Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.Cl>>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:26][CH:27]=1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CCNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CCNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 4 °C

Procedure:
6.27 g (25 mmoles) of Z-Val-OH and 7.52 g (25 mmoles) of H-Tyr(But)-NH-C2H5.HCl are subjected to a condensation reaction analogously to Example 30 C. After being precipitated by means of water, the substance is dissolved in 70 ml of 95 percent strength alcohol and the solution is filtered hot and cooled (3 hours at 4° C.). The precipitate is filtered off. Yield 9.01 g (72.5%), melting point 181°, [α]D23 =-39.8° (c=1, dimethylformamide).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].CCOCC>C1C(O)=CC=CC=1C>[ClH:2].[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:12]([NH:14][C:15]([NH2:17])=[NH:16])=[NH:13]
Reactant: CCc1cccc(Cl)c1N
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: CCc1cccc(Cl)c1NC(=N)NC(=N)N

Procedure:
A mixture of 3 g. (0.0156 mole) of 2-chloro-6-ethylaniline hydrochloride and 1.35 g. (0.016 mole) of cyanoguanidine in 25 ml of m-cresol is heated on a steam bath for 1 hour. The reaction mixture is then cooled and 250 ml of ether is added. The preciptate is filtered off and dissolved in 100 ml of warm water, charcoaled and filtered and cooled in an ice bath. 10% sodium hydroxide solution is then added to make the mixture strongly basic. The mixture is then filtered and washed with water. This is then dissolved in methanol, the pH is adjusted to 7 with methanolic hydrochloric acid and the mixture evaporated to dryness, triturated with ether and filtered to obtain 1-(2-chloro-6-ethylphenyl)biguanide hydrochloride (m.p. 209°-210°C).
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[N:9]([CH2:16][CH2:17][C@@H:18]([OH:31])[CH2:19][O:20]S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[N:12]=1.[F:32][C:33]([S:36][C:37]1[CH:56]=[CH:55][C:40]([CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)=[CH:39][CH:38]=1)([F:35])[F:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(O)C>[Cl:7][C:8]1[N:9]([CH2:16][CH2:17][C@@H:18]([OH:31])[CH2:19][O:20][C:51]2[CH:50]=[CH:49][C:48]([N:45]3[CH2:46][CH2:47][CH:42]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([S:36][C:33]([F:32])([F:34])[F:35])=[CH:56][CH:55]=4)[CH2:43][CH2:44]3)=[CH:53][CH:52]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[N:12]=1
Reactant: Oc1ccc(N2CCC(Cc3ccc(SC(F)(F)F)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cn(CC[C@@H](O)COc2ccc(N3CCC(Cc4ccc(SC(F)(F)F)cc4)CC3)cc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Sodium tert-butoxide (0.412 g) was added to an ethanol solution (20 ml) of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (1.671 g) under an argon atmosphere in an ice water bath, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 4-[4-(4-trifluoromethylsulfanylbenzyl)piperidin-1-yl]phenol (1.50 g) and tripotassium phosphate (0.867 g) were added thereto, and then the mixture was heated at reflux for 4 hours. Thereafter the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→0:10) to afford the title compound as a brown oil (1.47 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[CH:7]=[C:6]3[CH:13]([CH2:16][N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH2:14][CH2:15][C:4]=1[C:5]=23.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC(CS)=CC=1.Cl>ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[CH:7]=[C:6]3[CH:13]([CH2:16][N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH2:14][CH2:15][C:4]=1[C:5]=23
Reactant: COc1ccc2c3c(cn2C)C(CN(C)C(C)=O)CCc13
Agent: Cl
Agent: SCc1ccccc1
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)N(C)CC1CCc2c(O)ccc3c2c1cn3C

