Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]4[CH:20]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Reactant: C1CCNCC1
Product: c1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C

Procedure:
The product of Example 16 Step A (60 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (60 mg). 1H-NMR (CD3OD) δ8.30 (m, 1H), 8.00 (s, 1H), 7.74 (m, 2H), 7.43 (m, 1H), 7.20 (m, 1H), 6.90 (m, 2H), 6.80 (m, 1H), 3.98 (t, J=6.0 Hz, 2H), 2.47 (m, 6H), 1.93 (m, 2H), 1.55 (m, 4H), 1.41 (m, 2H)
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[NH:23][C:24]([C:26]2[N:27]=[N:28][N:29]([OH:31])[CH:30]=2)=[O:25])=[CH:17][CH:16]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:4][CH2:5][O:31][N:29]1[CH:30]=[C:26]([C:24]([NH:23][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=3[Cl:7])=[CH:16][CH:17]=2)=[O:25])[N:27]=[N:28]1)(=[O:3])[CH3:2]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: CC(=O)OCBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCOn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 55 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
Bromomethyl acetate (15.3 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 55° C. for 1 hour. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (5.2 mg, purity 96%) as a white solid. MS m/z [M+H]+ calc'd for C22H21Cl2N5O2, 538.08. found 538.1.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]([S:11][C:12]1[CH:31]=[CH:30][C:15]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1)([F:10])[F:9].C(=O)(O)[O-:33].[Na+].[OH2:37]>O.[Ru](Cl)(Cl)Cl>[F:9][C:8]([F:7])([F:10])[S:11]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)=[CH:14][CH:13]=1)(=[O:33])=[O:37]
Reactant: O
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(SC(F)(F)F)cc2)CC1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)CC1

Procedure:
2.55 g sodium periodate and 0.4 mg ruthenium (III) chloride hydrate were added to 60 mL solution mixture (carbon tetrachloride/acetonitrile/water=1:1:2) of 1.5 g t-butyl 4-(4-trifluoromethylsulfanyl-phenoxy)piperidine-1-carboxylate (compound in Production Example 454) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water and a sodium bicarbonate solution were added thereto, and the reaction solution was extracted with ethyl acetate, dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.3 g t-butyl 4-(4-trifluoromethylsulfonylphenoxy)piperidine-1-carboxylate. 2 mL solution of 4 N hydrogen chloride in ethyl acetate was added thereto and left for 1 hour. The solvent was removed, and the precipitated crystals were washed with ethyl acetate/ether to give 965 mg of the title compound as colorless crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[C:5]2=[O:22].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][C:39]#[CH:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:40]#[C:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:3]=2)[N:8]=[CH:7][N:6]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: C#CCc1ccccc1
Reactant: O=C(O)c1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of the compound obtained in Step 1 (0.3 g, 0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is heated to 50° C. for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3×100 ml of water, 1×100 ml of brine. The organic layer is then dried over MgSO4, and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with a mixture of hexane/ethyl acetate: 8/1 to yield 225 mg of the pure desired product as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.Cl>C(OCC)(=O)C.O.CN(C=O)C>[CH2:12]([O:11][C:9]([CH2:8][N:19]([C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=1)[C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(N(CC(=O)OCc2ccccc2)C(=O)c2ccc(F)cc2)cc1

