Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]#[N:15])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.O1CCCC1>O1CCCC1>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH2:14][NH2:15])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(C#N)c1cccc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(CN)c1cccc([N+](=O)[O-])c1
Yield: 116.2 %

Procedure:
To a solution of 3-hexyl-6-(3-nitrophenyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carbonitrile (Preparation 111, 250 mg, 0.732 mmol) in anhydrous tetrahydrofuran (3 ml) stirred under nitrogen was added dropwise borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 2.9 ml, 2.9 mmol). The reaction mixture was heated at reflux for 2 h, before cooling and quenching with dry methanol (2 ml). The solution in methanol was heated under reflux for 18 h before concentrating in vacuo. The residue was again dissolved in methanol (ca 5 ml) and heated at reflux for 3 hours, followed by evaporation to dryness in vacuo. This process was repeated once more and extensive drying gave a brown oil (270 mg) which was purified by column chromatography on silica gel (13 g) eluting with dichloromethane:ethanol:0.88 ammonia (150:8:1). This gave the title compound as an orange oil (124 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(F)c(CO)cc1F
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
A solution of 2,5-difluoro-4-formylbenzonitrile (Preparation 20, 280 mg, 1.68 mmol) in ethanol (8 mL) was cooled to 0° C. in an ice/water bath. Sodium borohydride (63.4 mg, 1.68 mmol) was added and the reaction stirred at 0-5° C. for 5 hours. The mixture was quenched with aqueous hydrochloric acid (2 N, 20 mL) and extracted with EtOAc (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL), dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a yellow oil, which crystallised on standing (182 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39]>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:39])([F:40])[F:41])[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-2-trifluoromethyl-benzene following the procedure of Example 478: MS (ESI) m/z 552.
Reaction SMILES: [CH3:1][CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:16]=[O:17].N1C=CC=CC=1.Cl>CO.CCOCC>[CH3:1][C:2]([CH2:16][OH:17])([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)C(=O)c1ccc(Cl)cc1
Reactant: C=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)(CO)C(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 98.1 %

Procedure:
Into a 5 liter RBF is placed 1000 g (4.37 mole) of methyl 2-methyl-3-(4-chlorophenyl)-3-keto-propanoate, 157 g (5.25 mole) of paraformaldehyde, 1000 ml of pyridine, and 50 g of Triton B (40% in MeOH). The resulting mixture was heated 50° C. for 2 hours. After cooling to room temperature, the reaction mixture was transferred to a 12 liter separatory funnel and 1.5 liters of ether and 2 kgs of ice are added. The mixture is slowly acidified by 1.0 liters of conc HCl and the organic phase is separated, washed with 2 liters of brine and dried over MgSO4. On concentration, it affords 1100 g (100%) of a red oil, methyl 2-methyl-2-hydroxymethyl-3-(4-chlorophenyl)-3-keto-propanoate. NMR data was consistent with the structure.
Reaction SMILES: [OH:1][CH:2]([CH2:11][OH:12])[CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[C:13]1([CH2:26][O:27][C:28](C2CC(=O)N(O)C2=O)=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[C:13]1([CH2:26][O:27][C:28]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH2:11][OH:12])=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CSCC(O)CO)C(=O)O
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)C1CC(=O)N(O)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H](CSCC(O)CO)C(=O)O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 63.8 %

Procedure:
S-(2,3-dihydroxypropyl)cysteine (2.45 g, 12.6 mmole) was dissolved in 9% sodium carbonate (20 ml). A solution of fluorenylmethoxycarbonyl-N-hydroxysuccinimide (3.45 g, 10.5 mmole) in acetonitrile (20 ml) was added and the mixture stirred for 2 h, then diluted with water (240 ml), and extracted with diethyl ether (25 ml×3). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and was then extracted with ethyl acetate (70 ml×3). The extract was washed with water (50 ml×2) and saturated sodium chloride solution (50 ml×2), dried over sodium sulfate and evaporated to dryness. Recrystalisation from ether and ethyl acetate at −20° C. yielded a colourless powder (2.8 g, 6.7 mmole, 63.8%).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C[O-].[Na+]>CN(C=O)C>[NH2:11][C:10]1[C:3]2=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: COc1cnc(C#N)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cc(OC)cnc2c1N
Reaction time: 1 h
Yield: 71.3 %

