Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:49][CH2:48][CH2:47][C@:40]3([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]3)[CH2:39]2)[C:34]([F:50])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:49][CH2:48][CH2:47][C@:40]5([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]5)[CH2:39]4)[C:34]([F:50])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CN1C[C@@]2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)OC1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
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: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@]5(C4)CN(C)C(=O)O5)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one, 63c, (0.019 g, 0.060 mmol) and degassed under N2. Na2CO3 (0.091 mL of 2 M, 0.1810 mmol) was added followed by Pd(PPh3)4 (0.010 g, 0.009 mmol). The reaction was sealed and heated in a microwave at 120° C. for 30 min. The mixture was then concentrated in vacuo. The material was diluted in CH2Cl2 and silica gel chromatography (Hexanes:EtOAc then 20% MeOH in CH2Cl2) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:9][CH:10]=1)=[O:5]
Reactant: C1CCNC1
Reactant: COC(=O)c1cnc(CCl)n1C
Agent: Cl
Product: COC(=O)c1cnc(CN2CCCC2)n1C

Procedure:
2-Chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride (224 mg, 1 mmol) was dissolved in pyrrolidine (2.3 ml, 28 mmol) and stirred at ambient temperature for, the title compound was obtained as light yellow oil 45 min. After evaporation to dryness, the residue is taken up in ethyl acetate and saturated aqueous sodium carbonate (20 ml) and the phases separated. The aqueous phase is extracted twice with ethyl acetate (20 ml each) and the combined organic layers are dryed with magnesium sulfate and evaporated to dryness. Flash chromatography (silica, eluent dichloromethane7methanol 19:1) afforded the title compound as light yellow oil (61% yield). MS: m/e=224(M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:14])[C:11]([OH:13])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(OC(Cl)=O)C(C)C.[NH2:35][CH:36]1[C:42](=[O:43])[N:41]2[CH:37]1[S:38][C:39]([CH3:48])([CH3:47])[CH:40]2[C:44]([OH:46])=[O:45].C(=O)(O)[O-].[Na+]>O.C(N(CC)CC)C.O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:14])[C:11]([NH:35][CH:36]3[C:42](=[O:43])[N:41]4[CH:37]3[S:38][C:39]([CH3:48])([CH3:47])[CH:40]4[C:44]([OH:46])=[O:45])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C(O)c1ccc2c(c1)CCO2
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)SC2C(NC(=O)C(O)c3ccc4c(c3)CCO4)C(=O)N2C1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-5-benzofuranyl)hydroxyacetic acid (10 mmole), triethylamine (10 mmole) and bistrimethylsilylacetamide (BSA) (10 mmole) are added to 50 ml of tetrahydrofuran and refluxed for 2 hours. The reaction mixture is cooled to about -10° C. and 10 mmole of isobutylchloroformate is added dropwise. After 30 minutes at -10° C., 10 mmole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid in 50 ml of water-20 ml of tetrahydrofuran containing 10 mmole of triethylamine is added dropwise to the previously prepared solution which is at about -10° C. After the addition is complete, the temperature is allowed to rise to room temperature from -10° C. About 50 ml of saturated sodium bicarbonate and 100 ml of water are added to the reaction mixture which is then twice extracted with ether. The aqueous phase is layered with ethyl acetate and the pH is adjusted to 1.5 by the addition of hydrochloric acid. The ethyl acetate is separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(Cl)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (52 mg, 0.158 mmol) (from Example 3 supra) in THF (3 mL) were added diisopropylethylamine (44 mg, 0.35 mmol) and then 4-chlorobenzoyl chloride (30.8 mg, 0.174 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (50 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[3-(4-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 41.4 mg, 56%).
Reaction SMILES: [CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH:5]=[C:6]([F:11])[C:7](OC)=[O:8])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH:5]=[C:6]([F:11])[CH2:7][OH:8])[CH2:2][CH2:3]1
Reactant: CCOc1ccc(C(C=C(F)C(=O)OC)C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOc1ccc(C(C=C(F)CO)C2CC2)cc1
Yield: 97.3 %

