Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:17][CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[OH:17][CH:18]([CH2:22][CH3:23])[C:19]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH2:10]1)=[O:20]
Reactant: CCC(O)C(=O)O
Reactant: c1ccc(-c2nc3c(o2)CNCC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.14 g (4.80 mmol) 2-phenyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine×HCl, 500.00 g (4.80 mmol) 2-hydroxybutanoic acid are placed in 10 mL DMF. Then 2.60 mL (18.51 mmol) triethylamine and 2.10 g (5.52 mmol) HATU are added and the mixture is stirred for 30 min at RT. The DMF is eliminated i.V., the residue is added to DCM and extracted 1 time each with 5% potassium hydrogen carbonate solution and 1N HCl. The solvent of the org. phase is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: C(O[CH:5]([C:12]1[N:17]([CH2:18][O:19][CH2:20][CH3:21])[C:16](=[O:22])[NH:15][C:14](=[O:23])[C:13]=1[CH:24]([CH3:26])[CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C>O1CCOCC1.[Pd]>[CH2:5]([C:12]1[N:17]([CH2:18][O:19][CH2:20][CH3:21])[C:16](=[O:22])[NH:15][C:14](=[O:23])[C:13]=1[CH:24]([CH3:25])[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOCn1c(C(OC(C)=O)c2ccccc2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOCn1c(Cc2ccccc2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of 6-(α-acetoxybenzyl)-1-ethoxymethyl-5-isopropyluracil (13.3 g) in dioxane (53 ml) was added 5% Pd/C (0.66 g) and the mixture stirred for 4 hr at 50° C. under an atmosphere of hydrogen at ordinary pressure. After removal of Pd/C, the solvent was removed by distillation under reduced pressure. The residue was crystallized from ethanol (50 ml) in a refrigerator to yield 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442) (10 g). M.p., 109°-110° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[ClH:19].Cl.Cl.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:25][CH2:24]1.N1CCCCC1>C(N(CC)CC)C.C1COCC1>[ClH:19].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:13]([C:11]3[S:12][C:8]([C:5]4[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:30]2)[CH2:25][CH2:24]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CN1CCN(C2CCCNC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(N4CCN(C)CC4)C3)s2)noc1C(F)(F)F
Yield: 53 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-Methyl-4-piperidin-3-yl-piperazine, tri-hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. An additional 3 equivalents of triethylamine was used. The reaction mixture was evaporated to an oil, triturated and filtered with the aid of water, then with a saturated aqueous NaHCO3 solution. The residual oil was then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude oil was then dissolved in diethyl ether (1 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (47 mg, 53%). LC/MS 4.62 min, [M+1]+ 443.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:18]4[CH2:20][CH2:19]4)[CH:13]=[C:14]([C:15]([OH:17])=O)[C:9]=3[C:8]([CH3:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:18]4[CH2:19][CH2:20]4)[CH:13]=[C:14]([C:15]([NH:22][CH2:23][C:24]4[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=4[CH3:30])=[O:17])[C:9]=3[C:8]([CH3:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (160 mg, 0.561 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (119 mg, 0.785 mmol), 1-hydroxy-7-azabenzotriazole (153 mg, 1.121 mmol), EDC (215 mg, 1.121 mmol), N-methylmorpholine (0.247 mL, 2.243 mmol) and DMSO (10 mL). The final product was collected as 0.205 g (87%). LCMS E-S (M+H)=420.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.06 Hz, 4H), 1.85 (dd, J=9.35, 5.05 Hz, 3H), 2.12 (s, 4H), 2.16-2.28 (m, 6H), 2.30-2.44 (m, 7H), 2.63 (d, J=19.96 Hz, 3H), 4.34 (d, J=4.29 Hz, 2H), 5.31 (t, J=8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br. s., 1H), 11.52 (br. s., 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17]CC)=[O:16])[CH2:9][CH2:8][CH2:7]2.ClC1C=C2C(=CC=1)N([C@@H](C(C)C)C(O)=O)CCC2>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([OH:17])=[O:16])[CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)[C@@H](CC(C)C)N1CCCc2cc(Cl)ccc21
Agent: CC(C)[C@@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
