Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].CO.[F:17][C:18]([F:24])([F:23])[C:19](OC)=[O:20]>O>[F:17][C:18]([F:24])([F:23])[C:19]([NH:5][C@@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]([OH:3])=[O:1])=[O:20]
Reactant: COC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
1.97 g L-DOPA (10 mmol) and 5 ml of dry methanol was added into an oven-dried 25 ml round-bottomed flask equipped with a Teflon stirring bar and rubber septum and purged with dry argon. Then, 1.3 ml of TMG (10 mmol) and 1.4 ml of methyl trifluoroacetate (12.5 mmol) was added. The mixture was stirred vigorously at room temperature until DOPA had completely dissolved (after about 24 hr). At this point, the flask was immersed in cold water (0° C.) and 5 ml of methanol and 4 g Dowex 50 resin (H+ form) were added. The mixture was filtered after stirring for 10 min. The filtrate was evaporated under reduced pressure. The crude product was re-crystallized from ethyl acetate and the yield of N-trifluoroacetyl-L-DOPA was 78%. See Curphey, T. J. Trifluoroacetylation of amino acids and peptides by ethyl trifluoroacetate. J. Org. Chem. 1979, 44, 2805-2807; Lapidot, Y.; Rappoport, S.; Wolman, Y. Use of ester of N-hydroxysuccinimide in the synthesis of N-acrylamino acids. J. Lipid Research 1967, 8, 142-145.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:23]([O:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@H:13]3[O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=1.N(OC(C)(C)C)=O.N([O-])=O>C1COCC1>[C:15]([O:14][C@@H:13]1[C@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C@H:12]1[N:8]1[C:6]2[N:7]=[CH:2][NH:3][C:4](=[O:45])[C:5]=2[S:10][C:9]1=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: CC(C)(C)ON=O
Agent: O=N[O-]
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]cnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 6 (6.65 g, 10.6 mmol) in dry THF (350 mL) was added ter-butyl nitrite (6.2 mL, 52.3 mmol) and the mixture was stirred at room temperature for 1 h. Additional nitrite reagent (2.0 mL) was added and the mixture was stirred at 50°-60° C. overnight. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 8-10% acetone in CH2Cl2 followed by 10-11%. The desired product eluted last to yield 3.45 g (46%) of 9 as a foam: UV λmax (EtOH) 220 nm (ε46600), 259 sh (11000), 271 sh (8400): 1H NMR (DMSO-d6) δ6.31 (d, J=6.45 Hz, 1H, C1, H), 7.38-7.98 (m, 15H, benzoyl aromatics), 8.25 (s, 1H, C5H), 13.16 (b, 1H, N6H, exchanged with D2O), and other sugar protons. Anal. Calcd. for C31H23N3O9 :
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)=[N+:12]=[N-:13]>>[ClH:1].[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:17]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCc1ccsc1
Agent: Cl
Product: Nc1nc(Cc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 60 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.641 mmol was reacted with 3-(2-Azido-ethyl)-thiophene (0.118 g, 0.769 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Thiophen-3-yl-ethyl)-1H[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.119 g, 60%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.19 (t, 1H), δ 6.90 (s, 1H), □ 6.78 (d, 1H), δ 6.09 (s, 1H), δ 4.47 (t, 2H), δ 3.67 (s, 2H), δ 3.09 (t, 2H) ppm; 13C; (75 MHz, CD3OD) δ 151.2, 145.7, 137.7, 130.5, 127.8, 125.8, 122.9, 121.9, 110.3, 50.798, 30.7, 23.3 ppm; HRMS (ESI) calcd for C12H14N6S (M+) 274.1001. Found 274.1007.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NCC(F)(F)F)s1
Yield: 84 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (87 mg, 84%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=413.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[O:13])=[N:8][CH:7]=1.O[Li].O>C1COCC1.O>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:14]([CH2:15][C:16]([CH3:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[C:12](=[O:13])[NH:11][C:9]2[S:10][C:6]([S:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:7][N:8]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CSc1cnc(NC(=O)N(CC(C)(C)c2ccccc2)C2CCC(C)CC2)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {2-[3-(4-methyl-cyclohexyl)-3-(2-methyl-2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (350 mg, 0.737 mmol) in THF(50 mL) was added LiOH.H2O (186 mg, 4.42 mmol) in water (3 mL) at RT. The mixture was stirred at RT for 16 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(trans-4-Methyl-cyclohexyl)-3-(2-methyl-2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH2:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([N:28]([CH3:36])[C:29](=[O:35])[C@@H:30]3[CH2:34][C@@H:31]32)=[CH:26][C:25]=1[CH:37]=O.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14][NH:15][CH2:37][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][C:24]=3[O:23][CH3:22])[C@H:31]3[CH2:34][C@H:30]3[C:29](=[O:35])[N:28]4[CH3:36])([CH2:11]2)[C@@H:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CN)[C@@H]1c1ccccc1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)[C@@H]1C[C@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1CNC[C@@]13C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H]3c1ccccc1)N(C)C(=O)[C@@H]1C[C@H]21
