Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[O:21]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCC3=O)c1
Yield: 52 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(1-oxo-indan-5-yl)-benzamide (73 mg, 0.26 mmol, 52% yield) as a yellow powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/10 to 1/9).
Reaction SMILES: C(B(CC)OC)C.[BH4-].[Na+].[Cl:10][CH2:11][C@@H:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1.CO>[Cl:10][CH2:11][C@@H:12]([OH:22])[CH2:13][C@@H:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)C[C@H](O)CCl
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](O)C[C@H](O)CCl
Reaction time: 2 h

Procedure:
Diethyl methoxy borane (88 ml) followed by sodium borohydride (16 grams) was added to a pre-cooled mixture of (S)-ethyl 6-chloro-5-hydroxy-3-oxohexanoate (110 grams) in tetrahydrofuran (550 ml) and methanol (220 ml) at −75° C. under nitrogen atmosphere and stirred for 2 hrs. The reaction mixture was quenched with 50% hydrogen peroxide at 0° C. The reaction mixture was extracted into methylene chloride and washed it with 10% sodium bicarbonate followed by saturated sodium chloride solution. The methylene chloride layer was dried with sodium sulfate and distilled off under reduced pressure to get the title compound.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C1CCCCC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C2CCCCC2)CC1

Procedure:
L34. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with cylohexanone in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclohexyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 436.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C(#N)C>[OH:20][CH:18]([CH3:19])[CH2:17][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: CC1CO1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: CC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 68.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazol (1.5 g, 6.8 mmol) and propylene oxide; (2 g, 34.4 mmol) in 25 ml acetonitrile was heated to 50° C. in an autoclave for 3 days. The cooled reaction was concentrated in vacuo and purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fraction afforded 1.3 g (68.4%) of 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1, 2-benzisoxazole. M.p. 45°-47° C. MS (70 eV): m/z 278 (M+, 18%), 233 (100), 190 (28), 109 (12), 96 (70), 82 (25), 68 (14), 55 (22).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46]C)[N:41]=2)[C:30]=1[CH3:48]>CN1C(=O)CCC1>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:48])[C:31]([C:40]3[N:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=3)=[N:32]2)=[CH:37][CH:36]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cccc(O)n2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (87 mg, 0.32 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (66 μL, 0.25 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (80 mg, 0.25 mmol) (described herein), and NMP (440 μL), and heating in a microwave at 150° C. for 180 min. Purification afforded 6-(7-fluoro-3-methyl-4-(6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)-2-quinolinyl)-2-pyridinol as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.65-7.85 (2H, m), 7.48-7.61 (1H, m), 7.27-7.32 (1H, m), 7.15 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=6.7 Hz), 6.73 (1H, d, J=9.4 Hz), 6.37 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 3.98-4.09 (2H, m), 3.88-3.98 (2H, m), 3.62-3.78 (4H, m), 3.47-3.61 (2H, m), 2.84-3.03 (4H, m), 2.51 (3H, s), 2.09-2.24 (2H, m), 1.83-1.93 (1H, m), 1.71-1.83 (1H, m). Mass Spectrum (ESI) m/e=527 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:16]([O-])=O)=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:16])=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Agent: [Pd]
Product: CCOc1ccc(N)c(N2CCCCC2)c1
Yield: 94 %

Procedure:
Using a procedure similar to Example 3, step (c), 1-(5-ethoxy-2-nitro-phenyl)-piperidine (78 mg, 0.31 mmol, as prepared in the previous step) was stirred with 42 mg of 5% Pd—C under H2 to afford 64 mg (94%) of the title compound which was used immediately without further purification. Mass spectrum (ESI, m/z): Calcd. for C13H20N2O, 221.1 (M+H), found 221.1.
Reaction SMILES: [Si]([O:8][CH:9]1CCCC(=O)CC[CH2:10]1)(C(C)(C)C)(C)C.N.C(B1OC(C)(C)C(C)(C)O1)C=C.[CH2:31]([C:34]1([NH2:41])[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[CH:32]=[CH2:33]>CO>[CH2:31]([C:34]1([NH2:41])[CH2:39][CH2:38][CH2:37][CH:9]([OH:8])[CH2:10][CH2:36][CH2:35]1)[CH:32]=[CH2:33]
Reactant: C=CCC1(N)CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: N
Solvent: CO
Product: C=CCC1(N)CCCC(O)CCC1

Procedure:
0.89 g of 5-Allyl-5-amino-cyclooctanol (30) were synthesized as a diastereomeric mixture starting from 1.50 g (5.85 mmol) of 5-(tert-butyldimethylsilyloxy)cyclooctanone, 8.4 mL (58.5 mmol) of 7N ammonia in methanol, and 1.7 mL (9.36 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, following the protocol described for 4-allyl-4-amino-cyclohexanol (16). Rt=0.44 min, 0.49 min (Method C). Detected mass: 184.3 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH:5]([CH3:24])[CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:8].[Cl-].[NH4+].C(OCC)(=O)C>CCCCCC>[CH2:18]([C:10]1[N:9]([C:7](=[O:8])[CH2:6][C@@H:5]([CH3:24])[CH2:4][C:3]([OH:25])=[O:2])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1cc2ccccc2n1C(=O)CC(C)CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2ccccc2n1C(=O)C[C@@H](C)CC(=O)O
Reaction time: 24 h

