Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:11][C:10]=1[C:29]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([S:36][CH3:37])[N:30]=1.C(Cl)Cl.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>>[F:8][C:9]1[C:10]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([S:36][CH3:37])[N:30]=2)=[CH:11][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:18][CH2:17]2)=[CH:13][N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1nc(C)nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was slowly added to a stirred solution of tert-butyl 4-((6-fluoro-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.853 g, 1.963 mmol) in DCM (5.00 mL, 78 mmol) cooled in an ice bath, and the mixture was then stirred at room temperature for 1 h. The mixture was concentrated, and the sticky residue was dissolved in DCM (10 mL) and cooled in an ice bath, and triethylamine (1.368 mL, 9.82 mmol) was added. Methanesulfonyl chloride (0.459 mL, 5.89 mmol) was slowly added to the mixture, which was then stirred at the same temperature for 1 h, concentrated, and the residue was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (pure DCM to 10% MeOH in DCM) to give a solid which was washed with IPA to give 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (0.64 g, 79%) as a white solid. LCMS (API-ES) m/z 413 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.58 (dd, J=9.29, 2.25 Hz, 1H) 8.37 (s, 1H) 3.67 (s, 2H) 3.01-3.19 (m, 4H) 2.87 (s, 3H) 2.61 (s, 3H) 2.60 (s, 3H) 2.47-2.49 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]([OH:37])[C:33]([F:34])([F:35])[F:36])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:34])([F:35])[F:36])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-c1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: Cc1ccccc1-c1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(o-tolyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-6-oxo-2-(o-tolyl)-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 12, 1.20 g, 3.05 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 709 mg, 3.23 mmol), WSCI hydrochloride (701 mg, 3.66 mmol) and HOBT (824 mg, 6.10 mmol) in DMF (15 mL) to give 1.66 g (92%) of the target compound as colorless crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[S:30](N)([NH2:33])(=[O:32])=[O:31]>O1CCOCC1>[NH2:33][S:30]([N:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:3]1)(=[O:32])=[O:31]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CN(S(N)(=O)=O)C1

Procedure:
A solution of tert-butyl azetidin-3-ylcarbamate hydrochloride (prepared according to J. Antibiot. 1986, 39, 1243-1256, 0.755 g), Proton-Sponge® (0.85 g) and sulfamide (0.42 g) in dioxane (23 ml) was heated at reflux for 48 h. The residue was partitioned between H2O and EtOAc, and the aqueous layer then extracted with further EtOAc (×4). The combined organic extracts were washed quickly with 2M aqueous hydrochloric acid (×3) then with saturated aqueous sodium bicarbonate, H2O and saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to afford the subtitle compound as a pale brown powder.
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)O.C1C=[N+]([C@@H]2[O:23][C@H:22](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[K+].[C:63](#N)C>C1(C)C=CC=CC=1>[CH3:22][O:23][C:7]1([O:8][CH3:63])[CH2:5][CH2:3][O:12][CH2:11][C@@H:9]1[OH:10]
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC#N
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC1(OC)CCOC[C@@H]1O
Temperature: 30 °C
Reaction time: 17 h

Procedure:
The above organic solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one was extracted 3× with phosphate buffered water (0.55 L). To the combined aqueous extracts was added D-glucose (180 g, 100 mmol), and the solution was heated to 30° C. When the solution exceeded 27° C. upon heating B-NADP+ (1.60 g, 499 mmol), GDH-103 (1.60 g, 499 mmol), and KRED-130 (1.60 g, 499 mmol) were added and the mixture was stirred for 17 h at 30° C. Potassium chloride (200 g, 2.68 mol) and acetonitrile (1.3 L) were added. After 30 min, the reaction mixture was transferred to 6 L sep funnel and additional MeCN (0.67 L) and toluene (0.87 L) were added. The aqueous layer was back extracted 1× with a mixture of acetonitrile (1.95 L) and toluene (0.65 L), and 1× with acetonitrile (1.5 L). The combined organic extracts were concentrated in vacuo to provide (3S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:21])=[C:18]([O:19]C)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:19][C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]=1[CH3:21]
Reactant: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 78 %

Procedure:
Using N-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 36, the title compound was synthesized in the same manner as in Example 134. Yield: 78%. Melting point: 181-182° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2](O)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si]([Br:24])(C)C>ClCCl.CCOCC>[C:13]1([C:2]([Br:24])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCC(C)(O)c1ccccc1
Reactant: C[Si](C)(C)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(Br)c1ccccc1
Reaction time: 1 h

