Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:13]=[C:12]([C@@H:14]2[CH2:16][C@H:15]2[C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][NH2:27])[CH:19]=2)[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].N>>[NH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:15]1[CH:14]=[C:12]2[C:13](=[CH:30][CH:16]=1)[CH:3]=[C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11]2)=[O:28].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]
Reactant: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(OCCN)c2)ccc1OCC(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cccc(C(=O)c2ccc3cc(OCC(=O)O)ccc3c2)c1

Procedure:
Ex. 315. (+/-)-trans-[[2-methoxy-4-[2-((3-(2-aminoethoxy)benzoyl))cyclopropyl]phenoxy]]acetic acid·trifluoroacetic acid MS (NH3): 404 (5% M+NH4), 386 (base, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(O)[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:25](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C:23]([CH3:33])([CH3:34])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1(O)CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 104 °C

Procedure:
To the product of Step A this example (192 mg, 0.382 mmol) was added p-toluenesulfonic acid monohydrate (72.6 mg, 0.276 mmol) in toluene (3 mL). The reaction was heated to 104° C. After 80 min the reaction was cooled and diluted with EtOAc. The solution was washed with brine and saturated aq NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane affording the title compound as the faster eluting isomer on silica gel. (LC-2) HPLC/MS: 502.1 (M+1), 504.1 (M+3); Rt=4.52 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:26]([NH:28][C@H:29]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=1>C(Cl)CCl>[NH2:8][C@H:9]([C:26]([NH:28][C@H:29]([C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
160 ml of TFA was added to 86 g of Boc-His(Tos)-Lys(Z)-OBzl dissolved in 100 ml of ethylene chloride under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for an hour. The solvent and TFA were distilled off, chloroform was added to the residue, and neutralization was carried out with aqueous potassium carbonate. After the reaction mixture was washed with saturated saline, passed through silica gel and sodium sulfate anhydride columns, the solvent was distilled off. Then, methanol was added to precipitate crystals, which were filtered out and dried to obtain 61.2 g of His(Tos)-Lys(Z)-OBzl. (By this process, the product is obtained in the crystallized form).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[OH:24][CH2:20][CH2:21][C:22]#[C:23][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CCCO)cc1
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
To 50 ml of triethylamine were added 5.52 g of ethyl p-iodobenzoate, 1.54 g of 3-butyn-1-ol, 41 mg of cuprous iodide and 77 mg of bis(triphenylphosphine) palladium chloride, and the mixture was stirred for 2.5 hours under nitrogen flow. After adding 50 ml of ethyl acetate, the mixture was filtered to remove the precipitate, washed three times with 30 ml of water, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 4.4 g of ethyl p-(4-hydroxy-1-butynyl)benzoate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1.[OH-].[K+].[N+:24](C)([O-:26])=[O:25]>>[N+:24]([C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1)([O-:26])=[O:25]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-c2csc3c2-n2cc([N+](=O)[O-])cc2C3=O)cc1

Procedure:
A solution of 1 mmol of the compound obtained in Example 12 in 50 ml of nitromethane is stirred for 12 hours at ambient temperature and the reaction mixture is then poured into a 1M potassium hydroxide solution. After extracting with dichloromethane, the organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (chloroform) allows the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.BrC1N=CC2C(=C(OC3C=NC(F)=CC=3)C=CC=2)N=1.[S:39]([NH2:49])(=[O:48])([C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)=[O:40]>CC(O)C>[F:19][C:16]1[N:15]=[CH:14][C:13]([O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([NH:47][C:44]2[CH:45]=[CH:46][C:41]([S:39]([NH2:49])(=[O:40])=[O:48])=[CH:42][CH:43]=2)[N:11]=[CH:10]3)=[CH:18][CH:17]=1
Reactant: Fc1ccc(Oc2cccc3cnc(Cl)nc23)cn1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Fc1ccc(Oc2cccc3cnc(Br)nc23)cn1
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cccc(Oc4ccc(F)nc4)c3n2)cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a 0.13 M solution of the 2-chloro-8-(6-fluoropyridin-3-yloxy)quinazoline and 2-bromo-8-(6-fluoropyridin-3-yloxy)quinazoline mixture in i-PrOH was added sulfanilamide (1.0 eq.) and the solution was heated to refluxed for 12 hr. Cooled to room temperature and the precipitate was filtered off and washed with i-PrOH to give the desired product in 61% yield. The solid was 96% pure by HPLC. ES/MS m/z 412.0 (MH+) for 595644-4-(8-(6-fluoropyridin-3-yloxy)quinazolin-2-ylamino)benzenesulfonamide.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccncc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
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: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 83 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (400 mg, 0.726 mmol), 4-methylpyridine-3 boronic acid (130 mg, 0.944 mmol), sodium carbonate (0.8 mL, 2M), tetrakistriphenylphosphine palladium (7.8 mg, 0.00726 mmol) was added in dioxane (4 mL) and stirred under argon before heating in the microwave at 110° C. for 30 minutes, added more 4-methylpyridine-3 boronic acid (67.5 mg, 0.49 mmol) and tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. therefore added more 4-methylpyridine-3 boronic acid (51 mg, 037 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated under microwave conditions at 110° C. for 30 minutes, therefore added 4-methylpyridine-3 boronic acid (47 mg, 0.34 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. Residue partitioned between EtOAc and Brine. Aqueous layer was extracted with EtOAc ×3. Combined extracts were dried and solvent evaporated. Residue purified on a 12+M horizon column eluting with Pet Ether to 1:1 EtOAc: Pet Ether. Unable to isolate clean fractions. Sample sent to be purified by Mass Directed Auto-Prep (MDAP) chromatography, white solid didn't dissolve was found to be desired material. This was combined with product isolated from the MDAP to afford the title compound as a white solid in an 83% yield.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][Cl:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14].Cl>>[ClH:9].[ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1nc[nH]c1CCl
Reactant: NCCS
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Reaction time: 7 h
Yield: 98 %

