Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:13][C:14](=[O:34])/[C:15](=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([F:33])[CH:22]=2)/[CH2:16][CH2:17][CH2:18]Cl)[C@H:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:20]\[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([F:33])[CH:22]=3)/[C:14]2=[O:34])[C@H:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)N[C@H](c3ccc(F)c(F)c3)[C@@H](C)O)cc2F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc(/C=C3\CCCN([C@H](c4ccc(F)c(F)c4)[C@@H](C)O)C3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (10 mL) was added to a solution of tert-butyl [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]carbamate (960 mg) in methanol (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (747 mg). DIEA (1.59 mL), WSC (880 mg), and HOBT (620 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene]valeric acid trifluoroacetate (1.00 g) and (1R,2R)-1-amino-1-(3,4-difluorophenyl)propan-2-ol hydrochloride (612 mg) in DMF (20 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with heptane to obtain (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg). (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-1-(3,4-difluorophenyl)-2-hydroxypropyl]amide (977 mg) was dissolved in DMF (25 mL). 60% sodium hydride (95 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system), solidified with ethyl acetate and heptane, and separated by filtration to obtain 740 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([C:11]1[C:15]2[NH:16][C:17]([C:19]3[S:20][C:21]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:22][N:23]=3)=[CH:18][C:14]=2[S:13][C:12]=1[CH3:29])[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:26]1[CH2:27][CH2:28][C:21]2([S:20][C:19]([C:17]3[NH:16][C:15]4[C:11]([N:2]([CH3:1])[S:3]([C:6]5[S:7][CH:8]=[CH:9][CH:10]=5)(=[O:5])=[O:4])=[C:12]([CH3:29])[S:13][C:14]=4[CH:18]=3)=[N:23][CH2:22]2)[CH2:24][CH2:25]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1sc2cc(C3=NCC4(CCNCC4)S3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CN=C(c1cc3sc(C)c(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a mixture of N-methyl-N-[2-methyl-5-(1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-4H-thieno[3,2-b]pyrrol-3-yl]thiophene-2-sulfonamide (180 mg), triethylamine (78 μL) and tetrahydrofuran (5 mL) was added acetyl chloride (32 μL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-[5-(8-acetyl-1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl]-N-methylthiophene-2-sulfonamide (115 mg, yield 57%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(CCCBr)c1
Reactant: CCc1ccncc1C
Product: Cc1cnccc1C(C)CCCc1cccc(C(F)(F)F)c1
Yield: 47.4 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl-4-ethylpyridine and 4.03 g (15.1 mmol) of 1-bromo-3-(3-trifluoromethylphenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.20 g of the desired compound (yield: 47.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4OC)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), o-methoxyphenylboronic acid (140 mg, 0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield 100.5 mg (32%) as an oil. Rf=0.38 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.97 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.33-7.29 (m, 2H), 7.01 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.80-6.74 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 538.2 (M+Na)+, 516.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00 equiv) in THF/Et2O (450/50 mL) under nitrogen at −78° C. was added dropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C., was added 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). The resulting solution was stirred for 0.5 h at −78° C. and then warmed to room temperature, and stiffed overnight. The reaction was quenched by carefully adding 200 mL of water. The pH of the mixture was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extracted with 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 38.9 g (crude) of the title compound as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:12]1[C:45](=[O:46])[N:44]2[CH2:47][C@@H:41]([CH2:42][C@H:43]2[C:48]([O:50][CH3:51])=[O:49])[O:40][C:24]2=[N:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]([O:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH2:52][C@H:16]2[O:15][C:14](=[O:53])[NH:13]1)([CH3:11])([CH3:10])[CH3:9].[I-].[K+].[CH3:56][O:57][CH2:58][CH2:59]Br>CN(C=O)C.C(N(CC)CC)C>[C:8]([C@H:12]1[C:45](=[O:46])[N:44]2[CH2:47][C@@H:41]([CH2:42][C@H:43]2[C:48]([O:50][CH3:51])=[O:49])[O:40][C:24]2=[N:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]([O:33][CH:34]3[CH2:39][CH2:38][N:37]([CH2:59][CH2:58][O:57][CH3:56])[CH2:36][CH2:35]3)=[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH2:52][C@H:16]2[O:15][C:14](=[O:53])[NH:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCNCC1)O2
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCN1CCC(Oc2c3c(nc4ccccc24)O[C@@H]2C[C@@H](C(=O)OC)N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]2C[C@H]2CCCCC3)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The amine from Step 2 (70.9 mg) was dissolved in DMF (0.3 mL) and triethylamine (53 μl), potassium iodide (1.6 mg) and 2-bromoethyl methyl ether (20 μl) were added sequentially. The reaction mixture was stirred at 60° C. for 24 hours. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of sodium bicarbonate. The mixture was extracted (3×) with ethyl acetate and the combined organics were dried with sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (ISCO, 0 to 10% methanol in DCM) gave the desired product (50.6 mg). LRMS (ES+) m/z 695.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-])=O.Cl[Sn]Cl.[NH4+].[OH-]>Cl>[S:10]1[C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [NH4+]
Product: Nc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 6-nitrobenzothiazole (3.8 g, 0.02 mol) in 40 ml 2N HCl was added SnCl2 (15.9 g, 0.06 mol), and the mixture was stirred at room temperature overnight. The reaction mixture was treated with concentrated NH4OH to pH 11 and extracted with ethyl acetate (3×150 ml). The combined organic phase was concentrated under reduced pressure. The residue was purified (silica gel chromatography) to give benzo[d]thiazol-6-amine (3 g, 72%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24]#[CH:25]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[N:26]1([CH2:23][C:24]#[C:25][C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CCN1CCCC1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A 100 mL Schlenk flask was charged with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (4.0 g, 12.6 mmol), tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.3 mmol, 10 mol %), cuprous iodide (0.48 g, 2.5 mmol, 20 mol %), triethylamine 50 mL and 1-(prop-2-ynyl)pyrrolidine (2.8 g, 25.2 mmol), and then the flask was flushed with nitrogen three times. The mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as a yellow solid (2.2 g, 44.9% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[CH3:13]I>O1CCCC1>[CH3:13][N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C@H:4]1[C:3]([O:2][CH3:1])=[O:10]
Reactant: CI
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
(L)-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0° C. using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml). The aqueous layer was then extracted with dichloromethane. Evaporation of the dichloromethane gave crude methyl 1-methyl-5-oxo-prolinate (0.308 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (105 mg) is was dissolved in 1 M hydrogen chloride-ethyl acetate (6 ml), and the mixture was stirred at room temperature for 13 hr. The reaction mixture was concentrated to give the object compound (93 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(O)CC2)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC4(O)CC4)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.996, m/z=461.1; 1H NMR (CDCl3) 0.35 (m, 1H), 0.17 (m, 3H), 0.51 (m, 1H), 0.61 (m, 1H), 1.48 (d, 3H), 2.11 (s, 2H), 2.28 (m, 1H), 2.42 (m, 2H), 2.56 (s, 3H), 2.71 (s, 1H), 2.95 (m, 1H), 5.63 (m, 1H), 6.91 (m, 2H), 6.98 (m, 2H), 7.19 (m, 1H), 7.26-7.38 (m, 5H), 8.49 (d, 1H).
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COCc1ccccc1NC(=O)OC
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1CBr
Reaction time: 2 h

