Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:35]3[C:29]4[C:30](=[N:31][CH:32]=[C:27]([N:24]5[CH2:25][CH2:26][O:21][CH2:22][CH2:23]5)[CH:28]=4)[C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:34]3)=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CC4(CCOCC4)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (50 mg, 0.17 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (48.0 mg, 0.17 mmol), sodium tert-butoxide (33.5 mg, 0.35 mmol), XPhos precatalyst (26 mg, 0.035 mmol), and toluene (1.7 mL) at 90° C. for 18 h. Purification by reverse-phase HPLC (0-70% acetonitrile in water) gave 1′-(7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo-[3,2-b]pyridine] as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.60 (1H, d, J=5.1 Hz), 7.87 (1H, dd, J=9.8, 2.5 Hz), 7.69-7.75 (2H, m), 7.59-7.61 (1H, m), 7.29-7.36 (1H, m), 7.23-7.27 (1H, m), 5.89 (1H, s), 4.14-4.21 (2H, m), 4.02 (2H, s), 3.70-3.81 (4H, m), 3.50-3.62 (2H, m), 2.95-3.09 (4H, m), 2.51 (4H, s), 2.45 (1H, s), 2.38 (3H, s), 1.81-1.90 (1H, m), 1.70-1.81 (1H, m). Mass Spectrum (ESI) m/e=526.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 30 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 100 mg of ethyl 4-aminobenzoate in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 30 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 202 mg of expected product is thus obtained in the form of white-cream crystals.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][CH:9]([CH3:12])[CH2:10][OH:11].[CH2:13]([Sn:17]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]I)[CH2:14][CH2:15][CH3:16]>O.CCCCCCC.CN(C)C=O>[CH2:24]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:11][CH2:10][CH:9]([CH3:12])[CH3:8])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)CO
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of sodium hydride (66%, 250 mg, 7.0 mmol) and tetrahydrofuran (20 ml) were added 2-methylpropanol (0.69 ml, 7.4 mmol) and N,N-dimethylformamide (20 ml) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added dropwise tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 5 hours and a half. To the reaction mixture were added heptane and water, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (1.7 g, 4.4 mmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:3]([N:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(Nc1ccccc1)c1c(Cl)cccc1C(=O)O
Yield: 66.7 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido) benzoic acid from Example 39 (4.6 g, 15.7 mmol), aniline (3.58 mL, 39.3 mmol) and DMF (45 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (400 mL) and 5% KOH (125 mL) and washed with CH2Cl2 (3×125 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (50 mL) and dried under high vacuum at 45° C. to yield 3.19 g (67%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.1 (broad s, 1H), 9.85 (s, 1H), 7.74 (d, J=7.6, 1H), 7.71 (d, J=8.0, 1H), 7.35 (t, J=7.6, 1H), 7.10 (t, J=7.6, 2H), 6.65-6.58 (m, 3H), 6.1 (broad s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 169.62, 166.77, 148.33, 133.87, 132.70, 131.53, 130.93, 128.90, 128.82, 127.21, 116.59, 112.57, 47.16; MS (LSIMS, m/z) 305 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.[H-].[Na+].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[CH2:23]([N:5]1[C:4](=[O:20])[CH2:3][CH:2]([CH3:1])[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6]1)[CH3:24]
Reactant: CCBr
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1N=C(c2ccc3c(c2)CCC(=O)N3C)C(C)CC1=O
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 5.4 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one in 50 ml of dimethylformamide was added 1.1 g of 50% sodium hydride. After stirring for about 30 minutes, 2.4 g of ethyl bromide was added and the mixture was stirred at about 40° C. for one hour. The reaction mixture was poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3.7 g of 6-(2-ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 170°-172° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[BH4-].[Na+]>C1COCC1.C(O)C.Cl>[OH:22][CH:19]1[CH2:18][CH2:17][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: CCCc1ccc(C2=CCC(C3CCC(=O)CC3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1ccc(C2CCC(C3CCC(O)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 1-(4-propylphenyl)-4-(4-oxocyclohexyl)-1-cyclohexene described above in an amount of 9.5 g (32 mmol) was dissolved in mixed solvent of 200 ml of THF and 50 ml of ethanol, and cooled down to 0° C. Sodium borohydride in an amount of 1.2 g (32 mmol) was gradually added thereto and the mixture was stirred at the same temperature for 1 hour. The reaction solution was added in 150 ml of 1N hydrochloric acid and extracted with diethyl ether. After the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, the solvent was distilled off under a reduced pressure. The residue was dissolved in 80 ml of mixed solvent of ethanol/ethyl acetate (1/1), the solution was subjected to a hydrogenation by using Raney Nickel catalyst, and then the catalyst was filtered off. The solvent was distilled off and then the residue was recrystallized by using toluene to give 2.5 g (8.3 mmol) of 4-(4-(4-hydroxycyclohexyl)cyclohexyl)-1-propylbenzene. Yield of this compound was 26%.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]([C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: c1cc(OCC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 22, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[S:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (45.3 mg) with purity >90%: MS (pos) m/z 399.1, 401.1; HRMS m/z 397.9711 (calc. of monoisotopic mass for C16H12Cl2N2O2S2 gives 397.9117).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH:17]=O.[C:19]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[CH:19]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1nc2c(N3CCOCC3)ccnn2c1Br
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of compound 14b (0.78 g, 2.5 mmol) in MeOH (20 mL) was added K2CO3 (1.1 g, 7.5 mmol) and a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (0.53 g, 2.7 mmol) in MeOH (5 mL). The reaction mixture was stirred at rt overnight, diluted with DCM (200 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0-20% EtOAc/DCM) to give compound 18a as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.13 (d, J=5.56 Hz, 1H), 6.11 (d, J=5.56 Hz, 1H), 3.94-4.01 (m, 4H), 3.86-3.93 (m, 4H), 3.41 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:38](O)=[O:39])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:38]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:39])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a suspension of 60% sodium hydride (91 mg, 2.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (278 mg, 2.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.23 mmol) and 1,1′-carbonyldiimidazole (75 mg, 0.46 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (25 mg, 20%) as a white solid: LC/MS m/e calcd for C28H30N2O5S2 (M+H)+: 539.69, observed: 539.1.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:23][CH:24]=1)=[O:34]
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2,2-dimethyl-propionamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2].O.[PH2]([O-])=[O:20].[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH:15]=[O:20])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc2ccc(C#N)cn12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cnc2ccc(C=O)cn12
Temperature: 75 °C
Yield: 44.4 %

