Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][O:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cocc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1Cc2cocc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan (6.2 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan.
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1.[CH3:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH3:38])[CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Acetonitrile (10 ml) was added to the compound (1) (139 mg), 2-methylbenzyl bromide (0.03 ml), and potassium carbonate (81 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (46 mg, yield 45%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:21][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 155.9 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 26.0 g (0.2 mol, 2.0 eq.) of 1-octanol were added to 64 mL of toluene, and the mixture was heated to reflux for 3 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 39.2 g of 4-octyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: C(OC(N1CCN([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)CC1)=O)(C)(C)C.[CH3:55][S:56]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])=[O:57]>>[CH3:35][C@:32]12[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20][C@@H:19]1[C@H:18]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]1([NH:16][CH2:15][CH2:14][N:62]1[CH2:63][CH2:64][N:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]1)[CH2:34][CH2:33]2
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(methylsulfonyl)piperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (220 mg, 89%). LCMS: m/e 720.58 (M+H)+, 2.25 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.74-3.38 (m, 7H), 3.37-3.25 (m, 1H), 3.17 (br. s., 4H), 2.94 (s, 3H), 2.91-2.80 (m, 1H), 2.35-1.01 (m, 22H), 1.77 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][C:6]1[C:7]([CH3:16])=[N:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:18]1[CH2:22][C:21]2([CH2:29][C:27](=O)[O:26][C:24](=[O:25])[CH2:23]2)[CH2:20][CH2:19]1>O1CCOCC1>[CH3:16][C:7]1[C:6]([CH2:5][CH2:4][C:3]2[N:17]=[C:27]([CH2:29][C:21]3([CH2:23][C:24]([OH:26])=[O:25])[CH2:22][CH2:18][CH2:19][CH2:20]3)[O:1][N:2]=2)=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1
Reactant: Cc1nc2c(cc1CC/C(N)=N/O)CCCN2
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: C1COCCO1
Product: Cc1nc2c(cc1CCc1noc(CC3(CC(=O)O)CCCC3)n1)CCCN2
Temperature: 100 °C

Procedure:
A stirred mixture of the product of EXAMPLE 7, STEP 3 (100 mg), 3,3-tetramethyleneglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.66 (8H, m); (1.93, 2H, p); 2.40 (3H, s); 2.42 (2H, s); 2.77 (2H, t); 2.97 (2H, t); 3.00 (2H, t); 3.14 (2H, s); 3.46 (2H, t); 7.51 (1H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33](C2C=C(C=CC=2)N)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:33]3[N:32]=[C:31]([CH3:30])[O:35][N:34]=3)[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1nc(-c2cccc(N)c2)no1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1nc(-c2cccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)c2)no1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(5-methyl-1,2,4-oxadiazol-3-yl)aniline in step 1. MS: 409.28 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][C:53]1[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][C:58]=1[CH3:59].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:55]3[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([CH3:52])[CH:54]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.N#N.B.S(C)C>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Agent: B
Agent: N#N
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Yield: 26.4 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g) in anhydrous THF (1.3 L), under protection of N2, was heated to reflux followed by the dropwise addition of 10 M H3B.SMe2 in THF (70 mL, 0.7 mol). The mixture was stirred at reflux overnight. The reaction was quenched with MeOH (500 mL) and the solvent removed in vacuo, the residue was purified by column chromatography to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (24 g, 0.062 mol).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1COCC1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:20]4[O:21][C:28](=[O:29])[NH:23][N:22]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.0 g, 2.60 mmol) obtained in Step 2 of Example 56 was dissolved in THF (12 mL), and the mixture was stirred at room temperature for 2 hours after adding 1,1′-carbonyldiimidazole (464 mg, 2.86 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 4 by addition of a 6 mol/L aqueous hydrochloric acid solution. The precipitated white solid was then filtered off to give (S)-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.07 g, quantitative).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH:16]2[C:20](=[O:21])[C:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[C:18]([O:31]C)[CH2:17]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:20](=[O:21])[CH:19]([C:22]3[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[CH3:28])[C:18](=[O:31])[CH2:17]/2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OCc3ccccc3)CC2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)C/C(=C\C3CCC(OCc4ccccc4)CC3)C2=O)c(C)c1
Yield: 469.2 %

Procedure:
Into six 20 ml microwave vials is added the 5-[(4-benzyloxy-cyclohexyl)-hydroxy-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1 g, 2.2 mmol) in a mixture of acetone (7.5 ml) and 2N aqueous hydrochloric acid (7.5 ml). Each vial is therefore heated for 1 hour to 120° C. by microwave irradiation. The reaction mixtures were then combined and diluted with water (100 ml) and extracted with dichloromethane (2×50 m). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow gum. The gum is purified by flash chromatography to give 4-[1-(4-benzyloxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (4.3 g).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+].Cl>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[CH3:26]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Sc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.11 g), methanol (5.0 mL), water (1.0 mL) and 5.0 M aqueous sodium hydroxide solution (0.5 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 1 by the addition of 1.0 M aqueous hydrochloric acid. The resulting mixture was purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (30% to 90% of organic modifier) to afford title compound as a white solid, 0.045 g.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]#[N:7].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.Cl>CO>[ClH:4].[Cl:4][CH2:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[NH:7]
