Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10](=[O:23])[O:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:13][C:8]=2[CH:7]=1)(=[O:4])[CH2:2][CH3:3].[CH2:26]([OH:28])[CH3:27].C(N(CC)CC)C.C(O)(=O)C>O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]([NH:13][C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][C:9]=2[C:10]([O:28][CH2:26][CH3:27])=[O:23])=[O:11])=[CH:19][CH:18]=1)([OH:22])=[O:21]
Reactant: CCC(=O)Nc1ccc2c(=O)oc(-c3ccc(C(=O)O)cc3)nc2c1
Reactant: CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NC(=O)CC)cc1NC(=O)c1ccc(C(=O)O)cc1

Procedure:
A mixture of 12 g of 7-(propionamido)-2-(4-carboxyphenyl)-4H-3,1-benzoxazine-4-one, 120 ml of absolute ethanol and 9 ml of triethylamine was heated under reflux for a period of 8 hours. After being allowed to cool, the mixture was added with 9 ml of acetic acid and 500 ml of water, the precipitating crystal was filtered, and recrystallized from a solvent mixture of ethanol and water to yield 10 g of ethyl 2-(4-carboxybenzamido)-4-propionamidobenzoate having a melting point in the range of from 246° to 248° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([CH:37]([CH3:39])[CH3:38])=[N:35][N:36]=4)[N:33]=3)=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+]>C1COCC1.O>[OH:4][CH2:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([CH:37]([CH3:39])[CH3:38])=[N:35][N:36]=4)[N:33]=3)=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[N:18]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CCC(c2nc(-c3cc(F)c(F)cc3F)c(-c3ccc4nnc(C(C)C)n4n3)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)CO)CC4)nc3-c3cc(F)c(F)cc3F)nn12
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A round-bottomed flask equipped with rubber septum and nitrogen inlet needle was charged with 2-(4-(5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2,4,5-trifluorophenyl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl acetate (0.22 g, 0.39 mmol, prepared using General Procedure Q.1 from Preparation #O.1.1.1 with TFA, General Procedure T.1 with acetoxyacetyl chloride) in THF (5.0 mL). A 1.0 M aqueous NaOH solution (2 mL, 2 mmol) was added. The reaction mixture was stirred at about 40° C. for about 1 h. The reaction was diluted with water and then extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by RP-HPLC (Table 1, Method f) to give the title compound (0.145 g, 71%): LC/MS (Table 1, Method a) Rt=2.89 min; MS m/z: 518.1 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]([CH2:5][C:6]([OH:8])=[O:7])[NH2:4].[C:10](Cl)(=[O:12])[CH3:11].Cl>[OH-].[Na+].O1CCOCC1>[F:1][CH:2]([F:9])[CH:3]([NH:4][C:10](=[O:12])[CH3:11])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: NC(CC(=O)O)C(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)NC(CC(=O)O)C(F)F

Procedure:
To a solution of 2 mmole of beta-difluoromethyl beta-alanine in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 160 mg of acetyl chloride diluted in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 3-difluoromethyl-3-(1-oxo-ethylamino) propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:45][C:46]([NH:48][C:49](N1C=CC=N1)=[N:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH:37]/[C:49](/[NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[N:48]\[C:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@@H](N)Cc1ccccc1
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)N/C(=N\C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-[(2S)-2-amino-3-phenylpropyl]-D-alaninamide (330 mg, 0.64 mmol) from preparation 33 in THF (5 mL) was added N,N′-Bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (268 mg, 0.71 mmol) and N,N-diisopropylethylamine (173 uL, 0.97 mmol). The reaction was stirred for 2 hours at 60° C. and then quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (10 mL), the extract was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 25% ethyl acetate in heptane as eluent increasing to 33%) to afford the title compound as a colourless oil in 81% yield, 430 mg. 1H NMR (400 MHz, MeOH-d4) δ : 1.05 (d, 3H), 1.28 (s, 9H), 2.22 (s, 6H), 2.73-3.11 (m, 4H), 3.41-3.52 (m, 1H), 3.95-4.23 (m, 2H), 4.38-4.59 (m, 2H), 4.98-5.28 (m, 4H), 6.45 (s, 2H), 7.09-7.46 (m, 15H). LRMS APCI m/z 823 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20]I.[H-].[Na+]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH3:20])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)imidazole (300 mg, 1.0 mmol) from Step A and methyl iodide (0.10 mL, 2.0 mmol) in DMF (5 mL) was added sodium hydride (80 mg 60% in mineral oil, 1.5 mmol) all at once at rt. After stirring for 1 hr, the reaction was quenched into water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (10% methylene chloride, 30% ethyl acetate in hexanes) to provide the title compound as a white solid.
Reaction SMILES: CS(C)=O.[O:5]=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].C(=O)C1OC=CC=1>O>[O:5]=[CH:6][C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: CS(C)=O
Solvent: O=Cc1ccco1
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 160 °C

