Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1CC[CH:15]1[CH2:18]C#N)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+].[CH2:23]([OH:25])[CH3:24]>O>[CH:1]([N:14]1[CH2:15][CH2:18][CH:24]1[C:23]([OH:21])=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCC1CCN1C(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN1C(c1ccccc1)c1ccccc1

Procedure:
A mixture of the 1C, 2.5 g of sodium hydroxide, 36 ml of ethanol and 24 ml of water was refluxed for 6 hours, then left to cool for 16 hours. The mixture then was poured into water, washed with ether and acidified to pH 5. The solvent was evaporated, the residue was taken up in methanol, the solution was filtered and the methanol was evaporated. The residue was dissolved in chloroform; the solution was washed with brine, dried and the solvent was evaporated, to give 1-benzhydryl-2-azetidine carboxylic acid (1D).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]1[CH2:24][CH2:23][CH2:22][C:21]21[O:28][CH2:27][CH2:26][O:25]2
Reactant: O=C1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(OC2CCCC23OCCO3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.2 g. of N-[4-bromo-3-(cyclopentanon-2-yloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 0.68 g. of ethyleneglycol, 0.2 g. of p-toluenesulfonic acid and 30 ml. of benzene was refluxed with stirring under removing water for 8 hours and the reaction mixture was cooled to room temperature and then, 20 ml. of ethyl acetate was added to the reaction mixture to extract the product. The extract was washed with water and dehydrated over sodium sulfate and the solvent was distilled off and the product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:4) to obtain 1.35 g. of Compound No. 9 shown in Table 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]CC)=[O:13])=[CH:9][CH:8]=1.[OH-].[Na+]>CCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccccn2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of ethyl 5-pyridin-2-yl-2-furoate (2.00 g, 9.21 mmol) in EtOH (10 mL) was added NaOH (0.74 g) in water. The reaction mixture was allowed to stir at rt for 1 h and then concentrated. The residue was diluted with 1M HCl to pH 3-4. A precipitate formed and was collected by filtration and identified as 5-pyridin-2-yl-2-furoic acid (0.41 g). The aqueous solution was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give additional 5-pyridin-2-yl-2-furoic acid (0.57 g). LCMS: (FA) ES+ 190.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([N:1]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)[S:24]([CH3:23])(=[O:26])=[O:25])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2n1
Temperature: 0 °C
Yield: 42.3 %

Procedure:
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was dissolved in THF (10 ml). Triethylamine (9.75 mmol, 0.986 g) was added and the mixture was cooled to 0° C. Methanesulfonyl chloride (9.75 mmol, 1.116 g) was slowly added and the mixture was allowed to cool to RT. The stirring continued at RT until the reaction was finished. The solvent was evaporated, DCM was added and washed with NaHCO3 solution and water. The organic phase was dried, filtered and evaporated. The crude product was purified with flash chromatography. 0.149 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 3.61 (s, 6H), 4.34 (q, 2H), 7.50 (dd, 1H), 7.69-7.74 (m, 1H), 8.54-8.56 (m, 1H), 9.00-9.02 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1.CCOCC>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([B:16]([OH:17])[OH:15])=[CH:7][N:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(B(O)O)cn1
Temperature: -78 °C
Yield: 60.9 %

