Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:12]
Reactant: c1ccc([C@@H]2C[C@H]2NCn2nnc3ccccc32)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CN[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
To a mixture of 7.3 g (0.112 g-atom) of zinc powder (−325 mesh) and 120 mL of anhydrous tetrahydrofuran was added 10.7 mL (0.084 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 10.8 mL (0.084 mole) of ethyl bromodifluoroacetate in 10 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 14.8 g (0.056 mole) of benzotriazol-1-ylmethyl-(trans-2-phenyl-cyclopropyl)-amine in 60 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 1.7 g of 2,2-difluoro-3-(trans-2-phenyl-cyclopropylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>>[Cl:5][CH2:4][CH2:3][CH2:2][NH:10][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: ClCCCBr
Reactant: CC(C)(C)N
Product: CC(C)(C)NCCCCl
Reaction time: 8 h

Procedure:
A round-bottom, 250 milliliter, three-necked flask was equipped with a magnetic stir bar, a Claisen adapter, equipped with a thermocouple and a dry-ice condenser with a gas inlet, and a pressure-equalizing dropping funnel. This apparatus was baked in an oven overnight at 125° C., assembled hot, and purged with argon until cool. The reaction flask was charged with 1-bromo-3-chloropropane 15.74 grams, (0.10 moles, 1 equivalent). t-Butylamine 29.26 grams, (0.40 moles, 4 equivalents) was added dropwise via the addition funnel over a period of one hour. After addition was complete, samples of the reaction mixture were removed periodically, washed with saturated sodium bicarbonate solution, and assayed for unreacted 1-bromo-3-chloropropane by gas chromatography (GLC). The reaction was allowed to stir until 1-bromo-3-chloropropane was consumed. Next, 75 milliliters of saturated sodium bicarbonate solution and 25 milliliters of distilled water were added to the reaction flask. The reaction mixture was then transferred to a separatory funnel and extracted 2×75 milliliters with ethyl ether. The organic layer was then dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator, to afford a colorless, slightly hazy solution with a yield=10.47 g (70%); (GC assay=93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.B1([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 90 %

Procedure:
Argon is bubbled for 10 minutes into a mixture of 4.64 g (20.0 mmol) of the product prepared in step 4.1, 6.25 g (20.2 mmol) of 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (Frontier Scientific) and 8.29 g (60.0 mmol) of potassium carbonate in 125 mL of anhydrous DMF. 0.98 g (1.2 mmol) of PdCl2dppf.CH2Cl2 is added and the mixture is heated under argon at 90°C. for 3 hours. The resulting mixture is diluted with ethyl acetate and washed twice with water and once with saturated aqueous NaCl. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. The crude solid obtained is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (75/25 to 70/30). 6.02 g of a pale yellow solid are obtained, and are triturated in cyclohexane and then drained by suction and dried in an oven. 5.89 g of the expected product are finally recovered in the form of a white solid. Yield=88%.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1.CN(C)C(=O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH:23]([CH3:24])[CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)CC(C)Br
Reactant: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)N(C)C
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1OC(C)CC(C)C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A mixture of 10 g (35 mmol) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone, 11 g (66 mmol) of 2-bromo-4-methylpentane and 9.7 g (70 mmol) of potassium carbonate in 50 ml of xylene and 20 ml of N,N-dimethylacetamide is heated with stirring and held at 125° C. for 6 h. The reaction mixture is cooled, then treated with 30 ml of water and extracted with ethyl acetate. The resulting solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is distilled in a bulb tube (200° C./0. 1 mbar). 11.2 g (86.4%) of the compound are obtained as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(O)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A slurry of 2,4-dihydroxyquinoline (20.7 g, 0.13 mol), potassium carbonate (35.5 g, 0.26 mol), and dimethyl sulfate (14.6 ml, 0.15 mol) in acetone (800 ml) was heated at reflux for 3 days. The reaction was cooled to ambient temperature then evaporated under reduced pressure. The residue was slurried in a system of water (1000 ml) and ethyl acetate (500 ml) for 1 hour. The solids were collected then rinsed with water (3×250 ml) and ethyl ether (3×250 ml). Vacuum dried over phosphorus pentoxide to give 2-hydroxy4-methoxyquinoline (16.3 g, 72%) as a tan powder. [M+H]+ 176, M+CH3CN=217.
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[O:9]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][S:1][C:12]2[C:11](=[O:20])[C:10](=[O:21])[C:19]3[C:14]([C:13]1=2)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: OC1(CS)CCCCC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCCC1)O2

