Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7C(=O)C(C7CC7)NC(OC)=O)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64][C:65]([CH3:76])([CH3:75])[CH:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[C:67]([OH:69])=O>>[CH3:74][O:73][C:71](=[O:72])[NH:70][CH:66]([C:67]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:7])[CH3:8])=[N:22][CH:21]=6)=[CH:24][CH:25]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:69])[C:65]([O:64][CH3:63])([CH3:76])[CH3:75]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)(C)OC)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 35 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.020 g, 0.096 mmol) to provide [2-Methoxy-1-(3-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl]-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.019 g, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24]CC3C=CC=CC=3)=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:40](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[Pd]>[C:22]([N:21]([CH3:32])[CH2:20][CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15]1=[O:33])(=[O:24])[CH3:40]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.023 g, 0.043 mmol) in CH2Cl2 (1.5 mL) was combined with diisopropylethylamine (0.0038 mL, 0.22 mmol), acetic anhydride (0.021 mL, 0.22 mmol) and Pd/C (0.012 g, 10% w/w). The resulting suspension was flushed with nitrogen and evacuated several times the charged with hydrogen under a balloon and stirred at ambient temperature overnight. The reaction mixture was filtered, washed with CH2Cl2, and concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with 1N NaHSO4, and brine, concentrated the organics to afford the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.59 Hz, 3 H), 1.86 (s, 3 H), 2.94 (s, 3 H), 3.50 (t, J=6.86 Hz, 2 H), 4.18 (s, 2 H), 4.28 (q, J=6.83 Hz, 4 H), 7.12 (t, J=8.69 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.02 (d, J=6.40 Hz, 1 H), 8.47 (s, 1 H); ES+ MS: 442 (M+H+).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([C:24]2[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH:26]=[CH:27][N:28]=2)=[O:23])=[CH:14][C:8]=1[CH:9]=[CH:10][C:11](O)=[O:12])([O-])=O.[H][H]>[C].[Pd].C(N(CC)CC)C>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:25]1[CH:26]=[CH:27][N:28]=[C:24]1[S:22]([CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[C:8]2[C:7](=[CH:17][CH:16]=1)[NH:4][C:11](=[O:12])[CH2:10][CH2:9]2)=[O:23]
Reactant: [H][H]
Reactant: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc([N+](=O)[O-])c(C=CC(=O)O)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
To 50 ml of ethanol were added 300 mg of 2-nitro-5-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]-propoxy}cinnamic acid, 100 mg of 10% palladium carbon and 0.6 ml of triethylamine. Hydrogenation was conducted at a hydrogen pressure of 4 atm. at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered to remove the catalyst. To the filtrate was added 200 mg of 10% palladium carbon, and hydrogenation was conducted at a hydrogen pressure of 4 atm. at 60° C. for 6 hours. Ethanol was removed by distillation. The residue was made acidic with hydrochloric acid, followed by extraction with methylene chloride. The extract was washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=50/1→20/1). The crude crystals were recrystallized from ethanol-n-hexane to obtain 70 mg of 6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:27]=2)=[CH:14][C:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20]2)=[N:16][CH:17]=1>C(Cl)Cl.CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:27]=2)=[CH:14][C:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][C@H:21]([CH:24]=[O:25])[CH2:20]2)=[N:16][CH:17]=1
Reactant: OC[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame-dried argon purged 20 mL conical flask, oxalyl chloride (0.025 ml, 0.281 mmol) was dissolved in DCM (0.5 ml) and cooled to −78° C. under argon. DMSO (0.030 ml, 0.422 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the previous solution (I don't see issues here). This was stirred for 30 min at −78° C. ((1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl)methanol (60 mg, 0.141 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture. The resulting mixture was stirred for 60 min at −78° C. TEA (0.078 ml, 0.562 mmol) was dissolved in DCM (0.5 ml) and added dropwise to the reaction mixture, after which the reaction mixture was allowed to stir and warm to ambient temp over 2 hr. The reaction mixture was diluted with EtOAc, washed with saturated NH4Cl (30 mL×3), H2O (30 mL), brine (30 mL), dried over Na2SO4 and reduced. The resulting residue was used without further purification. LCMS (m/z): 425.2 (MH+), retention time=0.72.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 66.1 %

Procedure:
4-Cyclohexylbenzoic acid (0.50 g, 2.45 mmol) was suspended in thionyl chloride (3 mL) and heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow oil which was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.67 g, 3.64 mmol) and N,N-diisopropylethyl amine (0.94 mL, 5.4 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 50% dichloromethane in hexane followed by 25% ethyl acetate in hexane gave a white foam which crystallized upon sonication from hexane/ethyl acetate to provide the title compound (0.60 g) as a white solid, m.p. 127–129° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.O>[C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:26][CH:27]5[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]5)=[O:22])=[CH:24][CH:25]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Nc3nc4cccc(-c5ccccc5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
tert-Butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzamido) piperidine-1-carboxylate. A mixture of 4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (200 mg, 0.6 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (121 mg, 0.6 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (460 mg, 1.2 mmol) and N-methylmorpholine (306 mg, 3.0 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. Water (5 mL) was added, and the precipitate was collected by filtration and washed with water to give tert-butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzamido)piperidine-1-carboxylate (220 mg, 72% yield) as a solid. MS (ESI): m/z 535.1 [M+23]+.
