Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1

Procedure:
4-methylbenzoic acid (0.408 g, 3 mmol) was dissolved in thionyl chloride (10 mL) and the mixture was stirred at reflux for 6 hr. The mixture was condensed under vacuum to yield 4-methylbenzoyl chloride. To a suspension of 3-hydroxyanthranilic acid (0.153 g, 1.0 mmol) in toluene (10 mL) was added 4-methylbenzoyl chloride (0.464 g, 3.0 mmol) followed by pyridine (0.275 g, 3.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes then heated to 80° C. for 1 hr. The mixture was cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (20 mL). Subsequent separation of the layers, drying the organic over anhydrous magnesium sulfate and filtration afforded a solution. After removal of the solvent, the residue was dissolved in toluene (20 mL) and the solution treated with 4-methylbenzenesulfonic acid (0.4 g, 2.1 mmol). The reaction mixture was then heated to reflux overnight. After this time the reaction was cooled and poured into water (100 mL), the organic layer was separated then washed with water (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to get a solid. Re-crystallization of this solid from ethyl acetate gave 2 p-tolybenzo[d]oxazole-4-carboxylic acid as a white solid (0.15 g, 60% yield). LC-MS (ESI) m/z 254 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([S:41][CH2:42][CH2:43][NH2:44])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH:44][CH2:43][CH2:42][S:41][C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:20])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of 7-(benzyloxy)-1H-indole-2-carboxylic acid (0.80 g), 2-(tritylthio)ethylamine hydrochloride (1.07 g), 1H-1,2,3-benzotriazol-1-ol (0.49 g), triethylamine (0.50 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.69 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.60 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 156-157° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([C:15]2([OH:25])[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[OH-].[Na+]>O>[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([C:15]2([OH:25])[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]2)=[N:13][CH:14]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)cnc1C1(O)CCC(=O)CC1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
Trifluoroacetic acid (11 ml) and water (1 ml) were added to 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (7.45 g) described in Reference Example 105(1) and stirred at room temperature. After completion of the reaction, water was added and neutralized by the addition of 1N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxy-cyclohexanone (2.69 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1.[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)[CH2:3][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([OH:15])[CH2:17]1
Reactant: c1ccc(-c2cc(C3CO3)no2)cc1
Reactant: OC1CCCNC1
Product: OC1CCCN(CC(O)c2cc(-c3ccccc3)on2)C1
Temperature: 70 °C
Yield: 77.3 %

Procedure:
A mixture of 3-(1,2-epoxyethyl)-5-phenylisoxazole (1.05 g) and 3-hydroxypiperidine (1.13 g) is heated at 70°C for 20 minutes and then chromatographed on silica gel to give 3-[1-hydroxy-2-(3-hydroxypiperidino)ethyl]-5-phenylisoxazole (1.25 g). To a suspension of the compound in water (6.5 ml) is added 60% perchloric acid (516 ml), the precipitate is collected by filtration, and recrystallized from a mixture of 99% ethanol (2 ml) and ethyl acetate (8 ml) to give the perchlorate which melts at 151°-153°C. The perchlorate is suspended in aqueous sodium hydroxide solution and extracted with methylene chloride. After being dried with sodium sulfate, the extract is evaporated to give 3-[1-hydroxy-2-(3-hydroxypiperidino) ethyl]-5-phenylisoxazole (544 mg). Recrystallization from a mixture of ethyl acetate and hexane gives colorless prisms (388 mg) melting at 94°-96°C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[H-].[Na+].[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:40]I)[CH3:24].O>CC(OC)(C)C>[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)=[N:27][C:26]=1[CH2:40][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)[CH3:24]
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](CO)C1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
300 mg of tert-butyl 2-((1R,3S)-3-hydroxymethylcyclohexylmethoxy)-2-methylpropionate are dissolved in 10 ml of MTBE, and 50 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 600 mg of 5-ethyl-4-iodomethyl-2-(4-trifluoromethylphenyl)oxazole are added, and the suspension is heated under reflux overnight. After addition of water and MTBE, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue is purified by preparative HPLC, resulting in 190 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]-cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12]Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: ClCCl
Solvent: O
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cold solution of 2-amino-5-nitro phenol (40.0 g, 259.52 mmol) in DCM (1.0 L), was added bromine (13.38 mL, 259.52 mmol) drop wise. The resulting reaction mixture was stirred at room temperature for 45 min. After the completion of the reaction (TLC monitoring), water was added and extracted with EtOAc (3×1.0 L). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (55.0 g, 92%) was carried forward to the next step without further purification.
Reaction SMILES: [CH:1]([O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)([CH3:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH:1]([CH3:3])[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)OC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-isopropoxy-4-oxopiperidine-1-carboxylate obtained in Example (147c) (105 mg, 0.408 mmol) in 1,2-dichloroethane (2 mL) was cooled in an ice water bath. Benzylamine (87.6 μL) and sodium (triacetoxy)borohydride (212 mg, 1.0 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate) to obtain 120 mg of the title compound as a colorless oily substance (85%).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([O-])(=O)/C=C/C([O-])=O.[NH4+].[NH4+].[Ca:20]>>[C:7]([O-:9])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Ca+2:20]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: [Ca]
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [NH4+]
Product: [Ca+2]

