Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CC(C)CCO>[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: Clc1ccncc1
Reactant: CC(=O)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CC(=O)NC1CCN(c2ccncc2)CC1

Procedure:
A mixture of the product from step (ii) (1.79 g), 4-chloropyridine hydrochloride (1.50 g), sodium hydrogen carbonate (2.86 g) in 3-methyl 1-butanol (25 ml) was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by flash chromatography on silica, eluting with methanol/dichloromethane (1:2 v/v) gave 4-acetylamino-1-(4-pyridyl)piperidine as a foam, 0.69 g: NMR(d6DMSO) δ8.10(2H,d), 7.80(1H,bd), 6.80(2H,dd), 3.82(3H,m), 2.93(2H,dt), 1.78(3H,s), 1.77(2H,m), 1.33(2H,dq); m/e 220 (M+H)+.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14]Br)[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][O:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH2:8]1)=[O:6])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(CCON2C(=O)c3ccccc3C2=O)C1
Reaction time: 5 h
Yield: 47.6 %

Procedure:
To a suspension of (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (6.90 g, 20 mmol) and triethylamine (4.04 g, 40 mmol) in DMF (30 ml) was added N-hydroxyphthalimide (3.26 g, 20 mmol). The mixture was stirred for 5 h, filtered and the solvent was evaporated from the filtrate in vacuo. The residue was dissolved in dichloromethane (50 ml) and the resulting mixture washed with 10% aqueous potassium carbonate (3×20 ml) and water (20 ml). The solvent was evaporated in vacuo and the residue crystallised from absolute ethanol (25 ml). The precipitate was collected, washed with cold absolute ethanol and dried in vacuo to give 3.3 g of (R)-1-(2-((phthalimido)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C@H:21]1[C@@H:25]2[O:26][C:27]([CH3:30])([CH3:29])[O:28][C@@H:24]2[C@@H:23]([OH:31])[CH2:22]1.C1(C)C=CC=CC=1>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3].[OH:31][C@@H:23]1[C@H:24]2[O:28][C:27]([CH3:29])([CH3:30])[O:26][C@H:25]2[C@H:21]([NH3+:20])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2N
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)[O-]
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2[NH3+]
Temperature: 63 °C
Yield: 42.7 %