Procedure:
To a solution of 5-bromo-2-(tert-butyl)pyridine (1 g, 4.67 mmol) and triisopropylborate (1.29 mL, 5.60 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 2.06 mL, 5.14 mmol). The reaction was stirred at −78° C. for 2½ hours then allowed to warm slowly to −10° C. over 1 hour. The reaction was quenched by the addition of water (10 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous suspension was diluted with water (30 mL) and washed with ether (30 mL). The aqueous phase was acidified to pH 6 by the addition of acetic acid and the resulting milky suspension extracted with ether (2×20 mL). The combined organic extracts were washed with saturated brine (2×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a white foam. Ether (5 mL) and hexanes (40 mL) were added and the resulting suspension stirred vigorously for 30 minutes then filtered to give 2-(tert-butyl)pyridine-5-boronic acid (0.5093 g, 61% yield) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)cccc1F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluorophenyl)boronic acid gave 221. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.65 (s, 1H), 7.92 (s, 1H), 7.74-7.62 (m, 1H), 7.38 (t, J=8.8 Hz, 2H), 5.08 (t, J=5.7 Hz, 1H), 3.93-3.75 (m, 2H), 3.72 (s, 3H), 3.52-3.44 (m, 1H), 3.03 (s, 3H), 2.44-2.32 (m, 1H), 1.81-1.53 (m, 3H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: O1CCCC1.C(O)C.CN(C)/[CH:11]=[CH:12]/[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:23]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:20][O:19][C:17]([C:16]1[CH:15]=[C:14]2[C:13]([CH:12]=[CH:11][NH:23]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a mixed solvent of tetrahydrofuran (30 ml), ethanol (30 ml) and water (100 ml), added are methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (10.0 g) and sodium hydrosulfite (104.5 g), and stirred at 70° C. for 1 hours. After this is cooled to room temperature, a saturated saline solution is added thereto. Then, this is extracted with chloroform. The organic layer is dried, and the solvent is evaporated away. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/1) to obtain 6-methoxycarbonylindole (2.79 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C=O)C.O>[C:47]([O:46][C:44]([N:51]1[CH2:56][CH2:55][N:54]([C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]([F:10])([F:22])[F:21])[CH2:53][CH2:52]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
DIPEA (5.7 g, 44.30 mmol) was added drop wise to 2-trifluoromethyl benzoic acid (3.36 g, 17.72 mmol) in DMF (25 mL). EDCI (7.07 gm, 36.91 mmol) and HOBT (2.39 g, 17.72 mmol) were added consecutively and, after 15 minutes, N-Boc piperazine (2.75 g, 14.77 mmoles). The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 30:70 EtOAc:hexane as eluent) afforded 4-(2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester in 39% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])(O)O>>[CH3:26][C:18]1[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2)no1

Procedure:
The title compound was prepared from 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (1 g) and 4-borono-3-methylbenzoic acid (D74, 0.75 g) as a white solid (0.3 g, 24%) by the method described in Description 15.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][C:33]1[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]5[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: Cn1cnc(CCl)c1
Agent: Cl
Product: Cn1cnc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)c1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methyl-1H-imidazol-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride following General Procedure H.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[CH3:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][CH2:25][CH3:24])=[CH:33][N:32]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCc1ccc(C(=O)NCCCCn2c(CCOC)nc3c(N)nc4ccccc4c32)nc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine and fusaric acid were combined to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-butyl-2-pyridinecarboxamide as a tan solid, m.p. 54.9-55.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=6.1 Hz, 1H), 8.44 (m, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.94 (dd, J=8.0, 0.7 Hz, 1H), 7.80 (dd, J=8.0, 2.2 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.16-7.10 (m, 1H), 6.52 (broad s, 2H), 4.55 (t, J=6.9 Hz, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.23 (s, 3H), 3.18 (t, J=6.7 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H)., 1.83-1.72 (m, 4H), 1.63-1.53 (m, 2H), 1.34-1.24 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS(EI) m/e 474.2750 (474.2743 calcd for C27H34N6O2).
Reaction SMILES: [P:1]([Cl:12])(Cl)([O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15].CCN(CC)CC>C(Cl)Cl>[Cl:12][P:1]([NH:19][C@H:18]([C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])([O:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1* mixture of diastereoisomers.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(Cl)(Cl)Cl.Cl[C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: CC1(OC(=O)Cl)CCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=1
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: COc1nc(C)nc(Cl)n1
Product: COc1nc(C)nc(C2C(=O)Nc3c(F)cccc32)n1