Procedure:
ICBP Corn Cob (18.9 g, 1-2 mm, 92.5% dry matter) at 25% solid loading was placed in the reactor containing 0.15 M aqueous sulfuric acid (Comparative Example A) or 0.15 M aqueous hydrochloric acid solution (Comparative Example B) (51.1 g) and gradually heated to 160° C. over a period of 13 min and then maintained at this temperature for 30 min as described in the general procedure. At the end of the reaction, the reaction mixture was diluted with water (103.2 g) containing DMSO (1.33 g) and thoroughly mixed. A sample of this reaction mixture was analyzed as described above for xylose and furfural content. The reaction was repeated under identical conditions to validate the reproducibility of data. Results are presented in Table 2. A mixture of furfural, xylose and arabinose was obtained, indicating incomplete conversion of hemicellulose to the desired product furfural.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(O)=O>O>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[O:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=CNc1ccccc1
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Solvent: O=CO
Solvent: O
Product: CCN(CC)CCNc1ccc(CN(C=O)c2ccccc2)c2sc3ccccc3c(=O)c12
Temperature: 160 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.40 g, 9.59 mmol), formanilide (31g) and formic acid (3 mL) were heated to 160° C. for 2 hours. The mixture was cooled, poured into water (200 mL) and extracted with ether (3×150 mL). The aqueous layer was basified with 5N NaOH, extracted with CHCl3 (3×150 mL) and the combined organic extracts were dried over Na2SO4 and filtered through florisil eluting with CHCl3 (100%), then 5% isopropylamine/CHCl3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 0.5% to 1% isopropylamine/CHCl3 and then by recrystallization from benzene/hexane (2x) to afford 1.88 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=O)[CH2:16][CH2:15]1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:38]1([NH2:45])[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH2:44].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1.O>[N:44]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[NH:45][C:20]=1[C@H:17]1[CH2:18][CH2:19][C@H:14]([CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OCc1ccccc1
Reactant: Nc1ccccc1N
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C[C@H]1CC[C@H](c2nc3ccccc3[nH]2)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 13.6 g (0.044 mol) of trans-4-(N-benzyloxycarbonyl-N-methyl-aminomethyl)cyclohexanecarboxylic acid and 9.5 ml (0.068 mol) of triethylamine in 110 ml of tetrahydrofuran is treated at -15° within 30 minutes with 6.5 ml (0.049 mol) of isobutyl chloroformate. A solution of 5.8 g (0.053 mol) of o-phenylenediamine is then added dropwise at -15° within 45 minutes. The mixture is stirred at room temperature for 1 hour and left to stand for 20 hours. After concentration under reduced pressure the residue is partitioned between water and ethyl acetate and the organic phase is washed with a 5% solution of sodium hydrogen carbonate, then with a saturated aqueous solution of sodium chloride and finally with water. The solution, dried over magnesium sulphate, is evaporated and triturated with ether. The solid product obtained (9.3 g) is dissolved in 200 ml of toluene, 3 g of p-toluenesulphonic acid are added thereto and the mixture is heated to reflux for 4 hours with a water separator. The solution is cooled, washed with a 2N sodium carbonate solution and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from ethyl acetate. There are obtained 5.6 g of benzyl [[trans-4-(2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate, m.p. 146°-148°, as a colourless crystalline powder. After chromatography on 250 g of silica gel with ethyl acetate/methylene chloride (9:1) as the elution agent the mother liquor gives a further 1.1 g of the same product, m.p. 146°-148°. Total yield: 6.7 g (40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH3:21].CO.C(Cl)(Cl)Cl>CC(C)=O>[CH2:20]([O:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOCCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCOCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
In a 300 milliliter, three-necked oven-dried round bottom flask equipped with a magnetic stirrer, 25 grams (0.18 mole) of 1-(4-hydroxyphenyl)ethanone and 38.6 grams (0.27 mole) of potassium carbonate (K2CO3) were suspended in 200 milliliters of acetone and the mixture was stirred at room temperature for 1 hour, forming a thick slurry. 18.6 grams (0.198 mole) of (chloromethoxy)ethane was slowly added to the reaction mixture using a dropping funnel over a period of one hour and the reaction refluxed overnight for another 12 hours until completion was ascertained by TLC analysis (1:99 methanol/chloroform). The reaction was quenched by pouring the mixture slowly into 400 milliliters of 0.01% hydrochloric acid (HCl) solution, and the product was extracted into 300 milliliters of ethyl acetate, and washed with brine then water to a neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered, and concentrated on a rotary evaporator affording 34.58 grams (˜99% yield) of 1-(4-(ethoxymethoxy)phenyl)ethanone as an oil. The product was used without further purification. 1H NMR (500 MHz, Acetone-d6): δ 7.94-7.91 (d, 2H, 8.5 Hz), 7.13-7.07 (d, 2H, 8 Hz), 5.31 (s, 2H), 3.702-3.67 (q, 2H), 2.49 (s, 3H), 1.16-1.11 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)CBr
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (0.34 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and ethyl bromoacetate (0.15 ml) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (50 ml), and the crystals precipitated were recovered by filtration. The crude crystals obtained were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (410 mg, 84%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].O=[C:39](NC1C=CC=CC=1)[CH2:40]C(O)=O>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:26]4[CH2:40][CH2:39][N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:27]4=[O:28])=[O:36])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCN(c6ccccc6)C5=O)cc4F)c3s2)c1
Yield: 40 %