KOH (2.0 M in H2O, 0.34 mL, 0.68 mmol) was added to a 0° C., stirring solution of (R)-ethyl 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoate (50 mg, 0.17 mmol) in MeOH (0.32 mL). The reaction was allowed to warm to RT and stirred overnight. Due to the instability of the final product as a solid, the solution containing (S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid was used for the next step without further work up. LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=282.3; tR=3.72 min.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][C:10]4[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:11]=4[S:12][C:13]=3[CH:14]=2)[CH2:4][CH2:3]1.O=C1C2C3SC4=CCCC=C4C=C(C(O)=O)C=3C=CC=2CC1>>[OH:1][CH:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][C:10]4[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:11]=4[S:12][C:13]=3[CH:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3=O
Agent: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Product: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3O

Procedure:
Substituting an equivalent amount of 3-oxo-2,3,10,11-tetrahydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylic acid in Example 32 for 1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid provided the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@@H:20]([O:22][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a stirred solution of 250 mg (0.79 mmol) of (S)-1-[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (57 mg, 1.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 2-chloro-5-trifluoromethyl-pyridine (172 mg, 0.95 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 350 mg (96%) of the title compound as a colorless oil. ES-MS m/e: 461.3 (M+H+).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.B.CSC.C1C2CNC3C=CC=CC=3SC=2C=CC=1.[CH3:36][C:37]1[CH:54]=[CH:53][CH:52]=[CH:51][C:38]=1[C:39]([NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1)=[O:40]>O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH:9]1[C:8]2[CH2:2][N:3]([C:46]([C:45]3[CH:44]=[CH:43][C:42]([NH:41][C:39](=[O:40])[C:38]4[CH:51]=[CH:52][CH:53]=[CH:54][C:37]=4[CH3:36])=[CH:50][CH:49]=3)=[O:47])[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: B
Agent: CN(C)c1ccncc1
Agent: c1ccc2c(c1)CNc1ccccc1S2
Solvent: CSC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
As described for in Reference Example 12, a mixture of 3.3 g of 10,11-dihydro-11-oxodibenz[b,f] [1,4]thiazepine, 25 ml of tetrahydrofuran, 4.0 ml of 10 molar borane-dimethylsulfide (2.67 equiyalents) in tetrahydrofuran is stirred at room temperature 18 hours to give, after work-up, 10,11-dihydrodibenz[b,f][1,4] thiazepine as white crystals, m.p. 145°-148° C. The preceding compound (3.5 g) is suspended in 25 ml of dichloromethane and a solution of 1.8 g of 4-[(2-methylbenzoyl) amino]benzoyl chloride in 50 ml of di-chloromethane added. To the stirred mixture is added 4 ml of triethylamine and 0.2 g of 4-(dimethylamino) pyridine. The mixture is stirred at room temperature for 20 hours. The mixture is filtered and the filtrate concentrated. The residue is purified by chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solyent to give 2.2 g of yel]ow crystals. A sample (0.80 g) is further purified by thick layer chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give 0.50 g of crystals, 76°-78° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH2:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH:19]=O)[CH:17]=O)=[CH:12][CH:11]=1>C(O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]2[CH:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=3)[CH:19]=[N:7][C:6]=12
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: Nc1[nH]ncc1I
Solvent: CCO
Product: COc1ccc(-c2cnc3c(I)cnn3c2)cc1
Temperature: 23 °C

Procedure:
A solution of 4-iodo-1H-pyrazol-5-amine (640 mg, 3.9 mmol, 1 equiv) and 2-(4-methoxyphenyl)malonaldehyde (700 mg, 3.9 mmol, 1.0 equiv) in ethanol (20 mL) was heated at 75° C. for 4 hours. The reaction mixture was allowed to cool to 23° C., and the precipitate was filtered, washed with cold methanol, and air dried to afford 3-iodo-6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (2-1) as a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2