Procedure:
84 parts of 4-methyl-5-chloromethyl-imidazole hydrochloride, in the form of a fine powder, and 57 parts of cysteamine hydrochloride, also in the form of a fine powder, are mixed intimately and the mixture is heated in a solidstate reactor for 2 hours at 80° and then for 7 hours at 100°; the progress of the reaction can be followed by NMR spectroscopy or from the evolution of hydrogen chloride. 120 parts (98%) of 4-methyl-5-[(2-amino-ethyl)-thiomethyl]-imidazole dihydrochloride are obtained; the substance melts at 186°-189° C., after first sintering at about 181° C. A single recrystallization of the product from ethanol raises the melting point to 193°-195° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[N:4]1([CH2:3][CH2:2][NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-aminoethyl)morpholine (0.5 g) in dichloromethane (5 ml) at 0° C. was added methane sulphonyl chloride (0.33 ml) and triethylamine (0.59 ml) The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, the combined organics washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue which was purified by flash chromatography to yield N-(2-morpholin-4-yl-ethyl)-methanesulfonamide (596 mg).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:40])[C@H:15]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@@H:16]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[C@@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])C1C=CC=CC=1.[BH4-].[Li+]>C1COCC1>[CH2:20]([O:19][C@@H:17]([CH3:18])[C@H:16]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[C@@H:15]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[CH2:14][OH:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=C(C)CO[C@@H]([C@H](C)OCc1ccccc1)[C@@H](Cc1ccc(C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CO[C@H]([C@H](CO)Cc1ccc(C)cc1)[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (9.36 g, 17.3 mmol) in aqueous THF (4:1 THF/H2O; 86 mL) was added lithium borohydride (34.6 mL of 2.0 M in THF, 69.1 mmol) dropwise at −5° C., and the resulting yellow solution was vigorously stirred. After 1 h the yellow color (dba) had dissipated and the reaction was allowed to slowly warm to room temperature. The reaction was stirred for an additional 5 h and then poured into ice cold saturated aqueous NH4Cl (250 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (3×100 mL). The combined organics phases were dried over Na2SO4, filtered, and concentrated to a light yellow oil (10.11 g), which was purified by both reverse phase (RP; Cl 8, 0→100% CH3CN/H2O) and normal phase (NP: SiO2, 0→30% EtOAc/CH2Cl2) to give (2S,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentan-1-ol (4.04 g, 48% from Ex. 2, Step 1) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 5H), 7.06 (m, 4H), 4.98 (m, 1H), 4.87 (m, 1H), 4.64 (d, J=11.6 Hz, 1H), 4.44 (d, J=11.6 Hz, 1H), 4.08 (d, J=11.6 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.78 (p, J=6.2 Hz, 1H), 3.56 (m, 3H), 2.88 (dd, J=13.8, 4.7 Hz, 1H), 2.53 (dd, J=13.8, 10.1 Hz, 1H), 2.30 (s, 3H), 2.18 (ddd, J=14.4, 7.7, 4.3 Hz, 1H), 2.01 (dd, J=6.2, 4.9 Hz, 1H), 1.76 (s, 3H), 1.33 (d, J=6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.41, 138.50, 137.87, 135.28, 129.00, 128.37, 127.75, 127.57, 111.86, 83.08, 75.92, 75.73, 70.79, 62.83, 44.60, 32.63, 21.05, 20.99, 19.84, 16.33; ESIMS m/z 391 ([M+Na]+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1nnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1nnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of crude (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.065 g, 0.11 mol) in dichloromethane (1.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to give the title compound as a white solid (0.032, 0.064 mol, 59%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=9.2 Hz, 1 H), 7.41 (s, 1 H), 7.16-7.15 (m, 2 H), 7.03 (dd, J=2.0, 8.8 Hz, 1 H), 6.57 (s, 1 H), 6.24 (q, J=6.8 Hz, 1 H), 4.78-4.74 (m, 1 H), 4.02-3.76 (m, 4 H), 3.62-3.54 (m, 2 H), 3.22-3.16 (m, 1 H), 2.98-2.87 (m, 3 H), 2.14 (d, J=6.8 Hz, 3 H), 1.96-1.73 (m, 6 H); MS: (ES) m/z calculated for C24H29Cl2N6O2 [M+H]+ 503.2, found 503.4.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]=1[CH2:12][NH:13][CH3:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].O>C(Cl)Cl>[CH3:14][N:13]([CH2:12][C:4]1[CH2:5][C:6]2[C:11]([C:3]=1[CH3:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: CNCC1=C(C)c2ccccc2C1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)CC1=C(C)c2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a solution of 3-methyl-2-(methylaminomethyl)indene hydrochloride (0.132 g, 0.63 mmole), from Preparation 19, and triethylamine (0.19 g, 1.89 mmole) in CH2Cl2 (6 mL) at 0° C. was added a solution of acryloyl chloride (0.06 mL, 0.7 mmole) in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 1 hr. then was poured into water. The layers were separated, and the organic layer was washed with brine, dried over Mg SO4 and concentrated in vacuo to yield the title compound (0.145 g. quantitative) as an oily solid: MS (ES) m/e 228.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[NH:12][C:11]1=[O:19])[CH2:6][CH2:7][CH3:8])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(Cn1c(=O)[nH]c2cccnc21)C(=O)OCC
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)OCC
Temperature: 60 °C
Yield: 108.7 %

