Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:16][N:15]=1)=[O:13])[CH3:10]>C(#N)C.[N+]([O-])([O-])=O.[Ce].[NH4+]>[CH2:9]([NH:11][C:12]([C:14]1[C:18]([I:1])=[C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: CCNC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: O=C1CCC(=O)N1I
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reaction time: 18 h
Yield: 62.2 %

Procedure:
N-iodosuccinimide (9.0 g, 40 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (9.9 g, 20.4 mmol) in acetonitrile (60 ml). Ammonium cerium nitrate (0.25 g, 0.46 mmol) was added and the suspension stirred for ˜18 hrs. The resulting suspension was concentrated and the residue taken up in dichloromethane (125 ml). The resulting solution was washed aqueous sodium metabisulphite solution (2×100 ml, 5%), water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a pale red gum. Trituration with ethanol (25 ml) gave an off-white solid, solids were removed by filtration and washed with ethanol. Dried in vacuo (40° C.), to give 5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide as an off-white powder (7.75 g, 62%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=1.CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Cl:10][C:11]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[C:14]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][N:12]=1
Reactant: CCN(CC)C(=O)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnc(Cl)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
7.62 ml (7.62 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 0.60 g (2.54 mMol) 6-chloro-N,N-diethyl-nicotinamide in 3.0 ml THF cooled to 0° C. The reaction mixture was stirred 2 hours at room temperature, then cooled again to 0° C. and 0.41 ml methanol (10.1 mMol) were added followed by 692 mg 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.1 mMol). After stirring 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and 50 ml t-butyl-methylether were added at 50° C. The resulting suspension was filtered off, the filtrate was concentrated and the residue was purified by flash chromatography (eluent: ethyl acetate/n-heptane 1:1) to yield 0.67 g (86%) of 6-chloro-N,N-diethyl-4-o-tolyl-nicotinamide as a yellow oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[S:2]1.C(N(CC)CC)C.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>C1(C)C=CC=CC=1.CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[O:13])[S:2]1
Reactant: O=C(O)CCCCCC1CCSS1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CCCCCC1CCSS1
Yield: 13.2 %

Procedure:
The reaction was carried out as described in Example 47, but using 5 ml of a solution of 1.6 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 373 mg of N,N'-carbonyldiimidazole, 0.25 ml of triethylamine and 199 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2:1 and 3:1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2:3 and 1:1 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 61 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.28 (silica gel thin layer chromatography; using 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][C@H:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]2[N:20]=[C:19]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:18]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[O:33])=[C:17]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:16]1=2)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[Si:7]([O:14][C@H:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]2[N:20]=[C:19]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:18]([C@H:32]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)[OH:33])=[C:17]([CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:16]1=2)([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:9])[CH3:8]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C

Procedure:
At 0° C., 10.25 ml of a 1 M solution of lithium aluminium hydride (10.25 mmol, 1.1 eq.) in THF are added dropwise to a solution of 5.72 g (9.3 mmol) of the compound from Example 4A in 116 ml of dry THF. With stirring, the mixture is warmed to room temperature over a period of 6 h. For work-up, 120 ml of a saturated sodium potassium tartrate solution are added carefully. After the evolution of gas has ceased, the mixture is extracted three times with ethyl acetate, the combined organic phases are washed with a 1:1 mixture of sodium bicarbonate solution and saturated sodium chloride solution and this aqueous phase for its part is re-extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified chromatographically and at the same time separated into the diastereomers of the product (column: Chiralpak AD, 500 mm×40 mm, 20 μm; mobile phase: isohexane/isopropanol 97.5:2.5; flow rate: 50 ml/min).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:30]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccccc3)CC2)nc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) in DMF (8 ml) was added benzoyl chloride (124 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:27]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][NH2:35])[N:29]=[CH:28]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][NH2:35])[N:29]=[CH:28]1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of trifluoroacetic acid are added to 195 mg (0.53 mmol) of 3-(1-trityl-1H-imidazol-4-yl) propylamine dissolved in 8 ml of DCM and then immersed in an ice bath. After warming to room temperature, the reaction medium is stirred for 2 hours and the solvents are then evaporated off. The solid obtained is taken up in EtOAc and water. The aqueous phase is then concentrated and 110 mg of a white powder are obtained and used in the next step without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.Br[C:24]1[CH:35]=[CH:34][C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.O.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].C(Cl)Cl>[CH3:33][CH:29]1[O:28][C:27]2[CH:34]=[CH:35][C:24]([CH2:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][CH2:7]3)=[CH:25][C:26]=2[NH:31][C:30]1=[O:32]
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Reactant: C=C1CCN(c2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC1Oc2ccc(CC3CCN(c4ccccc4)CC3)cc2NC1=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a 20 mL screw cap vial, under N2, 4-methylene-1-phenylpiperidine (0.0906 g, 0.523 mmol) was diluted with 0.5M THF solution of 9-BBN (1.046 mL, 0.523 mmol) and stirred at 75° C. for 1 hr. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (0.127 g, 0.523 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0128 g, 0.016 mmol) and K2CO3 (0.145 g, 1.046 mmol) in DMF (1.0 mL) and water (0.1 mL) and stirred at 60° C. for 4 hr. The mixture was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10%-50% EA/Hex) provided the desired product as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.32 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 1.47 (br. s., 1 H) 1.64 (d, J=13.14 Hz, 2H) 2.45 (d, J=6.82 Hz, 2H) 2.52-2.62 (m, 2H) 3.59-3.70 (m, 2H) 4.55-4.67 (m, 1H) 6.65-6.78 (m, 3H) 6.81-6.94 (m, 3H) 7.11-7.22 (m, 2H) 10.58 (s, 1 H). ESI-MS: m/z 337.3 (M+H)+.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].C(OCC)C.[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=O)[CH2:17][C:18]([CH3:23])([CH3:22])[O:19]2)=[CH:14][CH:13]=1.CN1CCCN(C)C1=O>C1COCC1>[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH:1]([CH3:3])[CH3:2])=[CH:17][C:18]([CH3:23])([CH3:22])[O:19]2)=[CH:14][CH:13]=1
Reactant: CC(C)[Mg]Cl
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C1=CC(C)(C)Oc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2.0 M solution of isopropyl magnesium chloride in diethyl ether (15.5 mL, 31 mmol) was added slowly to a solution of 7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.58 g, 6.2 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro 2(1H) pyrimidone (DMPU) (7.5 mL, 30 mmol) in 30 mL THF at −30° C. The reaction mixture was warmed to room temperature and stirred for 15 hours. The reaction was then quenched with water (20 mL), saturated NH4Cl (aq) (15 mL) and 10% HCl (20 mL) at −78° C. The mixture was warmed to room temperature, was extracted with ethyl acetate (3×30 mL), the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then refluxed in 40 mL methanol with p-toluenesulfonic acid (160 mg) for 20 hours. The reaction mixture was made basic by addition of solid K2CO3, the solvent was removed and the residue was dissolved in diethyl ether (50 mL). The ether solution was washed with water (2×50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (hexane) to give the title compound as a clear oil: (650 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.44 g), which was subsequently deprotected.
Reaction SMILES: [Br:1][CH2:2][C:3](=[CH2:32])[C:4]([N:6]([CH:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])CC1C=CC(OC)=CC=1OC)=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3](=[CH2:32])[C:4]([NH:6][CH:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])=[O:5]
Reactant: C=C(CBr)C(=O)N(Cc1ccc(OC)cc1OC)C(CC(C)C)C(=O)NCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CBr)C(=O)NC(CC(C)C)C(=O)NCC(=O)OCC
Reaction time: 1 h