Procedure:
The compound of Example 27, dissolved in dichloromethane, is added dropwise at 0° C. to a suspension of aluminium chloride and benzylthiol. The reaction is monitored by TLC. When the reaction has ended, the reaction mixture is poured onto ice and then acidified using 1N HCl. Customary extraction is carried out and the title compound is isolated by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][C:18](OC)=[O:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:22]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(CCO)ccc2Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A mixture of Example 695D (6.32 g, 20 mmol) in 100 mL of THF was treated with 1.0 M LiAlH4 in THF (35 mL, 35 mmol) at 0° C. The reaction mixture was stirred for additional 30 minutes, quenched with MeOH, and concentrated under vacuum. The residue was partitioned between ethyl acetate and pH=3 water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:9 hexanes/ethyl acetate to provide 5.18 g (90%) of the desired product. MS (DCI) m/e 289 and 291 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.96 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.84 (m, 3H), 4.59 (t, J=6.0 Hz, 1H), 3.51-3.53 (m, 2H), 2.58 (t, J=6.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21]>CN(C=O)C.O.[Cl-].[Na+].O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccc(OC)nc2)C(C)C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (2 g, 9.79 mmol) in DMF (40 mL) at 0° C. was added NaH (60% in oil, 431 mg, 10.8 mmol). The reaction was stirred at 0° C. for 0.5 hour and a solution of 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 1(B) (2.95 g, 10.28 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 2 hours and was diluted with water, brine, and CH2Cl2. The aqueous solution was washed with CH2Cl2 (3×) and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (hexanes to 70% EtOAc in hexanes) provided 2.87 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.14 (s) and 7.93 (s, total 1H), 7.54 (m, 1H), 7.31 (m, 1H), 7.24-7.08 (m, 3H), 6.80 (m, 1H), 5.05 (m, 1H), 4.29 (m, 2H), 4.09 (m, 1H), 3.95 (m, 3H), 3.67 (d, 1H), 3.31 (d, 1H), 3.08 (d, 1H), 1.32 (m, 3H), 1.09 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].Cl>N1C=CC=CC=1>[I:11][C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:14]([C:13]([F:12])([F:27])[F:28])[CH:15]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(I)s1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 71.6 %