Procedure:
10.50 g (0.04 mol) of 1-methyl-1-phenylundecyl alcohol was dissolved in 50 ml of dichloromethane, cooled in ice bath, 10.6 ml (12.29 g, 0.08 mol) of trimethylsilyl bromide was added and the mixture stirred for 1 h under protection from moisture. The solution was diluted with 100 ml ether and washed four times with 50 ml water, brine, dried and evaporated to give crude 2-phenyl-2-bromododecane. 35 ml of 2.3 M hydrogen peroxide in THF (0.08 mol) was added to the 2-phenyl-2-dodecyl bromide and the mixture was cooled on ice bath. 8.84 g (0.04 mol) of silver trifluoroacetate was added. 70 ml of conc. NaHCO3 was added and the mixture filtered. The reaction flask and the filter cake was rinsed with diethyl ether. The aqueous phase was separated and the organic phase washed with conc. NaHCO3, 50 ml water, brine, dried and evaporated to give an oil. The oil was purified by flash chromatography using 2:8 ether:pentane as eluent. The yield of 1-methyl-1-phenylundecyl hydroperoxide was 30%.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CCOC(=O)c1c(Nc2cc(Cl)ccc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-chloroanilino)benzo[b]thiophene-3-carboxylate (2.6 g), 1-methylpiperazine (15 ml), anisole (50 ml) and titanium tetrachloride (2.3 ml), 8-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (363 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].BrC1C2OCN(C(C)(C)C)CC=2C=C(C(C)(C)C)C=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44]Cl>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (5.0 g, 21.8 mmol) and triethylamine (4.4 g, 43.5 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen was added dropwise 2-methoxyethoxymethyl chloride (2.5 mL, 21.9 mmol) and the reaction mixture stirred overnight. The reaction mixture was poured into water (100 mL), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (5.0 g, 72% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: OB(O)c1ccc(F)cc1F
Product: Nc1cnc(-c2ccc(-c3ccc(F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2,4-difluorophenyl)boronic acid. MS (ESI): mass calcd. for C16H10F3N3, 301.08; m/z found, 302.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.35 (m, 1H), 8.03 (d, J=1.4, 1H), 7.97 (m, 1H), 7.73-7.65 (m, 1H), 7.54-7.35 (m, 3H), 7.26-7.20 (m, 1H), 6.74 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([CH:6]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH2:19]([O:21][SiH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>C1CC=CCCC=C1.Cl[Pt]Cl.C1(C)C=CC=CC=1>[F:14][C:13]([F:15])([F:16])[S:10]([CH:6]([S:3]([C:2]([F:17])([F:1])[F:18])(=[O:4])=[O:5])[CH2:7][CH2:8][CH2:9][Si:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:21][CH2:19][CH3:20])(=[O:12])=[O:11]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Agent: Cl[Pt]Cl
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: CCO[Si](CCCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)(OCC)OCC
Reaction time: 11 h
Yield: 65.2 %

Procedure:
A three-necked flask equipped with a reflux condenser and having a volume of 100 ml was charged under nitrogen atmosphere with each of 100.2 g (0.313 mol) of 1,1-bis(trifluoromethanesulfonyl)-3-butene (hereinafter abbreviated as BTSB), 69.8 g of toluene, 11.7 mg (0.0001 parts by mass relative to BTSB) of dichloro(1,5-cyclooctadiene)platinum (II) (made by Tokyo Chemical Industry Co., Ltd.), and 155.0 g (155 parts by mass relative to BTSB) of triethoxysilane (made by Tokyo Chemical Industry Co., Ltd.). After that, under nitrogen atmosphere, it was stirred and mixed for three minutes. Then, the reaction was conducted for 11 hours, while this flask was heated by immersion in an oil bath adjusted to 85° C. After the termination of the reaction, triethoxysilane and toluene were distilled off and recovered under reduced pressure. Then, a distillation under reduced pressure was conducted to carry out a heating at 100° C. to 108° C. and distill it out under a reduced pressure of 533 Pa (4 mmHg), thereby obtaining 98.8 g of 4,4-bis(trifluoromethanesulfonyl)butyltriethoxysilane (hereinafter abbreviated as BTSB-TES).
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[OH:25][CH2:24][CH2:26][NH:27][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)ns1
Reactant: NCCO
Product: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCCO)sn1
Yield: 111.3 %

Procedure:
As described for example 34, 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.3 mmol), was converted, using ethanolamine (21 mg, 0.34 mmol), instead of isopropyl amine, to the title compound (60 mg, 58%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=360.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[NH2:14][C:15](N)=[S:16].O>S1(CCCC1)(=O)=O>[NH2:14][C:15]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 12 h