Procedure:
A process for the preparation of aspartic acid via a fermentation process for the preparation of ammonium fumarate, wherein the pH of the fermentation broth is controlled by the addition of a calcium base to produce a calcium fumarate precipitate, characterised in that ammonium fumarate is produced by separating said precipitated calcium fumarate from said fermentation broth, and reacting said precipitate with a reagent selected from ammonia, ammonium carbonate, ammonia in combination with CO2 and mixtures thereof, to form ammonium fumarate solution and a co-product selected from calcium carbonate and calcium hydroxide, wherein the energy of indirect neutralisation of fumaric acid by ammonia serves as the driving force for the conversion of calcium fumarate to the desired ammonium fumarate product with a conversion yield of at least 90% and for the regeneration of a calcium base reagent, and wherein said ammonium fumarate product is enzymatically converted to ammonium aspartate and acidulated to form aspartic acid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:11]/[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[N:11]1[CH:10]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1ccncc1/C=N/c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1-n1cc2cnccc2n1
Yield: 54.4 %

Procedure:
A solution of [1-(4-azidopyridin-3-yl)meth-(E)-ylidene]-(2-chloro-6-fluorophenyl)amine (17 mmol) in toluene (50 mL) was heated at 105° C. for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (60-70% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (2.29 g, 54% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, J=1.5 Hz, 1H), 8.38-8.33 (m, 2H), 7.65 (dd, J=6.4, 1.4 Hz, 1H), 7.52 (td, J=8.3, 5.6 Hz, 1H), 7.45-7.41 (m, 1H), 7.30-7.24 (m, 1H). LCMS (Method C): RT=1.42, m/z: 248 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][S:21]([O:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[C:4]([CH2:5][NH:6][C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(O)cc(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 81 %

Procedure:
To a stirring solution of 91.8 mg of tert-butyl 3-hydroxy-5-isopropylbenzylcarbamate in 3 mL of CH2Cl2 and 300 μL of pyridine at 0° C. was added 30 μL (0.386 mmol) of MsCl. The ice bath was removed, and after stirring at r.t. for 75 min. 50 μL of Et3N was added. After 30 min., the solution was concentrated and EtOAc and H2O were added. The organic layer was washed with 15 mL of brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 96.2 mg of 3-((tert-butoxycarbonylamino)methyl)-5-isopropylphenyl methanesulfonate as a pale yellow oil in about 80% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18](Br)=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1.[CH:36]1[C:49]2[CH:48]=[C:47](B(O)O)[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]=2[CH:39]=[CH:38][CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18]([C:48]5[C:49]6[C:40]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=7[CH:47]=5)=[CH:39][CH:38]=[CH:37][CH:36]=6)=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2cc(-c3ccc4ccc(-c5c6ccccc6c(-c6cc7ccccc7c7ccccc67)c6ccccc56)cc4c3)ccc2c1
Temperature: 25 °C
Yield: 29.4 %

Procedure:
Under the nitrogen atmosphere, [9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (2.0 g) as the tenth intermediate compound, phenanthren-9-ylboronic acid (1.1 g), palladium acetate (Pd (OAc)2) (0.06 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, manufactured by Aldrich Company) (0.02 g), potassium phosphate (1.7 g), and a mixture solvent (10 ml) of toluene and ethanol (toluene/ethanol=4/1 (volume ratio)) were added to a flask and refluxed for 10 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with water. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol, and then purified by silica gel column chromatography (solvent: toluene). Additionally, after re-crystallization with chlorobenzene, 9-([2,2′-binaphthalen]-7-yl)-10-(phenanthren-9-yl)anthracene (0.7 g) was obtained as the target compound represented by Formula (1-164). The scheme is shown in the following “Reaction 18”.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.CO.C([BH3-])#N.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH:23]3[CH2:24][CH2:25][C:20]([O:19][CH3:18])([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:22]3)[CH2:5][CH2:6]2)=[CH:17][CH:16]=1)[CH3:15]
Reactant: COC1(C2CCCCC2)CCC(=O)CC1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCN(C3CCC(OC)(C4CCCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 42.9 %