Procedure:
N-(tert-Butoxycarbonyl)-L-phenylalanine (4.1 g, 99%, 15.2 mmol), (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (2.6 g, 96%, 14.5 mmol), toluene (1.5 mL) and iso-propanol (19.5 mL) were taken to a flask with a stirrer. The mixture was heated under stirring to 63° C. when a clear solution was obtained. The solution was cooled and crystallization started at 53° C. The slurry was further cooled to 0° C. and stirred at this temperature for 60 min. The crystals were isolated on a glass filter, washed with cooled iso-propanol (17.5 mL) and dried in vacuum at 40° C. to give an amount of 2.73 g. The assay by titration was 99.7% and ee by LC 98.8%. The yield was 42.7%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CCN(C2CCCNC2)CC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCC(N4CCCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1,3′-bipiperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=12.88 Hz, 2H) 1.62-1.89 (m, 7H) 2.17 (d, J=10.86 Hz, 1H) 2.43 (s, 3H) 2.97-3.51 (m, 6H) 3.56-4.15 (m, 1H) 4.32-4.88 (m, 1H) 7.62-7.85 (m, 3H) 7.82-7.83 (m, 1H) 7.95-8.64 (m, 4H) 9.40 (br. s., 1H) 12.56-13.62 (m, 1H). ESI-MS m/z [M+H]+ 471.3.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].[NH2:19][O:20][CH2:21][C:22]([NH2:24])=[O:23].Cl>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:19][O:20][CH2:21][C:22](=[O:23])[NH2:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: NOCC(N)=O
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (4.63 g.) and sodium bicarbonate (1.95 g.) in water (230 ml.) was added 2-aminooxyacetamide (2.5 g.) and the mixture was stirred at room temperature for 6 hours while keeping at pH 5. After adjusting the solution to pH 1.5 with 10% hydrochloride acid, the precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 3.6 g.), mp 195° C. (dec.).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].[CH3:7][C:8]([C:10]1[C:15](O)=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[OH:18])=[O:9].[CH:19]([O:21]S([O-])(=O)=O)=O.[Na+].S(=O)(=O)(O)O>CN(C)C=O>[CH:8]1[C:10]([C:12]2[C:11](=[O:18])[C:10]3[C:8]([OH:9])=[CH:7][C:19]([OH:21])=[CH:14][C:15]=3[O:17][CH:13]=2)=[CH:11][CH:12]=[C:1]([OH:4])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=COS(=O)(=O)[O-]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To 159.8 g of anhydrous sodium carbonate (1.5 mol) in 950 ml of dimethylformamide were added 99.6 g of anhydrous phloroacetophenone (375 mmol) and the resulting yellow suspension was stirred for 3 hours under argon at 25° C., then cooled to 0° C. To this suspension was added the above solution of sodium formylsulfate within 2 minutes and the reaction mixture was stirred for 18 hours at 0° C., heated to 80° C., and held at that temperature during 30 minutes. To the hot mixture were added within 40 minutes 732 ml of sulfuric acid (36%). After gas evolution had ceased, 2.44 l water-dimethylformamide was distilled off at 80° C. and 15 mbar. To the thick suspension were added within 1.5 hours at 70° C. 3.99 l of hot water (50° C.). The white suspension was stirred and cooled to 20° C. overnight, then filtered. The filter cake was washed 3 times with 272 ml of water, then dried at 60° C. at 12 mbar overnight to yield 101.9 g of genistein as a light beige solid. The calculated yield was 95% (purity 93%, w/w, HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:33]3[CH2:32][CH2:31][N:30]([CH2:36][C:37](=[O:38])[N:39]4[CH2:40][CH2:41][CH2:42][CH2:43]4)[CH2:35][CH2:34]3)=[O:29])[NH:10][CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCCC3)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8%).
Reaction SMILES: [N:1]1[C:2]([CH:13]=O)=[CH:3][N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH:26]=[CH:13][C:2]3[N:1]=[C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][N:4]4[CH:3]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: O=Cc1cn2c(n1)-c1ccccc1C2
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(C=Cc3cn4c(n3)-c3ccccc3C4)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5H-Imidazo[2,1-a]isoindole-2-carbaldehyde (150 mg, 0.81 mmol) in dry THF (5.3 mL) was added to (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium chloride (374 mg, 0.81 mmol) under argon and 1,8-diazabicyclo [5.4.0]undec-7-ene (120 micro L, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours after which it was evaporated onto silica gel (2 g). Silica gel chromatography (gradient elution; A:B 100:0 to 0:100, where A is ethyl acetate and B is 10% MeOH in ethyl acetate) afforded the title compound as a mixture of the cis and trans isomers (139 mg, 52%). LC-MS: m/z=329.3 (MH+), tR=0.96 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC=C)(=O)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (200 mg, 0.492 mmol), vinyl acetate (182 μL, 1.97 mmol), di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (16.5 mg, 0.0246 mmol) and sodium carbonate (31.3 mg, 0.295 mmol) in o-dichlorobenzene (0.98 mL) was stirred at 100° C. for 2 hr. Vinyl acetate (100 μL, 1.08 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane to give the title compound (175.2 mg, 0.405 mmol, 82%) as a white yellow amorphous.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[N:7][CH:8]=1.OO.[OH2:14].C(O)(=[O:17])C>>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[N:7][CH:8]=1)(=[O:17])=[O:14]
Reactant: CC(=O)O
Reactant: CSc1ccc([N+](=O)[O-])nc1
Reactant: O
Agent: OO
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 117a (260 mg, 0.5 mmol) in acetic acid (15 mL) was added H2O2 (aq. 30%) (7.5 mL) and the reaction mixture was stirred overnight at 25° C. The reaction solution was poured into water and extracted with EtOAC and concentrated to a pale yellow liquid, purified by silica gel with (EtOAC/PE:1:3) to give 117b (2 g, 86%). MS: [M+H]+ 203.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:62][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=6)=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:63])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (14 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 846.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].[H-].[Na+]>CN(C)C=O.O>[NH2:16][C:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:8][C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccccc1Cl
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(-c2ccccc2)sc2ccccc12
Yield: 93.4 %

Procedure:
from 10.5 g (84 mmol) of benzylmercaptan and the equimolar quantity of sodium methoxide the corresponding salt is prepared. A solution of sodium benzylthiolate is stirred for 1 hour at ambient temperature in 150 milliliters of absolute dimethyl formamide after the addition of 10.5 g (76 mmol) of 2-chloro-benzonitrile and 8.0 g of a disbursion of NaH at 50% (0.167 mol). The mixture is then poured into water and the product extracted with CH2Cl2. By evaporating the organic phase dried over Na2SO4 and re-crystallising the residue in cyclohexane, 16.0 g (93% of theory) of 3-amino-2-phenyl--benzo(b)thiophene are obtained, yellow plates, mp 110°-112° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29].[Cl-].[NH4+]>C1COCC1>[Br:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,7-dibromoheptane (6.4 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2) then the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.27 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[OH:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[OH:17]
Reactant: COC(=O)c1c(O)cnc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2ncc(O)c(CO)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 3-hydroxy-6-methoxyquinoline-4-carboxylic acid methyl ester (5 g, 21.44 mmol, 1.0 eq) in tetrahydrofuran (40 mL) is added at 0° C. to a stirred solution of lithium aluminium hydride (1.63 g, 42.88 mmol, 2.0 eq) in tetrahydrofuran (200 mL). After 1 hour stirring at 0° C., the reaction mixture is cautiously quenched with ice-water (5 mL). After 30 minutes stirring at room temperature, the pH is adjusted to 6 by the addition of a 1N hydrochloric acid aqueous solution, the resulting mixture is filtered and the filtrate is concentrated to afford 4-hydroxymethyl-6-methoxy-quinolin-3-ol as a yellow solid (4 g, 90% yield).
Reaction SMILES: [CH:1]1[C:14]2[N:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[N:23](CC[OH:26])[C:22]([N+:27]([O-:29])=[O:28])=[CH:21][N:20]=1.N1[CH:35]=[CH:34]C=CC=1>O>[CH3:18][C:19]1[NH:23][C:22]([N+:27]([O-:29])=[O:28])=[CH:21][N:20]=1.[CH:1]1[C:14]2[N:13]([C:15]([O:16][CH2:34][CH3:35])=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C(Cl)N1c2ccccc2Sc2ccccc21
Solvent: O
Product: CCOC(=O)N1c2ccccc2Sc2ccccc21
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 90 °C
Yield: 53.28 %

