetate added, and the resulting precipitate was collected, dried and recrystallized from ethanol to give 1.6 g 1-cyclopropyl-7-(2,6-dimethylpyridinyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a cream-colored solid, m.p. 264°-266° C.
Reaction SMILES: C(OCC[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[NH2:13])C.[Cl:14][CH2:15][C:16](Cl)=[O:17].[O:19]1[CH2:24][CH2:23]O[CH2:21][CH2:20]1>>[Cl:14][CH2:15][C:16]([NH:12][C:8]1[C:7]([NH:13][CH2:21][CH2:20][O:19][CH2:24][CH3:23])=[CH:6][CH:11]=[CH:10][N:9]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1COCCO1
Reactant: CCOCCc1ccnc(N)c1N
Product: CCOCCNc1cccnc1NC(=O)CCl
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a stirred solution of 3.8 parts of N3 -(2-ethoxyethyl)-2,3-pyridinediamine in 50 parts of 1,4-dioxane were added 5.64 parts of 2-chloroacetyl chloride. The reaction mixture was stirred for 5 hours at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in methylbenzene. The whole was evaporated again, yielding 3.62 parts (70.4%) of 2-chloro-N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]acetamide as a residue (int. 24).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.S([O-])(=O)(=O)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:26]([O-])=O.BrC1C=C2C(=CC=1)[N:36]=[CH:35]C([N+]([O-])=O)=C2Cl>>[NH:36]1[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:26]=[CH:35]1
Reactant: O=[N+]([O-])c1cnc2ccc(I)cc2c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: CS(=O)(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Product: c1ccc2c(c1)ncc1nc[nH]c12

Procedure:
The imidazo[4,5-c]quinoline system is synthesised starting from 4-chloro-3-nitroquinolines D which are activated in the 6-position by a leaving group EWG, for example halogen, triflate or mesylate. Preferably 4-chloro-6-iodo-3-nitro-quinoline (D.1) or 6-bromo-4-chloro-3-nitro-quinoline (D.2) is used.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[C:20]=[O:21].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:21])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COc1ccccc1N=C=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 1-isocyanato-2-methoxy-benzene, and diisopropylethyl amine, are reacted to give the title product. LC-MS: 411 (M++1). 1H NMR (CDCl3) δ 3.15–3.25 (m, 4H), 3.7–3.85 (m, 4H), 3.9 (s, 3H), 4.6–4.8 (s, 2H), 6.2 (s, 1H), 6.86–6.9 (m, 1H), 6.94–7.02 (m, 2H), 7.16–7.21 (m, 2H), 7.62–7.65 (d, 1H), 7.74–7.78 (d, 1H), 8.14–8.19 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14]([NH:17][CH2:18][C:19]3([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH:30][CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:5]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)ccc1F)OCc1ccccc1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a 20 dram vial was added 2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzoic acid (320 mg, 0.8 mmol, 1.0 equiv), benzyl 2-aminoethylcarbamate (242 mg, 1.0 mmol, 1.3 equiv), HOBt (141 mg, 1.0 mmol, 1.3 equiv), EDC HCl (200 mg, 1.0 mmol, 1.3 equiv), DIPEA (550 μL, 3.8 equiv) and CH2Cl2 (5 mL). The reaction was stirred for 4 h and then concentrated and then purified using a silica gel column (50%-100% EtOAc/hexanes) to afford 230 mg (50%) of benzyl 2-(2-fluoro-5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate as a white foam.
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CO.[Br:14]Br.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:4]1([CH2:1][CH2:2][CH2:3][Br:14])[CH2:5][CH2:6]1
Reactant: BrBr
Reactant: C=CCC1(CC(=O)OC)CC1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC1(CCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 3.4 ml (3.4 mmol) of borane/THF complex solution (1 M in THF) were added dropwise to 1542 mg (10 mmol) of methyl [1-(prop-2-en-1-yl)cyclopropyl]acetate in 10 ml of anhydrous THF. After 30 min at 0° C., the reaction was stirred at RT for a further 30 min, and 22 μl (0.54 mmol) of methanol were then added. At −5° C., 0.62 ml (12 mmol) of bromine and 2971 mg (16.5 mmol) of sodium methoxide solution (30% in methanol) were then successively added dropwise to the reaction mixture. Once the reaction had reached room temperature, 10 ml of saturated sodium bicarbonate solution were added, the organic phase was separated off and the aqueous phase was extracted three more times with tert-butyl methyl ether. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 683 mg (2.9 mmol, 29% of theory) of the title compound as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15].O>CC#N>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH3:11])=[O:18])=[CH:3][CH:4]=1
Reactant: COC(=O)C(C)(C)Br
Reactant: Oc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)(C)Sc1ccc(O)cc1
Reaction time: 48 h
Yield: 84 %

