Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(S(C)(=O)=O)CC3)ccc1-2
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 hydrochloride salt (141 mg, 0.33 mmol) in DCM (3.3 mL) was added triethylamine (0.16 mL, 1.14 mmol). The reaction mixture was cooled to 0° C. then methanesulfonyl chloride (30 μL, 0.39 mmol) was added and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further triethylamine (45 μL) and methanesulfonyl chloride (30 μL) were added and the reaction mixture was stirred at 0° C. for 30 minutes. Water was added and the phases were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with an aqueous 10% citric acid solution, followed by an aqueous saturated sodium bicarbonate solution and then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-20% EtOAc in DCM). The resulting solid was suspended in cyclohexane and collected by filtration to give 395 as a white solid (78 mg, 50%). LCMS: RT=11.69 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=8.19 Hz), 7.90 (1H, s), 7.01 (1H, dd, J=8.23, 1.88 Hz), 6.90 (1H, d, J=1.84 Hz), 5.93-5.85 (1H, m), 4.39 (2H, t, J=5.03 Hz), 3.93 (2H, d, J=11.84 Hz), 3.39 (2H, t, J=5.04 Hz), 2.81-2.70 (5H, m), 2.60 (1H, tt, J=12.04, 3.68 Hz), 1.97 (2H, d, J=13.31 Hz), 1.89-1.76 (2H, m), 1.61 (6H, d, J=6.63 Hz)
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH:6]=[CH:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@]12CC[C@](O)(C(F)(F)F)C[C@H]1CC=Cc1cc3c(cnn3-c3ccc(F)cc3)cc12
Yield: 16 %

Procedure:
(3R,4aR,12bS)-12b-Ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.030 g, 0.067 mmol), NBS (0.013 g, 0.074 mmol), and AIBN (0.0011 g, 0.0067 mmol) were dissolved in CCl4 (1 mL) and then mixed at reflux for about 2 h. The reaction was diluted with DCM (10 mL) and then washed with water (2×3 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 10-95% MeCN in aq. NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aR,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (47, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0050 g, 16% yield); LC/MS, method 2, Rt=3.00 min.; MS m/z: 445 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.85-7.79 (m, 2H), 7.72 (s, 1H), 7.44-7.37 (m, 2H), 6.58 (dd, J=12.4, 2.5 Hz, 1H), 5.84-5.76 (m, 1H), 5.59 (s, 1H), 2.84-2.73 (m, 1H), 2.64-2.56 (m, 1H), 2.23-2.08 (m, 2H), 2.06-1.96 (m, 1H), 1.78-1.38 (m, 6H), 0.65 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([N:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CS(=O)(=O)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 1.11 g of methyl 3-[N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate, 447 mg K2CO3, 347 mL benzyl bromide in 20 mL DMF. The reaction was stirred overnight, concentrated in vacuo and partioned between ethyl acetate and water. The organic phase was washed with brine, dried and concentrated in vacuo to 1.2 g of a clear oil. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 730 mg of methyl 3-[N-(benzyl)-N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate. HRMS (M+Li): calcd. 444.1821, obs 444.1865.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[N:36]=[CH:35][O:34][N:33]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]5[N:36]=[CH:35][O:34][N:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: ClCc1ncon1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncon1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,2,4-oxadiazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-(chloromethyl)-1,2,4-oxadiazole following General Procedure H.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C@H:11]2[C@H:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[OH:20]>[Pd]>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][C:6]=1[OH:20]
Reactant: COc1cc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc([C@@H]2CCCC[C@H]2[N+](=O)[O-])ccc1O
Reaction time: 6 h