Procedure:
2-Amino-5-iodo-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (2 ml) and 3,5-bis-trifluoromethylbenzoylchloride (0.95 g) was added at room temperature with stirring. The mixture was stirred for 6 hr at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-3,5-bis-trifluoromethylbenzamide (1.3 g), m. p. 172-173° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:19]1[C:18]2[C:22](=[CH:23][C:15]([Cl:14])=[CH:16][CH:17]=2)[NH:21][CH:20]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=CCOCc1ccccc1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=CC[C@@H](COCc1ccccc1)c1c[nH]c2cc(Cl)ccc12
Yield: 75.7 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (143 mg, 0.750 mmol), 6-chloro-1H-indole (75.8, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 12.75 h to provide, after silica gel chromatography (CH2Cl2), the title compound as a colorless oil (124 mg, 73% yield, 97% ee) after silica gel chromatography in CH2Cl2. IR (film) 3383, 2953, 2930, 2834, 2734, 1718, 1623, 1603, 1548, 1453, 1403, 1378, 1273, 1184, 1104, 1069, 1019, 909, 804, 774, 714 cm−1; 1HNMR (300 MHz, CDCl3) δ 9.77 (dd, J=1.8, 1.8 Hz, 1H, CHO), 8.15 (s, 1H, NH), 8.02-7.99 (m, 2H, ArH), 7.65 (dd, J=0.6, 8.7 Hz, 1H, ArH), 7.58 (tt, J=1.5, 6.6 Hz, 1H, ArH), 7.48-7.42 (m, 2H, ArH), 7.37 (d, J=1.8 Hz, 1H NCH), 7.12 (dt, J=2.1, 8.7 Hz, 2H, ArH), 4.70 (dd, J=5.1, 10.8 Hz, 1H, CH2O), 4.42 (dd, J=8.4, 11.1 Hz, 1H, CH2O), 4.08 (m, 1H, ArCH), 3.06 (ddd, J=1.8, 6.3. 16.8 Hz, 1H, CH2CO); 2.95 (ddd, J=2.1, 7.8, 16.5 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 200.9, 166.5, 136.7, 135.4, 133.2, 129.9, 129.6, 128.5. 125.1, 122.3, 120.7, 119.8, 115.0, 111.4, 67.8, 46.5, 31.0; HRMS (CI) exact mass calcd for (C19H16ClNO3) requires m/z 341.0819, found m/z 341.0814.[α]D=−3.3 (c=1.0 CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=38.8 min and R isomer tr=43.3 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>CCO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Yield: 85.6 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (5 g, 18.36 mmol) and KOH (10.3 g, 184 mmol) in EtOH/H2O (1:1) (60 mL) was stirred at RT for 12 hrs. The solution was acidified with 1N HCl and the precipitate was filtered and dried, yielding 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (3.84 g, 86%) as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])=[CH:15][CH:16]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Reactant: Oc1ccccn1
Agent: Cl
Product: O=c1ccccn1Cc1c(-c2ccc(Cl)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and pyridin-2-ol. 1H-NMR (CDCl3, 400 MHz, δ) 8.45 (dd, J=2.4, 4.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.58 (dd, J=5.1, 9.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.76 (dd, J=1.9, 6.9 Hz, 1H), 6.59 (d, J=9.1 Hz, 1H), 6.00 (m, 1H), 5.62 (s, 2H) ppm; me/354 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[Cl:21][C:22]1[C:27]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1>>[Cl:21][C:22]1[N:23]=[C:24]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=3[F:20])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:25]=[CH:26][C:27]=1[C:28]([OH:31])([CH3:29])[CH3:30]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)c1ccc(Cl)nc1Cl
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(Cl)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (300 mg, 1.02 mmol) and 2-(2,6-dichloropyridin-3-yl)propan-2-ol (210 mg, 1.02 mmol) as starting materials.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([S:12]SC#N)#[N:11]>>[C:1]1([CH:7]([S:12][C:10]#[N:11])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CSSC#N
Reactant: O=CCc1ccccc1
Product: N#CSC(C=O)c1ccccc1

Procedure:
In synthesis of 5-phenylthiazole derivatives, the intermediate α-bromo-α-phenylacetaldehyde is first synthesized by allowing phenylacetaldehyde to react with bromine according to the method as disclosed in Helv. Chim. Acta. Vol. 30, pp.2058 (1945). As the next step, according to the method disclosed in J. Amer. Chem. Soc. Vol. 71, pp.4007 (1949), α-bromo-α-phenylacetaldehyde is allowed to react respectively with thioformaldehyde, thioacetamide, thiourea and ethylthiocarbamate at room temperature in methanol as a reaction solvent to obtain 5-phenylthiazole (m.p. 45°-46° C.), 2-methyl-5-phenylthiazole (m.p. 74°-76° C.), 2-amino-5-phenylthiazole (m.p. 206°-208° C.) and 2-hydroxy-5-phenylthiazole (m.p. 202°-204° C.). On the other hand, according to the method as described in U.S. Pat. No. 2,603,646 (1952), phenylacetaldehyde is allowed to react with thiocyanogen to obtain α-phenyl-α-thiocyanoacetaldehyde, which is then allowed to react with ammonium dithiocarbamate in the presence of an acid catalyst such as dilute sulfuric acid to obtain 2-mercapto-5-phenylthiazole (m.p. 207°-209° C.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1.[CH2:15]1[O:17][CH2:16]1>>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]1[CH2:15][CH2:16][OH:17]
Reactant: C1CO1
Reactant: COc1ccc(C)c2c1NC(C)CC2
Product: COc1ccc(C)c2c1N(CCO)C(C)CC2
Yield: 72.7 %