Procedure:
The method of Example 6 was repeated using methyl 4-cyclopropyl-4-(4-ethoxyphenyl)-2-fluorobut-2-enoate (Example 2) (1.2 g), diethyl ether (40 ml) and lithium aluminium hydride (0.2 g) to yield the title compound (1.05 g, 99%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:9]1COCC1>>[CH3:9][O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(C)C[C@H](N)CO
Product: COC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to a stirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF (10 ml) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for ˜10 minutes and then treated with Mel (0.121 ml, 1.939 mmol). After stirring for 30 minutes the reaction mixture was quenched by addition of saturated NH4Cl(aq) (˜20 ml) and extracted with EtOAc (25 ml×2). The combined organic phases were dried over MgSO4, filtered under vacuum and the filtrate was evaporated to afford an orange oil. The oil was purified by chromatography on silica eluting with 10% (2M NH3 in MeOH)/DCM to afford the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>O1CCCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([Cl:1])[CH:3]=1)=[O:33]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(6-chloro-2H,4H-benzo[e]1,3-dioxin-8-yl)methoxy]phenylamine (75 mg, 0.257 mmol) in anhydrous tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (0.090 mL, 0.514 mmol), followed by trichloroacetyl chloride (0.058 mL, 0.514 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give 2,2,2-trichloro-N-{2-[(6-chloro(2H,4H-benzo[e]1,3-dioxin-8-yl))methoxy]phenyl}acetamide, M+1=438.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22].N>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cnc2c(c1)CCCC2
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Reaction time: 0.12 h
Yield: 96 %

Procedure:
To 130 ml of methylene chloride are added 12.69 g of Compound 1 obtained in the above step (1) and 2.4 ml of triethylamine, and a solution of 10.5 ml of trichloroacetyl chloride in 30 ml of methylene chloride is dropwise added with ice cooling and under stirring over a period of 7 minutes. The reaction mixture is stirred at room temperature for 20 minutes, mixed with saturated saline, made weakly alkaline with aqueous ammonia and the organic layer is separated. The aqueous layer is shaken with methylene chloride. The organic layers are combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The residue is chromatographed on a silica gel column, eluting with 10% methanol/methylene chloride. The product is recrystallized from ethyl acetate to give 24.21 g of the titled compound 2. Yield: 96% mp.: 157° to 159° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:32])[CH2:17][CH2:16][CH2:15][CH:14]2[NH:18]C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br>C(O)(=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:32])[CH2:17][CH2:16][CH2:15][CH:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cc1F
Agent: Br
Solvent: CC(=O)O
Product: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1N
Temperature: 90 °C

Procedure:
To a solution (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}-2-methylcyclopentyl)carbamate (0.533 g, 1.16 mmol) in acetic acid (4 ml) was added HBr (6 M, 0.98 ml, 5.80 mmol). The reaction was sealed and heated at 90° C. for 24 hours. To this was then added further HBr (6 M, 0.50 ml, 3.00 mmol) and the reaction was heated at 90° C. for a further 6 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by SCX chromatography (2M ammonia in methanol) and then concentrated in vacuo. The crude product was further purified by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: C1(O)CCC1.[CH3:6][C:7]1([CH3:24])[CH:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18]CC2)=[O:13])[CH:8]1[C:21]([OH:23])=[O:22].[CH3:25][C:26]1(C)[CH:28](/C=C\C(O)=O)[CH:27]1C([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:24][C:7]1([CH3:6])[C@@H:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18]2)=[O:13])[C@H:8]1[C:21]([O:23][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:22]
Reactant: CC1(C)C(/C=C\C(=O)O)C1C(=O)[O-]
Reactant: CC1(C)C(/C=C\C(=O)OC2CCCCC2)C1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: OC1CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC2CCC2)C1(C)C

Procedure:
1.7 ml of cyclobutanol were added to a solution of 4 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 20 ml of methylene chloride and 3.45 g of dicyclohexylcarbodiimide and a solution of 28 mg of 4-dimethylamino-pyridine in 20 ml of methylene chloride were added thereto at 0° to 5° C. with stirring. The mixture was stirred for 2 hours at 5° C. and 2 hours at room temperature and was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 n-hexane-isopropyl ether mixture yielded 2.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclobutoxycarbonyl)-ethenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:5]2[NH:6][CH:7]([C:14]3[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=3)[CH2:8][CH:9]([C:10]([F:13])([F:12])[F:11])[N:4]2[N:3]=1>CO>[Br:1][C:2]1[CH:21]=[C:5]2[NH:6][C@H:7]([C:14]3[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=3)[CH2:8][C@H:9]([C:10]([F:11])([F:12])[F:13])[N:4]2[N:3]=1
Reactant: Cc1nn(C)cc1C1CC(C(F)(F)F)n2nc(Br)cc2N1
Solvent: CO
Product: Cc1nn(C)cc1[C@@H]1C[C@H](C(F)(F)F)n2nc(Br)cc2N1