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Racemic Intermediate 21, one enantiomer being (1R,2S,5S)-1-aminomethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.055 g, 0.19 mmol) was combined with (1aR,7bS)-6-methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde (0.046 g, 0.20 mmol) in methylene chloride (3 mL) and the mixture was stirred for 3.0 hours. APCI mass spec showed complete imine formation (m+1: 503). Methanol (1.0 mL) and sodium triacetoxyborohydride (0.053 g, 0.25 mmol) were added and the reaction allowed to stir for 16 hours. The solvent was removed at reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and methylene chloride, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (0.10 g, quantitative crude yield). This material was used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[O:21]=[C:22]1[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:24][CH2:23]1>C1COCC1>[CH3:33][C:30]([O:29][C:27]([NH:26][C@@H:25]([CH2:24][CH2:23][C:22](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:34]([O:36][CH3:37])=[O:35])=[O:28])([CH3:31])[CH3:32]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
n-Butyl lithium 1.6M solution in hexanes (0.88 ml, 1.4 mmol) was added dropwise to a solution of commercially available 1-bromo-4-[(phenylmethyl)oxy]benzene (390 mg, 1.48 mmol) in dry THF (2 ml) at −78° C. under nitrogen atmosphere. The resulting suspension was stirred at −78° C. for 40 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 300 mg, 1.23 mmol) in dry THF (2.4 ml) previously cooled to −78° C. The mixture was stirred at −78° C. for 40 minutes and at −40° C. for 1 h, then it was quenched at −40° C. with an aqueous saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude material, which was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (95:5), thus affording the title compound as a white solid (170 mg, 32%); Rf (cyclohexane:ethyl acetate=8:2): 0.30; 1HNMR (300 MHz, CDCl3) δ (ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:27][C:28]1[S:29][C:30](B(O)O)=[C:31]([CH3:33])[N:32]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[S:29][C:28]([CH3:27])=[N:32][C:31]=3[CH3:33])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Cc1nc(C)c(B(O)O)s1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3sc(C)nc3C)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and 2,4-dimethylthiazole-5-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.82, min, m/z=451; 1H NMR (CDCl3) 7.26 (t, 2H), 7.13 (d, 2H), 7.03 (t, 2H), 6.91 (d, 2H), 5.76-5.64 (m, 2H), 5.06 (dd, 2H), 2.98 (m, 1H), 2.74 (s, 3H), 2.42 (s, 3H), 1.53 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[NH2-].[Na+].ClC1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>C1C=CC=CC=1.C(O)CCC.Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCCCO
Solvent: c1ccccc1
Product: Fc1ccc(Cc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 100 g (740 mmol) of 4-fluorophenylacetonitrile in 200 ml of benzene was added to a cooled (0° C.) slurry of 40 g (945 mmol) of sodium amide in 600 ml of the same solvent. After the addition was complete the solution was warmed to ambient temperature and stirred for one-half hour. The reaction mixture was again cooled to 0° C., 73.2 g (370 mmol) of solid 4,7-dichloroquinoline was added in increments, and the mixture was then stirred at ambient temperature overnight. Quenching with NH4Cl followed by workup gave the crude disubstituted acetonitrile, which was dissolved in 500 ml of n-butanol saturated with anhydrous HCl. The acidic solution was heated at reflux for 18 hours. The majority of the solvent was removed via distillation, and the residue was diluted with solvent, and washed with 10% NaOH. The organic layer was dried, and the solvent was removed in vacuo. Purification via HPLC gave 67 g of the title product. Yield: 67%.
