Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(CC)CC)C>C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:15]2[C:10]([N:9]=1)=[N:11][CH:12]=[CH:13][CH:14]=2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.023 ml) was added in one portion to a stirred solution of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.069 ml) in THF (40 ml). The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. The product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness and the resulting solid was triturated overnight with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-methoxy-ethanone (80 mg) as a solid. Mass spectrum: M+H+ 434; RT 2.23 min
Reaction SMILES: O.NN.Cl.[NH:5]1[CH2:9][CH2:8][N:7]=[C:6]1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([N+:20]([O-])=O)=[CH:15][CH:16]=2)[CH2:11]1>[Ni].C(O)C>[NH:7]1[CH2:8][CH2:9][N:5]=[C:6]1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH2:20])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(C1=NCCN1)CC2
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CN(C1=NCCN1)CC2
Reaction time: 2 h

Procedure:
2 ml of hydrazine hydrate are added at 40° C. to a suspension of 2 g of the hydrochloride of the product obtained in Step 1 and 2 g of Raney nickel in 50 ml of ethanol. After 2 hours at 50° C., the catalyst is filtered off and the solvent is evaporated off.
Reaction SMILES: [ClH:1].CCO.[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]2[CH:18]=1)=[O:9])[CH3:6]>[Pd].CCO>[ClH:1].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[CH:18]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cn2ccncc2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)CNCC2
Reaction time: 15 h

Procedure:
0.46 M HCl-EtOH (169 mL) and 10% Pd—C (50% wet) (1.37 g) were added to the EtOH (546 mL) solution of imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (13.7 g). The mixture was hydrogenated under H2 at 40 psi at room temperature for 15 h. The reaction mixture was filtered and Pd—C was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (9/1˜2/1). The titled compound was obtained as brown crystals Yield: 10.4 g, 63%.
Reaction SMILES: [CH:1]([C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:8])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH:1]([C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)O
Reaction time: 14 h

Procedure:
To a suspension of 10% Pd—C (100 mg) in ethyl acetate (15 mL) under nitrogen was added a solution of compound (105) (0.7 g, 1.6 mmol) in ethyl acetate (5 mL). The resulting suspension was degassed three times and then hydrogen gas was introduced. The reaction mixture was stirred under 1 atm hydrogen atmosphere for 14 h, then filtered through a small plug of celite. The filtrate was concentrated in vacuo. The crude product (106) was carried to next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][C:18]([F:21])([F:20])[F:19].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:16]([CH2:17][C:18]([F:19])([F:21])[F:20])[C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=1
Reactant: COc1cccc(F)c1-c1ccncc1NCC(F)(F)F
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Product: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride after a reaction time of 12 hours. The compound was purified by preparative HPLC (ammonium acetate/acetonitril e). Off-white solid (27%). MS (ESI): m/z=551.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([OH:14])=O)=[O:5])[CH3:2].C([N:17]([CH:21]([CH3:23])C)[CH:18](C)C)C.N1CCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([N:17]1[CH2:18][CH2:23][CH2:21]1)=[O:14])=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1c(C(=O)O)cnn1C
Agent: C1CNC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a cooled solution of 5-(ethoxycarbonyl)-1-methyl-1H-pyrazole-4-carboxylic acid (1.5 g, 7.57 mmole), N-ethyldiisopropylamine (3.97 ml, 22.7 mmole) and azetidine (1.02 ml, 15.1 mmole) in ethyl acetate (30 ml) is added at 0° C. propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 11.4 ml, 18.9 mole). The ice-bath is removed and the light yellow solution is stirred for 3 hr at room temperature. The light yellow solution is adjusted to pH 9 with sat. aqueous sodium carbonate solution, the aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is removed in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.09 g, 60.7%) as a light brown viscous oil. MS: m/z=238.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][CH:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2]([C:20]([CH3:22])=[CH2:21])[C:11]=2[O:10]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, isopropenylboronic acid pinacol ester (0.293 ml), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→12% ethyl acetate/hexane) to give the title compound (274 mg, 74%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH2:9][C:10]([O:12]CC)=O)[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl.[NH2:20][CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:20][CH2:21][CH2:22][S:23](=[O:25])(=[O:24])[NH2:26])=[O:12])[S:8][C:4]=2[CH:3]=1
Reactant: NCCS(N)(=O)=O
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)CCNC(=O)Cc1nc2ccc(Br)cc2s1
Reaction time: 2 h
Yield: 45 %

