Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16]N[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[C:24]([BH3-])#[N:25].[Na+]>CO>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:25]([CH2:24][CH2:6][CH2:5][C:4]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: [BH3-]C#N
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: I
Agent: [Na+]
Solvent: CO
Product: Cc1onc2c1c(=O)n(C1CCCN(CCCc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in methanol (3 mL) add approximately 100 mg of finely ground 3 Å sieves and stir the mixture for 30 minutes at room temperature. To the suspension add sodium cyanoborohydride (21 mg, 0.34 mmol) and stir the mixture at room temperature under nitrogen overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform, wash with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 23.9 mg of the title compound as a yellow foam, 49% yield. 1H NMR: consistent with structure. MS (ion spray) 436 (M+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1.[CH3:31]C(O)=O.C=O.[BH3-]C#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:31])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1
Reactant: CC(=O)O
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-((tetrahydro-2H-pyran-4-yl)amino)benzamide (300 mg, 0.73 mmol) in MeOH (6 mL) was added AcOH (0.05 mL) and HCHO (548 mg, 7.3 mmol, 40% w/w). The mixture was stirred at 20° C. for 2 h. NaBH3CN (276 mg, 4.38 mmol) was added and the resulting mixture was stirred at 20° C. for 16 h. The reaction solution was concentrated, the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (105 mg, Yield 33.9%). 1H NMR (CD3OD, 400 MHz): δ 7.37-7.29 (m, 1H), 7.23-7.17 (m, 1H), 7.17-6.97 (m, 6H), 4.18-4.08 (m, 1H), 4.07-3.90 (m, 3H), 3.80-3.68 (m, 2H), 3.62-3.51 (m, 3H), 3.51-3.43 (m, 1H), 2.99-2.79 (m, 7H), 2.75-2.58 (m, 2H), 1.94-1.79 (m, 2H), 1.72-1.59 (m, 2H). LCMS (m/z): 424.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]I>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]([OH:20])[CH3:22])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]I
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL, 3 mmol) in Et2O at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with H2O and brine. After drying over Na2SO4, the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][S:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[CH:2]1([N:8]([OH:9])[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([S:11][CH3:10])[CH:13]=2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: CSc1cccc(N=C=O)c1
Agent: Cl
Product: CSc1cccc(NC(=O)N(O)C2CCCCC2)c1
Yield: 27.1 %

Procedure:
Using the general method used to prepare Compound 1, N-(cyclohexyl)hydroxylamine hydrochloride (1.5 g, 10 mmol) was reacted with 3-(methylthio)phenyl isocyanate (1.6 g, 10 mmol) to provide 0.76 g of the desired product as a white solid m.p. 147.2°-147.7° C. Analysis: Calculated for C14H20N2O2S: %C, 59.97; %H, 7.19; %N, 9.99; Found: %C, 60.16; %H, 6.95; %N, 9.96.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>CN1C(=O)CCC1>[Cl:22][C:20]1[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([N:2]([CH3:1])[CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:21]=1
Reactant: CNC1CCOCC1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN(c1cc(Cl)nc(N2CCOCC2)n1)C1CCOCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
The crude N-methyltetrahydro-2H-pyran-4-amine (104 mg, 0.9 mmol) was dissolved in NMP (0.8 mL). To the solution, Cs2CO3 (366 mg, 1.13 mmol) and 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as in Method 22) (80 mg, 0.34 mmol) were added at room temperature. The reaction mixture was heated to 95° C. After 90 minutes, the reaction mixture was cooled to room temperature, filtered and purified by reverse phase preparative HPLC yielding 24 mg (23%) of pure 6-chloro-N-methyl-2-morpholino-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine. LC/MS (m/z): 313.2 (MH+), Rt 2.61 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](I)=[C:4]([CH3:10])[CH:3]=1.C([Mg]Cl)(C)C.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:18]2[CH:19]=[CH:20][O:16][C:17]=2[CH2:21][OH:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=Cc1ccco1
Reactant: Cc1cc(Br)cc(C)c1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1-c1ccoc1CO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
4-Bromo-2,6-dimethyl-1-iodobenzene (5 g, 16 mmol) is dissolved in dry tetrahydrofuran (20 ml) and cooled to −78° C. under an atmosphere of dry nitrogen. Isopropylmagnesium chloride (2M solution in tetrahydrofuran, 10 ml, 20 mmol) is added dropwise with vigorous stirring over 30 minutes. When the addition is complete, the reaction is allowed to warm to room temperature and is stirred for 30 minutes at room temperature. The reaction mixture is cooled to −78° C. and a solution of 2-furaldehyde (2.4 g, 25 mmol) in dry tetrahydrofuran (10 ml) is added dropwise over 30 minutes. Once the addition is complete, the mixture is allowed to warm to room temperature and stirring continued for 2 hours. A solution of saturated aqueous ammonium chloride (30 ml). is added, and the mixture is extracted with dichloromethane (3×25 ml). The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give ([4-bromo-2,6-dimethylphenyl]furan-2-yl)methanol (3.71 g).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=O)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[Si:18]([O:17][CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1
Yield: 86.3 %