Procedure:
To a solution of 2-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylmethyl)-pentanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (5 ml) were added (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (75 mg, 0.22 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 60° C. for 3 hours. The solution was cooled and poured into water (100 ml) and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was purified via silica gel flash column chromatography (Companion, 4 g silica gel, 20-100% EtOAc/hexanes) to give 85 mg (108%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc(N)nc(N2CCC(c3ccc(F)cc3)CC2)c1C#N

Procedure:
In analogy to the procedure described in example 20b, the 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with the 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diiso-propylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid; MS: [M+H]+=344.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:17]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl>[CH2:17]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:27][C:14]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
Triethylamine (10.9 g) and piperidinocarbonyl chloride [16 g, see Synthetic Communications, vol. 17, 1887-1892 (1987)] were sequentially added to a solution of L-phenylalanine benzyl ester (39.6 g) in dichloromethane under ice-cooling and the mixture was stirred at room temperature for 24 hours. Water (250 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 0.1N hydrochloric acid (250 ml×2) and a saturated aqueous solution (250 ml) of NaHCO3, and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 29.3 g of the title compound as white crystals (see Table 8).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:30]=[C:31]=[O:32])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)[C@H]2CCCc3cccnc32)c(C)c1
Yield: 29.7 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (103 mg, 0.30 mmol) in 2-propanol (1.5 mL) was added trimethylsilyl-isocyanate (50 μL, 0.378 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 34 mg (29%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion of the white foam to the HBr salt gave COMPOUND 367 (47 mg, 81%) as a white solid. 1H NMR (D2O) δ 1.15-1.29 (m, 4H), 1.75-1.91 (m, 1H), 2.06-2.22 (m, 2H), 2.41-2.50 (m, 8H), 2.66-2.74 (m, 1H), 2.90-3.03 (m, 4H), 4.19 (d, 1H, J=17.7 Hz), 4.38 (d, 1H, J=17.7 Hz), 4.50 (dd, 1H, J=10.5, 5.1 Hz), 7.88 (dd, 1H, J=7.8, 6.0 Hz), 8.23 (s, 1H), 8.36 (d, 1H, J=7.8 Hz), 8.46 (s, 1H), 8.62 (d, 1H, J=5.1 Hz); 13C NMR (D2O) δ 16.97, 17.51, 20.49, 20.62, 25.43, 27.23, 27.83, 39.41, 52.08, 52.46, 61.55, 125.80, 136.35, 137.32, 137.59, 139.28, 140.55, 148.02, 149.13, 151.35; ES-MS m/z 382 (M+H). Anal. Calcd. For C22H31N5O.3.0HBr.1.8H2O: C, 40.24; H, 5.77; N, 10.66; Br, 36.50. Found: C, 40.22; H, 5.63; N, 10.62; Br, 36.50.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[CH:6]=1.[Br:19]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:12])[CH:4]=[C:5]([C:7](=[O:9])[CH2:8][Br:19])[CH:6]=1
Reactant: CC(=O)c1cc(C)n(S(=O)(=O)c2ccccc2)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)CBr)cn1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of 13.3 g (50 mmole) of 1-(2-methyl-1-phenylsulfonyl-pyrrol-4-yl)-1-ethanone in 320 ml of chloroform was stirred at -10° C. and a solution of 2.56 ml (8.0 g, 50 mmole) of bromine in 40 ml of chloroform was added dropwise over six hours. After the addition was completed, the mixture was stirred at -10° C. for 0.5 hours, then allowed to warm to room temperature. The mixture was concentrated, and the residue was chromatographed over silica gel using 1:1:0.1 hexane/toluene/ethyl acetate as eluent to give 10.0 g (59%) of the product as a white solid; m.p. 86°-88° C.