Procedure:
7-Fluoro-1,3-dihydro-2H-indol-2-one (3.05 g) and 2-chloro-4-methoxy-6-methyl-1,3,5-triazine (6.59 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 85% area (4.73 g, 73% of theory).
Reaction SMILES: [CH3:1][N:2](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([C:6]1[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[CH:9][N:10]=1)[OH:5].[ClH:49]>CC(C)=O.O1CCOCC1>[ClH:49].[ClH:49].[NH:7]1[CH:8]=[CH:9][N:10]=[C:6]1[CH:4]([OH:5])[CH2:3][NH:2][CH3:1]
Reactant: CN(CC(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CNCC(O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[methyl(trityl)amino]-1-(1-trityl-1H-imidazol-2-yl)ethanol (3.4 g, 5.43 mmol) in 70 mL of acetone was treated with a solution of 4N HCl in dioxane (5 mL) and stirred for 4 h at room temperature. The solvent was removed by evaporation in vacuum and the residue was suspended in EtOAc. The solid was collected by filtration and washed with hot EtOAc. A white solid, 0.92 g (79%) was obtained after drying under vacuum. mp 176.4-177.3° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:37][CH2:36][N:35]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (6.5 mg). Calcd for C22H19F3N2O3: 416.1348, found 416.1348.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[O:36])[C:11]1=[O:25])=[O:4]
Reactant: C=CC[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC=O)OC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.15 g, 7.10 mmol, 1.0 equiv) in acetone (40 mL) at 0° C. was added N-methylmorpholine oxide (2.51 g, 21.30 mmol, 3.0 equiv), water (14 mL) and osmium tetroxide (3.60 g, 2.5% wt in THF, 0.36 mmol, 0.05 equiv). The mixture was stirred at room temperature for 60 minutes. Acetone was removed under vacuum and the residue was partitioned between EtOAc (80 mL) and brine (15 mL). The phases were separated and the organic layer was dried (over Na2SO4) and concentrated. To the residue was added THF (40 mL) and water (14 mL). At 0° C., sodium periodate (2.28 g, 10.65 mmol, 1.5 equiv) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. After cooled at 0° C., another portion of sodium periodate (0.76 g, 3.55 mmol, 0.5 equiv) was added. The mixture was stirred at room temperature for another 30 minutes. Volatile solvent was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and brine (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Heptane, 25% to 50%) to give product (2.1 g, 66%). MS: 446.3 [M−H+].
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]([S:13][CH3:14])=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.C(Cl)[Cl:16]>>[ClH:16].[CH3:1][S:2][C:3]1[C:12]([S:13][CH3:14])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CSc1ccc2ccncc2c1SC
Product: CSc1ccc2c(c1SC)CNCC2
Product: Cl
Reaction time: 8 h

Procedure:
7,8-Bismethylthioisoquinoline (553 mg., 2.5 mm.) was dissolved in 25 ml. of methylene chloride and 8 ml. of a solution of 1 M borane-dimethylsulfide complex in methylene chloride. The solution was refluxed under argon for eighteen hours and allowed to stand at room temperature overnight. The excess hydride was destroyed with methanol and the volatiles stripped off. The residual solid was treated with methanol and then refluxed for one hour in 20 ml of hydrochloric acid/methanol. The volatiles were evaporated and the resulting semi-solid was converted to the free base with sodium hydroxide-methylene chloride and chromatographed on silica gel employing 10% methanol-methylene chloride as the eluent. The resulting oil was dissolved in methanol and treated with hydrochloric acid ether to yield a white solid which was recrystallized in methanol to yield 7,8-bismethylthiotetrahydroisoquinoline hydrochloride having a melting point of 247°-249° C. (dec.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][OH:28])[CH2:22]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:28][CH2:27][C@H:23]1[O:24][CH2:25][CH2:26][N:21]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:22]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCO[C@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
Benzyl chloroformate (0.598 mL, 0.956 mmol, 3.5 equiv) was added slowly to a solution of DIPEA (0.477 mL, 2.73 mmol, 10 equiv) and 2.20.1a (64 mg, 0.547 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 4 hours. EtOAc and saturated aqueous NaHCO3 solution were then added to the mixture. The phases were separated and the organic layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The remaining oil was purified by silica gel column chromatography (EtOAc/heptane, 40-100%) to give product 74 mg (54% yield). MS m/z (M+1) 252.2.