Procedure:
A reaction mixture of phenothiazine-10-carbonyl chloride (261 mg, 1.0 mmol), metronidazole (165 mg, 0.96 mmol) and pyridine (4 ml) was heated at 90° C. for 4 h. After cooling, water was added. The mixture was filtered. The collected solid was washed with 5% aqueous Na2CO3 and H2O, and then dried. The crude solid was recrystallized from EtOH to give 201 mg (53.28%) 2-methyl-5-nitro-1H-imidazole-1-ethyl phenothiazine-10-carboxylate. m.p.: 198-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:13].[K+].[CH:15]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])[CH3:16]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:16][CH:15]([O:18][C:19]([CH2:20][N:1]([CH2:20][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:3]=[C:4]([CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=[CH:6][CH:7]=1)=[O:22])[CH3:17]
Reactant: Nc1cccc(C2OCCO2)c1
Reactant: CC(C)OC(=O)CBr
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Product: CC(C)OC(=O)CN(CC(=O)OC(C)C)c1cccc(C2OCCO2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
165.19 g (1.00 mol) of 2-(3-aminophenyl)-1,3-dioxolan (CA 108 (15): 131815 r), 156.35 g (3.00 mol) of pulverized potassium hydroxide and 11.39 g (0.05 mol) of benzyltriethylammonium chloride are vigorously mechanically stirred under argon and heated to 80° C. 543.09 g (3.00 mol) of bromoacetic acid isopropyl ester is instilled in the suspension and the reaction mixture is stirred for about 8 hours at 80° C. Then, it is filtered, the filtrate is shaken out several times with concentrated aqueous sodium bicarbonate solution, the organic phase is dried on anhydrous magnesium sulfate, filtered and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel 60 (Merck) with methylene chloride/methanol. After concentration by evaporation, the product fractions yield a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18]Cl)([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([OH:33])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH2:16][CH2:15][C:12]2([CH2:17][CH3:18])[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:27]=1
Reactant: COC(=O)Cc1ccc(Cl)c(O)c1
Reactant: CCC1(CCCl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CCOc2cc(CC(=O)OC)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A mixture of 6-chloro-2-[4-(2-chloroethyl)-4-ethyl piperidine-1-yl]benzothiazole (150 mg), (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (176 mg), cesium carbonate (285 mg) and dimethylformamide (2 mL) was stirred at 75° C. for 24 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 79%.
Reaction SMILES: C([NH:4]C(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.O.O.O.C([O-])(=O)C.[Na+].N[O:37][S:38]([OH:41])(=O)=O>O1CCCC1>[S:38]([C:20]1[O:19][C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=1)(=[O:41])(=[O:37])[NH2:4]
Reactant: c1cc2occc2cn1
Reactant: NOS(=O)(=O)O
Reactant: CC(C)NC(C)C
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: NS(=O)(=O)c1cc2cnccc2o1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
To a solution of distilled diisopropylamine (16.2 ml, 0.116 mol) in distilled tetrahydrofuran (115 ml), cooled at -10° C., under a nitrogen atmosphere, was added 1.56M butyl lithium in hexane (75.3 ml, 0.117 mol). After 15 minutes, the solution was cooled to -70° C. and there was added dropwise a solution of furo[3,2-c]pyridine (11.74 g, 0.0987 mol) in tetrahydrofuran (70 ml). With vigorous stirring the gummy precipitate formed a salmon-colored powder. After one hour, sulfur dioxide gas was bubbled over the surface with gradual warming to room temperature. The suspension was diluted with diethyl ether (200 ml) and the precipitate was collected by filtration. This crude lithium sulfinate intermediate (29.1 g) was dissolved in water (200 ml) and sodium acetate trihydrate (61 g, 0.45 mol) and hydroxylamine-O-sulfonic acid (18 g, 0.16 mol) were added. The solution was stirred for 18 hours as the product slowly precipitated. The precipitated product was collected by filtration and redissolved in ethyl acetate/methanol, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated to give white crystalline product (8.0 g, 41% yield). This material was recrystallized from ethyl acetate/methanol to give 6.7 g, m.p. 216°-218° C.