Reactant: NC1Cc2ccccc2C1
Reactant: N#CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(CCl)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.54 g. (0.01 mole) of sodium methoxide in 100 ml. methanol was added 7.6 g. (0.1 mole) chloroacetonitrile with cooling. The solution was stirred at room temperature for 1 1/2 hours. Then there was added a solution of 10.9 g. (0.1 mole) of 2-aminoindane in 50 ml. of methanol and 16.66 ml. of 6N ethanolic hydrochloric acid (0.1 mole). The solution was stirred at room temperature for 4 hours and concentrated to dryness at room temperature under high vacuum. The product was recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:33][CH2:34][CH2:35][OH:36])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 3-(3-chlorophenylsulfonyloxy)-5-methylphenol (450 mg, 1.5 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl) dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (480 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.41 (s, 1H), 6.37 (s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.99 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@@H:15]([CH3:31])[C:16](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[BH4-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@@H:15]([CH3:31])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](CO)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of 156 mg (0.36 mmol) of (3-(1-t-butoxycarbonyl-piperidin-4-yl)-2-(R)methylpropyl)-4-(S)-benzyloxazolidin-2-one (from EXAMPLE 99, Step A) in 3 mL of THF at O° C. was treated with 0.03 mL (0.73 mmol) of MeOH followed by 16 mg (0.73 mmol) of lithium borohydride. The cooling bath was removed, the mixture was warmed to rt and stirred for 3 h. The reaction was quenched with H2O and sat'd sodium potassium tartrate. The quenched mixture was diluted with CH2Cl2 and stirred for 1 h, then extracted 3× with CH2Cl2. The combined organic layers were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. Purification by silica gel column chomatography with 0-25% EtOAc/hexanes (v/v) provided 72 mg (77%) of the title compound: 1H NMR (500 MHz) δ 0.92 (d, J=6.8,33H). 1.01-1.12 (3H), 1.27-1.33 (m, 1H), 1.45 (s, 9H), 1.46-1.50 (m, 1H), 1.61-1.75 (4H), 2.69 (bq, 2H), 3.41 (dd, J=3.9,6.6 Hz, 1H). 3.49 (dd, J=4.8, 5.7, 1H). 4.07 (bd, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20](O)=[O:21])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:19][C:20]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:21])[C:23]([CH3:25])([CH3:24])[CH3:26])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]
Reactant: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)NS(C)(=O)=O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 250 mg (0.42 mmol) of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]-carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride and 49 mg (0.51 mmol) of methanesulfonamide in 2 mL of DCM are successively added 52 mg (0.42 mmol) of DMAP and 89 mg (0.47 mmol) of EDC.HCl. The reaction medium is stirred for 16 hours at room temperature. A further 0.42 mmol of EDC.HCl and 0.42 mmol of methanesulfonamide are added and the reaction mixture is stirred for a further 3 days and then concentrated under reduced pressure. The residue is taken up in 100 mL of EtOAc and the organic phase is washed with 30 mL of water and then with 30 mL of aqueous 4M NaHCO3 solution. After drying over Na2SO4 and concentrating under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a DCM/methanol gradient of from 0 to 10% methanol. After concentrating under reduced pressure, the residue is taken up in 2 mL of methanol and 0.5 mL of aqueous 1N HCl solution and then purified by reverse-phase HPLC (RP18), eluting with a 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile over 90 minutes. After concentrating under reduced pressure and freeze-drying, 130 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-2,2-dimethyl-1-{2[(methylsulfonyl)amino]-2-oxoethyl}propyl]-5-(2-methylphenyl)pyridine-2-carboxamide hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH3:23][NH:24][CH3:25]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:24]([CH3:25])[CH3:23])=[O:15])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: CNC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N(C)C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (CD17) (100 mg) and dimethylamine (1 ml) was heated at 120° C. for 15 h to obtain 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N,N-dimethylpropanamide (CD52) after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its HCl salt by treatment of ethanol-HCl.
Reaction SMILES: C1C=C(C(O)=[O:8])C(C(OO)=O)=CC=1.[C:14]1([S:20][CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:14]1([S:20]([CH2:21][C:22]2[NH:23][C:24]([CH3:47])=[C:25]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1=C(C)NC(CSc2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(CS(=O)c2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of monoperphtalic acid in AcOEt (0.37 M solution; 20 ml) is added at 0° C. to a mixture of 2-(phenylthio) methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (3.5 g) and NaHCO3 (3 g) in AcOEt (20 ml). After 30 minutes the mixture is filtered and the eluate is washed with 1N solution of sodium thiosulfate (2×20 ml) and then with water (3×10 ml). The organic layer is dried on Na2SO4 and evaporated to dryness; the residue is purified by chromatography on SiO2 (hexane/AcOEt 85/15, as eluent) to give 3.5 g of 2-(phenylsulfinyl)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. 160°-162° C.