Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(O)(C2C=CC=CC=2)C(OCC2CCN(CCCCCC=O)CC2)=O)CCCCC1.[CH:32]1([C:38]([OH:65])([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]([O:41][CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]3OCCO3)[CH2:45][CH2:44]2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O1[C:70]2([CH2:75][CH2:74][NH:73][CH2:72][CH2:71]2)[O:69]CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:32]1([C:38]([OH:65])([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]([O:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][N:73]3[CH2:74][CH2:75][C:70](=[O:69])[CH2:71][CH2:72]3)[CH2:47][CH2:48]2)=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(OCC1CCN(CCCCCC2OCCO2)CC1)C(O)(c1ccccc1)C1CCCCC1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=CCCCCCN1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(CCCCCCN2CCC(COC(=O)C(O)(c3ccccc3)C3CCCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (1-(6-oxohexyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (prepared as Preparation intermediate 15 but using (1-(5-(1,3-dioxolan-2-yl)pentyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (0.20 g, 0.47 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.133 g, 0.93 mmol) in THF (5 mL), sodium triacetoxyborohydride (0.294 g, 1.39 mmol) was added. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was partitioned between DCM and saturated aqueous sodium hydrogen carbonate. The organic phase was removed, and the aqueous phase was extracted with further DCM. The combined organics were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude product was dissolved in THF (2 mL) and 2M aqueous HCl and heated at 60° C. for 18 hours. The reaction mixture was allowed to cool to RT and then quenched with saturated aqueous sodium hydrogen carbonate. The mixture was extracted twice with ethyl acetate. The organic phases were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was isolated (0.193 g, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1>>[CH3:9][C@H:10]1[N:15]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1
Reactant: O=Cc1cccnc1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1Cc1cccnc1
Yield: 58 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(3R)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5, to give 6-[(3R)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 58% yield.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH:26]=[O:27])[C:24]=1F)[C:20]#[N:21].O>C(#N)C>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:24]2[C:23]([CH:26]=[O:27])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:16])[CH2:5][C@@H:6]([CH3:8])[O:7]1
Reactant: N#Cc1cc(F)c(F)c(C=O)c1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2c(F)cc(C#N)cc2C=O)C[C@@H](C)O1
Temperature: 80 °C
Yield: 103.5 %

Procedure:
(2R,6R)-2,6-dimethylmorpholine (8.0 g, 70.0 mmol) followed by triethylamine (13.7 mL, 98.0 mmol) is added slowly to a solution of commercially available 3,4-difluoro-5-formylbenzonitrile (11.1 g, 66.7 mmol) in acetonitrile (500 mL) at room temperature. The mixture is warmed to 80° C. for 16 hours. After allowing to cool to room temperature, water (500 mL) is added and the mixture extracted twice with ethylacetate (250 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (18.1 g): LCMS (M+H) 262.3.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][CH:21]1[NH:22][CH2:23][CH2:24][N:25]([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:26]1
Reactant: CC1CNCCN1
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Product: CC1CN(c2nccnc2OCC2COc3ccccc3O2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and 2-methylpiperazine (293 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (64%) of the title product. HRMS m/z calcd for C18H22N4O3 (M)+ 342.1692, found 342.1678. Anal. (C18H22N4O3) H, N; C: calcd, 63.14; found, 62.30.
Reaction SMILES: [F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14](O)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1.COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14]([F:38])[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (370 mg, 0.95 mmol) in DCM (10 mL) was added deoxo-Fluor® (50% solution in THF, 1.0 mL, 2.37 mmol) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution (10 mL) was added slowly and the mixture was stirred for 15 min. The aqueous layer was extracted with DCM (10 mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-fluoro-1,4-diazepane-1-carboxylate as a pale green gum (366 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.34-6.00 (m, 1H), 5.08-2.75 (m, 11H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].CO.Br[CH2:11][C:12](=O)[C:13]([O-:15])=[O:14].CO[CH2:19][CH2:20]OC>>[N:7]1[CH:11]=[C:12]([C:13]([O:15][CH2:19][CH3:20])=[O:14])[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: Nc1cnccn1
Reactant: O=C([O-])C(=O)CBr
Reactant: COCCOC
Solvent: CO
Product: CCOC(=O)c1cnc2cnccn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL×3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[C:7]([Cl:13])[CH:6]=2.[C:14]1(S(OCC)(=O)=O)C=CC=C[CH:15]=1>[OH-].[Na+]>[ClH:13].[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:12][CH2:14][CH3:15])=[CH:9][CH:8]=[C:7]([Cl:13])[CH:6]=2
Reactant: Nc1cnc2cc(Cl)ccc2c1S
Reactant: CCOS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCSc1c(N)cnc2cc(Cl)ccc12
Product: Cl
Reaction time: 2 h
Yield: 174.4 %

