Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:8][C:9]=1[CH2:10][C:11](O)=[O:12])[CH2:2][CH2:3][CH3:4].O>O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[S:8][C:9]=1[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
1.15 g crude [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetic acid were dissolved in 50 ml tetrahydrofuran and cooled in an ice bath to 0° C. At 0° C. 9.3 ml 1 M solution of borane tetrahydrofuran complex were added. The reaction mixture was warmed to 55° C. and stirred for one hour at this temperature. The reaction mixture was cooled in an ice bath and 50 ml water was added. The organic layer was added. The tetrahydrofuran was removed in vacuo and the residue extracted three times with portions of 80 ml ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo to provide 1.1 g crude 2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as brown oil. This material was used without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])=[O:15]
Reactant: COc1ccccc1Br
Reactant: O=C(Cl)c1ccccc1Br
Agent: [Mg]
Product: COc1ccccc1C(=O)c1ccccc1Br
Yield: 65.9 %

Procedure:
Following the Procedure described in Preparation VIa and starting from 9.4 g (0.050 mol) of 2-bromoanisole, 1.7 g (0.069 mol) of magnesium and 11 g (0.050 mol) of 2-bromobenzoyl chloride, 9.6 g of the expected product (yield: 66%) are obtained after crystallization from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH:23]1([CH2:26][C@H:27]([NH2:34])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][C@H:27]([NH:34][C:14]([C:12]2[CH:11]=[CH:10][C:9]([N:17]3[CH2:20][C:19]([F:21])([F:22])[CH2:18]3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:15])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=474.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Cl)[CH:23]=[CH2:24]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@:10]([OH:14])([CH2:24][CH:23]=[CH2:22])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Cl
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3S)-4-Benzyl-3-(4-fluorophenyl)-2-morpholinone (see International Patent Specification No. WO95/18124) (13.6 g, 47.6 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) and cooled to below -70° C. under an inert atmosphere. Allyl magnesium chloride (26.2 ml of a 2.0M solution in tetrahydrofuran; 52.4 mmol) was added dropwise over 15 minutes, maintaining the temperature below -70° C. After 30 minutes, the reaction was quenched by the addition of a saturated solution of ammonium chloride and allowed to warm to room temperature. The resulting suspension was extracted with ethyl acetate (3×100 ml), and the combined organic extracts dried (MgSO4) and concentrated in vacuo to yield the title compound in ~3:1 mixture of the lactols as a light yellow oil (15.3 g, 98%), which was used without further purification. MS (ES+) m/z 328 (M+1. 22%), 310 (M-OH, 61), 269 (100).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1CCCC1.[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH3:31]>>[C:24]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]([CH3:31])[C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: CNc1ccccc1-c1ccccc1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 272 mg (1.0 mmol) 3,5-bis(trifluoromethyl)phenylacetic acid in 1 ml tetrahydrofuran 162 mg (1.0 mmol) 1,1′-carbonyldiimidazole was added in one portion at 0°. The reaction mixture was stirred for 2 hrs at room temperature and 147 mg (0.8 mmol) biphenyl-2-yl-methyl-amine was added. Stirring was continued for 3 days at room temperature. The reaction mixture was evaporated and the residue was purified by chromatography (SiO2, hexane/ethyl acetate 3:1) to give 160 mg (46%) N-biphenyl-2-yl-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-acetamide as white crystals, MS (ISP): 438.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH:37][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NNC(=O)N1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
Morpholine-4-carbonyl chloride (297 mg, 1.99 mmol) was added dropwise over a period of 10 minutes to a solution of DMAP (24 mg, 0.199 mmol) and pyridine (0.16 mL, 1.99 mmol) in dry DCM (5 mL). The mixture was stirred at 0° C. for 20 minutes then, a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide hydrochloride (0.65 g, 1.99 mmol) in dry DCM (2.0 mL) was added over a period of 10 minutes. The mixture was stirred at 0° C. for 15 min and was then allowed to warm to rt and was stirred overnight. The reaction mixture was diluted with DCM (10 mL), and washed with 1N HCl (10 mL), and saturated sodium chloride (10 mL), then was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (0 to 1:100 MeOH/DCM, containing 1% TEA) to give N′-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)morpholine-4-carbohydrazide (0.38 g, 47%) as a white solid. ESI-MS (EI+, m/z): 404.19 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[O:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH:2]=[O:1])[C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]1=2
Reactant: c1cnc2c(c1)OCCN2CC1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=CCN1CCOc2cccnc21
Yield: 86.3 %

