Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.O[C:39]1[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:39]3[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47]CC)=[O:46])[CH2:44][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([OH:47])=[O:46])[CH2:44][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Temperature: 50 °C

Procedure:
To a solution of the product of Example 24b (7.8 g, 11.6 mmol) in tetrahydrofuran (40 ml)/ethanol (40 ml) was added an aqueous lithium hydroxide solution (0.84 g of lithium hydroxide in 40 ml of H2O). The resulting mixture was heated to 50° C. for two hours and cooled to room temperature. The organic solvents were mostly removed under reduced pressure, and the resulting residue was acidified with 10% citric acid aqueous solution and extracted with ethyl acetate (200 ml). The organic layer was separated, washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a light yellow solid, which was further dried in a vacuum oven at 45° C. for 18 h to afford 7.5 g of product 24c as a light yellow solid; MS-DCI/NH3: 643 (M+H)+.
Reaction SMILES: [Li+:1].[I-].[Si:3]([O:10][CH2:11][C@@H:12]1[N:17]([C:18]2[O:19][C:20]3[C:21](=[C:23]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:25][CH:26]=3)[N:22]=2)[CH2:16][CH2:15][O:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>N1C=CC=CC=1>[Si:3]([O:10][CH2:11][C@@H:12]1[N:17]([C:18]2[O:19][C:20]3[C:21](=[C:23]([C:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=3)[N:22]=2)[CH2:16][CH2:15][O:14][CH2:13]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5].[Li+:1]
Reactant: COC(=O)c1cccc2oc(N3CCOC[C@@H]3CO[Si](C)(C)C(C)(C)C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1COCCN1c1nc2c(C(=O)[O-])cccc2o1
Temperature: 25 °C

Procedure:
To a solution of LiI (298 mg, 2.22 mmol) in refluxing anhydrous pyridine (50 mL) was added (R)-methyl 2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate (226 mg, 0.55 mmol) and the reaction mixture was refluxed for 24 h. The mixture was cooled to room temperature, concentrated to dryness and dried in vacuum to provide lithium (R)-2-(3-((tert-butyldimethylsilyloxy)methyl)morpholino)benzoxazole-4-carboxylate as a yellow oil which was used without further purification. MS consistent.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[C:22]([C:24]1([CH3:28])[CH2:27][NH:26][CH2:25]1)#[N:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([N:26]3[CH2:27][C:24]([CH3:28])([C:22]#[N:23])[CH2:25]3)=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CC1(C#N)CNC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC(C)(C#N)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 47.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (15 mg, 0.077 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (9 mg, 47.3%). 1H NMR (400 MHz, DMSO-d6) δ 0.79 (dd, J=6.69, 2.91 Hz, 3 H) 0.96 (dd, J=9.09, 6.57 Hz, 3 H) 1.41-1.73 (m, 3 H) 2.26-2.44 (m, 1 H) 3.85 (dd, J=15.66, 9.85 Hz, 1 H) 4.06 (d, J=9.35 Hz, 2 H) 4.61 (s, 1 H) 4.88 (dd, J=19.20, 6.82 Hz, 1 H) 5.03 (d, J=11.12 Hz, 1 H) 5.07-5.18 (m, 1 H) 7.99 (t, J=3.16 Hz, 1 H) 8.25 (t, J=2.65 Hz, 1 H) 12.40 (br. s., 1 H). [M+H] calc'd for C19H20FN5O2, 370; found, 370.5
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1.[Br-].[Na+].N([O-])=O.[Na+].S(N)(=O)(=O)O.[OH-].[Na+].[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>O>[C:36]([O:39][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:8]=1)(=[O:38])[CH3:37]
Reactant: COC(=O)c1ccccc1-c1ccc(N)cn1
Reactant: CC(=O)OC(C)=O
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(OC(C)=O)cn1
Reaction time: 0.25 h