Procedure:
To a solution of D2 (12.7 g, 0.036 mol) and cyclohexene (excess, 20 ml) in ethanol (100 ml) was added 10% palladium on charcoal catalyst. Reaction was heated at reflux overnight and cooled. Catalyst was filtered and the filtrate concentrated to leave an oil (6.69 g) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC2(CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (0.5 g, 0.9 mmol) and lithium hydroxide monohydrate (0.415 g, 9.88 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid (0.29 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58 (t, 2H), 0.48 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=[O:49]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][C:45]3=[O:49])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: NCCCN1CCCC1=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCN3CCCC3=O)cc2)cc1

Procedure:
The product from Example 104A and 1-(3-aminopropyl)-2-pyrrolidinone were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, CDCL3) δ7.26 (m, 2 H), 7.19 (m, 6 H), 7.11 (m, 3 H), 6.88 (m, 5 H), 6.79 (m, 1 H), 6.16 (s, 1 H), 4.04 (d, 4 H), 3.38 (t, 2 H), 3.22 (t, 2 H), 3.16 (dd, 2 H), 2.95 (m, 5 H), 2.51 (t, 2 H), 2.42 (t, 2 H), 2.33 (s, 3 H), 2.06 (m, 2 H), 1.62 (m, 2 H); MS (ESI+) m/z 669 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C@H:9](O)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:13])[O:48][CH2:47][C:46]([CH3:50])([CH3:49])[NH:45][C@H:9]2[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: CC[C@@H](O)C(=O)c1cccc(Cl)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(Cl)c1

Procedure:
Compound 4s was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-chlorophenyl)-2-hydroxybutan-1-one (10j, 1.13 g, 0.0568 mol), Proton sponge (1.43 g, 0.0667 mol), triflic anhydride (1.0 g, 0.063 mol), and 2-amino-2-methyl-1-propanol (1.09 g, 0.0122 mol) in CH2Cl2 (13 mL). After purification, the free base 4r was converted to 0.230 g of its D-tartrate salt: mp 160-161° C.; [α]20D +5.6° (c 0.8, CH3OH); 1H NMR (methanol-d4) δ 7.49-7.46 (m, 1H), 7.41-7.35 (m, 3H), 4.37-4.34 (m, 1H), 4.30-4.24 (m, 1H), 3.81-3.62 (m, 2H), 1.57 (s, 3H), 1.47-1.36 (m, 2H), 1.33 (s, 3H), 0.81-0.71 (m, 3H); 13C NMR (methanol-d4) δ 178.5, 145.2, 135.6, 131.2, 130.3, 128.2, 126.5, 97.1, 75.0, 67.8, 61.1, 55.0; LCMS (ESI) m/z 270.4 [(M-tartrate)+, M=C16H23ClNO5); Anal. (C16H23ClNO5.0.25H2O) calcd: C, 55.01; H, 6.78; N, 4.01. found: C, 54.99; H, 6.85; N, 4.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and dimethyl-pyrrolidin-3-yl-amine according to conditions described in general procedure C. Mp: 106-108° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.07-2.17 (m, 10H), 2.45-3.15 (m, 3 H), 3.27 (t, J=4.4 Hz, 4 H), 3.77 (t, J=5.1 Hz, 4H), 6.15 (m, 1 H), 7.05 (d, J=12.1 Hz, 1 H), 7.27 (d, J=9.5 Hz, 1 H), 7.42-7.62 (m, 5 H), 7.85-7.87 (m, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.23 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.S([CH2:22][N:23]=C=O)(C1C=CC(C)=CC=1)(=O)=O.C(O[K])(C)(C)C>CN(C)C=O.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:22]#[N:23])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 1,4-Dioxa-spiro[4,5]decan-8-one (2.0 grams, 12.8 mmole) and tosyl-methyl isocyanate (5.0 grams, 25.6 mmole) in dimethylformamide (25 ml) at 0° C. was added 1.0 M tBuOK in tButanol (25.6 ml) and stirred at 0° C. for 1 hour and room temperature over night. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid (1.45 g). MW 167.209; MS (m/e) 168 (M++1).
Reaction SMILES: S(O)(O)(=O)=O.[F:6][CH:7]([F:22])[C@@:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1.[N+:23]([O-])([OH:25])=[O:24].N.O>OS(O)(=O)=O>[F:22][CH:7]([F:6])[C@@:8]1([C:15]2[CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@](c2ccccc2F)(C(F)F)COC1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: NC1=N[C@@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1