Procedure:
A solution of 3,4-dihydro-4-[(1,3-dioxolan-2-yl)methyl]-2H-pyrido[3,2-b]-1,4-oxazine (0.13 g) in acetone (10 ml) and water (1 ml) was heated under reflux in the presence of p-toluenesulfonic acid (2.24 g) for 3 days. The mixture was concentrated in vacuo and the residue was poured into aqueous saturated sodium hydrogen carbonate solution. The water layer was extracted with ethyl acetate three times and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixed solvent of methanol and dichloromethane (1:10) as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-[3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-4-yl]acetaldehyde (0.09 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:13])=[CH:9][C:10](Cl)=[O:11]>CCOCC>[CH3:7][C:8]([CH3:13])=[CH:9][C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: C1COCCN1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCOCC
Product: CC(C)=CC(=O)N1CCOCC1
Temperature: 0 °C

Procedure:
Morpholine (2 equivalents) is added to a well-stirred ice-cooled solution in dry ether of 3,3-dimethylacryloyl chloride (1 equivalent) and when addition is complete, the mixture is warmed for a few minutes. the mixture is then cooled, filtered, the solvent removed and the residue recrystallized from 60-80 petrol to give 3,3-dimethylacryloyl morpholine m.pt. 52°-4°.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH:16]3[O:19][CH:15]3[CH2:14]2)[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:23][NH2:24])[CH3:22]>CO>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH:16]3[O:19][CH:15]3[CH2:14]2)[CH2:8][C:7]=1[OH:20])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(C2CCC3OC3C2)CC1=O
Solvent: CO
Product: CCCC(=NOCC)C1=C(O)CC(C2CCC3OC3C2)CC1=O

Procedure:
3.5 parts by weight of 2-butyryl-5-(3,4-epoxycyclohexyl)-cyclohexane-1,3-dione and 0.8 part by weight of ethoxyamine in 100 parts by volume of methanol were stirred for 16 hours at room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, the solution was washed with 5% strength by weight hydrochloric acid and water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2-(1-Ethoxyiminobutyl)-5-(3,4-epoxycyclohexyl)-3-hydroxycyclohex-2-en-1-one (active ingredient No. 2) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.F[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:38]#[N:39]>>[CH3:43][C:42]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: Cc1ccc(C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1-n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 120 °C

Procedure:
To a mixture of 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-d]-pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120° C. for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile as a crude product, LC/MS (M+H)+: 430.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:25])[N:10]3[CH2:24][CH2:23][CH2:22][CH:11]3[CH2:12][N:13](C(OCC(Cl)(Cl)Cl)=O)[C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH3:29]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:25])[N:10]3[CH2:24][CH2:23][CH2:22][CH:11]3[CH2:12][NH:13][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH3:29]
Reactant: COc1cc2c(c(OC)c1OC)C(=O)N1CCCC1CN2C(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)C(=O)N1CCCC1CN2
Reaction time: 4 h
Yield: 63.4 %

Procedure:
10% Cd/Pb couple (2.57 g, 20.6 mmol Cd) was added to a stirred solution of 112 (2.00 g, 4.1 mmol) in THF (20 mL) and 1N NH4OAc buffer (20 mL) and left at room temperature for 4 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (2×100 mL). The organic layer was washed with brine (2×100 mL) and dried (MgSO4). The solvent was removed in vacuo to give 113 (0.76 g, 64%) as a yellow glass: Rf=0.1 (silica, EtOAc); [α]20.7D=+505° (c=0.1, DCM); IR (neat) cm−1 3339, 2976, 2939, 1614, 1455, 1428, 1392, 1359, 1275, 1245, 1203, 1113, 1052, 1035, 1000, 926, 804, 751, 665; 1H NMR (270 MHz, CDCl3) δ (1H, d, J=4.39 Hz), 6.61 (1H, s), 6.14 (1H, d, J=8.24 Hz), 4.36 (1H, d, J=8.79 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.84 (3H, s), 3.48-3.46 (2H, m) 2.26-2.23 (2H, m), 2.16-1.93 (2H, m); HRMS (FAB) calcd for C15H18N2O4 (M+1) 290.1266, found 290.1208.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[Br:1][C:2]1[C:7]([C:8]2([O:12][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(c2cccnc2Br)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccnc2Br)CCC1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of the above alcohol (410 mg, 1.80 mmol) in DMF (5 mL) was added NaH (60%, 108 mg, 2.70 mmol). After 1 h, MeI (0.23 mL, 3.60 mmol) was added. After 1.5 h, the reaction mixture was filtered and the filtrate was concentrated to afford an orange oil. Purification by flash column chromatography using hexanes/EtOAc (2:1) afforded 2-bromo-3-(1-methoxy-cyclobutyl)-pyridine as a pale yellow solid (308 mg, 71%). 1H NMR (CDCl3) δ 1.61-1.71 (m, 1H), 2.04-2.14 (m, 1H), 2.56 (t, 4H, J=7.5 Hz), 2.96 (s, 3H), 7.25-7.30 (m, 1H), 7.64 (dd, 1H, J=7.5, 2.1 Hz), 8.31 (dd, 1H, J=4.7, 1.8 Hz).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]2[CH3:11])=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]3[CH3:11])=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc21

Procedure:
2-(2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol (95 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via Procedure A and purified via reverse phase HPLC to give 89.3 mg of 131 as a white solid. MS (Q1) 370.3 (M)+
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)C1CC1
Yield: 82.5 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 87) (142 mg, 0.50 mmol, HPLC 0.776 min) and cyclopropylcarbonyl chloride (53 ul, 0.55 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (145 mg, 83%, HPLC 1.071 min), MS (ISP) m/e=352.2 [(M+H)+].
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[F:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40]C)=[O:39]>>[F:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH3:42])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1F
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(F)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and (S)-1-(4-fluoro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, followed by an ester hydrolysis step as outlined in Step 6, example 36.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CN(C)C=O>[I:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(I)cn1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: Ic1cnc(N2CCNCC2)nc1

Procedure:
0.02 mol of 2-chloro-5-iodopyrimidine, 0.06 mol of piperazine and 100 ml of absolute dimethylformamide are heated to 100° for 45 minutes and then evaporated. The crystalline residue is shaken with potassium bicarbonate solution and methylene chloride. The substance contained in the methylene chloride phase is purified by column chromatography over silica gel 60. The amine obtained by elution with methylene chloride/methanol (7:3) is stirred with isopropyl ether and filtered off with suction.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]=[C:26]=[O:27].O>CN(C)C=O>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:26]1=[O:27]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: O=C=NCc1cc(Cl)cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.01 5 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of addition, the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].C(OC([NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:19]1OCCOCCOCCOCCOC1.CI>C1COCC1>[CH3:19][O:18][CH2:17][C@@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Reactant: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H]1CC[C@@H](N)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (72 mg, 1.78 mmol, 60% by weight suspended in mineral oil) was washed three times with 10 mL portions of hexanes, and suspended in dry THF (12 mL). The suspension was cooled to 0° C. To this suspension, cis-(tert-butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.273 g, 1.20 mmol) and 15-crown-5 (0.250 mL, 1.25 mmol) were added. The reaction mixture was then stirred at 0° C. for about 30 min. Methyl iodide was then added dropwise (75 μL, 1.20 mmol). Since the reaction was not complete after overnight stirring at room temperature, the mixture was cooled to 0° C. and reacted with 100 mg of sodium hydride and 0.250 mL of 15-crown-5. After about 2 hours at room temperature, the reaction was complete. The reaction was quenched by the slow addition of water and the crude product was extracted with ethyl acetate. Purification was effected by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent. ES-MS (m/z) 244. cis-(Tert-butoxy)-N-[4-(methoxymethyl)cyclohexyl]carboxamide was dissolved in ethanol (5 mL) and the solution was treated with 1 mL of acetyl chloride at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting solid was used without further purification. (79% yield) ES-MS (m/z) 144.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[N:20][CH:19]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:41]3[C:40]([CH2:42][CH2:43][CH2:44][CH2:45]O)=[N:39][CH:38]=[N:37][C:36]=3[S:35][CH:34]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:41]3[C:40]([CH2:42][CH2:43][CH2:44][CH2:45][O:24][C:22]4[CH:21]=[N:20][CH:19]=[C:18]([CH:23]=4)[C:17]([O:16][CH3:15])=[O:25])=[N:39][CH:38]=[N:37][C:36]=3[S:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: OCCCCc1ncnc2scc(-c3ccc(F)cc3)c12
Reactant: COC(=O)c1cncc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reaction time: 16 h
Yield: 8 %

Procedure:
Diisopropyl azodicarboxylate (0.040 g, 0.20 mmol) was added to a mixture of 5-hydroxynicotinic acid methyl ester (0.038 g, 0.25 mmol), 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol (0.060 g, 0.20 mmol), triphenylphosphine (0.052 g, 0.20 mol) and tetrahydrofuran (3.0 mL) at room temperature with stirring. After 16 h, the solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (1×40 mL). The organic solution was concentrated and purified by column chromatography (1.5-5% methanol/dichloromethane) to give 7 mg (8%) methyl 5-4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxynicotinate as white solid. MS [M+H]=438.1, LC/MS (EI) tR 4.63 min (Method D), 1H NMR (CDCl3) δ (ppm) 9.02 (s, 1H), 8.82 (s, 1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.42-7.35 (m, 2H), 7.34 (s, 1H), 7.20-7.10 (m, 2H), 3.97 (s, 3H), 3.88 (t, J=6.3 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 1.81-1.66 (m, 2H), 1.66-1.53 (m, 2H).