Procedure:
Following the procedure described above for the synthesis of compound 5d (scheme 4), but replacing acid 1 with the acid 205, title compound 204 was obtained in 40% yield. 1HNMR (DMSO-d6) δ(ppm): 10.72 (s, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.96-7.90 (m, 2H), 7.72 (s, 1H), 7.67-7.65 (m, 2H), 7.53-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.16 (t, J=7.2 Hz, 1H), 6.70 (d, J=5.5 Hz, 1H), 4.06 (q, 2H), 3.93 (m, 2H), 3.77 (t, J=8.2 Hz, 1H), 4.42 (m, 2H), 1.40 (t, 3H). MS (m/z): 542.0 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([C:9]#[CH:10])[CH3:8].[CH2:18]([O:20][CH:21]([O:27][CH2:28][CH3:29])[C:22](OCC)=[O:23])[CH3:19].[NH4+].[Cl-]>CCOCC>[CH2:18]([O:20][CH:21]([O:27][CH2:28][CH3:29])[C:22](=[O:23])[C:10]#[C:9][C:7]([CH3:6])([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH3:8])[CH3:19]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: C#CC(C)(C)OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(OCC)C(=O)C#CC(C)(C)OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round bottom flask, 9.5 mL of n-butyl lithium (2.5 M solution in hexane, 23.8 mmol) was added via a syringe to a pre-cooled solution (−78° C.) of 2-(2-methylbut-3-yn-2-yloxy)-tetrahydro-2H-pyran 2 (4.0 g, 23.8 mmol) in 100 mL of Et2O. The resulting solution was stirred for 30 min at −78° C., then ethyl 2,2-diethoxyacetate (4.9 g, 27.7 mmol) was added with a syringe, and the stirring continued for 12 hours. The reaction mixture was poured in an ice-cold saturated aqueous solution of NH4Cl. The aqueous layer was extracted with Et2O (3×50 mL). The organic solvent was separated with a separating funnel and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting pale yellow oil was purified by radial chromatography (stationary phase silica gel, hexane/AcOEt 90:10) to provide 1,1-diethoxy-5-methyl-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-yn-2-one 3 as a colorless liquid. Yield: 3.2 g (10.7 mmol; 45%). 1H-NMR in CDCl3 (δ, ppm): 5.05 (1H, q, J=5.0, 3.5 Hz, THP), 4.73 (1H, s, acetal), 3.92 (1H, m, THP), 3.69 (2H, m, CH2, acetal), 3.62 (2H, m, CH2, acetal), 3.50 (1H, m, THP), 1.82 (1H, m, THP), 1.71 (1H, m, THP), 1.58 (3H, s, CH3), 1.54 (3H, s, CH3), 1.52 (4H, m, THP), 1.25 (6H, t, J=7.0 Hz, CH3, acetal). 13C-NMR in CDCl3 (δ, ppm): 182.6, 101.1, 97.87, 96.10, 81.25, 70.57, 62.95, 62.64, 62.61, 31.47, 29.45, 28.85, 25.06, 19.92, 14.90 IR (neat, cm−1): 2978, 2937, 2872, 2214, 1687, 1074. HR ESIMS+ with acetonitrile as the mobile phase, (m/z): 299.1837 (M+, C16H26O5, 299.1853), 321.1660 (m/z) ([M+Na]+, C16H26O5Na, 321.1672).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C(N(CC)CC)C>O1CCCC1.CO>[Cl:8][C:7]1[C:2]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccccc1S
Reactant: Clc1nccnc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1Sc1nccnc1Cl

