Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].[NH2:28][C:29]([NH2:31])=[O:30].Cl>CCO>[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:31][C:29](=[O:30])[NH:28]2)=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(O)c([N+](=O)[O-])c2)N1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a solution of 1,2-diphenylethanone (704 mg, 3.59 mmol), 4-hydroxy-3-nitrobenzaldehyde (500 mg, 2.99 mmol) and urea (538 mg, 8.97 mmol) in EtOH (40 mL) was added concentrated HCl (1.6 mL). The mixture was stirred at 85° C. for 3 days. The volatiles were removed under reduced pressure and standard aqueous workup procedure was followed. Purification by silica gel column chromatography (PE:EA=1:1) gave Compound 95 as an off-white power (102 mg, 9%). 1H NMR (DMSO-d6 500 MHz TMS): δ 10.09 (s, 1H), 8.69 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.52-7.57 (m, 2H), 7.21-7.26 (m, 5H), 7.13 (d, J=10.5 Hz, 1H), 7.01 (t, J=27.5 Hz, 3H), 7.81 (d, J=8.5 Hz, 2H), 5.26 (d, J=3.5 Hz, 1H); MS (ESI): m/z 388.1 [M+1]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1[C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28]>>[CH3:1][C:2]1[CH:3]([C:10](=[O:15])[CH2:11][CH:12]([OH:14])[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:23])([CH3:24])[C:18]=1[C:25](=[O:30])[CH2:26][CH:27]([OH:29])[CH3:28]
Reactant: CC(=O)CC(=O)C1=C(C)CCCC1(C)C
Reactant: CC(=O)CC(=O)C1C(C)=CCCC1(C)C
Product: CC1=C(C(=O)CC(C)O)C(C)(C)CCC1
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)O

Procedure:
By replacing in the above Example 2,6,6-trimethyl-1-[1,3-dioxo-but-1-yl]-cyclohex-2-ene by 2,6,6-trimethyl-1-[1,3-dioxo-but-1-yl]-cyclohex-1-ene the corresponding test samples have an analogous organoleptic note. Similar, but less pronounced effects, were obtained by the use of 2,6,6-trimethyl-1-[3-hydroxy-butan-1-oyl] -cyclohex-2-ene or 2,6,6-trimethyl-1-[3-hydroxy-butan-1-oyl]-cyclohex-1-ene.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([O:33][CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])[CH2:21][O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>FC(F)(F)C(O)=O.O>[CH2:41]([O:40][P:35]([CH2:34][O:33][C@H:20]([CH2:19][OH:18])[CH2:21][O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])([O:37][CH2:38][CH3:39])=[O:36])[CH3:42]
Reactant: CCOP(=O)(CO[C@@H](COn1cnc2c(N)ncnc21)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: O
Product: CCOP(=O)(CO[C@H](CO)COn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
(S)-9-[3-(t-Butyldiphenylsilyloxy)-2-(diethoxyphosphorylmethoxy)propoxy]adenine (0.61 g, 1 mmol) was dissolved in trifluoroacetic acid/water, 2:1 (6 ml) and the solution stirred at ambient temperature for 3 hours. Hexane (10 ml) was added and the mixture shaken. The aqueous phase was separated, washed once more with hexane (10 ml) and evaporated to dryness. The residue was treated with ethanolic ammonia solution (5 ml), at ambient temperature, for 5 minutes after which the solution was evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane/methanol 90:10 as eluant to give (R)-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]adenine as a colourless oil (0.3 g, 80%) which on prolonged standing, crystallised as white needles m.p. 98°-102°. IR: νmax (film) 3340, 3210, 2995, 2930, 2910, 1660, 1645, 1600, 1470, 1445, 1415, 1395, 1370, 1330, 1300, 1240, 1210, 1165, 1125, 1045. 1020, 980, 825, 95, 735 cm-1. 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz (OCH2CH3)2), 3.5-3.7 (2H, m, CH2OH), 3.75-3.85 (1H, m, CH), 3.95-4.15 (6H, m, (OCH2CH3)2, OCH2P), 4.38 (1H, dd, J=11.3 Hz, J=6.6 Hz, NOCHB), 4.55 (1H, dd, J= 11.3 Hz, J=3.0 Hz, NOCHA), 4.88 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.38 (2H, br.s., D2O exchangeable NH2), 8.15 (1H, s, H-2 or H-8), 8.43 (1H, s, H-2 or H-8). Found: C, 39.26; H, 6.05; N, 17.33%. C13H22N5O6P 1.25 H2O requires: C, 39.25; H, 6.20; N, 17 61%. m/z: (FAB, thioglycerol matrix) 376 (MH+).