Procedure:
21.06 g (0.1 mole) of 3-amino-7-chloro-4-quinoline-thiol are dissolved in 100 ml of a 2 molar sodium hydroxide solution, whereupon 23.30 g (0.125 mole) of ethyl benzene sulfonate are added. The reaction mixture is heated to boiling for 2 hours and the product thus formed is extracted with chloroform. The chloroform solution is clarified with activated charcoal, dried and acidified with alcohol containing hydrogen chloride. Thus 24.0 g of 3-amino-4-ethylthio-7-chloro-quinoline-hydrochloride are obtained. After crystallization from methanol the product melts at 212°-216° C. under decomposition. Yield 85%. The product thus obtained is identical with the compound prepared according to Example 5.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:27][CH2:26][CH2:25][C:13]3([CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[ClH:4].[ClH:4].[ClH:4].[N:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:27][CH2:26][CH2:25][C:13]3([CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccncc3)C2)C1
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: c1cc(N2CCCC3(CCNC3)C2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The synthesis was carried out analogously to the synthesis of amine AMN-07. For this, in step (i) tert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylate was reacted with 4-chloropyridinium chloride (yield: 53%). The Boc protective group was then split off. In step (ii), ethanol (8 ml) and acetyl chloride (0.37 ml, 5.355 mmol) were added to tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.5]decane-2-carboxylate (0.34 g, 1.071 mmol) and the mixture was stirred at room temperature for 12 h. When the reaction was complete, the solvent was removed in vacuo. Yield: 0.28 g (80%)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42]N)[CH:38]=[C:39]([CH3:41])[CH:40]=1.C[N:45](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[C:39]([CH2:41][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:32][CH3:33])[C:21]([C:23]2[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH2:45])=[O:27])[CH:24]=2)=[O:22])[CH:38]=[C:37]([CH3:42])[CH:36]=1
Reactant: Cc1cc(Br)cc(CN)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cc(C)cc(Br)c1)C(=O)c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (1000 mg, 2.05 mmol), [(3-bromo-5-methylphenyl)methyl]amine (605 mg, 2.25 mmol), HBTU (932 mg, 2.45 mmol) and Et3N (0.57 mL, 4.10 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(3-bromo-5-methylphenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as an oil (652 mg, 50%). LC-MS m/z 634 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH2:21]([N:24]([CH2:37][CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH2:22][CH3:23].N>ClCCl.C1CCCCC1.CO>[CH2:37]([N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=3[C:8](=[O:16])[NH:7][C:6]3[CH:17]=[CH:18][CH:19]=[N:20][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Reactant: Cc1ccc2c(c1)N(C(=O)Cl)c1ncccc1NC2=O
Agent: N
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3cc(C)ccc3C(=O)Nc3cccnc32)CC1
Yield: 63 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-1-yl]ethanamine in a yield of 63% of theory. Colourless crystals, m.p. 195° C. (D.), RF =0.5 (Macherey-Nagel, Polygram® SIL G UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/15/2 v/v).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CC1C=CC(S(O[CH2:42][C@@H:43]2[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]2)(=O)=O)=CC=1.[I-].[Na+].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][C:45]1([CH3:49])[O:44][C@H:43]([CH2:42][N:21]2[CH2:22][CH2:23][C:17]3[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)[CH2:47][O:46]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C[C@@H]2COC(C)(C)O2)C3)cc1
Yield: 64.7 %

Procedure:
A solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (jk) (270 mg, 0.69 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (377 mg, 132 mmol), sodium iodide (104 mg, 0.69 mmol), DIPEA (0.48 mL, 2.8 mmol), and DMF (1.0 mL) was heated at 110° C. for 22 h. The mixture was partitioned between ethyl acetate and sat. NaHCO3. The phases were separated, and the aqueous layer extracted with ethyl acetate (2×). The combined organic phases were dried over Na2SO4, filtered and concentrated onto Celite, and the residue chromatographed: ISCO 12 g column 0-20% IPA in DCM to afford 228 mg (64%) of the title compound jz as an off-white solid: LC-MS: m/z=+511 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:15]2[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=3)=[C:18]([CH2:19][OH:20])[O:17][N:16]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (5.8 g, 15.6 mmol) in THF (39 mL) was added a solution of lithium hydroxide monohydrate (762 mg, 31.2 mmol) in water (36 mL) and MeOH (10 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified with HCl (1 N, 30 mL) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to afford the title compound (660 mg, 12%) which was obtained as a white solid. MS: m/e=343.0 [M−H]−.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16]C(C)(C)C)(=[O:15])[CH3:14].[CH:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[NH4+].[F-]>CCCCCC.C(OCC)C>[OH:26][C@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][C:13]([OH:16])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)CC=O
Agent: [F-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)C[C@@H](O)CC(=O)O
