Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=CC=1.[H-].[Na+].[CH3:16][C:17]1([CH3:34])[O:21]C(COS(C2C=CC(C)=CC=2)(=O)=O)C[O:18]1>CN(C)C=O>[CH3:16][C:17]1([CH3:34])[O:21][CH:2]([CH2:1][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:7][O:18]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2CCNCC2)O1
Reaction time: 8 h

Procedure:
A solution of 2.6 ml N-benzylpiperazine in dimethylformamide (30 ml) is treated slowly with sodium hydride (510 mg). To this suspension is added toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (0.8 g) and the mixture stirred overnight. The reaction mixture is evaporated, the residue is trated with water and the product extracted with ethyl acetate. The organic extract is dried and evaporated. The crude product is purified by flash chromatography on silica gel using heptane/ethyl acetate 1:1 as eluent. The purified intermediate (0.9 g) is dissolved in methanol (30 ml) and hydrogenated over palladium on charcoal (0.3 g). The catalyst is filtered off and the filtrate is evaporated to yield 0.54 g of the title compound as a waxy solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:31])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CS(O)(=O)=O.C(O[C:40](OCC)(OCC)[CH2:41][CH3:42])C>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([C:20]2[C:21]([C:22]3[O:23][C:40]([CH2:41][CH3:42])=[N:25][N:24]=3)=[CH:26][C:17]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[O:16])=[C:18]([CH3:31])[CH:19]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Cc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)o1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide (compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane (5 mL). MeSO3H (7 mg, 0.07 mmol, 0.20 equiv), and 1,1,1-triethoxypropane (190 mg, 1.08 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 20 min at 110° C., then cooled to room temperature and diluted with 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (64.0% CH3CN up to 76.0% in 6 min, up to 100.0% in 4 min, down to 64.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 129 mg (79%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m, 3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m, 1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets, amide rotamers, CH3, 3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][CH:23]=1>>[CH3:27][C:25]1[NH:24][C:23]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:22][N:26]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: Cc1ncc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)[nH]1
Yield: 51 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo-2-methyl-1H-imidazole were reacted to give the title compound as an off-white foam (28 mg, 51%).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[OH-].[NH4+]>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:6]1[CH2:5][CH2:4][NH:3][CH2:8][CH:7]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
44 g of the hydrochloride of 4-piperidone monohydrate were added at 100° C. to a solution of 12.6 g of 5-methoxy-1H-indole in 240 ml of acetic acid and the mixture was held at 100° C. for 30 minutes and was then cooled. The mixture was poured into ice water containing 400 ml of concentrated ammonium hydroxide and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to obtain 20 g of raw product. The latter was chromatographed over silica gel and was eluted with a 7-2-1 chloroform-methanol-triethylamine mixture to obtain 5.26 g of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole in the form of a resin.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>O1CCCC1.C(Cl)Cl>[CH3:1][NH:2][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To 20 ml of a 2 molar solution of methylamine in tetrahydrofuran chilled in an ice bath was added a solution of 5.16 g of 4-(4-chlorophenyloxy)benzene-sulfonyl chloride in 50 ml of tetrahydrofuran and 20 ml of CH2Cl2. The mixture was refluxed for 2 hours and the solvent removed under vacuum and the residue partitioned between CH2Cl2.H2O (1:1). The CH2Cl2 layer was separated and washed with 2 N citric acid, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated to give 4.5 g of N-methyl-4-(4-chlorophenoxy)benzene-sulfonamide as a yellow solid, m.p. 80-83° C.
Reaction SMILES: [CH3:1][C:2]12[O:7][CH:6]1[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3]2.C(=O)=O.CO>CO>[CH3:1][C@:2]12[O:7][C@H:6]1[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3]2
Reactant: CC12CN(C(=O)OCc3ccccc3)CC1O2
Agent: O=C=O
Solvent: CO
Product: C[C@@]12CN(C(=O)OCc3ccccc3)C[C@@H]1O2