Procedure:
Potassium carbonate and benzyl bromoacetate were added to DMF solution of ethyl (4-aminophenoxy)acetate and stirred under heating. After adding water and ethyl acetate to the reaction mixture, the organic layer was separated, washed and dried, and then the solvent was evaporated under a reduced pressure. Dichloromethane solution of the thus obtained crude product was mixed with TEA, 4-fluorobenzoyl chloride was added dropwise thereto under ice-cooling and then the reaction solution was stirred. After adding 1 M hydrochloric acid to the reaction solution, the organic layer was separated, washed and dried, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by SCG, ethyl {4-[benzyloxycarbonylmethyl-(4-fluorobenzoyl)amino]phenoxy}acetate (colorless oil) was obtained.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[N:8]([O-])=O.[Na+].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CC(O)=O.O.CC(O)=O.O.[Zn]>[CH2:19]([O:18][C:12]([C:13]1[C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[NH:8][C:14]=1[CH3:16])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c(C(C)=O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
Pentane-2,4-dione (10.3 mL, 0.1 mol) was diluted with AcOH and cooled to 0° C. NaNO2 (6.9 g, 0.1 mol) was dissolved in H2O (10 mL) and added dropwise, keeping the internal temperature ≦10° C. The mixture was stirred for 1 h with cooling then 3 h at room temperature. Ethyl acetoacetate (14 mL, 0.11 mol) was dissolved in 1:1 AcOH/H2O (100 mL) and Zn powder (7.19 g, 0.11 mol) was added. To this the oxime solution was added and the mixture was heated at 100° C. for 30 min then poured into H2O (0.8 L). The aqueous mixture was extracted with EtOAc (3×500 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by SiO2 chromatography (heptane/EtOAc gradient elution) to afford 5-acetyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (4.32 g). An aliquot (3.5 g, 16.7 mmol) was added to KOH (4.22 g, 75.3 mmol) dissolved in H2O (5 mL) and the mixture was heated at 130° C. for 18 h. It was then cooled, diluted with H2O (50 mL) and acidified with 2 M aq HCl. This mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by SiO2 chromatography (EtOAc) to afford 1-(3,5-dimethyl-1H-pyrrol-2-yl)-ethanone (1.05 g). An aliquot (536 mg, 3.9 mmol) was suspended in N,N-dimethylformamide dimethyl acetal (1.2 mL, 8.8 mmol) in a N2-flushed flask and heated at 90° C. for 48 h. The mixture was cooled and triturated in cold EtOAc. The resulting precipitate was filtered and washed with EtOAc to afford the title compound (444 mg) as a buff. 1H-NMR (DMSO-d6) δ: 1.41 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.23 (br. s, 6H, CH3), 4.77 (d, 1H, J=12.4 Hz, CH), 4.95 (s, 1H, pyrrolyl-H), 6.85 (d, 1H, J=12.4 Hz, CH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH2:14][SH:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[H-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([CH2:20][S:15][CH2:14][CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:23][CH2:22]1
Reactant: CCOC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CSCC1CC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
14.7 g (59 mmol) of N-Boc-L-cysteine ethyl ester dissolved in 300 ml of dimethylformamide are added dropwise at 0° to a suspension of 2.49 g (64.8 mmol) of sodium hydride (60% in oil) in 200 ml of dimethylformamide and the mixture is stirred at 0° for 30 minutes. Subsequently, 8.37 g (62 mmol) of bromomethylcyclopropane in 30 ml of dimethylformamide are added dropwise thereto. The solution is stirred at room temperature overnight. The dimethylformamide is evaporated under reduced pressure, the residue is partitioned between ether and water and the aqueous phase is extracted 4 times with ether. The combined organic phases are washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed on silica gel using a 1:19 mixture of ethyl acetate and hexane as the eluent. There are obtained 8.4 g of tert-butyl rac-[2-[(cyclopropylmethyl)thio]-1-(ethoxycarbonyl)ethyl]carbamate as a colourless oil, MS: 304 (M+H)+.
Reaction SMILES: [CH2:1]([P:3](Cl)([CH2:5][CH3:6])=[O:4])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:20]=1[CH2:21][N:22]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:23]([C:25]1[C:26](=[O:37])[N:27]([CH3:36])[C:28]2[C:33]([C:34]=1[O:35][P:3]([CH2:5][CH3:6])([CH2:1][CH3:2])=[O:4])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24]
Reactant: COc1ccc(CN(C(=O)c2c(O)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Reactant: CCP(=O)(Cl)CC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCP(=O)(CC)Oc1c(C(=O)N(Cc2ccc(OC)cc2OC)c2ccccc2)c(=O)n(C)c2ccccc12
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Diethylphosphorylchloride (150 mg, 0.87 mmol) was added to a solution of EtNiPr2 (129 mg, 1.00 mmol), DMAP (10 mg, 0.08 mmol) and N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (222 mg, 050 mmol) in CH2Cl2 (3.0 mL). The reaction mixture was stirred for 30 min and was then concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (196 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[CH2:10]Br)=[O:4].[O-:16][CH2:17][CH3:18].[Na+].[CH2:20](O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[CH2:10][O:16][CH2:17][CH3:18])=[O:4])[CH3:20]
Reactant: CC[O-]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1CBr
Reactant: CCO
Agent: [Na+]
Product: CCOCc1c(C(=O)OCC)cnn1C(C)(C)C
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
A solution of 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester (220 mg, 0.79 mmol) in ethanol (4.0 mL, 0.2M) was treated with sodium ethoxide (65.4 mg, 0.96 mmol). The reaction mixture was warmed to 90° C. where it was stirred for 2.5 h. At this time, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate (75 mL) and water (50 mL). The organics were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (102.8 mg, 51%) as an orange oil. The material was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:21])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)O)CC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)NS(C)(=O)=O)CC1
Yield: 41.6 %