Procedure:
To a solution of 5-(2-hexyl-indol-1-yl)-3-methyl-5-oxo-pentanoic acid methyl ester in hexane and buffer was added lipase and was stirred for 24 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[C:32]([OH:34])=O.[C:50]1([CH3:59])[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH:56]([NH2:58])[CH3:57]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[C:50]1([CH3:59])[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH:56]([NH:58][C:32](=[O:34])[C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[CH2:30][CH2:29][CH2:28][Cl:27])[CH3:57]
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: Cc1ccccc1C(C)N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)c2ccccc2C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
IPEA (0.5 mL), EDC (128 mg) and HOBT (90.4 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (100 mg) and 1-o-tolylethylamine (60 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-o-tolylethyl)amide. Sodium hydride (containing mineral oil at 40%, 50 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-o-tolylethyl.)amide in DMF (4 mL), and the reaction solution was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 60 mg of the title compound as a racemate. The compound (10 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=7:3) to obtain the title optically active substance with a retention time of 39 minutes (4.4 mg; >99% ee) and the title optically active substance with a retention time of 48 minutes (4.4 mg; >99% ee). The physical properties of the compounds are as follows.
Reaction SMILES: [C:1]([C:14]1[CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:24][C:25]([CH2:28][C:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N+:44]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([CH3:46])[CH3:45])=[CH:36][CH:37]=1)([CH3:31])[CH3:30])([CH3:27])[CH3:26].C(=O)([O-])[O-]>C(O)C.CO>[CH3:27][C:25]([CH2:28][C:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N+:44]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([CH3:45])[CH3:46])=[CH:36][CH:37]=1)([CH3:30])[CH3:31])([CH3:24])[CH3:26].[C:1]([C:14]1[CH:22]=[C:18]([C:19]([O-:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: CC(C)(C)CC(C)(C)c1ccc(OCCOCC[N+](C)(C)Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (6.4 mmol) of 5-dodecanoylsalicylic acid, dissolved beforehand in 100 ml of ethanol, are added to a solution of 2.82 g (3.2 mmol) of benzethonium carbonate dissolved in 100 ml of methanol; the mixture is stirred for 1 hour at room temperature, the solution is then filtered and the filtrate is evaporated to dryness to give 4.5 g (97% yield) of benzethonium 5-dodecanoylsalicylate.
Reaction SMILES: O=[C:2]([CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:3][C:4]([O:6]C)=O.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26]>C1(C)C(C)=CC=CC=1>[C:13]1(=[O:14])[N:9]([CH2:8][C:2]2[CH2:3][C:4](=[O:6])[NH:27][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]12
Reactant: Nc1ccccc1N
Reactant: COC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1C
Product: O=C1CC(CN2C(=O)c3ccccc3C2=O)=Nc2ccccc2N1
Yield: 81.5 %

Procedure:
A mixture of methyl 3-oxo-4-phthalimidobutyrate (15.4 g, 59 mmol), o-phenylenediamine (6.37 g, 59 mmol) and xylene (150 mL) was refluxed for 20 minutes using Dean-Stark apparatus. The reaction mixture was cooled, and resulting crystals were collected by filtration and washed with toluene to give the object compound (15.36 g, 81%), m.p.244°-246° C.
Reaction SMILES: ClC1C=CC(S[C:9]2C3C(=CC=C(C(OC)=O)C=3)[NH:11][C:10]=2C)=CC=1.C([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][C:36]([OH:38])=[O:37])[C:30]([CH3:39])=[C:29]2[S:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)(O)=O>>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([S:40][C:29]2[C:28]3[C:32](=[CH:33][CH:34]=[CH:26][C:27]=3[NH:11][CH2:10][CH3:9])[N:31]([CH2:35][C:36]([OH:38])=[O:37])[C:30]=2[CH3:39])=[CH:46][CH:45]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2cc(C(=O)O)ccc2n1CC(=O)O
Reactant: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Product: CCNc1cccc2c1c(Sc1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
The compound was prepared using the method of example 55 part (ii) using the by product from example 2 part (i). Purification by reverse phase preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.O.[CH2:13]([NH:20][C:21]1[C:22]([NH2:28])=[CH:23][CH:24]=[C:25]([Br:27])[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(OC)(OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:28]1[C:22]2[CH:23]=[CH:24][C:25]([Br:27])=[CH:26][C:21]=2[N:20]=[C:13]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cc1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH.H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N′-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=5.44 (s, 2 H, 7.05-7.08 (m, 3 H), 7.30-7.36 (m, 4 H), 7.44-7.50 (m, 3 H), 7.66-7.68 (m, 2 H) and 7.99 (dd, 1 H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[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.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([O:26][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:24][C:23]([CH3:28])([CH3:27])[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: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 30 °C
Reaction time: 15 h

