Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][CH2:14][CH2:15]O.O>CCOCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[S:11][CH2:15][CH2:14][CH2:13][N:12]=1
Reactant: NCCCO
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1NC1=NCCCS1
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
2,6-Dimethylphenylisothiocyanate (15.0 g, 0.093 mole) was added to 3-amino-1-propanol (6.9 g, 0.093 mole) in 60 ml of ether, and the mixture was heated to reflux for 0.5 hr. After the ether was evaporated, 60 ml of concentrated hydrochloric acid was added and refluxing was continued for 0.5 hr. The cooled reaction mixture was treated with 60 ml of water and filtered. The filtrate was made basic with dilute sodium hydroxide, and the precipitate was collected by filtration and washed with water. Recrystallization from ethanol-water (charcoal) gave 16.3 g (80%) of xylazine, m.p. 136°-138° C. (lit. m.p. 140°-141° C.). This step was run three times with yields ranging from 80 to 93%.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH2:8]=[O:9]>C(Cl)(Cl)Cl>[CH3:6][C:5]1([CH3:7])[CH2:4][C:2](=[O:1])[CH2:3][CH2:8][O:9]1
Reactant: C=O
Reactant: CC(=O)C=C(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)CCO1
Temperature: 165 °C
Reaction time: 16 h

Procedure:
Mesityl oxide (11.6 mmol) and aqueous formaldehyde (11.6 mmol) were combined and heated at 165° C. for 2 hours. The reaction mixture was cooled, partitioned between ethyl acetate and brine, dried over sodium sulfate and evaporated to an oil. The crude reaction product was subjected to flash column chromatography (silica gel) eluting with ethyl acetate-hexane (1:9) to give an oil. The oil was dissolved in chloroform (250 ml), amberlyst 15 resin (11 g) was added and the mixture stirred for about 16 hours. Filtration and evaporation yielded the crude product which was subjected to flash column chromatography (silica gel) eluting with diethyl ether-hexane (1:9) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Cl.ClC[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (7 ml) was treated with TEA (0.49 ml, 3.52 mmol) and 2-(chloromethyl)pyridine hydrochloride (145 mg, 0.89 mmol), and stirred at RT for 48 h. Catalytic amount of KI was added and the reaction was stirred at RT overnight. The mixture was then washed with water and brine, dried and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.2) to give (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (136 mg).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:22][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: N[C@@H]1CCc2ccccc21
Product: O=[N+]([O-])c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 92.9 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.89 g, 12.0 mmol; HPLC: 4.446 min) and commercially available (R)-(−)-1-aminoindane (1.54 mL, 12.0 mmol; HPLC 0.4 min) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (3.45 g, 93%; HPLC 1.954 min), MS (ISN) m/e=308.5 [(M−H)−].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:20](=[O:22])[NH2:21])([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.O>[Pd].C1(C)C=CC=CC=1>[O:22]=[C:20]1[C:11]2([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[N:21]1
Reactant: NC(=O)C1(N2CCCCC2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N=C2CCCCN2C12CCNCC2
Yield: 70 %

Procedure:
A mixture of 10 g of 1-benzyl-4-carbamoyl-4-piperidino-piperidine, 3 g of 5% palladium-on-charcoal catalyst and 100 ml of water is boiled under reflux for 8 hours, while the toluene formed is removed. The reaction mixture is then cooled, and the catalyst is removed by filtration. The filtrate is concentrated to 10 ml under reduced pressure and is allowed to stand. The precipitated crystals are collected by filtration, dried and recrystallized from chloroform to give 2,3,5,6,7,8-hexahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine as colorless crystals, m.p. 220° C., 70% yield.
Reaction SMILES: [OH:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[H-].[Na+].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:23]
Reactant: COC1C=CC(Br)=CC1(O)Cc1cnccn1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1C=CC(Br)=CC1(Cc1cnccn1)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of 2-(1-hydroxy-2'-methoxy-5'-bromo-benzyl)pyrazine were dissolved in 15 ml of methylene chloride. At 0° C., 0.2 g of NaH were added, resulting in the evolution of a gas and formation of a precipitate. 0.4 ml of trimethylacetyl chloride were added in one portion. The reaction mixture was stirred at room temperature overnight. The solvent was then stripped from the reaction mixture, and the residue was extracted with ice water and methylene chloride. The methylene chloride layer was washed with water, dried (MgSO4), filtered and stripped of the solvent to yield 0.9 g of 3-(1-trimethylacetoxy-2'-methoxy-5'-bromobenzyl)-pyrazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/N2CCCC2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C@H:24]([OH:26])[CH3:25])[CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:24]([OH:26])[CH3:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6]2[C:7]=1[CH:8]=[CH:9][N:11]=[N:10]2
Reactant: C#Cc1c(Cl)cc([C@@H](C)O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Solvent: Clc1ccccc1Cl
Product: C[C@@H](O)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 154.5 °C
Reaction time: 1.42 h