Procedure:
To an ice cooled solution of ethyl 4-(piperazin-1-yl)benzoate (1.23 g) and 1-methoxy-1,1′-bicyclohexane-4-one (916 mg) in a mixed solvent of methanol (20 ml), tetrahydrofuran (15 ml) and acetic acid (0.74 ml) was added sodium cyanoborohydride (301 mg) in a stream of nitrogen. The mixture was stirred at this temperature for 1.5 hours and at room temperature for 7.5 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution. Dichloromethane was added to the solution. The organic layer was taken, washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexane-methanol elution) to give 4-[4-(1-methoxy-1,1′-bicyclohexan-4-yl)piperazinyl]benzoic acid ethyl ester (801 mg).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:20]=[C:21]([CH3:23])[O:22][C:3]=12>C(Cl)Cl>[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:20]=[C:21]([CH3:23])[O:22][C:3]=12
Reactant: Cc1nc2cc3c(c(Br)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Solvent: ClCCl
Product: Cc1nc2cc3c(c(Br)c2o1)CCNCC3
Yield: 99.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 10-bromo-2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine-7-carboxylate (71 mg) in DCM (2.1 ml) TFA (0.9 ml) was added dropwise. After 30 min. the mixture was diluted with DCM and washed with 5% K2CO3. The organic phase was dried (Na2SO4) and concentrated to afford the title compound (52 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C.O>ClCCl.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:16])[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCc2nc(-c3ccccn3)no2)CC1
Yield: 47.2 %

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.60 g) was dissolved in dichloromethane (10 ml). 1,1-Carbonyldiimidazole (0.33 g) was added followed by tert-butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5 g) and triethylamine (0.31 ml). After 2 hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate:methanol (33:1) to give the subtitle compound (0.40 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH2:16])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([NH2:16])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@](N)(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid methyl ester (30.7 g, 127.3 mmol) prepared in Step A was dissolved in DCM. Et3N (26.4 g, 190 mmol) and (BOC)2O (27.7 g, 127.3 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove DCM, and was used in the next reaction without further purification.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[N:11]=[CH:10][N:9]=[CH:8]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][CH:2]2[O:1][C:6]3=[C:7]4[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3]2)[N:11]=[CH:10][N:9]=[CH:8]4)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncncc4c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6ncncc6c5O4)CC3)c2c1

Procedure:
(2R)-2,3-Dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethyl-4-methylbenzenesulfonate (800 mg, 3.7 mmole) was dissolved in a mixture of DMF/THF 1:1 v/v (30 mL) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (800 mg, 4 mmole) added, followed by the addition of sodium bicarbonate (1.0 gm, 9.4 mmole) and the mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between methylene chloride and water. The organic phase was separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a foam. Treatment of this foam with 3% methanol in chloroform yielded 320 mg (35%) of the (S)-enantiomer of the title compound as a yellow crystalline hemihydrate, m.p. 233-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH:26]([CH3:28])[CH3:27])=[N:23][C:22]=2[CH:29]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]([CH3:27])[CH3:28])=[N:23][C:22]=4[CH:29]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: CC(C)c1nc2cc(CCl)ccc2o1
Product: CC(C)c1nc2cc(COc3ccc(CCCn4ccnc4)cc3)ccc2o1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-isopropyl benzoxazole to give 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-isopropyl-benzoxazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 76-77° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Yield: 76 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-bromopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (microwave −120° C., 10 minutes) to afford 2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 76% yield. MS: 342.96 (M+H); 1H NMR (d6-dmso): δ 11.96 (s, 1H), δ 8.85 (br s, 1H), δ 8.57 (s, 1H), δ 8.47 (d, J=9 Hz, 1H), δ 7.79 (d, J=8 Hz, 1H), δ 7.57 (t, J=8 Hz, 1H), δ 7.22 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).