Reaction SMILES: C1([C@H](C2C=CC=C([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20](C4C=C(OC)C=CC=4F)=[C:19]([C@@H:32]4[CH2:36][CH2:35][CH2:34][C:33]4([CH3:38])[CH3:37])[CH:18]=3)C=2)CC(O)=O)CC1.[C:39](=O)([O-])[O-:40].[K+].[K+].[F:45][CH:46]([F:63])[C:47]1[CH:48]=[CH:49][C:50]([F:62])=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:52]=1>CN(C=O)C.O.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:63][CH:46]([F:45])[C:47]1[CH:48]=[CH:49][C:50]([F:62])=[C:51]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:40][CH3:39])=[O:15])=[CH:18][C:19]=2[C:32]2[C:33]([CH3:38])([CH3:37])[CH2:34][CH2:35][CH:36]=2)[CH:52]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2F)OC1(C)C
Reactant: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3)cc2[C@@H]2CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
To a stirred solution of 66.6 I (1.12 g, 2.96 mmol) in DMF (10 mL) at 23° C. was added potassium carbonate (1.23 g, 8.87 mmol) followed by tetrakis(triphenylphosphine)palladium (0.34 g, 0.29 mmol). The mixture was purged three times with argon and placed under vacuum three times. Before heating, 83.3A (1.60 g, 5.89 mmol) was added via syringe, and then the mixture was heated to 90° C. After 19 hours, the mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to give 83.3B as a clear oil (0.99, 90%). 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, dd, J=8.0, 1.8 Hz), 7.94 (1H, d, J=1.6 Hz), 7.50 (3H, m), 7.16 (1H, t, J=9.0 Hz), 6.63 (1H, t), 5.53 (1H, s), 3.96 (3H, s), 2.25 (2H, td, J=7.0, 2.3 Hz), 1.65 (2H, t, J=7.0 Hz), 0.85 (6H, s).
Reaction SMILES: C[Al](C)C.[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.C1(C)C=CC=CC=1>[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([N:6]3[CH2:7][CH2:8][C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:5]3)=[O:29])[CH2:24][CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Temperature: 50 °C
Yield: 90.8 %

Procedure:
251 ml (594 mmol) of trimethylaluminium (at a concentration of 25% in hexane) are introduced under an argon atmosphere into 400 ml of tolune. The solution is cooled in an ice bath and 81.5 g (612 mmol) of 1,2,3,4-tetrahydroisoquinoline, dissolved in 200 ml of toluene, are added. The mixture is heated to approximately 50° C. and 95 g (384 mmol) of ethyl 1phenylmethyl-4-piperidinecarboxylate, dissolved in 400 ml of toluene, are added. The mixture is heated under reflux for 2 h, approximately 250 ml of solvent being removed by means of a Dean and Stark apparatus. The mixture is cooled in an ice bath and hydrolysed by slowly adding 250 ml of water, and the insoluble material is filtered off, it being rinsed with ethyl acetate. The filtrate is washed three times with water, the organic phase dried over sodium sulphate, the solvent evaporated off and the residue recrystallized in cyclohexane. 116.6 g of product are obtained. Melting point: 98°-100° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[Cl:7][CH2:8][C:9](OC)=[O:10]>CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9](=[O:10])[CH2:8][Cl:7]
Reactant: NCC(O)CO
Reactant: COC(=O)CCl
Solvent: CO
Product: O=C(CCl)NCC(O)CO
Reaction time: 5 h
Yield: 95 %

Procedure:
A solution of 25 grams (g.) (0.27 mole) of 3-amino-1,2-propanediol in 50 milliliter (ml.) methyl alcohol is added slowly to a solution of methyl chloroacetate, 33.0 g. (0.30 mole) in 50 ml. methyl alcohol at 5°-10° C. The solution is stirred for five hours at 5°-10° C. and is then allowed to stand in the cold for four days. The solution is then evaporated in vacuum to leave 43 g. of the desired product, a viscous oil, nD30 1.5148. (95% yield).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:19]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)[CH2:26][CH2:25]2)[CH:19]=1