Procedure:
Concentrated sulfuric acid (0.14 ml) were added to a suspension of methyl 3-aminopyridine-6-ylbenzoate (425 mg) and sodium bromide (383 mg) in water at 0° C. (10 ml) and then a solution of sodium nitrite (295 mg) in water (1.5 ml) was added dropwise to the mixture at 80° C. The mixture was stirred at the same temperature for 15 minutes. At the end of this time a solution of amidosulfuric acid and concentrated sulfuric acid (0.21 ml) in water (1.60 ml) was added to the reaction mixture and this mixture was stirred for 1.5 hours at 80° C. and at ambient tmperature for 1 hour and then allowed to stand for 14 hours. The pH of the reaction mixture was adjusted to pH 8 with aqueous sodium hydroxide solution (1N). After addition of acetic anhydride (2.00 ml) to the solution, the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water and the ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure to afford a mixture (457 mg) of methyl 5-acetoxypyridine-2-ylbenzoate and methyl 5-hydroxypyridine-2-ylbenzoate. In a similar manner to that described in Example 2, a reaction was carried out using the mixture obtained above and aqueous sodium hydroxide solution (1N, 2.10 ml) and the reaction mixture was treated to afford 5-hydroxypyridine-2-ylbenzoic acid as a white powder. In a similar manner that described in Reference example 1(c) a reaction was carried out using 5-hydroxypyridine-2-ylbenzoic acid obtained above, sodium hydride (55% suspension in oil, 174 mg) and methyl iodide (0.35 ml) and the reaction mixture was treated to afford the desired compound (429 mg) as colorless crystals
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[F:16][CH:17]([F:23])[C:18](OCC)=[O:19]>CCOCC>[F:16][CH:17]([F:23])[C:18]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10])=[O:19]
Reactant: CCOC(=O)C(F)F
Reactant: COc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(=O)C(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To 1-bromo-2-fluoro-4-methoxybenzene (123 g, 0.6 mol) in 1300 mL Et2O at −78° C. was added n-BuLi (276 mL, 2.5 M) dropwise. After stirring at −78° C. for 2 hours, ethyl difluoroacetate (82.6 g, 0.67 mol) was added dropwise at −78° C. The reaction was stirred overnight at 25° C., and was quenched with saturated ammonium chloride solution at −20° C., followed by 1N HCl (final pH=4). The organic layer was separated and aqueous layer was extracted with Et2O. The combined extracts were dried over MgSO4, filtered and concentrated, and the residue was purified by column chromatography (PE/EA 20:1) to afford 2,2-difluoro-1-(2-fluoro-4-methoxyphenyl)ethanone as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH2:9][NH:8][C:7]=2[CH:11]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27])#[N:22].O>ClCCl>[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:34]([F:35])([F:37])[F:36])[C:31]=1[O:32][CH3:33])[C:26]([N:8]1[C:7]2[CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[CH:5][C:6]=2[S:10][CH2:9]1)=[O:27])#[N:22]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(c1)NCS2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(C#N)cc(C(=O)N2CSc3ccc(C(F)(F)F)cc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (5 mL), and triethylamine (0.56 mL) and 3-cyano-4-methoxy-5-trifluoromethylbenzoyl chloride (839 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (479 mg) as a pale yellow amorphous product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]1.C(N(CC)CC)C.[OH-].[Na+]>C(O)C(C)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C@@H:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)CO
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Temperature: 80 °C
Reaction time: 13 h
Yield: 74 %

Procedure:
2.07 g of N-(2-amino-4,6-dichloro-5-pyrimidinyl)formamide were heated to 80° C. in 40 ml of isobutanol (white suspension). A solution of 1.97 g of (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride, 3.8 g of triethylamine and 15 ml of isobutanol was added to the mixture. The mixture was stirred at 80° C. for a further 13 h. 10 ml of 1N NaOH were added to the clear solution at 20° C., followed by evaporation to dryness. The residue underwent flash chromatography (silica gel 60 column, length 8 cm, diameter 6.5 cm, eluent ethyl acetate/ methanol 95/5). After evaporating off the eluent and drying the residue, 2.1 g of title compound were obtained. The yield was 74%.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH2:12][CH:7]12.[Cl-].C(CC1C2C(=C(I)C=CC=2)CCN1C(=O)C[NH3+])(O)=O.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+].CO>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12
Reactant: O=C1CC2c3cccc(I)c3CCN2C(=O)CN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9-iodo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione. A suspension of 2-(1-(carboxymethyl)-5-iodo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminium chloride (46.1 g, 112 mmol) and Et3N (95 mL, 682 mmol) in dry DMF (1.1 L) was treated with a solution of T3P in DMF (98 mL, 169 mmol)—exothermic. The mixture was stirred at RT overnight. The mixture was then concentrated in vacuo and the residue obtained was taken up in AcOEt and diluted with an saturated aq. solution of NaHCO3. The aqueous phase was extracted with AcOEt and the combined org. layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a brown solid. The crude product obtained was suspended in MeOH and filtered. The filter cake was washed with MeOH and DCM, and then dried in vacuo to give the title compound (12.4 g) as a beige powder that was used as it is in the next step. UPLC-MS: MS 357.1 (M+H+); UPLC rt 0.73 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.C[CH2:16][N:17](C(C)C)C(C)C.CN>C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>[CH3:16][NH:17][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([NH:2][CH3:1])[CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CNC(=O)c1ccc([N+](=O)[O-])c(NC)c1