Procedure:
The crude 1-(mercaptomethyl)cyclohexanol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione. The crude spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product (0.183 g) as a purple solid. M.p.=194-195° C., 400 MHz 1H NMR CDCl3 δ 8.05-8.0 (m, 1H), 7.8-7.72 (m, 1H), 7.68-7.6 (m, 1H), 7.5-7.4 (m, 1H), 2.91 (s, 2H), 2.15-2.0 (m, 2H), 1.8-1.53 (m, 7H), 1.5-1.35 (m, 1H); LCMS=301 [M+H].
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.Cl.[OH:45][CH:46]1[CH2:49][NH:48][CH2:47]1>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][N:48]3[CH2:49][CH:46]([OH:45])[CH2:47]3)[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: OC1CNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: Cl
Product: COc1ccc(Nc2ncc(CN3CC(O)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.22 g, 0.381 mmol) and 3-hydroxyazetidine hydrochloride (Oakwood Products, Inc., West Columbia, S.C.) (0.063 g, 0.571 mmol). 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H); 8.53 (br. s., 1H); 8.36 (d, J=2.54 Hz, 1H); 8.14 (d, J=2.15 Hz, 1H); 8.09 (dd, J=8.90, 2.64 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 4.46-4.55 (m, 1H); 3.94 (s, 3H); 3.64 (s, 2H); 3.59 (t, J=7.73 Hz, 2H); 3.30-3.40 (m, 2H); 2.56 (s, 3H). m/z (ESI, +ve ion) 395.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].BrBr>CC(O)=O.O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-aminobenzoic acid (1.37 g, 14 mmol) in AcOH (16 mL) may be added with potassium thiocyanate (3.9 g, 40 mmol) and may be stirred for 15 minutes. A solution of bromine (0.5 mL, 10 mmol) in AcOH (6 mL) may then be added slowly into the reaction mixture in water bath, where the temperature may be maintained at about 25° C. The resulting mixture may be stirred overnight. The mixture may then be filtered, and the pale yellow precipitate may then be further recrystallized with the minimal volume of aqueous hydrochloric acid (6 M). A pale yellow product of formula (2) may be collected with the following characterization: 1H NMR (CD3OD, 500 MHz): δ 4.96 (2H, brs), 7.58 (1H, d, J=8.0 Hz), 8.14 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.47-8.47 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=O>O1CCCC1>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride and 13.7 g (0.254 mol) of sodium methylate in 170 ml of tetrahydrofuran was heated under reflux for 1 hour, and cooled to 25° C. A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-2′,4′-dichloroacetophenone in 120 ml of tetrahydrofuran was added dropwise in such a manner that the reaction temperature did not exceed 30° C. After the addition was complete, 13.7 g (0.254 mol) of sodium methylate was added, and the mixture was heated under reflux for 1 hour. Subsequently, the reaction solution was cooled to room temperature, and insolubles were filtered off. The filtrate was evaporated to dryness under reduced pressure to recover a solid. The solid was successively washed with water and toluene and then dried, to give 33.8 g (46.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile to give pale yellow purified crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(O[N:34]1N=N[C:36]2[CH:37]=[CH:38][CH:39]=C[C:35]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.CC1CCCN1.BrCl>CN(C)C=O.ClCCl.C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:35][CH2:36][CH2:37][CH:38]1[CH3:39])=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC1CCCN1
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CC1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Br
Yield: 22 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-bromo-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine and rac.-2-methylpyrrolidine in dimethylformamide. Yield: 22%; Rf value: 0.45 (silica gel: dichloromethane/ethanol=9:1); C22H22BrClN4O2 (489.799); mass spectrum: (M+H)+=489/491/493 (bromo-chlorine isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:22][C@H:11]([C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 2-(4-nitropheyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22,(0.41 g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1mmol) and 1-hydroxybenzotriazole (HOBt)(0.07 g, 0.05 mmol) in DMF (5 ml) at 0°, is added 1-(3-dimethylaminoprpyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is stirred at 0° for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCI, 5% aqueoue NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60% yield) of the desired product wich is used without further purification. SEI-MS 428 (M-1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([C:32](=[O:34])[CH3:33])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CCC3CCCCC3)c2C1
Yield: 26 %

