Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=O)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>ClCCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:37]4[CH2:38][CH2:39][N:34]([C:31](=[O:33])[CH3:32])[CH2:35][CH2:36]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a RBF 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.00 g, 0.0029 mol) and sodium triacetoxyborohydride (1.30 g, 0.006 mol) were dissolved in 1,2-dichloroethane (65.0 mL) and a solution of 1-acetylpiperazine (0.39 g, 0.003 mol) in 1,2-dichloroethane was added to the reaction. The reaction mixture was stirred at rt for 2 h. The crude product was concentrated in vacuo and the dissolved in CH2Cl2 (25.0 mL) and washed with saturated NaHCO3 solution (1×40 mL). The product was dried with sodium sulfate and concentrated in vacuo to yield a light yellow solid; MS (ES+): m/z 459.84 (100) [MH+], 461.80 (40) [MH+++], HPLC: tR=1.81 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 3H) 2.26-2.50 (m, 6H) 2.55-2.72 (m, 2H) 2.83-2.99 (m, 1H) 3.29-3.52 (m, 3H) 3.56-3.67 (m, 2H) 7.29 (d, 1H) 7.58 (d, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[C:25](B4OC(C)(C)CC(C)(C)O4)[CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH3:37])=[O:16])[N:14]=2)[CH2:3]1.Br[C:39]1[CH:40]=[C:41]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:42]([Cl:45])=[N:43][CH:44]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:45][C:42]1[N:43]=[CH:44][C:39]([C:25]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][N:22]3[CH3:37])=[C:18]([NH:17][C:15]([C:13]3[N:14]=[C:10]([CH2:9][N:4]4[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]4)[S:11][CH:12]=3)=[O:16])[CH:26]=2)=[CH:40][C:41]=1[NH:46][S:47]([CH3:50])(=[O:49])=[O:48]
Reactant: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(B4OC(C)(C)CC(C)(C)O4)cc4c3cnn4C)cs2)C[C@H](C)O1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4c3cnn4C)cs2)C[C@H](C)O1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
2-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-N-[1-methyl-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg), N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamide (27 mg), tripotassium phosphate (61 mg) and Pd(dppf)Cl2 (7 mg) were added to 1,4-dioxane (0.5 ml) and water (0.5 ml) and heated under microwave irradiation for 10 min at 100° C. The reaction was passed through a 2 g silica SPE cartridge, washing with MeOH then evaporating to dryness. The residue was purified on silica, eluting with 0-100% EtOAc/cyclohexane over 30 min to give the title compound (27 mg).
Reaction SMILES: C([NH:4][C:5]1[C:6](=[CH:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:7]([OH:9])=[O:8])(=O)C>Cl>[Cl:14][C:12]1[CH:13]=[C:5]([NH2:4])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Product: Nc1cc(Cl)ccc1C(=O)O
Temperature: 80 °C

Procedure:
The damp N-acetyl-4-chloroanthranilic acid is suspended in 400 ml of concentrated hydrochloric acid (12M) and stirred and heated at 80° C. for 8 hours. The mixture is cooled to 10° C. and the resulting 4-chloroanthranilic acid hydrochloride is recovered by filtration. The solid is suspended in 300 ml water and sodium acetate is added, portionwise until the pH is 5. The resulting 4-chloroanthranilic acid is recovered by filtration and recrystallized from the minimum of hot ethanol. The final yield of off-white crystals was about 50 g, melting at about 239°-240° C.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[S:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1.ClCCCl.[OH-].[Na+]>[Cl-].[Cl-].[Zn+2].CC(=O)CC>[NH2:9][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=[C:12]2[CH2:13][CH2:14][S:10][C:11]=12
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCSC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCC(C)=O
Product: Nc1c2c(nc3ccccc13)CCS2
Reaction time: 2 h
Yield: 31.8 %

Procedure:
Anthranilonitrile (4.80 g) and tetrahydrothiophen-3-one (8.17 g) were stirred until a homogeneous mixture was obtained and then freshly fused ZnCl2 (8.0 g) was added and the reaction mixture heated at 120°. After 2 hours, 30 ml of 1,2-dichloroethane was added and the reaction mixture refluxed for an additional 2 hours. At the end of this time the reaction mixture was distributed between 10% NaOH solution and 2-butanone, after which the organic phase was separated, dried, concentrated and purified by flash chromatography (5% i-PrOH/CH2Cl2). Combination of the product-containing fractions gave 2.61 g of product that was pure to thin layer chromatography. This product was combined with that obtained in another run and recrystallized from EtOAc to give analytically pure material, mp 210°-212°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][CH:22]2[C:27]([N:29]([C:36]1[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][CH:22]2[C:27]([N:29]([C:36]1[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:35]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCOCCO
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: COCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 394 using diethylene glycol monomethyl ether (1 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.0 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH3:16][S:17]SC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:17][CH3:16])[S:10][C:3]=12
Reactant: CSSC
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc2nccc(Cl)c2s1
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of 2 (200 mg, 1.18 mmol) in dry THF (11 ml) at −78° C. was added n-BuLi (0.57 mL, 2.5M solution on hexane, 1.41 mmol) and the resultant brown precipitate was stirred for 10 minutes. Methyl disulfide (0.16 ml, 1.77 mmol) was added slowly, the mixture was stirred at −78° C. for 3 hours and partitioned between DCM and water. Organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford title compound 229 (0.240 g, 94% yield, crude) as a yellow solid. MS (m/z): 216.1 (100%), 218.1 (39%) (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:23]4[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:17][C:16]=2[CH3:33])[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CS(C)=O.CCOC(C)=O>[CH3:33][C:16]1[CH:17]=[C:18]([NH:21][C:22]2[C:23]3[CH:31]=[C:30]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:29]=[CH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1