Procedure:
Ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 250 mg, 0.83 mmol) in THF (4 mL) was treated with sodium hydroxide (1N NaOH, 0.92 mL, 0.92 mmol). After 2 hours, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was co-evaporated with toluene (5 mL), re-dissolved in DMF (4 mL), and treated with 2-aminoethanesulfonamide hydrochloride (201 mg, 1.30 mmol), TEA (1.2 mL, 8.3 mmol) and HATU (475 mg, 1.30 mmol). After 16 hours, the reaction mixture was diluted with water (20 mL), extracted with DCM (3×10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in DMF/methanol and purified using reverse phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100 mm, 30 to 100% B over 15 minutes with 10 minute hold time, solvent A: 90% water/ACN/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254). The pooled fractions were lyophilized to Compound A1a, (170 mg, 45% yield) as a white solid. HPLC: RT=0.75 (LCMS Method O). MS (ES): m/z=379.7 [M+H]+. 1H NMR (400 MHz, DMF-d7) δ 8.40 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 6.97 (s, 2H), 3.82-3.61 (m, 2H), 3.46 (s, 3H), 3.33 (dd, J=7.9, 6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([CH2:40][CH2:41][NH:42][C:43](=[O:45])[CH3:44])=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:43]([NH:42][CH2:41][CH2:40][C:39]1[CH:38]=[C:37]([CH3:49])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:47]([CH3:48])[CH:46]=1)(=[O:45])[CH3:44]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CC(=O)NCCc1cc(C)c(Br)c(C)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCNC(C)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(4-bromo-3,5-dimethylphenethyl)acetamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.53 min; Mass spectrum (ESI+): m/z=532 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: OC1CCNCC1
Reactant: Cc1cnc(Br)cn1
Product: Cc1cnc(N2CCC(O)CC2)cn1

Procedure:
The title compound is prepared from 2-bromo-5-methyl-pyrazine and 4-hydroxy-piperidine following a procedure analogous to that described in Intermediate 47. LC (method 8): tR=0.94 min; Mass spectrum (ESI+): m/z=194 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:26][CH:25]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: ClCCCOc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 3.0 g (0.01 mole) of [α,α-bis(p-fluorophenyl)]4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-4-(3-chloropropoxy)benzene, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was heated at reflux for 20 hr to give, after working up as in Example 1 (recrystallizing the free base from isopropyl alcohol), 1.7 g (36%) of white solid, m.p. 92°-93° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[C:14]([O:17][CH2:18][CH2:19][CH3:20])[C:15]=3[N:16]=2)[CH:5]=[C:4]([CH3:23])[C:3]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C)C=O>[C:36]([O:35][C:33](=[O:34])[CH2:32][O:24][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]2[O:9][C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[C:14]([O:17][CH2:18][CH2:19][CH3:20])[C:15]=3[N:16]=2)=[CH:5][C:4]=1[CH3:23])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12

Procedure:
To a solution of 2.00 g of 2,6-dimethyl-4-(5-methylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-phenol in 20 ml of N,N-dimethylformamide was added 3.20 g of potassium carbonate, followed by 0.93 ml of tert-butyl bromoacetate. The mixture was reacted for 1 h at 60° C., then allowed to cool and poured onto water. The resulting precipitate was collected by filtration with suction and dried in vacuo. 2.45 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25]>CN(C=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH:23]([CH2:22][CH3:21])[C:24]([OH:26])=[O:25]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Product: CCC(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O
Temperature: 55 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of (+) 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (14.25 g, 0.046 mole) potassium carbonate (12.5 g, 0.09 mole) and ethyl 4-bromobutanoate (17.5 g, 0.08 mole) in DMF (150 ml) is stirred at 55° C. for 4 hours then poured into ice water and extracted with ether, washed with water and the ether evaporated at reduced pressure. The residual oil is dissolved in acetic acid (150 ml) and 5% hydrochloric acid (50 ml), heated at 95° C. for 21/2 hours, cooled and treated with ie (50 g) to give 17.65 g of (+)[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]butanoic acid which melts at 75°-77° C. [α]D25 (C=2, acetone)=+36.8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:34])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ncc(C(C)O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (641.5 mg, 1.440 mmol) was suspended in THF (14 mL) and the reaction was cooled in an ice bath under nitrogen. Then, methylmagnesium bromide (3.0 M solution in diethyl ether, 1.65 mL, 4.95 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 1 h and 45 min, the reaction was cooled in an ice bath and the reaction was treated with saturated ammonium chloride, dropwise at first as gas evolution was observed. Then, the reaction was warmed to room temperature and diluted with water (15 mL). The layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. The organic layer and the organic extracts were combined, concentrated, and dried under high vacuum to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (725 mg). 1H NMR (CDCl3, 400 MHz) δ 12.52 (s, 1H), 9.81 (s, 1H), 8.43 (s, 1H), 8.36-8.19 (m, 3H), 6.83-6.77 (m, 1H), 5.88 (d, J=9.00 Hz, 1H), 5.01 (d, J=5.87 Hz, 1H), 4.21 (d, J=10.95 Hz, 1H), 3.89-3.81 (m, 1H), 2.91 (s, 3H), 2.21-1.65 (m, 6H), 1.63-1.61 (m, 3H). m/z (ESI, pos. ion) 462 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[N:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:30][S:29][C:26]1[N:27]=[CH:28][C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)=[N:24][CH:25]=1
Reactant: CSc1cnc(N=C=S)cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.4 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.375 g, 1.637 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (1.333 g, 4.09 mmol) and 2-isothiocyanato-5-(methylthio)pyrazine (0.3 g, 1.637 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.765 mL, 4.9 mmol) was then added and the mixture was continued to stir at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (R)—N-(5-(methylthio)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.014 g, 0.04 mmol, 16% yield) as a yellow solid. M.P. 155-60° C. 1H NMR (400 MHz, MeOD) δ ppm 8.13 (1H, d), 8.06 (1H, s), 3.96 (1H, d), 3.66 (1H, d), 3.20 (1H, d), 3.08 (1H, d), 2.87-2.96 (2H, m), 2.72-2.82 (2H, m), 2.52 (3H, s), 2.00-2.19 (2H, m), 1.51-1.81 (3H, m). LCMS R.T.=1.01; [M+H]+=306.12.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH:26]=O>CO>[CH:1]1([CH2:4][N:5]2[C:10]([NH:11][N:12]=[CH:26][C:19]3[C:18]4[C:23](=[CH:24][CH:25]=[C:16]([Cl:15])[CH:17]=4)[N:22]=[CH:21][CH:20]=3)=[CH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:2][CH2:3]1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: NNc1cc(=O)[nH]c(=O)n1CC1CC1
Solvent: CO
Product: O=c1cc(NN=Cc2ccnc3ccc(Cl)cc23)n(CC2CC2)c(=O)[nH]1
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a suspension of 1-cyclopropylmethyl-6-hydrazinopyrimidine-2,4[1H,3H]dione (5.05 g) in methanol (75 mL) was added 6-chloroquinoline 4-carbaldehyde (5.30 g). After stirring overnight, the reaction was filtered, yielding a yellow solid (10 g).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH2:14]1COCC1>>[CH3:14][S:1][C:2]1[CH2:3][CH2:4][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:6]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Product: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reaction time: 3.5 h
Yield: 91 %