Procedure:
A racemic mixture of benzyl 1-methyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (12 g) was resolved under the following conditions: Column: Chiralpak AD-H (5×25 cm, 5 μm), BPR pressure: 100 bars; temperature: 40° C.; flow rate: 290 mL/min; mobile Phase: CO2/MeOH (90/10); Detector Wavelength: 215 nm; injection: 0.83 mL with cycle time 2.6 min; sample preparation: 12.0 g/400 mL MeOH, 30.0 mg/mL. The desired (1R,5S)-benzyl 1-methyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate was obtained as the slower eluting peak (4.5 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH:19]5[CH2:29][CH2:28][CH:22]([C:23]=4[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[CH2:14]2)[CH2:21][CH2:20]5)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[O:17][C:16]2[C:18]3[CH:19]4[CH2:29][CH2:28][CH:22]([C:23]=3[C:24]([O:26][CH3:27])=[CH:25][C:15]=2[CH2:14]1)[CH2:21][CH2:20]4)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2c(c3c1C1CCC3CC1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Product: COc1cc2c(c3c1C1CCC3CC1)OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate (5.45 g, 13.1 mmol) with sodium azide (3.419 g, 52.6 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.350 g) generally according to the procedure described for Example 2 gave 2.88 g (74%) of (±)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>210° C.; Anal. calcd. for C16H21NO2HCl: C, 64.97; H, 7.5; N, 4.74. Found: C, 64.71; H, 7.69; N, 4.54.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[N:50][CH:51]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:45][C:46]4[CH:51]=[N:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)=[N:3][CH:4]=[C:5]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:37][CH:36]=4)[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (503 mg, 0.820 mmol) and 5-amino-2-methoxypyridine (112 mg, 0.905 mmol) were dissolved in THF (8.0 mL) and the flask was cooled in an ice water bath while the reaction was stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran (2.5 mL, 2.500 mmol) was added via syringe, and the reaction was stirred for 40 min. Then, the reaction was treated with ice water (0.60 mL) and the reaction was diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to100:1 DCM/MeOH to 50:1 DCM/MeOH). The pure fractions were set aside, while the impure ones were collected, concentrated, and purified on another silica gel filter (30 mL fritted filter with about 1 inch of silica gel; DCM to 100:1 DCM/MeOH). The fractions with product were combined with the pure fractions from the first column and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (412 mg). 1H NMR (CDCl3, 400 MHz) δ 11.58 (s, 1H), 8.61 (d, J=2.35 Hz, 1H), 8.26 (d, J=2.54 Hz, 1H), 8.13 (d, J=2.35 Hz, 1H), 7.87 (dd, J=8.90 Hz, 2.64 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.61 Hz, 2H), 7.15 (d, J=8.61 Hz, 2H), 6.87 (d, J=8.61 Hz, 2H), 6.82 (d, J=8.41 Hz, 2H), 6.70 (d, J=8.80 Hz, 1H), 4.85 (s, 2H), 4.77 (s, 2H), 4.00 (s, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H). m/z (ESI, +ve ion) 718 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21])=[CH2:12].[C:22]1(SC[Li])C=CC=CC=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:22][CH2:12]1
Reactant: C=C(c1ccc(C)cc1OC)c1ccccc1OCOC
Reactant: [Li]CSc1ccccc1
Product: COCOc1ccccc1C1(c2ccc(C)cc2OC)CC1
Yield: 44 %

Procedure:
The general procedure of Example 34 was followed using 1-(2-methoxymethoxyphenyl)-1-(4-methyl-2-methoxyphenyl)ethene and, initially, 3.3 moles of phenylthiomethyl lithium reagent per mole of olefin. The title compound was obtained as a clear oil in 44 percent yield and its structure was verified by proton NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH3:28][C:29](C)=O>>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH3:29]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1=Cc2cc(O)cc(C)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1=Cc2cc(OCC)cc(C)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 98 %

Procedure:
The ethyl 6-hydroxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 613b, Step 2 (0.2 g, 0.66 mmole) and K2CO3 (0.48 g, 3.44 mmole) was suspended in acetone (7.5 mL). lodoethane (1.03 g, 6.60 mmole) was added and heated to 55° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give an orange solid (0.22 g, 98%). GCMS m/z 330.0 (M+). LCMS m/z 331.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.62 (s, 1H), 6.71 (s, 1H), 6.55 (s, 1H), 5.65 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.93 (m, 2H), 2.19 (s, 3H), 1.33 (m, 6H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21][CH3:22])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClC(Cl)C.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21]([CH3:22])=[O:31])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl)S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.25 g (30 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-methylthioethyl)pyrimidine were placed in 120 ml of dichloroethane, and a solution of 7.40 g (30 mmol) of 70% 3-chloroperbenzoic acid in 50 ml of dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hours and extracted by stirring with sodium bicarbonate solution and water. The organic phase was dried and concentrated, to give 10.5 g (98% of theory) of a colorless resin (diastereomer mixture).
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:46])[C@H:10]([N:17]2[CH2:21][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:19]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([F:45])([F:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:31][CH2:30]3)[CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:45][C:37]([F:44])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:36][CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][C@@H:19]2[C@@H:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][N:17]([C@H:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]([OH:46])=[O:8])[CH2:18]2)[CH2:34][CH2:33]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCC(F)(F)c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
2-(R)-(3-(S)-((4-(3,3-Difluoro-3-phenylpropyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid (4-methoxy)benzyl ester (32 mg, 0.049 mmol) dissolved in 95% ethanol (2.5 mL) was hydrogenated at atmospheric pressure using 20% Pd(OH)2/C (5.8 mg). After 3 h, additional Pd(OH)2/C (3.5 mg) was added and the reaction was continued for 1 h. The mixture was filtered, the catalyst was washed with 95% ethanol, and the filtrate was evaporated. The crude product was purified by flash column chromatography on silica gel packed in CH2Cl2. Elution with 95:5:1 v/v/v CH2Cl2/CH3OH/NH4OH followed by 90:10:1 v/v/v CH2Cl2/CH3OH/NH4OH gave 26 mg of the title compound as a colorless brittle glass: RF: 0.5 (10% CH3OH/2% conc. aq. NH4OH/CH2Cl2). 1H NMR (400 MHz, CD3OD) δ 7.48-7.30 (m, 4H), 7.38-7.30 (m, 4H), 7.30-7.23 (m, 1H), 3.62-3.51 (m, 2H), 3.44 (d, J=4, 11), 3.10 (td, J=10, 8, 1H), 2.88 (bd, J=12, 1H), 2.73 (bd, J=10, 2H), 2.46 (dd, J=12, 10, 1H), 2.30 (dd, J=13,4, 1H), 2.11 (tm, J=16, 2H), 1.96 (bt, J=12, 1H), 1.90-1.64 (m, 8H), 1.59 (bt, J=12, 2H), 1.50-1.00 (m, 11H); ESI-MS 539 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](=O)[CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.O.NN.[OH-].[K+].O>C(O)COCCO>[CH2:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)[CH3:12]
Reactant: CC(=O)c1ccc2ccn(C)c2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCc1ccc2ccn(C)c2c1
Temperature: 62 °C
Yield: 96.3 %