Procedure:
A solution of (1R)-1-(4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-yl}ethanol (20 g, 54 mmol, ˜70% pure by HPLC) [CAUTION: this material was shown to exhibit a large energy release in its solid state during DSC analysis. Care should be taken in heating up this material in solution as an mild exotherm was observed in the initial heating of this reaction] in 1,2-dichlorobenzene (500 mL) was degassed with nitrogen for 10-15 minutes. The reaction mixture was heated in an oil bath that was pre-heated to 154-155° C. After 80-90 minutes, the heating was discontinued and the reaction mixture was cooled to room temperature, diluted with hexanes (500 mL), and stirred. Solid precipitated and settled at the bottom of the flask. The upper clear solution was filtered under vacuum through a pad of silica gel (30 g) packed in a filter funnel. The solid was rinsed with hexanes (100-200 mL) and the solution was filtered. The silica gel was mixed with the solid, diluted with dichloromethane (250 mL), and concentrated to dryness for solid loading flash column purification. The crude material adsorbed on silica gel was purified by flash column chromatography using ethyl acetate in hexanes (0 to 40% in 12 column volumes and then at 40% for 8 column volumes) to give the desired product (yields ranged from 5.6 to 7 g) as a brown foam. LCMS for C16H13ClFN2O (M+H)+: m/z=303.1; Found: 303.0; 1H NMR (300 MHz, CDCl3): δ 9.41 (d, J=6.2 Hz, 1H), 8.22-8.19 (m, 2H), 7.50-7.42 (m, 1H), 7.21-6.99 (m, 3H), 5.07-4.99 (m, 1H), 2.14-2.08 (m, 1H), 1.46-1.42 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:49][N:50]([CH3:55])[C:51](=[O:54])[CH:52]=[CH2:53].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:26][C:23]1[CH:24]=[CH:25][C:11]2[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2](/[CH:53]=[CH:52]/[C:51]([N:50]([CH3:55])[CH3:49])=[O:54])=[CH:3][CH:4]=3)=[O:9])=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[S:13][C:12]=2[CH:22]=1
Reactant: O=C(c1ccc(Br)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a screw cap seal tube is added 0.84 g (2.0 mmol) of the product from Example 2, 0.20 g (0.66 mmol) of tri-o-tolylphosphine, 0.21 g (2.1 mmol) of N,N-dimethyl acrylamide, 0.040 g (0.2 mmol) of palladium acetate, 40 mL of acetonitrile and 4 mL of triethylamine. The solution was purged with nitrogen then capped and heated to 85° C. for 3 hours. At the end of this time, the solution was concentrated, then taken up in 100 mL of water:ethyl acetate (1:2). The organic layer was separated and the water layer extracted once with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated an the residue subjected to column chromatography on silica. Elution with 50% ethyl acetate:hexane then ethyl acetate:hexane:isopropanol (60:35:5) yielded 0.63 g of product which was crystallized from chloroform:acetone:hexane to yield 0.47 g of product as a yellow solid, m.p. 208°-211° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])OCC[O:11]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[CH3:15])[CH3:2]
Reactant: CCOC(=O)CN(CCCC1(C)OCCO1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CN(CCCC(C)=O)C(=O)OC(C)(C)C

Procedure:
To a solution of 2-5 (35 g, 0.1 mol) in 600 mL acetone was added p-toluenesulfonic acid (1 g). The mixture was heated at reflux for 2 h. After cooling, the mixture was evaporated to one-fifth its initial volume, diluted with EtOAc and then washed with sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 2-6 as a yellow oil. TLC Rf =0.31 (silica, 30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 4.20 (m, 2H), 3.92 (s, 0.85H), 3.83 (s, 1.15 H), 3.3 (m, 2H), 2.52 (m, 2H), 2.14 (s, 3H), 1.78 (m, 2H), 1.51-1.42 (3s, 9H), 1.28 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]1([C@H:45]([NH2:47])[CH3:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[NH:47][C@@H:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:46])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C(=O)N[C@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (0.60 g, 2.32 mmol) and HATU (1.06 g, 2.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then (R)-1-phenylethanamine (0.28 g, 0.3 mL, 2.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.839 g, 99.9% yield): HPLC retention time: 2.17 min (method A). MS (ESI) (M+H)+ 362/364.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.O.O.O.O.O.O.O.O.O.[S-2:41].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[SH:41])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S)n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (400 mg, 0.781 mmol, intermediate 14) in DMF (10 mL) was added sodium sulfide nonahydrate (375 mg, 1.563 mmol). The reaction was stirred at 85° C. for 16 h. The mixture was cooled, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (230 mg, 63.4%) as orange oil. LCMS retention time 1.517 min; LCMS MH+-THP 381.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.I[CH2:27][CH:28]1[CH2:32][CH2:31][C:30]2([O:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:29]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:27][CH:28]1[CH2:32][CH2:31][C:30]2([O:33][CH2:34][CH2:35][CH2:36][O:37]2)[CH2:29]1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCC2(C1)OCCCO2
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 76.7 %