Procedure:
To a solution of thiolactam 1b (10.50 g, 52.2 mmol) in 200 mL THF at rt, was added Mel (13.0 mL, 208.7 mmol). The mixture was stirred for 3.5 h, then concentrated. The residue was partitioned between CH2Cl2 and sat. NaHCO3 and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic extract was dried (Na2SO4) and concentrated to afford 10.17 g (91%) of the title compound, 1c, as a brown oil. 1H NMR (300 MHz, CDCl3) δ 4.60 (dd, J=6.2, 7.3, 1H), 2.83–2.58 (m, 2H), 2.49 (s, 3H), 2.37–2.22 (m, 1H), 2.17–2.03 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.COC1C=CC=C(OC)C=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=[C:11]([C:15]#[N:16])[CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C#N)cc1N
Agent: COc1cccc(OC)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(C(=O)O)c(N)c1
Reaction time: 6 h

Procedure:
To a mixture of 3-amino-5-cyano-pyridine-2-carboxylic acid tert-butyl ester (60 mg, 0.274 mmol) and 1,3-dimethoxybenzene (0.358 ml, 2.74 mmol) was added dropwise within 10 min TFA (0.59 ml, 7.66 mmol) and the reaction mixture was stirred for 6 h. Toluene was added and the solvents were evaporated to provide the title compound as yellow solid. The product was used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6](O)[O:7][C:8]2=[O:9])([O-])=O.[CH:15]1([CH2:21][CH:22]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>C(O)(C)C.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[CH:15]1([C:21]2[CH:22]=[N:1][C:4]3[CH:13]=[CH:12][CH:11]=[C:10]([C:8]([OH:7])=[O:9])[C:5]=3[CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=CCC1CCCCC1
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: C[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)O
Product: O=C(O)c1cccc2ncc(C3CCCCC3)cc12

Procedure:
A mixture of 50 g of 4-nitro-3-hydroxyphthalide in 200 ml of isopropanol is hydrogenated with 5 g of Pd/barium sulphate under 3.5 bar, during which the temperature rises to 55° C. When the hydrogenation has ended (about 30 minutes), the catalyst is filtered off hot with suction. 33 g (260 mmol) of cyclohexylacetaldehyde are added to the filtrate and, after addition of a catalytic amount of sodium methylate, the mixture is heated under reflux for 20 hours. After cooling, the crystals which have precipitated out are filtered off with suction and washed with isopropanol. 15 g of virtually colourless product with a melting point of over 280° C. are obtained.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH2:6]>>[CH:8]1([O:7][CH:5]=[CH:6][C:1]([Cl:4])=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=COC1CCCCC1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)C=COC1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
50 g (0.5 mol) of phosgene are condensed into a stirred apparatus fitted with −78° C.-cooling. Over a period of 3 hours, 50.5 g (0.4 mol) of cyclohexyl vinyl ether are subsequently added dropwise at 20° C. The mixture is then stirred at 50° C. for 5 hours. The excess phosgene is flushed out with nitrogen, and the crude product is worked up by distillation. At 110° C./2.5 mbar, 66.4 g (88%) of the product of value were obtained.