Reactant: Cc1ccc(CBr)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 2.53 g, 63.1 mmol) was added portionwise to a stirring solution of 5-bromoindole (8.25 g, 42.1 mmol) in DMF (80 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed up to room temperature. After the reaction mixture was stirred at room temperature for 1 hour, 4-methylbenzyl bromide (12.0 g, 63.1 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous phase was extracted with ethyl acetate. The organic extract was washed with water and brine, then dried over anhydrous magnesium sulfate. This mixture was concentrated to give a crude oil (14.1 g, 71%). Crystallization from petroleum ether afforded the title compound as a white solid, m.p: 56-57° C. Mass spectrum (APCI, [M+H]+) m/z 300. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.18 (d, 1H, J=10.5 Hz), 7.09 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.2 Hz), 6.45 (s, 1H), 5.35 (s, 2H), and 2.22 ppm (s, 3H). Elemental Analysis for C16H14BrN: Calculated: C, 64.02; H, 4.70; N, 4.67. Found: C, 63.66; H, 4.59; N, 4.71.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C@H:4]([CH3:6])[NH2:5].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C@H:4]([CH3:6])[NH:5][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: C[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing N,N-dimethylalaninamide obtained in C) and triethylamine (2 mL) in ethanol (20 mL) was added 4-thioxothiazolidin-2-one (1998 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (960 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:38][C:6]2[C:7]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([O:28]CC4C=CC(OC)=CC=4)[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:39])[CH2:3]1>FC(F)(F)C(O)=O>[CH3:1][C:2]1([CH3:40])[CH2:38][C:6]2[C:7]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][C:18](=[O:28])[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:39])[CH2:3]1
Reactant: COc1ccc(COc2cc(-c3c(N4CCOCC4)sc4c3CC(C)(C)CC4=O)cc(-c3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cc(-c4ccccc4)[nH]c(=O)c3)c2C1
Yield: 42.5 %

Procedure:
A solution of Example 339 (36 mg, 0.065 mmol) in trifluoroacetic acid (10 mL) was heated at reflux for 4 h. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane) to give the title compound (12 mg, 42%) as an off-white solid. δH (CDCl3) 7.70-7.64 (2H, m), 7.58-7.52 (3H, m), 6.70 (1H, d, J 1.3 Hz), 6.46 (1H, d, J 1.3 Hz), 3.77-3.70 (4H, m), 3.17-3.11 (4H, m), 2.61 (2H, s), 2.45 (2H, s), 1.07 (6H, s). LCMS (ES+) 435.3 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:12])=[O:6])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C

Procedure:
6 Grams of 2-formylbenzoic acid and 6 g of potassium carbonate were added to 30 ml of dimethylformamide, then 6 g of methyl iodide were added dropwise thereto at room temperature with stirring. The reaction mixture was continuously stirred at room temperature overnight, then was concentrated. The residue obtained was extracted with chloroform, and the chloroform layer was washed with water, and was dried with anhydrous magnesium sulfate, then concentrated. The residue obtained was purified by distillation under reduced pressure to yield 3 g of methyl 2-formylbenzoate. Boiling point: 95° C. (at 0.5 mm-Hg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](OCC)OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[SH:15][CH2:16][C:17]([OH:19])=[O:18].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]1[S:15][CH2:16][C:17](=[O:19])[O:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(OCC)OCC
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)OCC1OC(=O)CS1
Temperature: 25 °C
Yield: 85 %

Procedure:
A well-stirred solution of 28 (6.13 g, 30 mmol), mercaptoacetic acid (4.14 g, 3.13 ml, 45 mmol) and p-TsOH. H2O (60 mg, 0.31 mmol) in dry toluene was refluxed for 2 hours. Solvent was occasionally removed with a Dean-Stark trap, and fresh dry toluene was added. After cooling to room temperature, the reaction mixture was diluted with AcOEt (50 ml) and successively washed with: concentrated NaHCO3 (2×100 ml) and brine (2×100 ml), dried, filtered and evaporated to afford 25 (5.2 g, 25.5 mmol, 85%) as a yellow liquid that was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:4][NH:5][C:6]3[N:26]=[C:10]([NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=4)[CH2:17][CH2:18][CH2:19][O:20][C:21]([CH:24]=2)=[CH:22][CH:23]=1)[N:9]=[CH:8][C:7]=3[Cl:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH:25]=3)[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:24]=[C:3]([CH2:4][NH:5][C:6]=1[N:26]=2)[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:23][CH:22]=3
Reactant: OB(O)c1ccccc1
Reactant: Clc1cnc2nc1NCc1cc(ccc1Br)OCCCc1cccc(c1)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1cnc2nc1NCc1cc(ccc1-c1ccccc1)OCCCc1cccc(c1)N2
Yield: 27 %

Procedure:
A mixture of 11-bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene (30.0 mg, 0.067 mmol) (prepared according to Example 14, Step E), phenylboronic acid (9.8 mg, 0.081 mmol), tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0067 mmol), 1,2-dimethoxyethane (0.50 mL), and a solution of sodium carbonate in water (0.17 mL, 2.0 M) was sealed into a microwave vial and the resultant suspension was de-gassed by bubbling with N2. After degassing, the vial was microwaved at 150° C. for 20 min. The reaction mixture was diluted with EtOAc, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to provide the desired product (8 mg, 27%) as a white powder. LCMS for C26H23ClN4O (M+H)+: m/z=443.1. 1H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (dd, J=6.0, 1.2 Hz, 2H), 7.32 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.87 (m, 2H), 6.75 (m, 1H), 5.70 (t, 2H), 4.62 (m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 2.68 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1([F:15])[CH2:14][O:13][CH2:12]1.[CH:16]1([CH2:19][OH:20])[CH2:18][CH2:17]1.CC([O-])(C)C.[Na+]>CN(C=O)C.C1COCC1>[CH:16]1([CH2:19][O:20][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]2([F:15])[CH2:14][O:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: OCC1CC1
Reactant: O=C(O)c1ccc(C2(F)COC2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
6-Chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134 e, 44 mg, 190 μmol) and cyclopropylmethanol (CAN 2516-33-8, 17.8 mg, 20.0 μL, 247 μmol) were dissolved in DMF (1.32 mL). A solution of sodium 2-methylpropan-2-olate (42.0 mg, 437 μmol) in THF (800 μL) was added and the mixture was heated to 50° C. for 3 h and for additional 3 h to 70° C. After cooling to ambient temperature, the reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by thin layer chromatography (2 mm SiO2, dichloromethane/MeOH 19:1, elution with EtOAc) to give the title compound (11 mg, 22 mg) as colorless oil, MS (ESI) m/e=268.2 [MH+].
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Cl:14])=[CH:6][CH:5]=1)(=[O:3])C.Cl[O-:16].[Na+]>Cl>[Cl:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([C:1]([OH:3])=[O:16])=[CH:5][CH:6]=1
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(Cl)c2ccccc12
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(Cl)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
The compound (8.33 g) obtained in (1) above and a 5% sodium hypochlorite solution (380 ml) were stirred with refluxing for 44 hours. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid (10 ml) was dropwise added. The resulting solid was collected by filtration. The obtained solid was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 1.96 g of a red-brown solid (yield 23%).
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].N1C=CN=C1.[CH2:17]([Si:19]([CH2:23][CH3:24])([CH2:21][CH3:22])Cl)[CH3:18]>CN(C)C=O>[CH2:1]([C:4]1([CH2:10][O:11][Si:19]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(CO)CCCCC1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1(CO[Si](CC)(CC)CC)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1-allylcyclohexyl)methanol (1.0 g) in N,N-dimethylformamide (7 mL) were added imidazole (661 mg) and triethylchlorosilane (1.41 mL) at room temperature. After stirring the solution at room temperature for 3 hours, N,N-dimethylformamide was added thereto and it was extracted with hexane. The combined hexane layer was washed with acetonitrile and concentrated under reduced pressure to give the title compound (1.70 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]([CH:17]([F:19])[F:18])([CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O)[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].Cl>[OH-].[Na+]>[C:20]([NH:1][C:2]([CH:17]([F:18])[F:19])([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(CCCN)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.9 g of 2-amino-5-tert-butoxycarbonylamino-2-difluoromethylpentanoic acid in 10.5 ml of 1M sodium hydroxide is added at 0° C. simultaneously 0.19 g of acetylchloride and 5 ml of 2M aqueous sodium hydroxide. The reaction mixture is stirred for 3 hours at room temperature. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. After usual work-up the solvent is evaporated and the residue taken up in trifluoroacetic acid. After concentration and purification by ion exchange chromatography on a resin 5-amino-2-acetylamino-2-difluoromethylpentanoic acid is obtained.