Reactant: Nc1nc2c(N3CCOCC3)cccn2n1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2CCC(Nc3nc4c(N5CCOCC5)cccn4n3)CC2)ncn1

Procedure:
Prepared in analogy to example 1h, starting from 8-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a white solid (yield: 34%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc3ccccc3c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 74% overall yield. mp. 171°-172°. FDMS m/e=400 (M+ of free base). α[D]589 =-13.51 (c=1.04, methanol).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:23][O:24][CH2:25][CH:26]1[CH2:28][O:27]1.Cl>C1COCC1>[CH3:23][O:24][CH2:25][CH:26]([OH:27])[CH2:28][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: COCC1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(O)Cc1ccnn1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To an THF solution (450 ml) of 1-phenylpyrazole (15 g) was added 1.6M butyllithium/hexane solution at −78° C., and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added 2-(methoxymethyl)oxirane (27.8 ml) at −78° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:28][CH:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[OH:27])[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: COc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CCN(C)C3)cc1
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1.0 g, 5.0 mmol) was dissolved in 15 mL DMF and sodium hydride (600 mg, 15 mmol) was added portionwise at 0° C. and stirred for 10 min. 2-(4-Methoxy-phenyl)-oxirane (900 mg, 6.0 mmol) was added dropwise at the same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water and filtered through a Celite bed. A cake of compound was formed which was dissolved in MeOH and DCM. This was again filtered through a Celite bed and the filtrate concentrated. The solid thus obtained was crystallized in ether & hexane to get 600 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-methoxy-phenyl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 7.27 (m, 3H), 7.24 (d, 1H), 7.00 (d, 1H), 6.98 (d, 2H), 4.98 (t, 1H), 4.09 (d, 2H), 3.81 (s, 3H), 3.67 (d, 1H), 3.32 (d, 1H), 2.79 (m, 3H), 2.7 (m, 1H), 2.49 (s, 3H), 2.45 (s, 3H). Separation by chiral HPLC provided enantiomers 20a and 20b. Optical rotations: Compound 20a, (−)10.20 (c 0.58, Chloroform, 99.61% HPLC purity); Compound 20b, (+)10.00 (c 0.59, Chloroform, 96.54% HPLC purity).
Reaction SMILES: Br[CH:2]1[C:8](=O)[CH2:7][CH2:6][CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]1=[O:19].[O:20]([CH2:27][C:28]([NH2:30])=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:4]2[CH2:5][CH2:6][CH2:7][C:8]3[N:30]=[C:28]([CH2:27][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:29][C:2]=3[C:3]2=[O:19])=[CH:12][CH:13]=1
Reactant: NC(=S)COc1ccccc1
Reactant: COc1ccc(CN2CCCC(=O)C(Br)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
A mixture of 3-bromodihydro-1-[(4-methoxyphenyl)methyl]-1H-azepine-2,4(3H,5H)-dione (0.78 g, 2.38 mmol) and 2-phenoxythioacetamide (0.36 g, 2.14 mmol) in DMF (12.5 mL) was stirred at room temperature for 15 minutes. Then NaHCO3 (0.32 g, 3.81 mmol) was added and the reaction was stirred at 100° C. for 30 minutes. The reaction was diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-5-[(4-methoxyphenyl)methyl]-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.58 g, 62% yield) as an orange oil. C22H22N2O3S LCMS: Rt 3.01, m/z 395 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][OH:26])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 83 (0.138 g, 0.319 mmol, 1 equiv) in CH2Cl2 (3 mL) was cooled to 0° C. prior