Procedure:
To a solution of 2,3-dichloropyrazine (7.45 g, 50 mmoles) and ortho-aminothiophenol (6.25 g, 50 mmoles) in tetrahydrofuran (50 ml) was added dropwise a solution of triethylamine (6 g) in THF (25 ml) over a period of 10 minutes. A cold water bath was used to control the modest exotherm and maintain the temperature below 20°. The triethylamine chloride was removed by filtration and the filtrate was evaporated to yield a solid that was slurried for 1 hour in methanol (75 ml). The solid thus obtained was recrystallized from methanol to yield the title compound, m.p. 130°-135° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][S:19](=[O:24])(=[O:23])[CH2:18]1.[Li+].[OH-]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][S:19](=[O:23])(=[O:24])[CH2:18]1
Reactant: CCOC(=O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12

Procedure:
A mixture of ethyl 5-bromo-3-((1,1-dioxo-tetrahydro-2H-thiopyran-3-yl)methyl)-1H-indole-7-carboxylate (1.42 g, 0.034 mol) and LiOH (3.4 mL, 3 M) in MeOH (50 mL) was heated at reflux for one hour. The solvent was evaporated, and the mixture was acidified with 1N HCl and extracted with EtOAc (3×100 mL). The organic layer was dried, filtered and concentrated under reduced pressure, 1.30 (98.5%) of the title compound, which was carried on as is for the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]([NH:41]C(=O)OC(C)(C)C)[CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]4[N:31]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:30]5[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=5[N:28]=4)[CH2:22]3)=[O:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]([NH2:41])[CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]4[N:31]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:30]5[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=5[N:28]=4)[CH2:22]3)=[O:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(N4CCN(C(C)=O)CC4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(N4CCN(C(C)=O)CC4)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.6 %

Procedure:
tert-Butyl (R)-1-(4-(4-acetylpiperazin-1-yl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (122A) (0.29 mmole, 202 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (10-25% CH3CN in H2O) to afford (R)-4-(4-(4-Acetylpiperazin-1-yl)phenyl)-3-amino-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (232) (0.0018 mmole, 1.5 mg, two-step yield: 0.9%). ESI-MS: m/z 561.5 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.90-2.12 (m, 3H) 2.15 (s, 3H) 2.18-2.37 (m, 3H) 2.58-3.04 (m, 2H) 3.11-3.24 (m, 6H) 3.27 (s, 3H) 3.39-3.60 (m, 4H) 3.65-3.76 (m, 4H) 3.79 (dd, J=9.13, 4.58 Hz, 1H) 3.94 (d, J=14.21Hz, 1H) 4.14 (d, J=15.03 Hz, 1H) 4.42-4.60 (m, 1H) 4.64 (t, J=6.92 Hz, 1H) 4.72 (d, J=14.15 Hz, 1H) 6.96-7.05 (m, 2H) 7.14-7.24 (m, 2H) 7.56-7.66 (m, 2H) 7.75-7.82 (m, 1H) 7.86-7.93 (m, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccccc1
Yield: 9 %

Procedure:
Using the procedure described for Example 43 with benzoic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]benzamide (9 mg, 9%) as an off-white solid: mp 206-208° C.; 1H NMR (300 MHz, CD3OD) δ6.31 (1H, s), 6.67 (1H, s), 7.43-7.51 (9H, m), 7.89-7.92 (2H, m), 8.02 (1H, d, J=5.6 Hz), 8.60 (1H, s); ESI MS m/z 328 [C21H17N3O+H]+; HPLC (Method A) >99% (AUC) tR=16.2 min.