Procedure:
38.6 g (150 mmol) of boron tribromide are added dropwise to 10 g (51 mmol) of methyl N-(2-methoxymethylphenyl)-carbamate (Example 2b) in 100 ml of methylene chloride. Stirring is carried out for 2 hours, after which the vigorously stirred reaction mixture is added dropwise to a solution of 11.8 g (0.17 mol) of NaHCO3 in water. The organic phase is separated off and the aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over MgSO4 and evaporated down. 9.5 g (39 mmol=76%) of the title compound are obtained as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1[C:6]#[N:7])([O-])=O.Cl>CO.[Fe]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(Oc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: N#Cc1c(N)cccc1Oc1ccccc1
Yield: 22.6 %

Procedure:
To a solution of 2-nitro-6-(phenoxy)benzonitrile (Example 113c) (1.94 g, 8.08 mmol) in MeOH (164 mL) was slowly added concentrated HCl (7.23 mL) followed by iron powder (1.58 g, 28.3 mmol). The reaction was refluxed for 30 min and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 1N NaOH, water and brine. The organic layer was dried over MgSO4, filtered, concentrated and purified by flash chromatography 1:1 Hexane:EtOAc to yield 2-amino-6-phenoxybenzonitrile (384 mg, 22.6%). 1H NMR (400 MHz, MeOD) δ 5.97 (d, J=8.3 Hz, 1H), 6.50 (d, J=8.6 Hz, 1H), 7.06 (m, 2H), 7.18 (m, 2H), 7.40 (m, 2H). MS 210 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O.O>O1CCOCC1>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([NH:32][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:6][N:5]=2)[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CSc1ncc(C(=O)OCc2ccccc2)c(C)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C(=O)OCc1ccccc1
Yield: 34.8 %

Procedure:
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (6.0 g) and 1-benzyl-3-aminopyrrolidine (5.78 g) in dioxane (10 ml) was stirred at 130° C. for 15 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on allunima eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give benzyl 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (3.06 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11](Cl)Cl.C[N+](C)=C.[I-].[Cl-].[NH4+]>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Cc1ccc(CC=O)cc1
Agent: C=[N+](C)C
Agent: [Cl-]
Agent: [I-]
Solvent: CCN(CC)CC
Product: C=C(C=O)c1ccc(C)cc1
Reaction time: 2.5 h

Procedure:
2.57 g of aldehyde 37 is introduced into 300 ml of methylene chloride under nitrogen, and 6.5 ml of triethylamine and 7.1 g of Eschenmoser's salt are added at 0° C. After 2.5 hours at 0° C., saturated ammonium chloride solution is added, extracted with methylene chloride, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.94 g of title compound 38 accumulates as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(N(CC)CC)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-amino-2-(trifluoromethyl)benzonitrile (commercially available, for example from Maybridge, Cornwall, United Kingdom, 85.0 g) in DCM (1 liter) at 0° C. was added triethylamine (92.2 g, 0.913 mol) and the reaction stirred for 15 minutes. Then acetoxyacetylchloride (74.5 g, 0.547 mol) was added at 0° C. and the reaction stirred for 4 hours at room temperature. The reaction mixture was diluted with DCM and washed with ice water followed by aqueous NaHCO3. The organic layer was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by triturating with diethyl ether (500 mL) to yield 2-{[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (85.0 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1>ClCCl>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:5](=[O:7])[CH3:6])=[CH:11][N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(Cl)nc1
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)nc1
Reaction time: 12 h

Procedure:
78 μL (0.83 mmol) acetic anhydride are added to 100 mg (0.77 mmol) 2-chloro-pyrimidin-5-ylamine in 20 mL dichloromethane at 0° C. Subsequently 115 μL TEA are added and stirring is continued for 12 h at rt. After that time, the solvent is removed by evaporation and the residue is washed with water.
Reaction SMILES: O[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CCN(S(F)(F)[F:16])CC.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:16][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(CO)C(=O)OCC
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(CF)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 2-(hydroxymethyl)acrylate (5 g, 38 mmol) in 50 mL of methylene chloride was added DAST (6.0 mL, 46.1 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then warmed up to room temperature and continuously stirred overnight. 20 mL of saturated NaHCO3 aqueous solution and 20 mL of ethyl acetate were added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 ml×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue (2.8 g, yield: 56%). MS (m/z): 131 (M+1)+.