Procedure:
The title product was prepared according to the procedure described in Method A (step 1) starting from 4-mercaptophenol (0.500 g, 4.0 mmol) in 10 mL of anhydrous CH3CN, to which was added NaH 80% (0.144 g, 4.8 mmol). The mixture was cooled to 0° C. and after 5 minutes methyl-α-bromoisobutyrate (0.724 g, 4.0 mmol) was added. The reaction was left for two days at room temperature under magnetic stirring. After this period, the mixture was poured into H2O and extracted with ethyl acetate; the aqueous phase was then acidified with HCl 1N and extracted again with ethyl acetate. The pooled organic phases were dried on Na2SO4, filtered and evaporated. The residue obtained was purified by silica gel chromatography using CHCl3 as eluent. 0.760 g of product were obtained (yield: 84%); Mp: 110-112° C.; TLC: silica gel, eluent CHCl3, Fr: 0.11; 1H NMR (CDCl3, 300 MHz) δ: 7.30 (d, 2H), 6.73 (d, 2H), 5.57 (brm, 1H), 3.70 (s, 3H), 1.45 (s, 6H); HPLC: Column: Symmetry—C18, (5 μm) 4.6×250 mm, T: 30° C., mobile phase CH3CN/H2O 50/50 (v/v), pH: as is, flow rate: 0.75 mL/min, 205 nm UV detector, retention time 10.14 min; E.A. (elemental analysis) conforming for C11H14O3S.
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[C:23]([O:30]C)[CH:22]=1)([CH2:6][CH:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4].B(Br)(Br)Br>ClCCl.O>[NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[C:23]([OH:30])[CH:22]=1)([CH2:6][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4]
Reactant: COc1cc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(CC1c2ccccc2Oc2ccccc21)(C(=O)O)c1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-amino-2-(4-carboxy-3-methoxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid (140 mg, 0.33 mmol) in dry dichloromethane (10 ml) was added a solution of boron tribromide in dichloromethane (1.0M, 0.7 ml). The resulting suspension was stirred at room temperature for 3 days, diluted with water and stirred a further 2 h. The dichloromethane layer was separated and the aqueous phase purified by ion exchange as described in Example 1 (vi). The water-tetrahydrofuran fractions were found to contain the desired product and were combined, evaporated and freeze-dried from water to give the title compound as a white powder, m.p. 191°-194° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#CB1C2CCCC1CCC2.[CH3:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO.[CH2:27](CN)O>O1CCCC1.C(OCC)C>[CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:16][C:17]([CH3:27])([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C[Si](C)(C)C#CB1C2CCCC1CCC2
Reactant: NCCO
Reactant: CCCCCCC(C)=O
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(C)(O)C#C[Si](C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
Dissolve B-(2-(trimethylsilyl)ethynyl)-9-borabicyclo[3.3.1]nonane° tetrahydrofuran complex (2.63 g, 9 mmol) in tetrahydrofuran (30 mL) and add 2-octanone (1.41 mL, 9 mmol). Stir at 65° C. for 48 hours. Cool to room temperature and remove the solvent under a positive nitrogen pressure to give a yellow solid. Add ethyl ether (30 mL) and methanol (365 μL, 9 mmol). Cool to 0° C. and add, by dropwise addition, ethanolamine (543 μL, 9 mmol). Stir overnight, centrifuge the reaction mixture and separate the clear supernatant liquid. Wash the precipitate with pentane (2×10 mL) and combine the organic phases. Wash with water (2×25 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (20:5:1/ hexane, chloroform, methanol) to give the title compound as a pale yellow liquid (1,45 g, 71%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[Br:18][CH2:19][CH2:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:22]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CCBr)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(Trifluoromethyl)aniline (Aldrich, 16.11 g, 100 mmol) was added to a suspension of potassium carbonate (27.64 g, 200 mmol) in dichloromethane (225 mL) followed by the addition of 3-bromopropionyl chloride (10.08 mL, 100 mmol) in dichloromethane (40 mL). The mixture was stirred for 4 hours at ambient temperature, quenched with water (200 mL), the organic layer was washed twice with water (200 mL), dried over sodium sulfate, filtered through a silica gel plug, and rinsed with 1:1 ethyl acetate:hexane (400 mL), and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.99 (t, J=6.27 Hz, 2H), 3.74 (t, J=6.44 Hz, 2H), 7.41 (d, J=7.80 Hz, 1H), 7.56 (t, J=7.97 Hz, 1H), 7.77 (d, J=8.48 Hz, 1H), 8.11 (s, 1H), 10.39 (s, 1H). MS (DCI) m/z 312.99 (M+NH4)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1>>[CH:7]([N:6]1[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15][CH2:14]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[N:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CC(C)n1ncc([N+](=O)[O-])c1Cl
Product: CC(C)n1ncc([N+](=O)[O-])c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Yield: 92 %

Procedure:
Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and tert-butyl piperidin-4-ylmethylcarbamate gave tert-butyl (1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a pale yellow solid (0.45 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 4.78 (hep, J=6.7 Hz, 1H), 4.64 (s, 1H), 3.42-3.29 (m, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.95-2.87 (m, 2H), 2.05 (s, 1H), 1.81 (d, J=12.8 Hz, 2H), 1.46 (s, 9H), 1.43 (d, J=6.7 Hz, 6H), 1.37 (dd, J=12.1, 4.3 Hz, 2H)
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[N:9]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) 6.94–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.32 (s, 1H), 5.14 (s, 2H), 3.62–3.80 (m, 4H), 3.05–3.18 (m, 4H), 1.35 (s, 9H). MS (ES) M+H expected 412.43, found 413.1
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([NH:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:13][OH:14])=[O:10]>C(O)(CC)(C)C.CO.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2([CH3:15])[NH:11][C:9](=[O:10])[CH2:8][O:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(C)(CO)NC(=O)CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Solvent: CO
Product: COc1ccc(C2(C)COCC(=O)N2)cc1
Reaction time: 3 h

