Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:39])[NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]([NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 84 %

Procedure:
Preparation of example 54 from the title compound of Example 53 (30 mg, 0.056 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (26 mg, 0.047 mmol) as a yellow powder in 84% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:13]=[CH2:14])OB(C=C)O1.C1C=CN=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[C:36]=2I)=[O:34])=[CH:28][C:27]=1[C:49](=[O:54])[NH:50][CH:51]1[CH2:53][CH2:52]1>O.C(COC)OC.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>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[C:36]=2[CH:13]=[CH2:14])=[O:34])=[CH:28][C:27]=1[C:49](=[O:54])[NH:50][CH:51]1[CH2:53][CH2:52]1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(I)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)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: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(C(F)(F)C(F)(F)F)nn(C)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1

Procedure:
In succession, 18.5 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium, 0.044 g (0.320 mmol) of potassium carbonate in 1 ml of water, and 0.077 g (320 μmol of 2,4,6-trivinylcyclotriboroxane pyridine complex are added to a solution of 180 mg (0.32 mmol) of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-iodo-1H-pyrazole-5-carboxamide from Example Ik-4 in 3 ml of dimethoxyethane, and the reaction mixture is heated under reflux for 20 hours. The solvent is completely distilled off at reduced pressure on a rotary evaporator and the residue is purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate; gradient: 2 hours, from 0% to 100% ethyl acetate). This gives 0.107 g of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-ethenyl-1H-pyrazole-5-carboxamide (70%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (150 mg, 73%)
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[CH2:40][CH2:39][O:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[CH2:40][CH2:39][O:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
TFA (3.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (720.2 mg, 1.070 mmol) in DCM (3.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to give the title compound as a white solid (187.7 mg, 37%). LCMS calc. for C22H23F2N6O2S (M+H)+: m/z=473.1. found 473.2. 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.68-7.39 (m, 3H), 7.26 (t, J=8.8 Hz, 2H), 4.48 (t, J=8.9 Hz, 2H), 3.37 (t, J=8.5 Hz, 2H), 3.14-3.01 (m, 1H), 3.00-2.90 (m, 1H), 2.89-2.81 (m, 1H), 2.77-2.69 (m, 1H), 2.55-2.50 (m, 1H), 1.83-1.59 (m, 3H), 1.12-1.00 (m, 1H) ppm.
Reaction SMILES: [C:1]1(N)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[N:9]1[CH:14]=CC=CC=1.C(OC(=O)C)(=[O:17])C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:14]([NH2:9])(=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Yield: 49 %

Procedure:
Dissolving 8.0 g (30 mmol) of (4-bromo-phenyl)-(2-nitrophenyl)-amine into 80 milliliter of tetrahydrofuran, an aqueous solution prepared by dissolving 24 g (0.14 mmol) of sodium dithionite into 100 milliliter of water was added. Subsequently, adding 10 milliliter of methanol, the resultant solution was stirred at room temperature for 3 hours. After recognizing that the color (orange) of the resultant solution almost disappeared, water was added, followed by extracting with ethyl acetate. After sufficiently drying an organic layer with sodium sulfate, the solvent was removed by distillation, and as a result, phenylenediamine was obtained. Dissolving the resultant phenylenediamine into 150 milliliter of ethyl acetate, an organic layer was extracted. Further, 3.0 g (38 mmol) of pyridine, 1.8 g (18 mmol) of acetic anhydride and catalyst amount of 4-dimethylaminopyridine (DMAP) were added to the organic layer, and the resultant solution was stirred at room temperature for 3 hours, followed by left standing for a night. After completion of the reaction, adding water, separation with filtration was carried out for precipitated solids and then, they were sufficiently washed with water and methanol, thereby obtaining 4.1 g of benzamide as white solid (yield: 49%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Imidazole (5.00 g, 73.6 mmol) was dissolved in toluene (80 ml), and thereto were added triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (6.77 ml, 63.3 mmol), and the mixture was stirred at room temperature for 8 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to azeotropic distillation with hexane to give the title compound (10.9 g, 98%).
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH2:29]>>[OH:1][CH:2]([CH2:27][NH:29][CH3:28])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC1(C)CC(c2ccc3ccccc3c2)c2ccc(OCC3CO3)cc2O1
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccc2ccccc2c1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman with methylamine, by an analogous method to that described in Example 2 gave 7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-(2-naphthyl)chroman isolated as its hydrochloride salt m.p. 183°-188°.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:14]1[CH:27]=[C:26]([O:28][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloroquinoxaline (0.99 g 0.005 mole), ethyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (1.14 g, 0.005 mole), anhydrous potassium carbonate (0.76 g, 0.0055 mole) and dimethylformamide (20 ml) was stirred and heated at 100° C. for 2 hours. The mixture was cooled and then poured into water (200 ml) to give a white precipitate which was collected by filtration. Recrystallization from ethanol gave the product, ethyl 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionate, as colourless crystals (1.3 g; 66%), mp 110° C. Proton magnetic resonance spectrum (CDCl3, δ in ppm); 1.3, t, 3H (CH2CH3); 1.7, d, 3H (CHCH3); 4.3, q, 2H (OCH2CH3); 4.8, q, 1H (CHCH3); 6.9-7.5, m, 3H (phenoxy ring); 7.8, bs, 2H (C7, C8 of quinoxaline); 8.2, bs, 1H (C5 of quinoxaline); 8.8, s, 1H (C3 of quinoxaline).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][CH2:29]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[CH2:29]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:16]=1)[CH:28]=[CH2:27]
Reactant: ClCCCBr
Reactant: Cc1cccc(-c2nn3cc(CO)ccc3c2-c2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOCc1ccc2c(-c3ccc(F)cc3)c(-c3cccc(C)n3)nn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A solution of EXAMPLE 99 (0.13 g, 0.39 mmol) and 1-bromo-3-chloropropane (0.06 g, 0.39 mmol) in DMF (10 mL) was treated with cesium carbonate (0.14 g, 0.43 mmol) and heated to 80° C. The reaction is stirred overnight and is diluted with EtOAc and water. The organic phase is separated and washed with brine. After drying over Na2SO4, the organic phase is filtered, and the solvent removed to afford 0.04 g (27%) of product. MS ES+ m/e 374.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12](=O)[C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:3]=1.CC(N(C)C)=O.P(Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][C:10]2[CH2:11][S:12][C@@H:13]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:32](=[O:44])[N:14]3[C:15]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:3]=1
Reactant: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)cc(=O)o1
Solvent: ClP(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)cc(=O)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
A stirred solution of diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthio) -7β-phenylacetamidoceph-3-em-4-carboxylate 1-oxide (581 mg) in dichloromethane (5 ml) was cooled in an ice bath and dimethylacetamide (0.25 ml) was added followed by phosphorus trichloride (0.16 ml). The mixture was stirred at 0° C. for 15 mins. and then partitioned between sodium bicarbonate solution and chloroform. The chloroform layer was washed with water, then brine, dried over magnesium sulphate and evaporated. The title compound (509 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel, 1:1 hexane: ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 3400, 1795, 1725, 1710, and 1680 cm-1. δH (CDCl3) 2.16 (3H, s), 3.33 (1H, d, J 18.1Hz), 3.62 (1H, d, J 17.9Hz), 3.65 (2H, s), 5.03 (1H, d, J 5.1Hz), 5.66 (1H, s) 5.71 (1H, s), 5.94 (1H, dd, J 5.1 and 9.2Hz), 6.96 (1H, s), 6.98 (1H, d, J 9.1Hz), 7.2-7.4 (15H, m). [mass spectrum: +ve ion (3 NOBA, Na+) M Na+ 647].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1)[CH2:5]2.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43]>C1COCC1>[OH:31][C:28]([C:19]1[N:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:41](=[O:44])[CH2:42][CH3:43])[CH:3]=4)[CH2:7]3)[CH2:17][CH2:16]2)[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[N:20]=1)([CH3:29])[CH3:30]
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2c(c1)CC(CN1CCC(n3c(C(C)(C)O)nc4cc(C)ccc43)CC1)C2
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (50 mg, 0.12 mmol), N,N-diisopropylethylamine (46 mg, 0.36 mmol) in THF (3 mL) was added propionyl chloride (12 mg, 0.13 mmol). After stirring overnight, the reaction mixture was quenched with silica-supported diamine-3 (119 mg, Silicycle) to scavenge the excess propionyl chloride. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography to afford N-(2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-ylmethyl}-indan-5-yl)-propionamide (54 mg, 95%) as white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([B:33]([OH:35])[OH:34])=[CH:29][CH:28]=1>>[N:27]1[CH:32]=[CH:31][C:30]([B:33]([OH:35])[OH:34])=[CH:29][CH:28]=1.[CH3:26][O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[C:7]=2[N:8]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Agent: OB(O)c1ccncc1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3ccncc3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 208 using 8-Chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94) and pyridine-4-boronic acid for 30 minutes at each of 100° C., 110° C., 120° C. and 130° C.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].[CH2:7]=[O:8]>>[NH2:1][CH:4]([CH2:5][CH3:6])[CH2:7][OH:8].[N+:1]([CH:4]([CH2:5][CH3:6])[CH2:7][OH:8])([O-:3])=[O:2]
Reactant: C=O
Reactant: CCC[N+](=O)[O-]
Product: CCC(CO)[N+](=O)[O-]
Product: CCC(N)CO

Procedure:
2-Amino-n-butanol is prepared by condensing 1-nitropropane with formaldehyde in an aqueous medium in the presence of a phase transfer agent which acts both as a basic catalyst and as a surfactant, and the resulting 2-nitro-n-butanol obtained is subjected to catalytic hydrogenation using a hydrogenating mixture consisting of hydrogen and nitrogen at a pressure of 8 to 12 bars.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:39])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=4[S:23](=[O:37])(=[O:36])[N:22]=3)[C:11]2=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:41]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:39])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O-:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=4[S:23](=[O:36])(=[O:37])[N:22]=3)[C:11]2=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:41]
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A suspension of the product of Example 38C (0.339 g) in water (10 mL) was treated with 0.997N sodium hydroxide solution (0.595 mL, 0.593 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.334 g, 95%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.63 (m, 3 H) 0.98 (m, 8 H) 1.45 (m, 7 H) 1.68 (m, 1 H) 2.09 (m, 1H) 2.93 (m, 3 H) 7.30 (m, 3 H) 7.45 (m, 3 H) 8.05 (m, 1 H) 9.87 (m, 1 H) 15.45 (m, 1 H). MS (ESI−) m/z 570 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.C[CH2:28][N:29]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10]([NH:29][CH3:28])=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1
Reactant: COc1cccc(C(=O)c2cnn(-c3cc(C(=O)O)ccc3C)c2N)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(OC)c3)c2N)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a stirred solution of 3-[5-Amino-4-(3-methoxybenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid C (50 mg, 0.14 mmol, 1.0 eq) in 10 mL of DMF was added EDCI (41 mg 0.21 mmol, 1.5 eq), HOBt (29 mg, 1.5 mmol, 2.0 eq), and diisopropylethylamine (55 mg, 0.43 mmol, 3.0 eq) and the solution was stirred for 15 minutes at room temperature when methylamine hydrochloride (13 mg, 0.19 mmol, 1.5 eq) was added and the reation stirred for 1 hour. The mixture was diluted with EtOAc (300 mL) and washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography on silica gel to provide the product to provide the product (15 mg, 32%) as a brown solid: HPLC (4 minute 10-90 gradient) tR1.97 min; MS m/z 365.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:12]([O:14]CC)=[O:13])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCOC(=O)C1CC2(CC1CC)OCCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC1CC2(CC1C(=O)O)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with ethyl 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylate (0.32 g, 1.4 mmol) and sodium hydroxide (aqueous 1 N, 14.0 mL, 14.0 mmol). The solution was stirred overnight at rt. To the solution was added DCM (30 mL) followed by the addition of 20% aqueous citric acid (about 20 mL) to reach pH of about 2. The layers were separated and the aqueous solution was extracted with DCM (2×30 mL) and DCM/EtOAc (1:1, 30 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 8-ethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylic acid as a clear, colorless oil (0.27 g, 96%): LC/MS (Table 1, Method c) Rt=1.20 min; MS m/z: 201 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1.O1CCOCC1.CCN(C(C)C)C(C)C>O>[NH2:27][C:26]1[CH:28]=[CH:29][C:23]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:24][C:25]=1[N+:30]([O-:32])=[O:31]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 95 °C
Yield: 72.4 %

Procedure:
(4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (2.22 g, 7.57 mmol) and 4-bromo-2-nitroaniline (1.56 g, 7.20 mmol) were taken into dioxane (20 mL), water (4 mL) and DIPEA (5.4 mL, 31 mmol) followed by addition of dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (322 mg, 0.39 mmol) and the mixture was heated to 95° C. for 2 h. The mixture was cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The biphasic mixture was filtered through a celite pad and the organic filtrate was washed once with 0.5M aqueous hydrochloric acid, brine then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.01 g, 69% yield) as a yellow crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 74, step 6, from (S)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) and 4-boronobenzoic acid was prepared the title compound as an yellow foam.