Procedure:
The racemic 2-bromo-5-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.5 g, 4.1 mmol, Preparation 8) was dissolved in methanol (35 mL) and the cloudy solution was gently warmed providing a clear solution. The solution was then filtered through a medium porosity Buchner funnel. The clear filtrate was directly used for chiral HPLC purification. 1 mL of this solution was loaded onto a 2.1 cm×25 cm Chiralcel OD column and eluted with a mobile phase comprising of isopropyl alcohol and methanol (1:1 ratio) at a flow rate of 15 mL/min. The two (R and S) enantiomers were collected separately. 27 such injections were carried out and the pooled fractions of pure (R and S) enantiomers were concentrated under reduced pressure. The title compound was isolated as a white powder (0.71 g, 1.95 mmols, >95% ee).
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[F:15])/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=O.[NH:17]([C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:18]([NH2:20])=[NH:19]>O(CCO)C>[F:15][C:4]1[C:5]([C:7]2[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=2[CH3:14])=[N:19][C:18]([NH:17][C:21]2[CH:22]=[C:23]([S:27]([NH2:30])(=[O:28])=[O:29])[CH:24]=[CH:25][CH:26]=2)=[N:20][CH:3]=1
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CNc1nc(C)c(C(=O)/C(F)=C/N(C)C)s1
Solvent: COCCO
Product: CNc1nc(C)c(-c2nc(Nc3cccc(S(N)(=O)=O)c3)ncc2F)s1
Temperature: 140 °C

Procedure:
A mixture of (Z)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (1 mmol) and 3-guanidinobenzenesulfonamide (2 mmol) in 2.5 mL 2-methoxylethanol was heated at 140° C. for 45 minutes under microwave radiation. The mixture was purified by column chromatography using EtOAc/PE or EtOAc/MeOH to yield the titled compound as yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CS(O[CH:12]([C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27]([CH2:28][C@@H:29]([O:46]C4CCCCO4)[CH2:30][C@@H:31]2[O:39]C2CCCCO2)=[CH:26][CH:25]=3)[CH2:22][CH2:21]1)[CH3:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=O)=O.Cl>O1CCCC1.O>[CH3:17][CH:15]([CH2:14][CH2:13][CH2:12][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27]([CH2:28][C@@H:29]([OH:46])[CH2:30][C@@H:31]2[OH:39])=[CH:26][CH:25]=3)[CH2:22][CH2:21]1)[CH3:19])[CH3:16]
Reactant: CC(C)CCC(OS(C)(=O)=O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 0.10 g of lithium aluminum hydride in 5 ml of tetrahydrofuran was added 0.66 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate under heating and the mixture was refluxed for 2 hours. The resulting reaction mixture was cooled and, then, water and diluted hydrochloric acid were added in succession. The mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with diethyl ether. The extract was washed with diluted hydrochloric acid and aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off and the residue was purified by silica gel column chromatography and recrystallized from methanol. The procedure yielded 0.18 g of cholesta-5,7-diene-1α,3β-diol (yield: 45%) showing the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH:11]([S:19](Cl)(=[O:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH:11]([S:19]([N:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)(=[O:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(Cc1ccccc1)S(=O)(=O)Cl)OCc1ccccc1
Reactant: CC1CCNCC1
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)C(CC(=O)OCc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
The product from Step H (0.92 g, 2.6 mmol) was taken up in DCM (25 mL) with stirring and cooled to 0° C. TEA (362 μL, 2.6 mmol) and 4-methyl-piperidine (307 μL, 2.6 mmol) were added and the reaction warmed to room temperature and stiired overnight. The reaction was diluted with DCM and washed successively with water, 1 M HCl, water, brine, dried, filtered and concentrated in vacuo to give a yellow oil. This was purified by silica gel column chromatography eluting with hex /EtOAc 8:2 to give the titled compound as a yellow oil (440 mg, 41%). 1H-NMR δ (CDCl3) 7.40-7.18 (10H, m), 5.0 (1H, d, J=12.2 Hz), 4.95 (1H, d, J=12.2 Hz), 3.9 (1H, m), 3.68 (2H, m), 3.42-3.31 (1H, dd, J=4.4, 14.1 Hz), 2.91-2.80 (1H, dd, J=5.9, 17.1 Hz), 2.79-2.62 (3H, m), 2.58-2.47 (1H, dd, J=6.2, 17.1 Hz), 1.69-135 (2H, m), 1.30-1.10 (3H, m) and (3H, d, J=6.2 Hz).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C=CC([N-:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:31]([OH:33])=O)=[CH:29][N:30]=2)=[CH:22][CH:21]=1>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:31]([C:28]1[S:27][C:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)=[N:30][CH:29]=1)=[O:33]
Reactant: O=C(O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C(C=Cc1ccc(Cl)cc1Cl)[N-]CCCCO
Product: O=C(NCCCCO)c1cnc(-c2ccc(Cl)cc2)s1
Yield: 95 %