Procedure:
To a stirred solution of 4-(4-(2-tert-butylphenyl)piperazin-1-yl)-4-oxobutanoic acid obtained in Example 53 (0.100 g, 0.31 mmol), EDCI (0.090 g, 0.47 mmol), HOBt (0.064 g, 0.47 mmol) and diisopropylethylamine (0.163 g, 1.26 mmol) in methylene chloride (2.0 mL) was added methane-sulfonamide (0.031 g, 0.31 mmol) at room temperature. After 18 h the reaction mixture was diluted with ethyl acetate, washed with 1.0 M hydrochloric acid (5.0 mL), water (5.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 methylene chloride/MeOH) to provide 4-(4-(2-tert-butylphenyl)piperazin-1-yl)-N-(methylsulfonyl)-4-oxobutanamide (0.051 g, 41%) as an off-white solid, mp: 89-90° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4](C(OC(C)CC)=O)[C:5]2[C:6]([N:22]=1)=[N:7][CH:8]=[C:9]([C:11]1[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:21]=1)[CH:10]=2.Cl[C:31]1[C:36]([CH3:37])=[C:35]([Cl:38])[N:34]=[CH:33][N:32]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:38][C:35]1[N:34]=[CH:33][N:32]=[C:31]([N:17]2[CH2:16][C:15]3[CH:21]=[C:11]([C:9]4[CH:10]=[C:5]5[NH:4][C:3]([CH3:2])=[N:22][C:6]5=[N:7][CH:8]=4)[CH:12]=[CH:13][C:14]=3[O:20][CH2:19][CH2:18]2)[C:36]=1[CH3:37]
Reactant: CCC(C)OC(=O)n1c(C)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc(Cl)c3C)CCO4)cc2[nH]1
Yield: 28.8 %