Procedure:
A solution of 129.1 mmol of potassium tert-butoxide in 100 ml of tert-amyl alcohol is mixed at room temperature with 51.6 mmol of 2-chloro-N-[2-hydroxy-1-(4-methoxyphenyl)-1-methylethyl]acetamide and stirred for 3 hours. The reaction mixture is diluted with 50 ml of methanol and 3 ml of water and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60 F). Rf=0.10 (ethyl acetate-heptane 2:1), Rt=2.81 (gradient I).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br.O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:30])[CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(COCCc2ccccc2OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Benzyl 2-(2-benzyloxyethyl)phenyl ether (159 mg) and 123 mg of sodium acetate was suspended in 2 ml of acetic acid, 29 μl of bromine was added to the suspension with stirring at room temperature, and the mixture was subjected to 1 hour of reaction. Then, a solution of 100 mg of sodium sulfite heptahydrate in 20 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and water in that order and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/methylene chloride=2/1) to give 173 mg of benzyl 2-(2-benzyloxyethyl)-4-bromophenyl ether in an oily form.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH:12]([OH:59])[CH2:13][C:14](=O)[C@@H:15]([C@H:17]1[N:20]([C:21](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C:19](=[O:47])[C@@H:18]1[C@H:48]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH3:49])[CH3:16])=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH:12]([OH:59])[CH2:13][C:14]1[C@H:15]([CH3:16])[C@H:17]2[N:20]([C:19](=[O:47])[C@@H:18]2[C@H:48]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:53])[CH3:52])[CH3:49])[C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)CC(O)[C@@H]1CCCN1C(=O)OCC=C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(CC(O)[C@@H]2CCCN2C(=O)OCC=C)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12

Procedure:
A solution of allyl 2-[(3S,4R)-4-[(1R)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-4-hydroxy-1-methyl-2-oxobutyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (2.36 g) in degassed toluene (120 ml) was heated to reflux for 8 hours. After cooling, the toluene was evaporated to give a residue of allyl (4S,5R,6S)-3-[2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-2-hydroxyethyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the residue was taken up into dichloromethane (90.0 ml). To the mixture were added dropwise triethylamine (1.02 ml) and methane sulfonyl chloride (0.52 ml) at 5° C. with stirring and the stirring was continued for 30 minutes at 5° C. To the resultant mixture was added 1,8-diazabicyclo[5.4.0]-7-undecene (3.36 ml) and the resultant mixture was allowed to warm to around 40° C. After stirring at 40° C. for 2 hours, the mixture was diluted with ethyl acetate and washed in turn with aqueous ammonium chloride, water and brine, and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-4:1 V/V) to give allyl (4S,5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}ethenyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (1.12 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][NH2:40])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH:35]4[O:36][CH2:37][CH2:38][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCOC(CN)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CN(C)CCO3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4-methylmorpholin-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 2.78-2.94 (m, 4H) 2.98-3.15 (m, 1H) 3.31-3.58 (m, 4H) 3.68 (t, J=11.75 Hz, 1H) 3.78-3.95 (m, 1H) 4.08 (dd, J=12.88, 3.03 Hz, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.21 (d, J=6.32 Hz, 1H) 8.44 (d, J=7.07 Hz, 2H) 8.85-9.06 (m, 2H) 9.93 (br. s., 1H) 12.57-13.73 (m, 1H). MS m/z [M+H]+ 433.2.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[N:28](C(OC(C)(C)C)=O)[CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[NH:28][CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Yield: 83.5 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (30 mg, 0.055 mmol) in TFA/DCM (1:1, 10 mL) was stirred at RT for 2 h. The solvent was removed and the resulting crude material was reconstituted in MeOH/DCM (20 mL) and purified via preparative HPLC. The collected fractions were combined and stripped to dryness via rotary evaporation to yield the title compound (16 mg, 85%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79 (d, J=9.76 Hz, 1H), 2.12 (qd, J=12.94, 5.13 Hz, 1H), 3.56-3.68 (m, 1H), 3.75 (d, J=11.72 Hz, 1H), 3.89 (br s, 1H), 4.02 (d, J=11.72 Hz, 2H), 4.28-4.37 (m, 1H), 4.38-4.49 (m, 2H), 7.10-7.20 (m, 1H), 7.28 (d, J=4.88 Hz, 1H), 7.59-7.70 (m, 1H), 7.93 (br s, 2H), 8.52 (s, 1H), 9.02 (dd, J=3.91, 0.98 Hz, 1H). [M+H] calc'd for C16H17FN4O2S, 349. found, 349.