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
4.4 ml of 1.6M butyllithium in hexane are added under argon and at -25° C. to a solution of 1.12 ml of diisopropylamine in 15 ml of anhydrous diethyl ether (ether). After 25 minutes at -20° C., the mixture is cooled to -78° C. and 805 μl of tert-butyl acetate are added dropwise in the course of 10 minutes by means of a syringe. After stirring for 45 minutes at -78° C., a freshly prepared solution, precooled to -78° C., of 4.9 g of [(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-bis-(diphenylmethoxy)]-cyclopentadienyltitanium chloride (according to Example 2a) in approx. 100 ml of ether is added via a cannula in the course of 15 minutes. The mixture is stirred for 30 minutes at -78° C. and for 3 hours at -30° C. and cooled to -78° C. and 650 μl of isovaleraldehyde are added by means of a syringe in the course of 5 minutes. After 2 hours at -78° C., 20 ml of 45% NH4F solution are added and the mixture is warmed to room temperature. After stirring for 17 hours it is filtered, 10 ml of saturated sodium chloride solution are added to the filtrate and the mixture is extracted with three times 100 ml of ether. The organic phases are washed with saturated NaCl solution and 1N Hcl, dried (MgSO4) and evaporated. The residue (5.1 g) is stirred in 6 ml of 2N sodium hydroxide solution and 12 ml of methanol for 2 hours at 50° C. After the methanol has been removed by evaporation in vacuo, the residue is extracted with three times 50 ml of ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with three times 100 ml of ethyl acetate. The ethyl acetate phases are washed with twice 50 ml of saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue, 835 mg of 1-(R)-3-hydroxy-5-methylhexanoic acid of 78% optical purity, is recrystallized twice from cyclohexane (60 ml and 150 ml). Yield: 595 mg of product of 96% optical purity, melting point 86° C.; [α]D =-14.7° (c=1, CHCl3). (+)-(R)-Ipsenol can be prepared from this by the instructions in EP-A 0,254,685 (Example 41d to 41g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C@@H:42]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1)[CH2:43][OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:10][CH2:9]2)=[N:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:41][C@@H:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:43][OH:44])=[C:24]([F:31])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)CC1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To 4-(3-amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (222 mg, 0.516 mmol) was added DMSO (4 mL), Hünig's base (0.450 mL, 2.58 mmol), (S)-2-amino-2-(3-chlorophenyl)ethanol (133 mg, 0.774 mmol) and then HATU (392 mg, 1.031 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 50 mL of ethyl acetate, washed with water twice, saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue. The crude was purified by flash chromatography using 12 gram column (solid load) eluting with 10-95% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give 252 mg of product (which is 2:1 trans to cis ratio), used as is (83% over two steps). LCMS (m/z): 584.3 (MH+), 0.91 min for both.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Reactant: CCCCCBr
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(/C=C/c2nc3sccn3c2C(=O)OCC)cccc1OC(F)F
Yield: 100.2 %

Procedure:
Alkylation of Intermediate 6 (400 mg, 1.052 mmol) with 1-bromopentane (157 mg, 1.262 mmol) in presence of potassium carbonate (160 mg, 1.157 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A gave 475 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J=7.2 Hz, 3H), 1.30-1.40 (m, 5H), 1.44-1.52 (m, 2H), 1.72-1.78 (m, 2H), 3.93 (t, J=6.6 Hz, 2H), 4.40 (q, J=6.9 Hz, 2H), 7.19 (t, J=73.8 Hz, 1H), 7.21-7.30 (m, 2H), 7.43-7.49 (m, 1H), 7.53-7.58 (m, 1H), 7.77 (d, J=16.2 Hz, 1H), 7.86 (d, J=16.2 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 451.19 (M+H)+.
Reaction SMILES: [C]=O.[H][H].[CH3:5][C:6]1[C:11]2CO[C:14](=[O:15])[C:10]=2[C:9](O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=[C:8]([CH2:29]/C=C(/CCC(O)=O)\C)[C:7]=1OC.C(C1CC2CC1CC2C=O)=[O:41]>>[CH:14]([CH:10]1[CH2:9][CH:8]2[CH2:29][CH:11]1[CH:6]([CH:5]=[O:41])[CH2:7]2)=[O:15]
Reactant: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: O=CC1CC2CC1CC2C=O
Reactant: [H][H]
Agent: [C]=O
Product: O=CC1CC2CC(C=O)C1C2
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Next, the inside of the autoclave was sufficiently substituted by nitrogen, and then sufficiently substituted by a gas mixture having a volume ratio of carbon monoxide to hydrogen of 50/50. The same gas was injected until a pressure in the autoclave reached 0.6 MPaG, and the adjustment liquid was heated to 100° C. under stirring, thereby initiating a hydroformylation reaction. Since the pressure in the autoclave decreased with proceeds of the reaction, the gas mixture was continuously supplied so that the pressure was maintained at 0.6 MPaG, the temperature was adjusted so as to be maintained at 100° C., and the hydroformylation reaction was carried out for 6 hours. After the completion of the reaction, the gas mixture in the system was purged using nitrogen, and 280.1 g of a reaction liquid including 2,5-bisformyl bicyclo[2.2.1]heptane and 2,6-bisformyl bicyclo[2.2.1]heptane was obtained. An analysis showed that the reaction liquid contained 266.1 g (1.76 mol) of the compounds.