Procedure:
2,5-Dimethyl-8-methoxy-1,2,3,4-tetrahydroquinoline (189 g, 1.0 m) was reacted with ethylene oxide (52.0 g) in an autoclave at 160° C. for 10 hrs. The reaction mixture from the autoclave was distilled under vacuum to yield 169 g (72%) of product which boiled at 150°-138° C. at 1.7/0.5 mm Hg. A small amount of material was slurried in hexane, and after filtering and drying the product melted at 65°-67° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[CH3:25][NH2:26]>>[CH3:15][C:11]1[NH:12][C:13](=[O:14])[CH:8]([NH:26][CH3:25])[S:9][C:10]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: CN
Product: CNC1SC(c2ccncc2)=C(C)NC1=O

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one and methylamine were reacted to give the titled compound as pale brown needles.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[C:18]([C:22](Cl)=[O:23])(Cl)([Cl:20])[Cl:19].C(=O)(O)[O-].[Na+]>C(OCC)C.CC(N(C)C)=O.[Cu].[Zn]>[Cl:19][C:18]1([Cl:20])[C:22](=[O:23])[CH2:1][C:2]21[CH2:3][CH:4]([CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CC(CNC(=O)OCc2ccccc2)C1
Agent: [Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(NCC1CC2(CC(=O)C2(Cl)Cl)C1)OCc1ccccc1

Procedure:
Compound 4-3 (3 g, 12.98 mmol) and zinc-copper alloy (7.78 g, 64.9 mmol) were placed in 100 mL of diethyl ether, added dropwise a solution of CCl3COCl (6.97 g, 38.33 mmol) dissolved in 15 mL of DMA with stirring slowly. After the completion of addition, the mixture was stirred at room temperature for 18 hours. To the reaction mixture was poured 100 mL of saturated aqueous solution of sodium bicarbonate, and suction filtrated to remove insolubles, liquid separated, the aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtrated to remove the desiccant, and rotary evaporated to remove solvents, the resulting crude Compound 4-4 was used directly in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([OH:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][NH:20][CH3:21].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:20]([CH3:21])[CH3:19])=[O:16])[C:10]([OH:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-hydroxy-L-valine (1.00 g), 2M dimethylamine methanol solution (2.14 mL) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.11 g) in DMF (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.63 g) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (670 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][C:19]([OH:22])([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:55][CH2:54][N:46]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=3[CH:53]=[C:45]2[C:44]1=[O:56])(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][C:19]([OH:22])([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CC(C)(O)C3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(C)(O)C4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 42.9 %

Procedure:
A mixture of 207c (364 mg, 1.0 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (510 mg, 1.1 mmol), PdCl2(dppf) (110 mg, 0.15 mmol), K3PO4 (100 mg), and NaOAc (50 mg) in MeCN (20 mL) and water (4 mL) was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 207d (267 mg, 43%). MS: [M+H]+ 623.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:22][CH3:23])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].OS(O)(=O)=O>O1CCOCC1.O>[OH:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:22][CH3:23])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COc1cc(C2CCCCC2)ccc1C(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2CCCCC2)ccc1C(O)CCC(=O)O
Reaction time: 5 h

Procedure:
1.06 g of NaBH4 in 90 ml of dioxane-water (1:1) are added dropwise with stirring at room temperature to 1.16 g of 4-oxo-4-(4-cyclohexyl-2-methoxyphenyl)-butyric acid in 200 ml of dioxane-water (1:1). This is left to stand for 5 hours at 22° and then acidified with 2N H2SO4 to pH=2. Most of the dioxane is removed on rotary vapouriser and the aqueous solution is extracted three times with ethyl acetate. The organic phases are washed once with water, dried over Na2SO4 and concentrated. The residue is recrystallised twice from ether-petroleum-ether. M.p. 105°-106°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:7][N:8]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)nn(-c3ccccc3)c2c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Yield: 67.9 %

Procedure:
A mixture of 4.5 g of 6-fluoro-1-phenyl-3-(1-piperazinyl)-1H-indazole, 4.3 g of nitrourea, and 75 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized twice from toluene (one charcoal treatment) to yield 3.5 g (73%) of 4-(6-fluoro-1-phenyl-1H-indazol-3-yl)-1-piperazine carboxamide, m.p. 168°-170°.