Reaction SMILES: C([N:3]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10][N:9]([CH:23]([CH:30]([N:37]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH2:45][CH2:44][N:43](C=O)[CH2:42][CH2:41][N:40]([CH2:59][C:60]([O:62]C(C)(C)C)=[O:61])[CH2:39][CH2:38]2)[C:31]([O:33]C(C)C)=[O:32])[C:24]([O:26]C(C)C)=[O:25])[CH2:8][CH2:7][N:6]([CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])[CH2:5][CH2:4]1)=O.O.[Li+].[OH-].Cl>C(O)C>[C:16]([CH2:15][N:12]1[CH2:13][CH2:14][NH:3][CH2:4][CH2:5][N:6]([CH2:67][C:68]([OH:70])=[O:69])[CH2:7][CH2:8][N:9]([CH:23]([CH:30]([N:37]2[CH2:38][CH2:39][N:40]([CH2:59][C:60]([OH:62])=[O:61])[CH2:41][CH2:42][NH:43][CH2:44][CH2:45][N:46]([CH2:49][C:50]([OH:52])=[O:51])[CH2:47][CH2:48]2)[C:31]([OH:33])=[O:32])[C:24]([OH:26])=[O:25])[CH2:10][CH2:11]1)([OH:18])=[O:17]
Reactant: CC(C)OC(=O)C(C(C(=O)OC(C)C)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(C(=O)O)C(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a 250 mL RB flask, the compound of Example 13 (1.0 g, 1.5 mmol) is dissolved in ethanol (30 mL) and water is added until the solution turns slightly turbid. The reaction mixture is heated at 100° C. and 1N LiOH (12 mL) is added. After maintaining the mixture at 100° C. for 8 hours, the solution is adjusted to pH 0.5 with 5N HCl (aq), and the mixture is refluxed for 1.5 hours and stirred at ambient temperature for an additional 18 hours. The cooled reaction material is desalted by ion exchange chromatography using an AG5OW-X8 [80 mL, (H+ form)] strongly cation exchange resin. The product is eluted with 1.0N NH4OH. The fractions containing product are combined and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[O:10][C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a mixture of 3-amino-4-hydroxybenzonitrile (1.84 g, 0.0137 mol) in acetonitrile (140 mL) was added 4-bromophenyl isothiocyanate (2.93 g, 0.0137 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Cuprous chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol) were added to the reaction mixture. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the solid was suspended in methanol. The mixture was filtered through celite pad using methanol. The brownish filtrate was left at 40 for three days. The precipitate was filtered and washed with methanol to yield 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile (2.4 g, 0.0076 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.1 min. MS: MH−: 313
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7](=[O:31])[CH2:8][C@H:9]1[O:15][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]=2[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]1=[O:30])C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]([CH:27]([CH3:28])[CH3:29])[C:10](=[O:30])[C@@H:9]([CH2:8][C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])=[O:31])[O:15][C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[CH:22]=1
Reactant: CCOC(=O)CNC(=O)C[C@H]1O[C@@H](c2ccccc2)c2cc(Cl)ccc2N(C(C)C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)N1C(=O)[C@@H](CC(=O)NCC(=O)O)O[C@@H](c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
In a mixture of 2 ml of methanol and 1 ml of water was suspended 48 mg of N-(trans-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycine ethyl ester obtained in Example 55. To the suspension was added 0.1 g of potassium carbonate. The mixture was stirred for 6 hours at room temperature. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid, which was subjected to extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. Crystals obtained form the residue were recrystallized from ether and hexane to afford 29 mg of N-(cis-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetyl)glycine as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: COCC(=O)OC
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: COC(C)(C)C