Procedure:
A solution of 4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.21 mmol), NEt3 (0.67 g, 6.63 mmol), and morpholine (0.57 g, 6.63 mmol) in DMSO (10 mL) was heated to 120° C. in a sealed tube. After 24 h the reaction was diluted with EtOAc, the organic layer was washed 2× 1N NaOH and 2× water. The organic layer was treated with HCl (g) and the title compound was collected by filtration as a yellow solid (0.63 g, 67%). LRMS: 421.3 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.15 (br. s, 1H), δ 9.05 (br. s, 1H), δ 8.92 (s, 1H), δ 8.65 (s, 1H), δ 8.18 (s, 1H), δ 7.49-7.51 (m, 2H), δ 7.096 (d, J=9.55, 1H), δ 4.66-4.69 (m, 1H), δ 3.65-3.73 (m, 8H), δ 3.16 (br. s, 2H), δ 3.06 (br. s, 2H), δ 2.17 (s, 3H), δ 2.07-2.13 (m, 2H), δ 1.85-1.94 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:38][CH2:37][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: OCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1
Yield: 44.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.76 g (5.8 mmol) of 2-morpholin-4-yl ethanol and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.42 g (44% yield) of the title compound (26a) as a colorless oil. Rf=0.31 (EtOAc/Hxn=1.2). 1H NMR (400 MHz, CDCl3): δ=1.09 (s, 3H), 1.11 (s, 3H), 2.25-2.32 (m, 2H), 2.49-2.53 (m, 4H), 2.62-2.65 (m, 2H), 3.22-3.26 (m, 2H), 3.63-3.68 (m, 6H), 3.87 (s, 1H), 4.03 (d, J=9.2 Hz, 1H), 4.22 (d, J=9.6 Hz, 1H), 4.24-4.30 (m, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.37-4.43 (m, 1H), 4.67 (d, J=11.2 Hz, 1H), 7.26-7.36 (m, 5H) ppm. MS (ESI) m/z 492.04 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccccc1Cl
Product: CCOC(=O)CC(=O)Cc1ccccc1Cl
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(2-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[C:4]([CH3:11])[CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([CH2:15][CH2:16][CH3:17])[C:5]2=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)nc2cc[nH]c12
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1ccc2nc(Cl)cc(C)c21

Procedure:
A solution of 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (5 mmol) in dry DMF (10 mL) cooling on an ice bath was treated with NaH (60 mmol) under N2. After stirring at room temperature for 45 minutes iodopropane (10 mmol) was added. The mixture was allowed to react for further 3 hrs. Upon cooling on an ice bath it was treated with H2O (3 mL). The mixture was then extracted with diethyl ether (4×50 mL). The ether layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated to give 5-chloro-7-methyl-1-propyl-1H-pyrrolo[3,2-b]pyridine as orange oil. 1H-NMR (DMSO-d6) δ: 0.85 (t, 3H, J=7.6 Hz, CH3), 1.75 (m, 2H, CH2), 4.28 (t, 2H, J=7.6 Hz, CH2), 6.48 (d, 1H, J=3.2 Hz, Ar—H), 6.97 (s, 1H, Ar—H), 7.66 (d, 1H, J=3.6 Hz, Ar—H). MS (ESI+) m/z 209.0648 (M+H)+.
Reaction SMILES: [C:1]([C:3]([NH:6][S:7]([CH2:10][CH2:11][S:12][CH3:13])(=[O:9])=[O:8])([CH3:5])[CH3:4])#[N:2].[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[Cl:14][C:15]([Cl:21])([S:19][N:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[S:7]([CH2:10][CH2:11][S:12][CH3:13])(=[O:8])=[O:9])[CH:16]([Cl:18])[Cl:17]
Reactant: CSCCS(=O)(=O)NC(C)(C)C#N
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSCCS(=O)(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a stirred mixture of 3.53 g (0.0159 moles) N-(2-cyano-2-propyl)-2-(methylthio)ethylsulfonamide (the product of Example 27), 4.15 g of 89.9% 1,1,2,2-tetrachloroethylsulfenyl chloride (3.74 g [0.0159] moles) and about 1 g benzyltriethylammonium chloride in 25 ml methylene chloride, 0.8 g (0.02 l mole) sodium hydroxide in 5 ml water was added. The reaction mixture was stirred at room temperature for 18 hours. The layers were separated using a separatory funnel. The methylene chloride layer was washed three times with 30 ml water, dried and concentrated on a rotovap to about 20 ml. Hexane was added to the solution until turbidity. The mixture was warmed until clear. Cooling of the mixture gave a white powder which was isolated by filtration and then washed with hexane to give 2.4 g of crude product. A second crop of 1.8 g of crude product was obtained from the filtrate. The two crops were combined and recrystallized from ethanol to give 2.2 g of the above-identified product as a solid, melting point 83°-84° C. A second crop of 1.1 g solid was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OB(O)c1cccs1
Reactant: OCCCCc1ccccc1Br
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCCCCc1ccccc1-c1cccs1

Procedure:
To a solution of 4-(o-bromophenyl)-1-butanol (1.222 g, ca 0.0053 mol) and tetrakis(triphenylphosphine) palladium (0) (650 mg, 0.562 mmol) in 1,2-dimethoxyethane (55 mL) was added thiophene-2-boronic acid (2.057 g, 0.016 mol) and 1N aqueous NaHCO3 (15 mL). The resulting mixture was heated at reflux under nitrogen atmosphere for 3 days. The dark reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered through a bed of Celite and concentrated to yield a crude which was purified by flash chromatography (30% EtOAc in hexane) to yield 4-(2-thien-2-yl-phenyl)-butan-1-ol as a light brown oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40]>CCOCC>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Yield: 98.2 %

Procedure:
To a mixture of 2.3 g (0.007 mol) of (--)-3-phenoxy-N-methylmorphinan, 150 ml of benzene and 0.35 g of potassium carbonate was added dropwise, 3.3 g of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at reflux for 6 days. The mixture was diluted with ether and extracted with 4 N hydrochloride acid. The organic phase was washed with dilute ammonium hydroxide, water, and dried. Removal of solvent gave 3.4 g (99%) of the product (--)-3-phenoxy-N-trichlorocarbethoxymorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05 mmHg, [α]25D-119.65° (c 0.95, MeOH).
Reaction SMILES: [F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:26].O>CO>[F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])[C:3]([O-:5])=[O:4].[Na+:26]
Reactant: CCOC(=O)C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 99.2 %

Procedure:
Sodium 2,2,6,6,7,7,8,8,9,9,9-undecafluoro-nonanoate (60 g, 99% yield, formula above) was prepared from ethyl 2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (61.5 g, 0.16 mol), sodium hydroxide (6.5 g, 0.163 mol), water (100 mL) and methanol (100 mL) according to the procedure of Example 7.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCC(O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-ol (2.20 g, 7.85 mmol) in CH2Cl2 was added the Des s-Martin periodinane (4.24 g, 10.00 mmol). After 12 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[CH2:10]Br)=[O:4].[CH3:16][O-:17].[Na+]>>[C:12]([N:8]1[C:9]([CH2:10][O:17][CH3:16])=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[N:7]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1CBr
Reactant: C[O-]
Agent: [Na+]
Product: COCc1c(C(=O)O)cnn1C(C)(C)C
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
A solution of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester (1.51 g, 5.48 mmol) (as prepared in Example 55, Step 1) in sodium methoxide (23.8 mL, 11.9 mmol, 0.5M solution in methanol) was warmed to 90° C. where it was stirred for 2.5 h. At this time, the reaction was concentrated in vacuo. The resulting white solids were taken up in water (100 mL) and extracted with ethyl acetate (1×150 mL). The organics were then washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. When it was discovered that the product was not in the organic extracts, the aqueous layers were combined and were acidified to pH=1 with concentrated aqueous hydrochloric acid and then were extracted with dichloromethane (1×150 mL). These organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (1.03 g, 88%) as a white solid. The material was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]=[N+]=[N-])[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][NH2:22])[CH2:19][CH2:20]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A suspension of lithium aluminum hydride (2.76 g, 72.6 mmol) in THF (225 mL) was cooled at 0° C. and a solution of trans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (15.0 g, 55.9 mmol) in THF (75 mL) was added over 1 hr. The reaction mixture was stirred at ambient temperature for 6 hr. The reaction was quenched with Na2SO4.10H2O, filtered through a pad of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 50% MeOH in CHCl3) to give trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (12.3 g, 91%) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH:14]1([C:17]([NH:13][C:12]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:18])[CH2:16][CH2:15]1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Product: O=C(O)c1ccc(NC(=O)C2CC2)c([N+](=O)[O-])c1

Procedure:
The acylation of 7.0 g (0.0384 mol) of 3-nitro-4-amino-benzoic acid with 4.42 g (0.0423 mol) of cyclopropanecarboxylic acid chloride was carried out as described in Example 3.