Procedure:
A solution of diisopropylamine (2.5 mL, 17.80 mmol) in dry tetrahydrofuran (26 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (7.1 mL, 17.80 mmol). The reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (prepared as in Example 1, 3.00 g, 13.69 mmol) in dry tetrahydrofuran (26 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL). The reaction mixture turned dark yellow in color and was allowed to stir at −78° C. for 10 min and then at 0° C. for 30 min. The reaction mixture was then cooled to −78° C., at which time, a solution of 2-iodomethyl-6,10-dioxa-spiro[4.5]decane (5.79 g, 20.54 mmol) in dry tetrahydrofuran (13 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was added dropwise. The reaction mixture stirred at −78° C. for 15 min, and was then allowed to warm to 25° C., where it was stirred for 20 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×200 mL), water (200 mL) and a saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 15% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (3.92 g, 77%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC(F)(F)F)N1CCC(F)(F)CC1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a white foam (85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>COCCOC.C([O-])([O-])=O.[Na+].[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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([CH3:34])[CH:32]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
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: COCCOC
Product: COc1ncc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cc1C
Temperature: 80 °C
Yield: 40.3 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.15 g, 0.41 mmol), 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.15 g, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.024 g, 0.02 mmol) in 1,2-dimethoxyethane (2.46 mL), aqueous saturated Na2CO3 (410 uL) was added. The reaction mixture was stirred and heated at 80° C. for 18 hours under N2 atmosphere. The reaction mixture was diluted with 1,2-dimethoxyethane, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.075 g, 40%). ESI-MS m/z calc. 453.44. found 454.5 (M+1)+. Retention time 2.24 minutes.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]=[N+]=[N-])[CH:13]=2)[N:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=2)[N:6]=1)=[O:4]
Reactant: CNC(=O)c1nc(-c2cccc(CN=[N+]=[N-])c2)cnc1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(CN)c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
3-Amino-6-(3-azidomethyl-phenyl)-pyrazine-2-carboxylic acid methylamide was dissolved in the mixture of THF (15 mL) and H2O (1.5 mL) followed by the addition of triphenylphosphine (1.07 g, 4.03 mmol) and it was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×50 mL) then dried over anhydrous sodium sulfate and filtered, concentrated and purified by column chromatography (50% Ethylacetae/hexanes) to give 3-amino-6-(3-aminomethyl-phenyl)-pyrazine-2-carboxylic acid methylamide, 564 mg (85.0% yield): MS (EI) for C13H15N5O: 258.13 (MH+).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:11][C:12]1([CH3:19])[O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:10][C:9]1[C:4]([O:18][CH2:17][CH:15]2[CH2:14][O:13][C:12]([CH3:19])([CH3:11])[O:16]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)OCC(COc2nccnc2Cl)O1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
9.6 g of sodium hydride are added in portions, whilst stirring, to a solution of 59.6 g of 2,3-dichloropyrazine and 52.8 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane in 500 ml of hexamethylphosphoric acid triamide at 0°-5° C. (duration of the addition: 40 minutes). The reaction mixture is then stirred for 40 hours at room temperature after which it is poured onto an ice-water mixture. The aqueous phase is extracted with diethyl ether. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated under a waterpump vacuum. 4-(2-Chloro-3-pyrazinyloxymethyl)-2,2-dimethyl-1,3-dioxolane is obtained as an oily residue.
Reaction SMILES: [ClH:1].Cl.N[C@@H]1CCN(C2CCCCC2(C(C2C=CC3C(=CC=CC=3)C=2)C)O)C1.[OH:28][C:29]1([CH:35]([C:51]2[CH:60]=[CH:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:52]=2)[C:36]([N:38]2[CH2:42][CH2:41][C@@H:40]([NH:43]C(=O)OC(C)(C)C)[CH2:39]2)=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:1].[ClH:1].[NH2:43][C@@H:40]1[CH2:41][CH2:42][N:38]([CH2:36][CH:35]([C:29]2([OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:51]2[CH:60]=[CH:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:52]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Agent: CC(c1ccc2ccccc2c1)C1(O)CCCCC1N1CC[C@@H](N)C1
Agent: Cl
Product: N[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-[2-[(3R)-3-aminopyrrolidin-1-yl]-1-(2-naphthyl)ethylcyclohexanol dihydrochloride was prepared from tert-butyl {(3R)-1-[(1-hydroxycyclohexyl)(2-naphthyl)acetyl]pyrrolidin-3-yl}carbamate. MS (ESI) m/z 339; HRMS: calcd for C22H30N2O+H+, 339.24309; found (ESI, [M+H]+), 339.243.