Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].CCCCCC>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4]
Reactant: COC(=O)C1CC(CC=CC(C)=O)CN1C(=O)OC(C)(C)C
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(=O)C1CC(CCCC(C)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 4-(4-oxo-pent-2-enyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (193 mg, 0.5 mmol, 1 equiv) in benzene (0.9 mL) was added a solution of triphenylphosphine-copper (I) hydride hexamer in benzene (3.6 mL). The mixture was stirred at rt overnight and hexane (13 mL) was added. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography to give 4-(4-oxo-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (127 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH2:14][CH2:15]Br.N#N.C([Li])CCC.CCCCCC.[NH4+].[Cl-]>O1CCCC1.CCCCCC.CO.CCOCC>[C:9]([C:4]1[C:3]2[O:13][CH2:14][CH2:15][C:2]=2[CH:7]=[CH:6][CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1OCCBr
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cccc2c1OCC2
Reaction time: 0.5 h

Procedure:
A cold solution of 1,5-dibromo-2-(2-bromoethoxy)-3-tert-butylbenzene (5.00 g, 12.05 mmol) in tetrahydrofuran/hexane (100 mL/20 mL) is cooled to -95° C. (MeOH/Et2O, liquid N2). A solution of n-butyl lithium in hexane (12 mL, 30.1 mmol) is added dropwise, and the reaction is allowed to stir for 0.5 h between -95° C. and -80° C. After 4 h, the reaction is poured onto saturated NH4Cl, and extracted with ethylacetate. The organic layer is washed twice with H2O and once with brine. The combined organic layers are dried (MgSO4), filtered, and evaporated. The resulting oil is purified by chromatography over SiO2 using hexanes. The resulting oil is distilled at reduced pressure to give 7-tert-butyl-2,3-dihydrobenzo[b]furan as a low melting white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27][C:28](O)=[O:29].[I-].ClC1C=CC=C[N+]=1C>>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[NH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: c1ccc(CC2CCCNC2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: COc1ccc2[nH]cc(CCCC(=O)N3CCCC(Cc4ccccc4)C3)c2c1

Procedure:
Equimolar amounts of 3-benzylpiperidine and 4-(5-methoxyindol-3-yl)butanoic acid (preparation analogous to Example 1a) are reacted at room temperature with addition of 2-chloro-1-methyl-pyridinium iodide. After customary work-up, 3-benzyl-1-[4-(5-methoxyindol-3-yl)butanoyl]piperidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]([OH:37])[CH2:34][NH:35][CH3:36].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:35]([CH2:34][CH:33]([OH:37])[C:29]4[NH:28][CH:32]=[CH:31][N:30]=4)[CH3:36])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ncc[nH]1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ncc[nH]2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(1H-imidazol-2-yl)-2-(methylamino)ethanol dihydrochloride (Preparation 99)(82 mg, 0.38 mmol) and diisopropylethylamine (230 μL, 1.3 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (61 mg) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>>[CH2:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:34])[CH:37]([CH3:39])[CH3:38]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CC(C)COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OCC(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 17 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and isobutyl chloroformate (Aldrich), to afford 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid iso-butyl ester. HRMS, observed: 428.2295; Calcd for (M+H)+: 428.2293
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[CH3:21][O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)=[O:24]>CN(C=O)C>[CH3:21][O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:27][CH2:26]1)=[O:24]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](CNc2cc(C(F)(F)F)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (1.6 g, 11.7 mmol), 2-Fluoro-1-nitro-4-trifluoromethyl-benzene (1.22 g, 5.8 mmol) and trans-4-Aminomethyl-cyclohexanecarboxylic acid methyl ester (1.00 g, 5.84 mmol) were dissolved in DMF (10 ml). The mixture was stirred at 50° C. overnight. The solvent was removed under reduced pressure and the crude product dissolved in DCM (15 ml) and washed with water (20 ml) and then with a solution of citric acid (1M, 5 ml). The organic solution was dried over Na2SO4, filtered and the solvent removed by evaporation to give solid material. This was washed with cyclohexane and then with isopropyl ether and purified by silica column using DCM/cyclo hexane (1:1) as eluent. 1.8 g (yield 86%) of the title compound were isolated.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]/[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]/[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C/c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C/c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 77.6 %

Procedure:
In the same manner as in Example 144, 90.9 mg of the title compound was prepared from 50.4 mg of chloromethyl N,N-diisopropylcarbamate and 87.8 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(E)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C(Cl)Cl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(CN)OC
Solvent: ClCCl
Product: COC(CNC(=O)n1ccnc1)OC
Yield: 69 %