Procedure:
N-Methyl-3-methylamino-4-nitro-benzamide (407 mg) was prepared by following General Procedure N starting from 3-methylamino-4-nitro-benzoic acid (500 mg), DPPA (550 uL), DIEA (445 uL), and methylamine (2 M in THF, 2.55 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[N+:31]([CH3:34])([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C@@:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([CH2:34][N+:31]([O-:33])=[O:32])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
Alternatively, 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.075 g, 0.163 mmol) and antracen-9-yl-methyl quininium bromide (0.020 g, 0.034 mmol) were dissolved in toluene (2.0 ml). Nitromethane (10 molar equivalents) and potassium carbonate (0.025 g, 0.181 mmol) were added and the resulting suspension was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.051 g, 60%) as a white foam. Chiral HPLC analysis (Chiralpack AS-RH, Heptane/2-propanol=90:10, 1 ml/min, retention time 6.13 minutes (major enantiomer), 7.35 minutes (minor enantiomer)) indicated that the reaction proceeded with 62% enantioselectivity.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]2)[C:21]([C:32]#[N:33])=[CH:20][N:19]=1>CS(C)=O>[CH:1]1([NH:7][C:18]2[N:23]=[C:22]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]3)[C:21]([C:32]#[N:33])=[CH:20][N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnc(Cl)nc1N[C@@H]1CCC[C@H](O)C1
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1cnc(NC2CCCCC2)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 70 °C
Yield: 88 %

Procedure:
A solution of cyclohexanamine (0.181 mL, 1.583 mmol) in DMSO (5 mL), 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)-pyrimidine-5-carbonitrile (0.200 g, 0.791 mmol; synthesis described herein) and DIEA (0.276 ml. 1.583 mmol) was heated at 70° C. overnight. After completion of reaction as indicated by LCMS and TLC the reaction mixture was allowed to cool to room temperature and concentrated. The resulting crude was purified by silica gel chromatography using a gradient of 0%-70% ethyl acetate (containing 10% ammonia saturated methanol) in hexanes. The desired product fractions were combined and concentrated to yield 2-(cyclohexylamino)-4-((1R,3S)-3-hydroxycyclohexylamino)-pyrimidine-5-carbonitrile (0.220 g, 88% yield, 98.1% pure) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08-8.21 (m, 1H), 7.08-7.56 (m, 2H), 4.74 (d, J=3.90 Hz, 1H), 3.93-4.13 (m, 1H), 3.44-3.77 (m, 2H), 1.83-2.02 (m, 2H), 1.65-1.82 (m, 6H), 1.58 (d, J=14.84 Hz, 1H), 1.32-1.45 (m, 2H), 1.08-1.30 (m, 7H); MS (ESI) m/z 316.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[C:13](Cl)(Cl)=[O:14].C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1>ClC1C=CC=CC=1>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][S:3][C:2]=1[N:1]=[C:13]=[O:14])#[N:8]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1csc(N)c1C#N
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: Clc1ccccc1
Product: CC(C)(C)c1csc(N=C=O)c1C#N
Yield: 60.1 %

Procedure:
A solution of 90 g (0.5 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene in 300 ml of chlorobenzene was added dropwise to a solution of 150 g of phosgene in 1.5 liters of chlorobenzene at 0°-5° C. Thereafter, the mixture was slowly heated to the boil, while passing further phosgene in, and excess phosgene was then driven off by passing dry nitrogen in. For working up, the solvent was stripped off under reduced pressure and the residue was distilled. 62 g of 3-cyano-4-tert.-butyl-thien-2-yl isocyanate, which boiled at 163° C. under a pressure of 20 mm Hg, were obtained in this manner.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[O:29][C:28]([CH2:30][NH2:31])=[CH:27][CH:26]=1>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:31][CH2:30][C:28]4[O:29][C:25]([CH3:24])=[CH:26][CH:27]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: Cc1ccc(CN)o1
Solvent: C1COCCO1
Product: COc1cc2c(NCc3ccc(C)o3)c(C(N)=O)cnc2cc1-c1c(C)noc1C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg,) and [(5-methyl-2-furanyl)methyl]amine (200 mg) in 1,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (177 mg) as a beige powder.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:25](O)(C)[CH3:26]>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:25][CH3:26]
Reactant: CC(C)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 30 °C

Procedure:
Behenic acid manufactured by Henkel Co. (trade name: Edenor C22-85R) in an amount of 100 kg was admixed with 1200 kg of isopropyl alcohol, and dissolved at 50° C. The mixture was filtrated through a 10 μm filter, and cooled to 30° C. to allow recrystallization. Cooling speed for the recrystallization was controlled to be 3° C./hour. The resulting crystal was subjected to centrifugal filtration, and washing was performed with 100 kg of isopropyl alcohol. Thereafter, the crystal was dried. The resulting crystal was esterified, and subjected to GC-FID analysis to give the results of the content of behenic acid being 96 mol %, lignoceric acid. 2 mol %, and arachidic acid 2 mol %. In addition, erucic acid was included at 0.001 mol % or less.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH:17]=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][NH:23][CH:20]2[CH2:22][CH2:21]2)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-methyl-carbamic acid tert-butyl ester (95 mg, 0.335 mmol) and cyclopropylamine (0.036 mL, 0.50 mmol) in MeOH (3.30 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (19 mg, 0.50 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc (20 mL), and this mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 90:10) yielded the title compound (81 mg, 75%). LC-MS: tR=0.73 min; ES+: 366.20.