Procedure:
The product from Example 27B (0.168 g, 1.0 mmol) and methyl thioglycolate (0.09 mL, 1.0 mmol) were combined in DMF (2 mL). To the solution was added 0.054 g NaOMe. After 1 hr, and additional 0.07 g NaOMe was added. After an additional 1 hr, the reaction was quenched in sat aq. NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4), and evaporated to yield 0.17 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H), 3.93 (s, 3H), 6.15 (br s, 2H), 7.44 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][NH:39][C:40]2=[O:45].[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[CH2:56][CH2:57]O>C1COCC1.O>[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][N:39]([CH2:57][CH2:56][C:47]1[CH:48]=[CH:49][C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:46]=1)[C:40]2=[O:45]
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]ncc2c(Br)cccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2cccc(Br)c2cnn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of PPh3 (699 mg, 2.67 mmol) in THF (50 mL) and DIAD (198 mg, 0.98 mmol), 5-bromo-2H-phthalazin-1-one (300 mg, 1.33 mmol) and then 2-quinolin-2-yl-ethanol from example a1 (254 mg, 1.46 mmol) were added dropwise at 15° C. under nitrogen. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with HCl (1 N). The aqueous phase was basified and extracted with DCM. The organic phase was washed with a NaHCO3-solution, dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from EA and dried to give the title compound as bright beige solid (300 mg, 59.2% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:32])[CH2:30][CH3:31])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.369 g, 1.3 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Propionyl chloride (450 μl, 5.2 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. Ethyl acetate was added to the residue and undissolved salts were removed by filtration. The filtrate was then applied to a silica gel column (4.8×13 cm) and eluted with methanol. After evaporation of the solvent, the product was eluted to a Chromatotron plate (4 mm silica gel) with a mixture of hexane:acetone (75:25). The product containing fractions were combined, concentrated, and further chromatographed on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (95:5). Product containing fractions were applied to preparative silica gel plates (20×20×0.2 cm) which were then developed in chloroform:acetone (85:15). Final purification was achieved by a third run on the Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.178 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((propanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (39% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O-:38].[Na+]>CO>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:38][CH3:37])[CH:20]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(C=Cc2ccnc(F)c2)c1)Cc1c[nH]c2ccccc12
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=Cc2cncc(OC[C@H](Cc3c[nH]c4ccccc34)NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
A mixture of Example 216B (100 mg, 0.2 mmol), NaOMe (25% in MeOH) (1 mL) in MeOH (10 mL) was refluxed for 8 hrs. The mixture was concentrated to give the crude product.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2[C:6](=[N:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:7]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].O>CN1C(=O)CCC1>[OH:24][CH2:23][C:22]([NH:21][C:2]1[N:3]([CH3:20])[C:4](=[O:19])[C:5]2[C:6](=[N:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(N)CO
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Temperature: 122.5 °C
Yield: 74.3 %

Procedure:
A mixture of 6-chloro-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (157 g, 444 mmol) and 2-amino-2-methylpropan-1-ol (236 g, 2.65 mol) in NMP (1.3 L) is heated at 120-125° C. for 2 h, and then poured into cold water. After filtration, the filter cake is washed with water twice, and then dried under vacuum to give 134 g of product (yield: 74%). MS (ESI) m/z 406.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([CH3:14])[C:8]1=[O:15].[Cl:16][CH2:17][C:18](O)=[O:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([CH3:14])[C:8]1=[O:15])=[O:19]
Reactant: O=C(O)CCl
Reactant: CC1=C(C)C(=O)N(CCOCCO)C1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCOCCOC(=O)CCl)C1=O