Reaction SMILES: BrC1C2C(=NC(N)=NC=2)N(C)N=1.[CH2:13]([NH:20][C:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[N:28]([CH3:32])[N:29]=[C:30](Br)[C:22]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>>[CH2:13]([NH:20][C:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[N:28]([CH3:32])[N:29]=[C:30]([C:36]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([F:33])[CH:35]=3)[C:22]=12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Cn1nc(Br)c2c(NCc3ccccc3)nc(N)nc21
Agent: Cn1nc(Br)c2cnc(N)nc21
Product: COc1ccc(-c2nn(C)c3nc(N)nc(NCc4ccccc4)c23)cc1F

Procedure:
This compound is prepared analogously to Example 88 by replacing 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) with N*4*-Benzyl-3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Intermediate 15) and by replacing 2-methoxy-5-trifluoromethylphenylboronic acid with 3-fluoro-4-methoxyphenylboronic acid to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([B:25]([OH:28])[OH:26])=[CH:11][C:12]2[CH2:16][CH:15]([CH3:17])[S:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1Cc2cc(Br)c(OCc3ccccc3)cc2S1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1Cc2cc(B(O)O)c(OCc3ccccc3)cc2S1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-benzyloxy-5-bromo-2-methyl-2,3-dihydrobenzo[b]thiophene (1.0 g, 3.0 mmol) in THF at 0° C. is added n-BuLi (1.8 mL, 4.5 mmol, 2.5 M in hexane) and the mixture is stirred for 1.5 h at 0° C. B(OMe)3 (1.67 mL, 15 mmol) is added dropwise and it is warmed to RT and stirred for 1.5 h. 3M HCl solution is added slowly at 0° C. and EtOAc is added to extract the product. The organic phase is dried with MgSO4 and concentrated. The residue is purified by chromatography to give the title compound as a white solid: (M+H)+=301.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[PH2](O)=O.[OH2:13]>>[C:7]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: OCCc1ccccc1
Agent: O=[PH2]O
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
The reaction was run as described in Example 2 except that the initial excess of 2-phenylethyl alcohol was 10% rather than 20%, and the organic layer that co-distilled with the water of reaction was returned to the batch at the end of each hold but the last one. After 4 h at 18014 210° C., the reaction mixture was cooled to room temperature, where the acid number was 5.50 (97.8% conversion), the APHA color was 114, and the excess 2-phenylethyl alcohol was 4.8% by GLC. A 9.94-g aliquot of 50% w/w aqueous hypophosphorous acid (H PA, 0.40% w/w based on H3PO2) was added. The excess 2-phenylethyl alcohol was removed by vacuum distillation as usual. The APHA color was 39 and the residual 2-phenylethyl alcohol was 0.19% by GLC. Treatment with activated carbon as usual afforded 1100 g (88%) of 2-phenylethyl benzoate. The APHA color was 36, the acid number was 2.10 mg KOH/g, the saponification number was 244 mg KOH/g, the residual tin was 270 ppm, and the residual phosphorous was 1300 ppm.
Reaction SMILES: [S:1](=[C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH2:5]1)(=[O:3])=[O:2].[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[CH:21]1([CH2:24][C:25]2[C:30]([C:31]3[CH:36]=[CH:35][N:34]=[C:33](S(C)=O)[N:32]=3)=[CH:29][N:28]=[C:27]([NH:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43])[N:26]=2)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([CH2:24][C:25]2[C:30]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:8][C:7]4[CH:6]=[CH:5][C:4]([S:1]([CH3:12])(=[O:3])=[O:2])=[CH:10][CH:9]=4)[N:32]=3)=[CH:29][N:28]=[C:27]([NH:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43])[N:26]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: NC1=CCC(=S(=O)=O)C=C1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 4-sulfonylaniline (71.1 mg, 0.415 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (69.4 mg, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 hour. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (11 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:18].C(N(CC)CC)C.C(OC(Cl)=O)C.Cl.Cl.NC1C2CCN(CC2)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Agent: CCOC(=O)Cl
Agent: Cl
Agent: NC1CN2CCC1CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)ccc2c1C1CCCCC1O2
Reaction time: 2 h

Procedure:
To a cold solution of 0.3 g 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 g ethylchloroformate in 10 ml chloroform. Stirring is continued for 2 hours. This is then added to a cold mixture of 3 g 3-aminoquinuclidine dihydrochloride in 20 ml water containing 7.5 g K2CO3. Stirring is continued overnight. The reaction mixture is then diluted with chloroform, the two layers separated and the chloroform layer washed twice with water, dried over magnesium sulfate, filtered and evaporated to dryness to give 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo [2.2.2.]oct-3-yl)carboxamide as an oily Product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (258 mg, 0.509 mmol) in DMF (10 mL) was added 60% NaH (204 mg, 5.09 mmol) and 2-chloro-N,N-dimethylethylamine (220 mg, 1.527 mmol). The resulting solution was stirred at 60° C. overnight, cooled to the ambient temperature, quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the title compound (100 mg, 29% yield).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+].[CH3:14][C:15]1[O:16][C:17](=[O:29])[C:18](=[CH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:19]=1>CC(C)=O>[C:15]([NH:19][C:18](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)[C:17]([NH:11][C@@H:7]([CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)[C:8]([OH:10])=[O:9])=[O:29])(=[O:16])[CH3:14]