Procedure:
To a solution of (R)-5-difluoromethyl-5-(2-fluoro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine sulphate (127.2 g, 371.6 mmol) in conc. H2SO4 (380 mL) was added at 5-15° C. HNO3 (25.8 g, 408.8 mmol). After addition, the reaction mixture was added slowly to 12% NH3 water solution (2.6 L) at 10-20° C. The resulted suspension (pH˜8) was filtered to provide the title compound as a yellow solid: ESIMS: 290; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.89 (m, 1H), 8.14 (m, 1H), 7.18 (dd, 1H), 6.10 (t, 1H), 5.65 (br s, 2H), 4.57 (dd, 1H), 4.13 (dd, 2H), 3.88 (m, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=[CH:13][CH:14]=1>>[CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1
Reactant: CCC(C=O)CC
Product: CCC(CC)CNc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Hydrogenation of 2-ethylbutanal and (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide following the method used in Example 31 gave N-(3-(3-(2-ethylbutylamino)phenyl)propyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.5 g, 90%); 1H NMR (400 MHz, DMSO-d6) δ 9.42 (bs, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.38-6.37 (m, 2H), 6.32 (d, J=7.2 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 3.21-3.16 (m, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.77-1.70 (m, 2H), 1.48-1.41 (m, 1H), 1.39-1.31 (m, 4H), 0.85 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])/[CH:15]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][C:5]=1[CH3:10])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(N)nc1C
Product: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Temperature: 100 °C

Procedure:
A mixture of 5-acetyl-2-amino-4-methylthiazole (12.5 g) and N,N-dimethylformamide-dimethylacetal (35.4 ml) is heated for 15 hours at 100° C. After cooling to room temperature the reaction mixture is evaporated, triturated with ethyl acetate, and filtered to give the title compound as an orange solid. MS (Method D) M+H 267.
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][O:34]C)[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][OH:34])[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1)=[O:15]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC show no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>CN(C)C=O.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>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc3ccccc3n2)nc1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
A solution of 2-bromoquinoline (1.00 g, 4.81 mmol) [Aldrich, cat. #716278] in N,N-dimethylformamide (10.0 mL) (degassed with nitrogen) was treated with 2-(tributylstannyl)pyridine (1.83 mL, 4.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.337 g, 0.481 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 110° C. for 17 h. The reaction mixture was then diluted with water (50 mL) and ether (50 mL) and filtered over Celite. The solids were washed with additional ether (150 mL). The filtrate was washed with water (150 mL) and brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.771 g, 78%). LCMS calculated for C14H11N2 (M+H)+: m/z=207.1. found: 207.1.
Reaction SMILES: [C:1]([CH:18]([OH:46])[C@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH:27]([C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[OH:28])[OH:26])[OH:24])[OH:22])[OH:20])(=[O:17])[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][CH3:16].Cl[CH:48]=[C:49](Cl)Cl>N1C=CC=CC=1>[C:1]([CH:18]([OH:46])[C@:19]([C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:48][CH3:49])([C@H:21]([C@@H:23]([C@@:25]([C:19](=[O:20])[CH2:21][CH2:23][CH2:25][CH2:27][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH:27]([C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[OH:28])[OH:26])[OH:24])[OH:22])[OH:20])(=[O:17])[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][CH3:16]
Reactant: ClC=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)C(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[C@@](O)(C(O)C(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@](O)(C(=O)CCCCCCC/C=C\CCCCCCCC)C(O)C(=O)CCCCCCCCCCCCCCC
Temperature: -18 °C
Reaction time: 4 h

Procedure:
3.3 g of 1,6-dipalmitoyl-D-mannitol and 0.53 of benzene boronic acid anhydride was added to a solution containing 20 ml of pyridine and 20 ml of trichloroethylene, and the mixture was dried with 5 g of molecular sieves. The mixture was cooled at -18° C. and 3.3 g of oleoyl chloride, dissolved in 10 ml of trichloroethylene, was added. The mixture was left standing over night at -18° C. and for four hours at room temperature. The reaction mixture was washed with 120 ml of 2 N hydrochloric acid and with water, and fractionated in a column containing 160 g of Sephadex LH 20 and eluting with a 1:1-mixture of chloroform and ethanol (90%), whereby the boronic acid protection was removed.