to sequential addition of Et3N (0.222 mL, 1.59 mmol, 5 equiv) and CH3SO2Cl (0.049 mL, 0.637 mmol, 2 equiv). The cooling bath was removed after 5 min and the mixture was stirred at 25° C. for 1 h. The reaction was quenched with the addition of saturated aqueous NaHCO3 (0.5 mL) and the layers were separated. The aqueous portion was extracted with EtOAc (2×5 mL) and the combined organic portions were dried (MgSO4), filtered, and concentrated. Radial chromatography (SiO2, 2 mm plate, 30% EtOAc-hexane) furnished 84 (0.143 g, 0.163 g theoretical, 89%) as a white solid: mp 134-135° C.; 1H NMR 400 MHz, CDCl3) major rotamer δ 8.40 (d, 8.2 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.60-7.35 (m, 7H), 6.63 (s, 1H), 5.26 (d, J=11.7 Hz, 1H), 5.17 (d, J=11.6 Hz, 1H), 4.49-4.44 (m, 2H), 4.38-4.30 (m, 2H), 2.69-2.64 (m, 4H), 2.26-2.05 (m, 2H), 1.73-1.70 (m, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) major rotamer δ 153.8, 153.6, 140.5, 136.7, 133.0, 128.8 (2C), 128.6, 128.1 (2C), 127.7, 127.6, 127.1, 125.2, 123.3, 122.8, 107.1, 80.8, 71.4, 70.2, 47.7, 37.1, 36.1, 28.3 (3C), 26.5, 24.4; IR (film) νmax 3056, 2974, 2933, 2862, 1692, 1615, 1590 cm−1; FABHRMS (NBA-NaI) m/z 534.1914 (M+Na+, C28H33NO6S requires 534.1926).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10])#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1C#N
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C#N)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:26](I)=[CH:25][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[N:8]([CH2:14][C:15]4[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=4)[C:7]=3[CH:21]3[CH2:24][CH:23]([C:4]=2[CH:3]=1)[CH2:22]3.[CH3:28][C:29]([OH:33])([C:31]#[CH:32])[CH3:30].ClCCl>N1CCCCC1.CO.[Cu]I.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>[NH3:8].[F:1][C:2]1[C:26]([C:32]#[C:31][C:29]([OH:33])([CH3:30])[CH3:28])=[CH:25][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[N:8]([CH2:14][C:15]4[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=4)[C:7]=3[CH:21]3[CH2:24][CH:23]([C:4]=2[CH:3]=1)[CH2:22]3
Reactant: Cn1nccc1Cn1c(C(N)=O)nc2c1C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: Cn1nccc1Cn1c(C(N)=O)nc2c1C1CC(C1)c1cc(F)c(C#CC(C)(C)O)cc1-2
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 157.1 %

Procedure:
To a solution of 8-fluoro-9-iodo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (67 mg, 0.14 mmol) in piperidine (2 mL) was introduced 2-methyl-3-butyn-2-ol (68 mg, 0.81 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 50° C. for 4 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2×10 mL), water (2×10 mL) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: dichloromethane containing a 0-4% gradient of 7M ammonia in methanol) furnished the title compound (47 mg, 0.11 mmol, 78%) as off-white fine crystals: 1H NMR (500 MHz, CDCl3) δ 1.64-1.72 (m, 8H), 2.43 (br. s., 1H), 2.90 (qd, J=7.93, 3.00 Hz, 2H), 3.31-3.40 (m, 1H), 3.54-3.61 (m, 1H), 3.92 (br. s., 3H), 5.49 (br. s., 1H), 5.87 (s, 2H), 6.83 (d, J=10.09 Hz, 1H), 7.42 (br. s., 1H), 8.42 (d, J=7.57 Hz, 1H); M+1=434.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@@H]1COC(C)(C)O1
Reactant: OB(O)c1cccnc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@@H]1COC(C)(C)O1
Yield: 65.5 %

Procedure:
(R)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 6.9 mmol) and pyridine-3-boronic acid (1.02 g, 8.27 mmol) were coupled according to the method described in Examples 118–121. The work-up procedure described in Part F of Examples 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitrile to provide 1.96 g of (R)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 155–156° C.