Procedure:
2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid (4-hydroxy-butyl)-amide (19A) is prepared as described for 17A starting with 2-(4-Chloro-phenyl)-thiazole-5-carboxylic acid.
Reaction SMILES: ClC1C=CC([C@@H]([N:10]2[C:22]3[C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[C:12]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:13]=[C:14]([F:27])[CH:15]=3)C)=CC=1.[CH3:32]O>[Pd]>[CH3:32][O:26][C:24](=[O:25])[CH2:23][C@@H:21]1[C:22]2[NH:10][C:11]3[C:16](=[CH:15][C:14]([F:27])=[CH:13][C:12]=3[S:28]([CH3:31])(=[O:29])=[O:30])[C:17]=2[CH2:18][CH2:19][CH2:20]1
Reactant: C[C@@H](c1ccc(Cl)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O
Reactant: CO
Agent: [Pd]
Product: COC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid ([α]D=−226° in MeOH) in MeOH (0.1M) was added 10% palladium on carbon (10% wt/wt). A stream of N2 was bubbled through the mixture for 5 min. The reaction was stirred at rt under H2 atmosphere (balloon) for 24 hrs and filtered through a celite pad eluted with CH2Cl2. The solvents were removed by evaporation under reduced pressure and the residue was swished in MeOH to give the title compound.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>O>[C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1oc(-c2ccccc2)cc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-acetyl-3-hydroxy-6-phenyl-4H-pyran-4-one (0.53 g), potassium carbonate (0.40 g), benzyl bromide (0.27 mL) and DMF (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH3:19])=[O:17].NCC(O)=O>C1COCC1>[CH3:19][O:18][C:16]([NH:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@@H](N)CO
Agent: NCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](CO)C(C)C
Temperature: -20 °C

Procedure:
39.7 g (0.385 mol) of D-valinol (Aldrich) are dissolved under nitrogen in 500 ml of dry THF. 58.7 ml (0.424 mol) of triethylamine are added, the mixture is cooled to -20° C. and 32.8 ml (0.424 mol) of methyl chloroformate (Aldrich) are added dropwise to the mixture with stirring. The mixture is subsequently stirred at this temperature for 30 minutes and then brought to room temperature. 60 g (0.078 mol) of glycine are added and the mixture is stirred once more for 15 minutes. The precipitate is filtered off with suction, the filtrate is concentrated and the residue is taken up in diethyl ether. The organic phase is washed with 1N HCl, saturated NaHCO3 solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated, and the residue is dried in a high vacuum.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: NCCCCN
Reactant: O=P(O)(O)CCl
Solvent: O
Product: NCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (7.0 g, 53.6 mmoles) and 1,4-diaminobutane (30.0 g, 340 mmoles) were heated under reflux in water (200 cm3) for 20 hours. The water was then distilled off and acetone (110 cm3) was added. The phosphonic acid was filtered off and dried. The crude yield was 9.8 g (91%). A sample was purified by recrystallization from water/ethanol to give N-(4-aminobutyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 258° C.