Procedure:
To the product of Example 68 (250 mg, 0.575 mmol) was added NaH (73.6 mg, 1.84 mmol, 60%) and ethyl 2-bromoacetate (0.23 mL 2.07 mmol) in DMF (3 mL). The reaction was stirred 3 h at 30° C. and 15 h at rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-33% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 520.1 (M+1), 522.0 (M+3); Rt=4.43 min.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[O:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]1[C:27]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:26][N:25]=[C:24]1[SH:33]>C(#N)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:33][C:24]3[N:23]([CH3:22])[C:27]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[N:26][N:25]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2nc(CCl)no2)c1
Reactant: Cn1c(S)nnc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(-c2nc(CSc3nnc(-c4cccs4)n3C)no2)c1
Yield: 89.6 %

Procedure:
The title compound was prepared from 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50 mg, 0.22 mmol), potassium carbonate (92.4 mg, 0.67 mmol), 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27 mmol) in acetonitrile (1 ml) at room temperature. Purification was performed by SPE (flash) chromatography using 30-40% ethyl acetate in hexanes afforded 76 mg (90%) of the title compound as a white solid. 1H NMR (CDCl3), δ (ppm): 7.68 (d, 1H), 7.57 (t, 1H), 7.49 (m, 2H), 7.41 (t, 1H), 7.15 (m, 2H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H). LC-MS (M+1)+ 386.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2nc(-c3ccccc3)ccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3ccccc3)ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 4-(3-chloro-6-phenyl-2-pyridyl)benzoate (1.00 g), 1M aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (20 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (5 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 4-(3-chloro-6-phenyl-2-pyridyl)benzoic acid (0.83 g, yield 91%) as colorless crystals. melting point: 254–255° C.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:10][CH2:11][N:12]1[C:16]([CH:17]=O)=[CH:15][CH:14]=[N:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:3]([O:10][CH2:11][N:12]1[C:16]([CH:17]=[CH2:2])=[CH:15][CH:14]=[N:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccnn1COCc1ccccc1
Reactant: [Li]C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccnn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyltriphenylphosphoniumbromide (7.85 g, 22.0 mmol) in THF (40 mL) is cooled to 0° C. then MeLi (12.2 mL, 1.6 M in ether) is added dropwise. The mixture is stirred for 1 h then a solution of 2-benzyloxymethyl-2H-pyrazole-3-carbaldehyde (3.4 g, 15.7 mmol) in THF (15 mL) is added dropwise. The reaction is stirred for an hour at 0° C., then warmed to RT over 1 h. The mixture is partitioned between aqueous NH4Cl and EtOAc and the organic layer is concentrated. Chromatography (10-15% EtOAc/hexane) affords the title compound as a yellow oil: (M+1)+=215.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.I[C:12]1[C:13]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:14][C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:16][C:17]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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.[Cu]I>[CH3:19][O:18][C:17]1[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=[C:13]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)[C:12]=1[C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[N:7]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: Cc1ccc2scnc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C)ccc2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 5-methyl-1,3-benzothiazole (52.2 mg, 0.35 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100.0 mg, 0.19 mmol, 1.00 equiv), cesium Carbonate (0.37 g, 6.00 equiv), Pd(PPh3)4 (40.4 mg, 0.03 mmol, 0.18 equiv) and copper (I) iodide (6.7 mg, 0.09 mmol, 0.18 equiv) in DMF (6 mL). The crude product was purified by chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (15:1-3:1) to afford the title compound as a light yellow solid. MS m/z [M+H]+ (ESI): 541.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH2:11][Br:15])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1OC
Reaction time: 18 h
Yield: 78.6 %

Procedure:
2-Methoxy-6-methylbenzoic acid ethyl ester (500 mg, 2.67 mmol), N-bromosuccinimide (483.8 mg, 2.72 mmol) and 2,2′-azobis(2-methyl-propionitrile) (30.2 mg, 0.123 mmol) in carbon tetrachloride (10 ml) were heated to reflux. After 18 hours, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (100 ml) and washed with water (2×50 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (702 mg) was purified by column chromatography using a mixture of hexanes/dichloromethane (1:1) as eluent, which afforded 573 mg (85%) of 6-bromomethyl-2-methoxy-benzoic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[N:14]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To a solution of compound (1R,2S) (2-Azidocyclohexyl-carbamic acid) tert-butyl ester (1.8 g, 7.5 mmol) in methanol (20 mL), 10% Pd—C (360 mg) was added and hydrogenated at 32 psi for 4 h Parr hydrogenator. The reaction mixture was filtered on a celite pad and the filterate was concentrated to give the title compound as a solid (1.1 g, 69%), which was used without further purification. MS: (M+1): 215.07