Reactant: CC1=NC(=Cc2ccc(C#N)cc2)C(=O)O1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)NC(=Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
(S)-Cyclohexylglycine (3.14 kg, 20 mol) in acetone (70 l) was heated with stirring at 35° C. With stirring, 1 N aqueous sodium hydroxide solution (20 l) was then added over a period of 10 min. The mixture was heated to 40° C., and at an internal temperature of 40° C., solid 4-(2-methyl-5-oxooxazol-4-ylidenemethyl)benzonitrile (4.66 kg, 22 mol) was metered in in portions, with vigorous stirring, over 20 min. After the addition had been ended, the reaction mixture was stirred at an internal temperature of 40° C. for 1 h. The reaction solution was then filtered through a pressure nutsch covered with a Seitz filter K1000 and activated carbon (1 kg), and the filter residue was washed with 10 l of acetone. The filtrate was then cooled to 14° C. With stirring, 2N hydrochloric acid (about 10 l) was then added over a period of 10 min until a pH of 2.3 had been reached. Stirring was continued for 15 min, and the pH was readjusted using 2N HCl. Over a period of 20 min, the solution was then admixed with stirring with deionized water (160 l), whereupon the title compound precipitated. With stirring, the mixture was cooled to 0° C. and stirred at this temperature for 1 h. For isolation, the product was pumped onto a centrifuge, washed three times with water (10 l each), tumble-dried and dried at 40° C. under reduced pressure. Yield: 4.21 kg (11.4 mol, 57% of theory). M.p.: 196–198° C.; MS(ESI+): m/z=370.2 [M+H+]; 1H-NMR (200 MHz, DMSO-d6): δ=0.98–1.35 (m 1.48–1.90 (m, 6H), 1.99 (s, 3H), 4.20 (dd, 1H), 6.98 (s, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.02 (d, 1H), 9.58 (s, 1H), 12.65 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1.C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][N:11]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CCc1cc(CCN)c(OC)nc1C
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(OC)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
To a solution of crude 2-methoxy-3-(2-aminoethyl)-5-ethyl-6-methylpyridine (332 mg) in ethanol (7 mL) was added N-(carbethoxy) phthalimide (406 mg, 1.85 mmol). After stirring at ambient temperature for three hours the solvent was evaporated and the residue was chromatographed on silica gel by gradient elution with 20-100% ethyl acetate/hexane. The appropriate fractions were combined, the solvent evaporated and the residue triturated with hexane as the product slowly crystallized out to yield 202 mg of pure product, m.p. 77°-79° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=2[O:25][CH3:26])[CH2:17]1>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([OH:10])[CH2:11][NH:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=3[O:25][CH3:26])[CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(c1OC)CC(N)C2
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CC(NCC(O)c1cccc(C(F)(F)F)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of m-trifluoromethylphenylglyoxal and 2-amino-4,5-dimethyoxyindane in toluene is refluxed for 2 hours, using a Dean-Stark trap to remove the formed water. The solution is concentrated in vacuo and the residue is dissolved in methyl alcohol. The resulting solution is cooled in ice, sodium borohydride is added in portions and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo, the residue is partitioned between water and methylene chloride and the layers are separated. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 1-(3-trifluoromethylphenyl)-2-(4,5-dimethoxyindan-2-yl)aminoethanol. Under anhydrous conditions, tetrahydrofuran, triethylamine and carbonyldiimidazole are added to the above compound and the mixture is stirred at room temperature for 20 hours. The reaction mixture is quenched with water and extracted with diethyl ether. The diethyl ether extracts are combined, washed with 2N hydrochloric acid, saturated sodium chloride, dried over magnesium sulfate. The solution is evaporated in vacuo to give a mixture of (R*,R*) and (R*,S*)-5-(3-trifluoromethylphenyl)-3-(2,3-dihydro-4,5-dimethoxy-1H-inden-2-yl)-2-oxazolidinone. This mixture is separated into the individual (R*,R*) and (R*,S*) racemates by chromatographic techniques described in Example 1. Each racemate is treated with boron tribromide and the individual products are reacted with diethyl dibromomalonate, as described in Example 1, to give (R*,R*) and (R*,S*)-7- 2-(3-trifluoromethylphenyl)-2-hydroxyethyl!amino!-7,8-dihydro-6H-indeno 4,5-d!-1,3-dioxole-2,2-dicarboxylic acid diethyl esters. These products are then hydrolyzed with 2.5N sodium hydroxide, as described in Example 3, to give the desired products.