Procedure:
1-(4-(2-Cyclohexylethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (51 mg, 26%) was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 54a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 459.4 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(F)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Intermediate 50 (50 g, 0.217 moles) was taken in a RB flask and to this acetic anhydride (424 ml) and sodium acetate (124 g, 1.51 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as colourless solid (44 g, 80% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87 (dd, J=8.3, 3.0 Hz, 1H), 7.47-7.35 (m, 5H), 7.29 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.CCOCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2([OH:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3]2)=[CH:20][CH:19]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CC(C)(C)CC(O)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 51.42 g (333.3 mmoles) of 3,3,5,5-tetramethylcyclohexanone in 200 ml of tetrahydrofuran (THF) was added dropwise to an ice cold solution made up of 200 ml of a 2M ether solution of 4-fluorophenyl magnesium bromide (400 mmoles) and 100 ml of THF. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then poured onto ice and 500 ml of 1N HCl. After stirring for 0.5 hour, the layers were separated. The aqueous layer was extracted once with ether and the combined organic layers were evaporated in vacuo to obtain the title compounds in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:14][O:15][NH2:16]>CO.O>[CH3:14][O:15][N:16]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=2[Cl:11])[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CO
Product: CON=C1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5,7-dichloro-1-indanone (0.34 mmol) in 2 mL MeOH was added O-methylhydroxylamine HCl (0.34 mmol). The reaction mixture was stirred at RT for 17 h and then heated to 50° C. for 24 h. The mixture was cooled to RT, diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][OH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ClC(Cl)(Cl)C(=N)O[C:29]([CH3:32])([CH3:31])[CH3:30]>CCOC(C)=O.C1CCCCC1>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][CH:19]([CH2:20][OH:21])[C:22]([O:24][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.3 %

Procedure:
To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc (40 ml), a solution of t-butyl 2,2,2-trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18 ml) was added dropwise. After stirring at room temperature for 24 hrs, the solution was evaporated and the residue was purified by flash chromatography (n-Hexane/EtOAc 70:3), yielding the title compound (1.20 g, 68%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1>C1COCC1>[F:1][C:2]([F:12])([F:13])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][OH:10])[CH2:7][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
BH3 (100 mL, 0.1 mol, 1.0 M solution in THF) was added dropwise to 0° C. solution of trans-4-(trifluoromethyl)cyclohexanecarboxylic acid (19.6 g, 0.1 mol) in dry THF (100 mL). The reaction was stirred at room temperature for 5 h, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated to give [trans-4-(trifluoromethyl)cyclohexyl]methanol. 1H NMR (300 MHz, CDCl3): δ 3.48-3.47 (d, 2H), 2.00-1.89 (m, 5H), 1.51-1.43 (m, 1H), 1.35-1.26 (m, 2H), 1.05-0.96 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1B(O)O.[C:12]([N:16]1[C:20](=[O:21])[CH:19]=[C:18](Cl)[S:17]1(=[O:24])=[O:23])([CH3:15])([CH3:14])[CH3:13].ClCCl.C(N(CC)CC)C>C1(C)C=CC=CC=1.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:12]([N:16]1[C:20](=[O:21])[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:17]1(=[O:23])=[O:24])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Temperature: 90 °C
Yield: 64.9 %

Procedure:
(2-Fluoro-4-methylphenyl)boronic acid (19.5 g, 0.127 mol), 2-tert-butyl-5-chloro-1,1-dioxo-1,2-dihydro-1λ6-isothiazol-3-one (30.5 g, 0.136 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (10.4 g, 12.7 mmol) were dissolved in toluene (500 mL) and treated with triethylamine (53.0 mL, 0.380 mol). The reaction was degassed and placed under an atmosphere of nitrogen. The reaction was then heated to 90° C. for 18 h. The reaction was diluted with ethyl acetate (500 mL) and washed with 1 N aqueous hydrochloric acid (500 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was filtered through celite and then silica gel. The crude material was then purified by silica gel chromatography (5–10% ethyl acetate:hexanes) to afford product as a white solid (24.5 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.85 (t, J=7.8 Hz, 1H), 7.11–7.03 (m2H), 6.86 (d, J=1.8 Hz, 1H), 2.42 (s, 3H), 1.73 (s, 9H).