Procedure:
A suspension of 1,1'-carbonyldiimidazole (162.15 g) in CH2Cl2 (500 ml) was stirred on an ice-bath. 2,2-Dimethoxyethanamine (105.14 g) was added dropwise and the resulting reaction solution was stirred for 16 hours. The reaction mixture was cooled on ice, stirred for 30 minutes, and was allowed to crystallize. The precipitate was filtered off, stirred for 15 minutes in ethylacetate (250 ml) at RT, then cooled on an ice-bath for 30 minutes. The precipitate was filtered off, washed twice with DIPE (50 ml), then dried, yielding 137.4 g (69%) of N-(2,2-dimethoxyethyl)-1-H-imidazole-1-carboxamide (interm. 26).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]([CH3:12])[Na]>CO>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:10][CH3:12])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CO[Na]
Solvent: CO
Product: COc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
16.4 g 2-amino-4,6-dichloropyrimidine (purchased from Aldrich Chemical Co., Milwaukee, WI 53201) was added to 200 ml of CH3OH. The mixture was cooled to 10° with an ice bath and 5.4 g of NaOCH3 was added in portions while maintaining the temperature. The reaction mixture was allowed to warm to ambient temperature and then heated to reflux for two hours. The reaction mixture was then allowed to cool to ambient temperature and it was stirred overnight. A yellow solid was filtered and recrystallized from butyl chloride. The resulting solid was chromatographed on a dry column of silica, and eluted with 40% EtOAchexane. The resulting yellow solid was further purified by recrystallization from butyl chloride. 9.4 g of product with m.p. 163°-166° was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]1[OH:8].CCN(C(C)C)C(C)C.[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.CN(C=O)C>[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][CH:40]([NH:1][C@@H:2]5[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]5[OH:8])[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: N[C@@H]1CC[C@@H](O)[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@@H]5CC[C@@H](O)[C@H]5O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
31 mg (0.199 mmol) of (1R,2S,3R)-3-aminocyclopentane-1,2-diol are dissolved in 3.5 ml of THF and 2 ml of DMF, and 33.8 μl of DIPEA are added. 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one are added. The mixture is stirred at room temperature for 30 min, 23 μl (0.398 mmol) of glacial acetic acid are added, and the mixture is stirred for a further 10 min. 89 mg (0.398 mmol) of sodium triacetoxyborohydride are subsequently added. The reaction mixture is stirred at room temperature overnight, a concentrated sodium hydrogencarbonate solution is added, and the mixture is extracted twice with EA. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH2:35][CH3:36])([CH3:33])[CH3:32]>>[CH2:35]([N:34]([CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:36]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CCNC(C)C
Product: CCN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1)C(C)C

Procedure:
The product from Example 23D and isopropyl(ethyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 3.3-3.8 (m, 15H), 1.41 (m, 9H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-(trifluoromethoxy)-benzylamine (93 mg, 0.49 mmol). The title compound was obtained as a solid (50 mg, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.42 (1H, m), 8.98 (2H, s), 8.47 (1H, s), 7.42 (2H, dd), 7.33 (2H, dd), 4.43 (2H, m). MS m/z: 521.98, 523.99 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:7][CH2:8]2)[CH3:1])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](c2ccccc2)CC1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-methyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 138°-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5](=[O:12])[N:6]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1.[F:14][C:15]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:20][C:19]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:9]1([CH2:8][N:6]2[C:5](=[O:12])[C:4]([CH3:13])=[CH:3][C:2]([C:23]3[CH:22]=[C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH:20]=[CH:19][C:18]=3[O:17][C:16]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:15]=3[F:14])=[CH:7]2)[CH2:11][CH2:10]1
Reactant: Cc1cc(Br)cn(CC2CC2)c1=O
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(C)c(=O)n(CC3CC3)c2)c1
Temperature: 75 °C
Yield: 28.8 %

Procedure:
5-bromo-3-methyl-1H-pyridin-2-one was N-alkylated with bromomethylcyclopropane to give 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one. 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol), [2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217 mg, 0.5 mol), K3PO4 (263 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 41.3 umol) in dioxane (8 mL)/water (1 mL) were purged with N2 and heated at 70-80° C. for 12 h. Preparative HPLC gave the title compound (56.0 mg, 28.6% yield) as dull-red semisolid. 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.61 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (br. s., 1H), 3.93 (d, J=7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H). LCMS: 475.1 (M+1)+
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]Cl)=[N:33][CH:34]=1>CN(C)C=O>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)=[N:33][CH:34]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(Cl)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (20 mg, 0.12 mmol) described in Manufacturing Example 63-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), and stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (41.1 mg, 93%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][C:29]#[N:30]>CN(C=O)C>[C:29]([CH2:28][N:11]1[CH:12]=[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(CC#N)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution of tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g in 2 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and a solution of chloroacetonitrile (0.138 g) in DMF (1 ml) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using ethyl acetate\hexane (2:8) as eluent to afford tert-butyl 4-(1-(cyanomethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate as pure solid product.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[CH3:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])=[O:9])[CH:16]=2)=[C:19]([CH3:27])[CH:20]=1
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea (794 mg) in ethanol (50 ml) were added electrolytic iron powder (442 mg), ammonium chloride (847 mg) and water (10 ml), followed by stirring at 90° C. for 1 hr. The reaction mixture was allowed to cool down to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1) to provide the titled compound (110 mg, 15%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:17]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCC>[Br:17][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Product: Brc1ccc2c(c1)OCCO2
Reaction time: 1 h

Procedure:
To a mixture of 1,4-benzodioxane (5.0 g) and sodium carbonate (5.9 g) in hexane (100 ml) was added dropwise at room temperature a solution of bromine (1.9 ml) in hexane (20 ml) for 1 hour and the mixture was stirred for 1 hour. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil of 6-bromo-2,3-dihydro-1,4-benzodioxine (7.48 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[C:11]([O:19][CH2:20][C@H:21]2[CH2:23][O:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][C@@H:21]([CH2:23][OH:22])[CH2:20][O:19][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of acetic acid 4-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl ester (1.34 g, 4.26 mmol) in THF (30 ml), was added aq 2 M NaOH (2.45 ml). The mixture was stirred overnight at RT, THF was removed under reduced pressure and water (50 ml) was added. The water solution was then extracted three times with EtOAc and the combined extracts washed with water and brine. The organic layer was dried (Na2SO4), and evaporated in vacuo. The crude product (1.07 g) was used without purification.