Procedure:
lin 300 ml methanol 8.4 g (33.7 mmol) of trans-2-methoxy-4-(6-nitro-cyclohex-3-enyl)-phenol are solved. To this solution 500 mg of 10% Pd/C are added. The mixture is hydrogenated at room temperature for 6 hours. The mixture was then filtered through Filter Cel and evaporation of the filtrate in vacuum, yielding trans-2 methoxy-4-(2-nitro-cyclohexyl)-phenol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:28])=[O:29]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: N#Cc1cccc(N)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminobenzonitrile (442 mg, 3.7 mmol, 1 eq) is dissolved in dry pyridine (606 ul, 7.5 mmol, 2 eq), under an inert atmosphere of argon. 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Intermediate A)(1.0 g, 3.7 mmol) in 1,4-dioxane (2 ml) is added and the reaction mixture is stirred at room temperature overnight. The solvents are removed in vacuo and the residue is dissolved in DCM and 0.5M HCl. The phases are separated and the organic portion is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:25]=3[CH3:35])=[CH:18][CH:17]=2)[CH:10]=1)(=O)=O.[NH:43]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:44]1[C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C.C(OCC)(=O)C>[CH2:36]([N:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][N:43]2[CH2:53][CH2:52][CH2:51][CH2:50][CH:44]2[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:25]=1[CH3:35])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCOS(C)(=O)=O)c2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCN1CCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: 80 °C

Procedure:
The product from Example 92C (0.057 g, 0.0934 mmoles) in anhydrous DMF (1.0 mL) was treated with ethyl pipecolinate (0.072 mL, 0.467 mmoles) and heated at 80° C. overnight. The reaction was diluted with ethyl acetate, washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([S:37]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(F)c1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(3-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (104 mg, 0.3 mmol), NEt3 (0.14 mL, 1.1 mmol), and 3-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product (90 mg, 70% yld) as an off-white solid. MS (ES+) 433.2(M+H)+.
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[SH:46]>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[Br:39])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: Sc1ccccc1Br
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-bromothiophenol.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[C:18]2=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[C:17]2[CH:16]=[N:15]1.[I:36]I>C1COCC1.O>[I:36][C:24]1[N:23]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])[C:20]2=[N:21][CH:22]=[C:17]3[CH:16]=[N:15][N:14]([CH3:13])[C:18]3=[C:19]2[CH:25]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnn(C)c23)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
Diisopropylamine (0.20 mL, 1.5 mmol) in THF (1.5 mL) was cooled to about −74° C. A solution of n-BuLi (1.6 M solution in cyclohexane, 1.03 mL, 1.65 mmol) was added drop-wise over about 15 min. After about 20 min, the solution was added to 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.250 g, 0.766 mmol) in THF (10 mL) at about −74° C. over about 10 min. After about 1 h at about −74° C., a solution of iodine (0.226 g, 0.889 mmol) in THF (5 mL) was added over about 5 min. After about 2 h at about −74° C., water (20 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-40% EtOAc in heptane to give 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.27 g, 78%): LC/MS (Table 2, Method d) Rt=2.34 min; MS m/z: 453 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Clc1ncccn1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1

Procedure:
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.3 g, 8.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloropyrimidine (0.914 g, 8.0 mmol) were stirred in anhydrous DMF (15 mL) at 140° C. for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NH4Cl solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×80 mL) and dried with MgSO4. The solvents were evaporated and the product was isolated by column chromatography (silica gel, EtOAc:Hexane=1:9 ) as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2cnc(N)c2)cc1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1

Procedure:
4-(4-Amino-imidazol-1-yl)-benzoic acid methyl ester was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 35.8, 43.1, 52.6, 53.3, 102.7, 103.0, 103.2, 106.1, 112.4, 112.6, 120.4, 129.2, 131.7, 132.1, 138.6, 139.0, 140.6, 161.9, 162.1, 164.4, 166.2, 169.6, 169.8; MS m/z 471.2 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.[CH3:19]I>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
NaH (1.707 g, 42.68 mmol, 40% dispersion in mineral oil) was added in small portions to a cooled (0° C.) mixture of 3-(2-chloropyrimidin-4-yl)-1H-indole (Intermediate 131, 8.168 g, 35.57 mmol) in THF (250 mL). The resulting mixture was stirred at 0° C. for 0.5 h and then CH3I (2.67 mL, 42.68 mmol) was added and the mixture stirred at 0° C. for a further 3 h. The reaction was quenched by the addition of sat. NaHCO3 (25 mL). The mixture was then diluted with EtOAc (100 mL), and the resulting solution was washed with sat. NaHCO3 (50 mL), water (50 mL) and sat. brine (50 mL). The organic solution was then concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (8.35 g, 96%) as a pale yellow solid; 1H NMR: 3.90 (3H, s), 7.30 (2H, pd), 7.54-7.60 (1H, m), 7.82 (1H, d), 8.38-8.44 (1H, m), 8.49 (1H, s), 8.53 (1H, d); m/z: ES+ MH+ 1244.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(SCc2ccc(F)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)Cc2ccc(F)cc2)CC1
Yield: 96.7 %