Procedure:
Compound 1 (117 mg, 0.23 mmol) was dissolved in methylene chloride (2 ml). Next, this was supplemented with trifluoroacetic acid (475 μl) at room temperature. The mixture was left for 1 hour while observing the colour change from clear to dark violet. The flask contents were transferred into a separator, and this was supplemented with methylene chloride (4 ml) and a saturated solution of sodium carbonate was added until the disappearance of the violet colour. The aqueous phase was extracted with methylene chloride (3×8 ml), and then the combined organic phases were dried with brine and the solvent was evaporated off. The remainder was purified using column chromatography in a hexane: ethyl acetate system (silica gel, Rf=0.25, 6:4, v:v).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (325 mg, 1.0 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (88 mg, 1.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (630 mg, 10.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (200 mg, Yield 48.9%). 1H NMR (CD3OD, 400 MHz): δ 8.44 (brs, 1H), 7.32-7.20 (m, 3H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 7.08-7.00 (m, 1H), 6.86-6.77 (m, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 1H), 4.03-3.89 (m, 2H), 3.63-3.40 (m, 7H), 3.31-3.07 (m, 4H), 2.06-1.92 (m, 2H), 1.55-1.40 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.C[O:10][C:11](=O)[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl>C1COCC1>[C:2]([CH2:1][C:11](=[O:10])[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]1)#[N:3]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Yield: 69.5 %

Procedure:
To a solution of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate (10 g, 34.5 mmol) in methanol (100 mL) was added Pd/C (1.0 g) and the reaction mixture was subjected to hydrogenolysis under balloon pressure of hydrogen, at room temperature for 8 h. The reaction mixture was filtered through celite bed and the bed was washed with methanol. The filtrate was concentrated under reduced pressure to afford the crude product which was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform to afford 4.8 g of (R)-tert-butyl 2-methylpiperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.[Cl:14]CCl>>[Cl:14][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: ClCCl
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromethane (200 mL) at 0° C. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 mL) and the combined organic layers were dried over sodium sulfate, filtrated, and evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) which was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CNc1ccc(F)cc1)NCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (8.3 g—obtained as described for intermediate 1), DIPEA (9.31 mL) and 4-fluoro-aniline (4.28 mL) in anhydrous DMF (60 mL) was stirred at 100° C. for 24 hours under a Nitrogen atmosphere and then left at r.t. for two days. The solution was poured into water (100 mL) and extracted with AcOEt (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 7:3) to give the title compound (7.73 g) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH3:13]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:13])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N
Product: Nc1nc(N)c(NC=O)c(Cl)n1
Yield: 89 %

Procedure:
N-(2-Amino-4,6dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg, 2.14 mmol) and ammonia (150 mL) was stirred in a Parr bomb at 50° C. for 18 hours. The ammonia was evaporated and the residual solid tritrated with water (10 mL). The solid was dried to give the title compound as red powder (400 mg, 89%), m.p.>300° C.; mass spectrum (CI/CH4): 190, 188 (M+1); 1H-N)MSO-d6)δ: 9.05 and 8.60 (both br s, total 1, NHCHO), 8.1 and 7:8 (both br s, total 1, NHCHO), 6.80-6.20 (4 br s, total 4, 2 NH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:31][C:29]#[N:30])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2cccc(CC#N)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-cyanomethylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=515.4 [M+H+].