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
At room temperature, a solution of 7.8 g (0.05 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 40 ml of methyl tert-butyl ether is mixed with stirring with 10.4 g (0.1 mol) of methyl methoxyacetate and then with 0.45 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at 60° C. and the progress of the reaction is monitored by gas chromatographic sample analysis. After 3 hours, the conversion is 54%. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chlorophenyl)-ethylamine has an ee value of 98.8%, while the (R)-enantiomer of N-(1-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 94.4%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH:19][C:20](=O)[CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][N:19]=[C:20]([Cl:3])[CH2:21][Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCl)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)c(NN=C(Cl)CCl)c(Cl)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
Phosphoryl chloride (500 microliters, 1.7 equivalents) was added in one portion to a stirred solution of N′-(2,6-dichloro-4-trifluoromethylphenyl)-chloroacetohydrazide (1.0 g, 3.11 mmol) in toluene (20 ml) and heated at 70° C. under an argon atmosphere for 20 hours. The cooled mixture was evaporated and the residue extracted with cyclohexane. The extracts were combined and evaporated to give the title compound (0.971 g) as an orange oil, NMR 4.4(s,2H), 7.55(s,2H), 7.7(s,1H). The yield was 90%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]=[C:5]2[C:14]3[CH:13]=[C:12]4[CH2:15][CH2:16][CH2:17][CH2:18][C:11]4=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:3]1[C:2]([CH3:1])=[C:6]2[C:7](=[O:19])[NH:8][C:9]3[CH:10]=[C:11]4[CH2:18][CH2:17][CH2:16][CH2:15][C:12]4=[CH:13][C:14]=3[C:5]2=[N:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1[nH]nc2c1c(=O)[nH]c1cc3c(cc12)CCCC3
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)[nH]c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-6) (10.2 g, 40.3 mmol, 1 equiv) and potassium carbonate (30.0 g, 217 mmol, 5.38 equiv) in DMF (100 mL) under nitrogen was added benzyl bromide (35.0 g, 205 mmol, 5.09 equiv) and the resulting mixture was stirred at 23° C. for 16 h. The reaction mixture was filtered and the filtered solid was washed with ether (3×200 mL) followed by water (3×250 mL) and dried to yield 2-benzyl-3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-7) as a white solid. LRMS m/z (M+H) 344.2 found, 344.2 required.
Reaction SMILES: [Br:1][C:2]1S[C:5]([N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[CH3:13])=[N:4][CH:3]=1.N[C:15]1[CH:20]=CC(Br)=CN=1>>[Br:1][C:2]1[CH:15]=[CH:20][C:5]([N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[CH3:13])=[N:4][CH:3]=1
Reactant: Cc1ccc(C)n1-c1ncc(Br)s1
Reactant: Nc1ccc(Br)cn1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1

Procedure:
Prepare using procedures essentially as described for 5-bromo-2-(2,5-dimethylpyrrol-1-yl)thiazole (Preparation 25) starting with 2-amino-5-bromopyridine. MS (ES): m/z 252 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N:21]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[C:22]=[S:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:22]([NH:21][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[S:23])[CH:17]=1)=[CH:5]2
Reactant: S=C=Nc1cccnc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cccnc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.277 g, 1.0 mmol) was mixed with 3-isothiocyanatopyridine (0.146 g, 1.07 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was removed on the rotary evaporator to give a solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v and was triturated a second time with hexanes/ethyl acetate, 4/1, v/v to give the product (0.309 g), mp 128-130° C.