Procedure:
(6-Cyano-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (1.80 g, 7.46 mmol) is dissolved in a mixture of water (5.0 ml), pyridine (10 ml) and glacial acetic acid (5.0 ml). Sodium hypophosphite monohydrate (6.03 g, 56.4 mmol, 8 equiv) and Raney nickel (approx. 1.2 g) are added at room temperature. The reaction mixture is heated to 75° C. for 1 h, cooled to room temperature and filtered through Celite. The filtrate is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (cylcohexane/EtOAc 1:1, +0.1% NEt3) affords the title compound (770 mg, 42%). 1H NMR (400 MHz, CDCl3): δ=10.01 (s, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 4.04 (s, 2H), 1.30 (t, J=7.4 Hz, 3H). MS (ES+): 233 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)([OH:9])[CH3:8])=[N:4][CH:3]=1.O.[NH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:25]1[CH:30]=[C:29]([C:2]2[S:6][C:5]([C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)([OH:9])[CH3:8])=[N:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(Br)s2)CC1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(N)c3)s2)CC1
Yield: 91.9 %

Procedure:
The product of Step 2 (87 mg, 0.222 mmol), 3-aminophenylboronic acid monohydrate (41.3 mg, 0.267 mmol), Pd(Ph3P)4 (12.85 mg, 0.011 mmol) and Na2CO3 (0.333 mL, 0.667 mmol) were stirred in DME at 100° C. overnight under N2. The reaction mixture was filtered through a pre-pack pad of celica with dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography to give tert-butyl 4-{1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]-1-hydroxyethyl}piperidine-1-carboxylate (82.4 mg, 0.204 mmol, 92%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Sn].Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccccc2)c(Cl)c1

Procedure:
To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tin powder (12 g) is added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60mL) is added and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension is filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the desired product as a yellow solid. Recrystallization from ethyl acetate-hexanes provided the product as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:31])=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[Cl:14])[NH2:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)ccc1Cl
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of 2-tert-butyl-1-chloro-4-nitrobenzene (505 mg, 2.36 mmol) in EtOAc (25 mL) was added SnCl2 hydrate (906 mg, 3.55 mmol). This mixture was heated at reflux and the solids dissolved. After 2 h, additional SnCl2 hydrate (906 mg, 3.55 mmol) was added and the solution was heated at reflux for another 2 h. The reaction mixture was purified by column chromatography (SiO2, 20% EtOAc/Hex) to give 210 mg of the title compound as a yellow oil (48%). 1H NMR (400 MHz, CD3OD) δ: 6.68 (d, 1H), 6.16 (d, 1H), 6.02 (dd, 1H), and 0.92 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[CH2:18][CH:19]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][C:31]3=NOC)[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:42]1CCOCC1>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:27][C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:19]([C:28]3[CH:29]=[C:33]4[C:34](=[CH:35][CH:36]=3)[C:30](=[O:42])[CH2:31][CH2:32]4)[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C1CCc2ccc(C(CC(=O)C3CCCN(C(=O)OCc4ccccc4)C3)C(=O)c3ccncc3)cc21
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)OCc5ccccc5)C4)oc3-c3ccncc3)ccc21
Temperature: 90 °C
Yield: 69 %

Procedure:
A solution of the product of Step 4 (4.0 g, 7.42 mmol) in 1,4-dioxane (100 ml) and acetone (250 ml) was treated with 5M hydrochloric acid (50 ml) and the mixture heated at 90° C. for 5 hours. After cooling to room temperature, the reaction was concentrated and re-dissolved in chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (4:6) to yield the title compound (2.50 g, 69%); MS(ES+) m/e 493 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2([NH:15][C:14](=[O:16])[O:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:15]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]2)[CH2:12][O:13][C:14]1=[O:16]
Reactant: O=C1NC2(CCN(Cc3ccccc3)CC2)CO1
Agent: [Pd]
Solvent: CO
Product: O=C1NC2(CCNCC2)CO1
Reaction time: 5 h

Procedure:
To a 250 ml round bottom flask was purged with nitrogen was added a solution of 8-benzyl-3-oxa-1,8-diazaspiro[4.5]decan-2-one (12.5 g, 51 mmol) in MeOH (70 ml) and 1.0 g of activated 10% Pd/C. The reaction mixture was placed under H2 (60 psi) for 5 h. The reaction mixture was filtered through celite, and the filtrate was evaporated under vacuum to yield the title compound as a solid.