Procedure:
A mixture of 90.6 g (0.41 mole) of N-(5-hydroxy-3-oxapentyl)dimethylmaleimide, 46.6 g of chloroacetic acid, 4.8 g of concentrated sulfuric acid and 400 ml of toluene are reacted and worked up as described in Example 1, affording 112 g of a slightly yellowish liquid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][C@@H:33]([CH3:37])[CH2:34][NH:35][CH3:36])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][C@@H:33]([CH3:37])[CH2:34][N:35]([CH3:36])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CN(C)C(=O)CO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 53 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.96 (s, 3H), 3.36 (dd, 1H), 4.04 (d, 2H), 4.21 (m, 1H), 4.37 (t, 1H), 5.09 (m, 1H), 5.29 (s, 1H), 7.25 (m, 2H), 7.35 (m, 2H), 7.57 (d, 1H), 7.65 (dd, 1H), 7.70 (t, 1H), 7.87 (dt, 1H), 8.12 (d, 1H), 8.46 (s, 1H), 8.58 (d, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 508.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:20]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (10 g, 0.06 mol) in the mixture of anhydrous DMF (30 mL) and dioxane (30 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a magnetic stirrer, thermometer and an additional funnel. Bromoacetyl bromide (11.8 g, 5 mL, 100 mol %) was added dropwise over a 20 min period, keeping the internal temperature between 0° C. to 1° C. After the addition was completed, the ice-bath was removed, and then stirring was continued overnight at rt. The reaction mixture was cooled in an ice-bath and stirred for 30 min, water (80 mL) was added, and then the light yellow precipitate which formed was filtered, washed with water, and then dried in a vacuum oven (20 h, 40°-45° C.) affording 11.4 g (67%) of the title compound: mp 210°-212° C. (dec.), 1H NMR (CD3OD) δ8.58 (d, 1H, J=9.2), 8.03 (d, 1H, J=2.8), 7.55 (dd, 1H, J=2.4, J=6.4), 4.11 (s, 2H); 13C NMR (CD3OD) δ196.94, 169.69, 140.49, 134.86, 131.94, 129.49, 122.87, 119.47, 30.04; MS (EI, m/z) 293 (M+).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[CH:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[I:1][CH2:2][C:3]1[N:4]=[C:35]([C:34]2[CH:33]=[CH:32][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:38][CH:37]=2)[O:36][C:7]=1[CH3:8]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-isopropylbenzaldehyde gave 4-iodmethyl-2-(4-isopropylphenyl)-5-methyloxazole.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH:9](C([O-])=O)[N:8]=2)=[CH:5][CH:6]=1.O[K].[K+].P(O)(O)([O-])=O.[K+]>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:10](=[O:11])[CH2:9][N:8]=[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:14]=2[CH:15]=1
Reactant: O=C([O-])C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: O=P([O-])(O)O
Agent: O[K]
Agent: [K+]
Solvent: O
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Yield: 80 %

Procedure:
2.1 g. (0.005 mole) of 4306 CB and 0.68 g. (0.005 mole) of monopotassium phosphate are dissolved at room temperature in 18 ml. of water. Solution proceeds rapidly and then colorless platelets slowly precipitate. The product is filtered by suction, washed first with chilled water and then with absolute alcohol. The product is dried at room temperature for 12 hours and then in a high vacuum. 1.8 g. of colorless crystals completely soluble in water are obtained. The aqueous solution has a substantially neutral reaction; yield 80%. This product is decarboxylated within a few minutes by heating an aqueous solution thereof, compound A being obtained in the crystalline state.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=[N:16]O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[ClH:18]>[Pd].C(O)C>[ClH:18].[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH2:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ncc(C=NO)cc2C)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2ncc(CN)cc2C)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2-L Parr-Shaker Reactor was charged 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde oxime (34f, 560 mmol), Pd/C (23 g, 112 mmol, 50 wt % wet), conc. HCl (94 mL), and ethanol (600 mL). The reaction mixture was shaked at rt under 40 psi H2 until H2 was consumed. After filtration through Celite, the filtrate was solvent-exchanged to ethanol by repeating the concentration and refilling with ethanol twice. The product was stirred in ethanol/iso-propyl acetate (800 mL, v 1/1) at rt for 18 h. The solid was collected by filtration and rinsed with EtOH/iso-propyl acetate (400 mL, v 1/1). The wet cake was dried at 50° C. under vacuum for 18 h to afford (2′,3-dimethyl-[2,4′-bipyridin]-5-yl)methanamine hydrochloride (34g) as a light yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.89 (s, 3H), 4.15 (q, J=5 Hz, 2H), 8.05 (dd, J=1.6, 6.0 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.13 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.88 (brd, 3H).
Reaction SMILES: [CH3:1][C:2]1([OH:7])[CH2:6][CH2:5][NH:4][CH2:3]1.FC(F)(F)S(O[C@H:14]([C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:15]([F:18])([F:17])[F:16])(=O)=O.C([O-])([O-])=O.[K+].[K+].C1COCC1>>[Cl:25][C:22]1[N:21]=[CH:20][C:19]([C@H:14]([N:4]2[CH2:5][CH2:6][C:2]([CH3:1])([OH:7])[CH2:3]2)[C:15]([F:18])([F:16])[F:17])=[CH:24][CH:23]=1
Reactant: CC1(O)CCNC1
Reactant: O=S(=O)(O[C@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(O)CCN([C@@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Temperature: 50 °C
Yield: 54.6 %