Procedure:
Using a similar method to that described in Example 107, step 1, 1-(tert-butoxycarbonyl)-4-(4-fluorobenzylthio)piperidine (1.5065 g, 4.63 mmol) was reacted with 57-86% 3-chloroperoxybenzoic acid (1.0190 g) in dichloromethane (100ml) to give 1.5287 g (97%) of the title compound as a white solid. δH (250 MHz, CDCl3) 1.46 (9H, s), 1.64-1.82 (3H, m), 2.02 (1H, m), 2.63 (1H, m), 2.81 (2H, m), 3.88 (1H, d, J=13.2 Hz), 3.98 (1H, d, J=13.2 Hz), 4.21 (2H, m), 7.08 (2H, t, J=8.6 Hz), 7.29 (2H, m); m/e (ES+) 683 (2M+H)+, 342 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(F)c(=O)[nH]c2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc(F)c(Cl)nc2c1
Yield: 97 %

Procedure:
3-Fluoro-7-methoxyquinol-2(1H)-one (300 mg, 1.55 mmol), (prepared as in Tetrahedron, Vol. 52, No. 9, pp. 3223-3228, 1996), was dissolved in thionyl chloride (3 ml), treated with DMF (1 drop) and heated at reflux for 1 hour. The excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene (3×). The residue was basified to pH8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (3×20 ml). The organic solution was washed with water and brine then dried (MgSO4) and evaporated to dryness to give 2-chloro-3-fluoro-7-methoxyquinoline (320 mg, 97%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1)=[O:4].[H-].[Na+].Cl.NC[C:26](C1C2C(=CC=CC=2)N(C(OC(C)(C)C)=O)C=1)=[O:27].C(Cl)(Cl)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.C(OCC)C.ClCCl.N1C=CC=CC=1>[C:17]([O:16][C:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3](=[O:4])[CH2:2][N:1]=[C:26]=[O:27])=[CH:6]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)CN)c2ccccc21
Agent: Cl
Agent: O=C(Cl)Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(C(=O)CN=C=O)c2ccccc21

Procedure:
To a stirred solution of 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole, which may be prepared as described in Step (e) above, (0.01 mol), optionally in the presence of from 1 to 3 mol equivalents of a volatile (i.e., boiling point <150° C.) non-nucleophilic base such as, for example, a volatile tertiary organic amine or pyridine, or a solid non-nucleophilic base such as, for example, sodium hydride, or 3-aminoacetyl-1-(tert-butoxycarbonyl)-indole hydrochloride, which may be prepared as described in Step (e) above, (0.01 mol), optionally in the presence of from 2 to 4 mol equivalents of said non-nucleophilic bases, in a solvent such as dichloromethane or ethyl acetate, is stirred. A suitable reagent such as, for example, 1 mol equivalent of phosgene or 0.33 mol equivalents of triphosgene is added. After stirring for from 10 minutes to about 24 hours, the mixture is diluted with up to an equal volume of a diluent such as diethyl ether or ethyl acetate (preferred diluent is diethyl ether), and any precipitates are filtered off. The filter cake is washed with additional diluent. The filtrate and washings are combined and rotary evaporated to give 2-(1-tert-butoxycarbonyl-indol-3-yl)-2-oxo-ethylisocyanate, which may be purified, if needed or desired, by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Br[C:23]1[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCN[C@@H]1CNCC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 84.1 %

Procedure:
The same operation as in Example (196c) was performed using trans(±)-4-chloro-5-ethyl-N-[3-(propylamino)piperidin-4-yl]-1H-imidazole-2-carboxamide obtained in Example (205a) (10.0 mg, 0.032 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.035 mmol) and sodium carbonate (10 mg, 0.096 mmol), to obtain 13 mg of the title compound (85%) as a colorless solid.