Procedure:
A mixture of 0.226 g 1-(1-methyl-1H-indol-6-yl)-ethanone, 1.35 mL of 85% hydrazine hydrate, 0.88 g of potassium hydroxide in 15 mL of diethylene glycol was stirred at 62° C. over night. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated to give 0.200 g of 6-ethyl-1-methylindole as a colorless oil after chromatographic purification on a silica gel column.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[CH3:27][O:28][NH2:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][O:28][CH3:27])=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CONC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 3.5 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (430 mg, 1.19 mmol) and methoxyamine hydrochloride (125 mg, 1.78 mmol) in 10 mL of DMF was added PyBOP (926 mg, 1.78 mmol) and TEA (496 uL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (16.4 mg, yield 4%). Analytical data for title compound. MS calcd for (C16H18BN3O6S): 391.2. MS found (ESI negative): (M−H)−=390.0. 1H NMR (DMSO-d6) δ (ppm): 11.14 (s, 1H), 9.74 (s, 1H), 9.10 (bs, 1H), 7.36-7.40 (m, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.36 (s, 1H), 6.31 (d, J=8.8 Hz, 1H), 4.80 (s, 2H), 3.58 (s, 2H), 3.56 (s, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[S:18][CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:36][C:22]1[N:21]=[C:20]([C:17]2[S:18][CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:16]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)cs2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(N)(=O)=O)c3)cs2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{2-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-thiazol-4-yl}-benzenesulfonamide (example 263) (0.40 g, 0.753 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.20 g, 56%). MS (ISP) 474.1 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([NH:7][C@@H:8]([CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](COC(C)(C)C)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC[C@H](Nc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of methyl (2S)-2-phenylamino-3-tert-butoxypropanoate (230 mg) in methanol (2.30 mL) was added 1N sodium hydroxide aqueous solution (2.75 mL) and the mixture was stirred at ambient temperature for 2 hours. The resulting solution was acidified with 1N HCl (2.7 mL) to pH=4 and diluted with water (2.7 mL). The mixture was stirred at 0° C. for 20 minutes and the precipitate was collected by filtration followed by washing with water (2.7 mL) to give (2S)-2-phenylamino-3-tert-butoxypropanoic acid (100 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1.[F:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][C:36]([N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[CH2:6][C:7]3[NH:8][C:9](=[O:17])[C:10]4[CH2:16][O:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[O:37])[CH2:33][CH2:34]2)=[O:28])=[CH:39][CH:40]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccccc2F)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2ccccc2F)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (52 mg) from 2-((2-fluorobenzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C29H30F2N4O4 536.6. found 537.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.12 (m, 2H) 7.16-7.45 (m, 5H) 7.04-7.14 (m, 1H) 4.69 (br. s., 1H) 4.61 (d, J=11.62 Hz, 3H) 4.48 (d, J=4.55 Hz, 3H) 4.31 (br. s., 1H) 3.84-4.08 (m, 7H) 3.39 (br. s., 1H) 3.28 (br. s., 1H) 2.63-2.79 (m, 2H) 2.28 (br. s., 2H) 1.97-2.20 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 48.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.65 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.36 g, 49%). The compound was characterized by the following spectroscopic data: