Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:32]3[N:35]4[CH2:34][C:33]([OH:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: C#CC1(O)CCCNC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(O)CCCN5C6)ccc43)cc2OC)cn1

Procedure:
7-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.5 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz, 1H), 7.59 (dd, J=8.5, 1.0 Hz, 1H), 7.29-7.26 (m, 1H, partially obscured by CHCl3), 6.89 (d, J=9.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m, 2H), 6.09 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.41-3.39 (m, 1H), 2.92-2.83 (m, 3H), 1.89-1.81 (m, 3H), 1.71-1.67 (m, 1H) ppm; (M+1)=499.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)[CH2:11][CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:15]2[CH:16]=[C:12]([CH:9]3[CH2:11][CH2:10]3)[NH:13][N:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The mixture of 2,4-dichloropyrimidine (2.0 g, 13.5 mmol, 1.0 equiv.), EtOH (6 mL) and 3-cyclopropyl-1H-pyrazol-5-amine (20.3 g, 20.3 mmol, 1.5 equiv.) was stirred at room temperature for 8 h. The reaction mixture was filtered to afford compound 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.4 g, 45%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][C:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:17]([C:12]3([CH3:11])[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)Cl)CCCC1
Reactant: Brc1cnc2[nH]ccc2n1
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCC1

Procedure:
(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclopentyl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-cyclopentanecarbonyl chloride following general procedures as described in these Examples. MP 206.9-207.9° C., M+H=308.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid [prepared according to the procedure of Braish et al., Syn. Comm., 3067-3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of 1,1′-carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 1-3, the benzyl bromide derivative was converted to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH3:28].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:15]2[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:14]2)=[O:35])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N2CC(C(=O)OC)N(S(=O)(=O)c3ccc(OC)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 μl of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the CH2Cl2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276 g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, (mp 187-190° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:8][C:6]1[N:7]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(NC2CCCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NC3CCCCC3)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N4-cyclohexyl-2,4-pyrimidinediamine (0.75 g, 3.31 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.546 g, 3.31 mmol) followed by 1,4-dioxane (13.2 mL) and saturated aqueous NaHCO3 (3.3 mL). The resulting mixture was degassed with nitrogen for 5 minutes. Pd(Ph3P)4 (0.19 g, 0.165 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature, decanted, and concentrated. The resulting orange oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. To the resulting yellow solid was added CH3CN (5 mL), and the mixture was sonicated. Filtration of the solid and washing with minimal CH3CN afforded the title compound (387 mg, 36%) as a light tan solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1)#[N:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: N#Cc1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C#N)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])=[O:5])[CH3:2].C(Cl)([Cl:27])=O.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:27][C:17]1[C:8]2[N:9]([C:23]([CH3:24])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of 2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 1) (88 g, 259 mmol) in DMF (1.5 l) was dropwise added a solution of 28% phosgene in toluene (0.5 l, 960 mmol). The mixture was stirred at 50° C. for 1 h and overnight at 25° C. followed by evaporation in vacuo. The residue was stirred with ice-cooled water. The solid was collected by filtration and washed with water to yield 83,4 g (95%) of 4-chloro-2-ethoxycarbonyl-1-methyl-7trifluoromethylimidazo[1,2-a]quinoxaline. M.p. 182°-183° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]2C=CN=[C:43](S(C)=O)[N:42]=2)[CH2:37][CH2:36]1)=[O:33].Cl.NC1CCN(C2[S:59][C:60]([C:63]([NH2:65])=[O:64])=CN=2)CC1>CN(C=O)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:36][CH2:37][N:38]([C:41]2[S:59][C:60]([C:63]([NH2:65])=[O:64])=[CH:43][N:42]=2)[CH2:39][CH2:40]1)=[O:33]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(S(C)=O)n3)CC2)c(Cl)c1Cl
Reactant: NC(=O)c1cnc(N2CCC(N)CC2)s1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
Diisopropylethylamine (0.19 ml, 1.12 mmol), EDC (0.098 g, 0.51 mmol) and HOAT (0.070 g, 0.51 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 0.1 g, 0.51 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride (Intermediate 81; 0.163 g, 0.62 mmol) was added. The reaction was stirred at room temperature overnight under nitrogen. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography (water/acetonitrile gradient, 20-95%) to give the desired product as a white solid (50 mg).
Reaction SMILES: [NH2:1][C:2](=[NH:16])[N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:17][C:18]([SH:21])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:17][C:18]1[S:21][N:1]=[C:2]([N:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]2)[N:16]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of tert-butyl 4-[amino(imino)methyl]piperazine-1-carboxylate (1.50 g, 5.67 mmol) and perchloromethyl mercaptan (0.609 ml, 5.67 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (0.907 g, 22.7 mmol) in water (2.5 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.03 g (59.5%) of the desired product as a solid.
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH2:14]Br.[O:21]1CCCC1>>[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH2:14][S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]([OH:21])=[O:6]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: C1CCOC1
Reactant: O=C1Cc2ccccc2S1
Product: O=C(O)Cc1ccccc1SCc1cc(F)ccc1F

Procedure:
A mixture of benzo[b]thiophen-2(3H)-one (11.2 g) aqueous sodium hydroxide (5.58 g in 100 ml water) and tetrahydrofuran (10 ml) was heated under reflux for two hours. A solution of 2,5-difluorobenzyl bromide (15.5 g) in tetrahydrofuran (10 ml) was added and the mixture refluxed for a further 2 hours and allowed to cool. The aqueous layer was clarified by ether extraction and then acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water and dried. The solid was recrystallised from dipropyl ether/hexane to give [2-(2,5-difluorobenzylthio)phenyl]acetic acid, mp 106.5°-107.5°. A solution of this product (14.4 g) in methanol (150 ml) containing concentrated sulphuric acid (0.5 ml) was heated under reflux for 4 hours, cooled and evaporated. The residue was dissolved in ethyl acetate/ether and washed with water and aqueous sodium bicarbonate, dried and evaporated to give methyl [2-(2,5-difluorobenzylthio)phenyl]acetate, as a light brown oil.
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=3)=[CH:19][C:12]2=[N:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)/[C:3]([O:5]CC)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[F:1]/[C:2](=[CH:8]\[C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=3)=[CH:19][C:12]2=[N:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)/[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)/C(F)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C(\F)C(=O)O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
The ethyl (Z)-2-fluoro-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (28 mg) obtained in (B) was dissolved in tetrahydrofuran (2 ml) and methanol (0.5 ml), added with a solution of lithium hydroxide(5 mg) in water (0.5 ml), and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with water and washed with ether. Then, the aqueous layer was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (26 mg) as yellow powder.
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][CH2:7][C@@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[NH2:9]>C(Cl)Cl.C(N(CC)CC)C>[C:7]([NH:9][C@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[CH2:7][OH:6])(=[O:6])[CH2:8][CH2:10][CH2:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
After stirring for 25 minutes at 25° C., this above-described mixture is added to a pre-prepared stirred suspension containing 4.68 g (11.5 mmoles) of phytosphingosine sulphate (purity 82%) in 15 ml of methylene chloride and 2.1 ml of triethyl amine.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:16]=[O:17])=[CH:9]2.O>CO.C1COCC1>[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH2:16][OH:17])=[CH:9]2
Reactant: COc1ccc2cc(C=O)ccc2c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2cc(CO)ccc2c1Br
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step d) Sodium borohydride (4.78 g, 128.3 mmol) was added portionwise in to a cold (0° C.) mixture of 5-bromo-6-methoxy-2-naphthldehyde (34.0 g, 128.3 mmol) in methanol (300 ml) and THF (200 mL). After stirring for 30 minutes the mixture was poured in to water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 2/1 ) gave a yellow solid (30.5 g, 90% yield, m.p. 85°-87° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:20]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][N:21]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][N:21]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:20]3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc([N+](=O)[O-])cc3)CC2)C1
Temperature: 100 °C

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (0.155 ml, 1.458 mmol) in DMSO was added N,N-diisopropylethylamine (0.926 ml, 5.30 mmol) followed by tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, 1.326 mmol). The reaction mixture was heated to 100° C. overnight, and cooled to room temperature. The reaction mixture was quenched with 75 mL water, filtered, washed with water and dried over high-vac to provide the title compound. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#N.[K+].[C:21]([OH:24])(=[O:23])C>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([OH:17])[C:21]([O:24][CH3:18])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(=O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Benzyloxy)-5-bromobenzenecarbaldehyde (9) (20 g, 69 mmol) was dissolved in MeOH (150 mL) and was then followed by the addition of potassium cyanide (20.1 g, 308 mmol). Acetic acid (6.3 mL, 109 mmol) was added dropwise over 20 min at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 h. Acetic acid (2 mL) was added and the mixture was stirred for an additional 1 h. Additional acetic acid (30 mL) was added and the mixture was diluted with H2O (60 mL). After concentration at reduced pressure, the aqueous residue was extracted with EtOAc (3×100 mL). The combined organics were washed with brine and dried over MgSO4. Filtration and concentration left a pale yellow oil, which was without further purification. The title compound (10) could be isolated in pure form by gradient column chromatography (10 to 20% EtOAc in Hexanes). 1H NMR (400 MHz, CDCl3) 7.53 (d, 1H); 7.24 (m, 6H); 6.86 (d, 1H); 5.52 (d, 1H); 5.13 (s, 2H); 3.38 (d, 1H). MS 199, 201(M-Bn-CN). HPLC 20.40 min. (95% H2O:5% CH3CN)+0.1% TFA to (10% H2O:90% CH3CN)+0.1% TFA over 22 min on a Vyadec 218TP54 C18 Column Step (c): Preparation of methyl 2-[2-(benzyloxy)-5-bromophenyl]-2-hydroxyacetate Crude 2-[2-(benzyloxy)-5-bromophenyl]-2-hydroxyacetonitrile (10), from above, was dissolved in anhydrous dioxane (25 mL), ether (25 mL) and MeOH (6 mL). After cooling the mixture to 0° C., it was saturated with HCl gas and warmed to ambient temperature. A precipitate formed and the mixture was stirred for 1.5 h. [If the mixture became too viscous to stir, anhydrous ether was added]. The reaction mixture was diluted with ether (200 mL) and filtered. The colorless solid was washed with ether and used as is.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A mixture of 2-hydroxy-4-fluorobenzaldehyde (log, 71.4 mmol), ethyl 4,4,4-trifluorocrotonate (15 mL, 100 mmol), and anhydrous potassium carbonate (14.8 g, 107.1 mmol) in 40 ml dry dimethylformamide was heated to 90° C. for five hours. LC-MS indicated that the reaction was done. After cooling to room temperature, to the reaction was added 500 mL of ethyl acetate. The organic phase was washed with brine (×3), and was then dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:18 EtOAc/hexane. It gave 12.5 g (60%) product as a light yellow oil. 1H NMR (CDCl3/300 MHz) 7.73(s, 1H), 7.30-7.22(m, 1H), 6.79-6.73(m, 2H), 5.76(q, J=6.9 Hz, 1H), 4.38(m, 2H), 1.37(t, J=7.2 Hz, 3H). 13C(CDCl3/300 MH) 167.2, 164.0, 163.9, 155.0(d, J=13.0 Hz), 136.3(d, J=1.28 Hz), 131.0(d, J=10.4 Hz), 123.5(q, J=287.5 Hz), 115.9(dd, J=2.4, 7.3 Hz), 110.2(d, J=22.5 Hz), 104.4(d, J=26.0 Hz), 71.0(q, J=33.2 Hz), 61.7(d, J=10.4 Hz), 14.4. 19F(CDCl3/300 MHz) −79.0(d, J=6.5 Hz), −104.8(m). LC-MS(ES+) 291.0(M+1, 100), HRMS (EI+) m/z calcd for (C13H10F4O3) 290.0566(M+), found 290.0586.