Procedure:
A mixture of 3-methylpyrrolidin-3-ol (1.41 g, 13.9 mmol), (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (4.30 g, 12.5 mmol) and K2CO3 (1.93 g, 13.9 mmol) in THF (69.7 mL, 13.9 mmol) was heated in a sealed tube to 50° C. overnight. The reaction was filtered, concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, 300 g, 10% MeCN/water to 95% MeCN/water over column volumes) to give 1-((S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ol (2.01 g, 48.9% yield).
Reaction SMILES: C(OC(N1C(C(=O)NC2C=C(Br)C=CC=2N)CC2(CC2)C1)=O)C1C=CC=CC=1.[CH2:29]([O:36][C:37]([N:39]1[CH:45]([C:46](=[O:56])[NH:47][C:48]2[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][C:49]=2[NH2:55])[CH2:44][C:41]2(CC2)[CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N1[C@H](C(O)=O)CC2([O:73][CH2:72][CH2:71][O:70]2)C1)=O)C1C=CC=CC=1>>[NH2:55][C:49]1[CH:50]=[C:51]([Br:54])[CH:52]=[CH:53][C:48]=1[NH:47][C:46]([C@@H:45]1[CH2:44][C:41]2([O:73][CH2:72][CH2:71][O:70]2)[CH2:40][N:39]1[C:37]([O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:38])=[O:56]
Reactant: Nc1cc(Br)ccc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2
Agent: Nc1ccc(Br)cc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Product: Nc1cc(Br)ccc1NC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2

Procedure:
Title compound was prepared in quantitative yield according to the method employed to make 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester, substituting (S)-5-(benzyloxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid with (S)-7-(benzyloxycarbonyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid (357 mg, 99%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: COc1ccc(CCl)cc1
Reactant: OCCNCCO
Product: COc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (10.5 g, 100 mmol), and 4-methoxy benzyl chloride (15.6 g, 100 mmol). Yield 21 g, (98%); yellow oil; MS: 226 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].C([O-])(=O)C.[Na+]>CO.[Pd]>[CH3:11][C:6]1[C:3]([C:4]#[N:5])=[CH:2][N:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccncc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
Referring to JP-A-7-10841, 2,6-dichloro-4-methylnicotinonitrile (manufactured by Mabridge) (17.0 g, 90.9 mmol) was dissolved in methanol (450 ml), and 10% Pd—C (1.7 g, 10 wt. %) and sodium acetate (15.2 g, 186 mmol) were added. The mixture was stirred at room temperature under hydrogen pressure for 16 hrs. and the catalyst and the like were filtered off. The solvent was concentrated under reduced pressure, and the resulting mixture was partitioned between dichloromethane (300 ml)-5% aqueous sodium hydrogen carbonate (200 ml). The organic layer was dried and the resulting mixture was concentrated under reduced pressure. Recrystallization from a small amount of isopropyl ether gave the title compound (9.2 g, 86%).