Procedure:
A suspension of 10.13 g of 2,4-dinitrochlorobenzene and 15.2 g of thiourea in 50 ml of sulpholane (tetrahydrothiophene 1,1-dioxide) is stirred at 110° to 120° C. for 12 hours. After cooling, the mixture is thoroughly stirred with 800 ml of water, and the solid is filtered off with suction and washed with water. After drying, 11.2 g of a yellow powder which, according to HPLC analysis (high pressure liquid chromatography), contains 69.5% of 2-amino-5-nitrobenzothiazole (corresponding to 80% of theory) are obtained. Recrystallisation from dimethylformamide raises the melting point to 307° C. (decomposition) (Zhur. Obschei Khim. 30, 1363-6 (1960) reports melting point 308°-309° C., decomposition).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH:10]([OH:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[CH3:23]I>CN(C)C=O>[CH3:23][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[NH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:12])[CH3:11])[C:4]=1[Cl:3]
Reactant: CC(O)c1cccc(Nc2ccccc2C(=O)O)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Nc1cccc(C(C)O)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
Sodium hydride (0.48 g, 19.9 mmol) is added to a solution of 2-[[2-chloro-3-(1-hydroxyethyl)phenyl]amino]benzoic acid (5.8 g, 19.9 mmol) in dimethylformamide (15 mL) at room temperature. After 15 minutes, the reaction mixture is cooled to 0° C, and methyl iodide (2.8 g, 19.9 mmol) is added dropwise. The reaction mixture is stirred at room temperature overnight, and then partitioned between water and ether. The organic layer is washed with water and brine, dried over magnesium sulfate, and evaporated. Recrystallization of the residue from ether/hexane gives pure 2-[[2-chloro-3-(1-hydroxyethyl)phenyl]amino]benzoic acid methyl ester (4.6 g, 76%), mp=94-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:24]=[C:25]([NH2:27])[CH3:26].O>CN(C=O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:7]2[O:9][N:27]=[C:25]([CH3:26])[N:24]=2)[CH:10]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2cncc(Br)c2)n1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5-bromo nicotinic acid(1.0 eq.) and CDI (1.1 eq) in DMF (0.25M) was stirred at 20° C. for 5 min and then N′-hydroxy ethanimidamide (1.1 eq) in pyridine (0.6 M) was added. The reaction mixture was stirred at 110° C. for 15 h, cooled to rt and poured into water. The title compound was isolated by filtration as a solid.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([CH2:12][CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])(=O)[CH3:10]>C(O)(=O)C>[CH3:10][C:9]1[NH:7][C:1]2[C:6]([C:12]=1[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: CC(=O)CCCC(=O)N1CCN(c2ccccc2)CC1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: Cc1[nH]c2ccccc2c1CCC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.8 g of phenylhydrazine in 100 ml of 30 % aqueous acetic acid was added 27.4 g of 1-(γ-acetylbutyryl)-4-phenylpiperazine and the resulting mixture was stirred for 30 minutes at room temperature. The precipitate was filtered, and washed with water. The precipitate was added to 180 ml of 5 % ethanolic hydrogen chloride, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure to the residue, to which was added 100 ml of water. The resulting solid substance was recrystallized from ethanol to give 1-[β-(2-methyl-3-indolyl)propionyl]-4-phenylpiperazine, melting at 120°-121°C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:27])[CH3:26])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:26][C:8]1([CH3:27])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.7 g, 4.5 mmol) in methanol (20 mL) and tetrahydrofuran (40 mL) was added 30% sodium hydroxide in water (20 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.4 g, 99%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=351.0.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][C:12]=1[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1nc(CN2CCOCC2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 2-amino-4-morpholin-4-ylmethylthiazole-5-carboxylic acid benzylamide (0.030 g, 0.09 mmol) in tetrahydrofuran (5 mL) at 0° C. was added hydrocinnamoyl chloride (0.1 mL, 0.67 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (0.2 mL, 1.4 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound (0.031 g); 1H NMR (DMSO-d6, 400 MHz) δ 7.40-7.15 (m, 10H), 4.46 (d, J=5.1 Hz, 2H), 3.62 (s, 2H), 3.19 (bs, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.74 (t, J=8.1 Hz, 2H), 2.24 (br, s, 4H); MS (ES+) m/z 465 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: CSc1nnc(N=C=O)s1
Reactant: CCNC(C=O)COC
Solvent: c1ccccc1
Product: CCN(C(=O)Nc1nnc(SC)s1)C(C=O)COC

Procedure:
5-Methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9]([C:10](=[O:17])[C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:19]([OH:21])[CH3:20].C(OCC)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:17])[C:11]=1[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:19](=[O:21])[CH3:20]
Reactant: COCCNC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COCCN(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A few drops of concentrated sulfuric acid was added to a solution of 2-chloro-3-[(2-methoxyethyl)amino]-1,4-naphthoquinone (33 g) in acetic anhydride (100 ml) and the mixture was stirred at 45° C. for 1 hour. By adding ethanol (100 ml) to the reaction solution, excess acetic anhydride was esterified. After cooling, ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from diethyl ether to give N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (29 g) as a yellow powder.