Procedure:
A solution of 1-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (0.213 g, 0.512 mmol, example 6, step 2), 4,6-dichloro-5-methylpyrimidine (0.100 g, 0.613 mmol), and diisopropylethylamine (0.330 g, 2.56 mmol) in N-methylpyrrolidinone (2 mL) was stirred at room temperature for 17 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (25 mL), and dried over sodium sulfate. Filtration, concentration and purification by column chromatography on silica (97:3 dichloromethane/methanol) provided 4-(6-chloro-5-methylpyrimidin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.06 g, 31% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 7.08 (d, 1H), 4.81 (s, 2H), 4.39-4.32 (m, 2H), 4.03-3.97 (m, 2H), 2.64 (s, 3H), 2.37 (s, 3H); MS (EI) for C21H19ClN6O: 407 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[C:16]([N+:20]([O-])=O)=[N:17][NH:18][CH:19]=2)[CH:5]=[C:4]([F:23])[C:3]=1[S:24]([NH:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)(=[O:26])=[O:25].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:16]1[C:15]([C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][C:6]2[CH:5]=[C:4]([F:23])[C:3]([S:24]([NH:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)(=[O:25])=[O:26])=[C:2]([F:1])[CH:7]=2)=[CH:19][NH:18][N:17]=1
Reactant: O=[N+]([O-])c1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of the 2,6-difluoro-4-{[(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide (167 mg, 0.343 mmol) prepared in Example 116c in ethanol (4.0 mL) and water (2.0 mL), ammonium chloride (92.0 mg, 1.72 mmol) and an iron powder (57.6 mg, 1.03 mol) were added, and the reaction solution was stirred for 2 hours under heated reflux. After allowing to cool, the reaction solution was filtered through celite, the filtrate was vacuum concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=93:7) to yield the title compound (145 mg, 92%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=1.C(OC([N:25]1[C:30]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:29][CH:28]([NH2:36])[CH2:27][CH2:26]1)=O)(C)(C)C>>[NH:25]1[C:30]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:29][CH:28]([NH:36][C:13]2[N:12]=[C:11]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1
Reactant: Fc1cccc2c(-c3ccnc(Cl)n3)c[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC12CCCCC2
Product: Fc1cccc2c(-c3ccnc(NC4CCNC5(CCCCC5)C4)n3)c[nH]c12

Procedure:
The racemic title compound was prepared as described in Example 244, starting from 7-Fluoro-3-(2-chloro-pyrimidin-4-yl)-1H-indole and 4-amino-1-aza-spiro[5.5]undecane-1-carboxylic acid tert-butyl ester from step A.
Reaction SMILES: [OH-].[Na+].[CH:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)=[O:4].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>O>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([CH:3]=[O:4])[CH2:14][CH2:13]2
Reactant: ClCC1CO1
Reactant: O=CN1CCc2cc(O)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=CN1CCc2cc(OCC3CO3)ccc2C1
Yield: 82.8 %

Procedure:
A solution of 6.8 g of sodium hydroxide in 90 ml of water is added dropwise over 1 hour to a mixture of 26.6 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline and 42.5 g of epichlorohydrin at 60° C. The reaction mixture is held at this temperature for an additional hour, then allowed to cool and extracted several times with methylene chloride. The organic phase, dried over sodium sulfate, is evaporated and the residue is rubbed with diethyl ether. 29.0 g of 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydro isoquinoline are obtained. m.p. = 78° - 79° C. (ethyl acetate - diethyl ether).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12].P(Cl)(Cl)(Cl)=O.[CH2:19](C1C(O)=C([N+]([O-])=O)C(=O)NC=1C)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:19])[NH:5][C:4](=[O:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCc1c(C)[nH]c(=O)c([N+](=O)[O-])c1O
Reactant: CCc1c[nH]c(=O)c([N+](=O)[O-])c1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1c(C)[nH]c(=O)c([N+](=O)[O-])c1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
As described for compound 6b in example 7, phosphorus oxychloride (8.3 ml, 88.8 mmoles) was added to a solution of compound 5c (4.00 g, 20.2 mmoles) and benzyltriethylammonium chloride (18.40 g, 80.8 mmoles) in acetonitrile (80 ml). The mixture obtained was agitated at 40° C. for 30 minutes and heated under reflux for 1 hour. After evaporation of the solvent, 150 ml of water was added and the mixture agitated at ambient temperature for 48 hours. The brown precipitate was collected, washed with cyclohexane (3×10 ml) and recrystallised in ethanol to give compound 6c (1.5 g, 34%) in the form of pale yellow crystals: NMR-1H (DMSO-d6) δ 12.98 (1H, s, NH-1), 2.58 (2H, q, L=7.5 Hz, CH2CH3), 2.38 (3H, s, CH3 -6), 1.08 (3H, t, J=7.5 Hz, CH2CH3 ).