Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:6]1[N:2]([CH3:1])[C:3]([CH:13]=[O:14])=[N:4][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1cc(-c2ccccc2)nc1C=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C=O)nc(-c2ccccc2)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 43 (0.299 g, 1.61 mmol) in CCl4 (6 mL) was added N-chlorosuccinimide (229 mg, 1.72 mmol). The reaction mixture was heated to reflux for 4 h, cooled to room temperature, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave 5-chloro-1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 44. Mass spectrum: calculated for C1H9ClN2O 220.0; found 221.3 (M++1).
Reaction SMILES: [I-:1].[I-].[I-].[CH2:4]([N:7]([C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[S+:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2)[CH2:8][CH2:9][CH3:10])[CH2:5][CH3:6].C(N([C:32]1[CH:33]=[CH:34][C:35]2C(C=1)=[S+]C1[C:37](=[CH:38][CH:39]=[CH:40]C=1)[N:36]=2)CCC)CC.C(N(C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)CCC)CC.C(NCCCC)CCC>>[I-:1].[CH2:35]([N:36]([C:19]1[CH:18]=[CH:17][C:16]2[C:21]([CH:20]=1)=[S+:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([N:7]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6])[CH:24]=1)[N:15]=2)[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33][CH3:32]
Reactant: CCCN(CCC)c1ccc2nc3ccccc3[s+]c2c1
Agent: [I-]
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)c1ccc2nc3ccc(N(CCC)CCC)cc3[s+]c2c1

Procedure:
This compound was obtained following isolation of 3-(N,N-dipropylamino)-phenothiazin-5-ium triiodide and subsequent treatment with dibutylamine. Precipitation from dichloromethane by addition of diethyl ether yielded purple lustrous crystals. Mass spectrometry: C26H35N3OS requires m/z=424; found m/z=424 (I− not detected by mass spectrometry).
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:8][CH2:9][CH2:10][CH3:11])[CH2:6][NH2:7])[CH2:2][CH3:3].Br[CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][NH:7][CH2:13][CH:14]1[O:19][CH:18]([CH3:20])[CH2:17][CH2:16][O:15]1)[CH2:10][CH3:11]
Reactant: CCCOC(CN)OCCC
Reactant: CC1CCOC(CBr)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCOC(CNCC1OCCC(C)O1)OCCC
Temperature: 25 °C

Procedure:
2,2-Dipropoxyethylamine (0.11 mole), 2-bromomethyl-4-methyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Cl:21][C:22]1[S:26][C:25]([C:27]([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)=[O:28])=[CH:24][CH:23]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:25]4[S:26][C:22]([Cl:21])=[CH:23][CH:24]=4)([C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[OH:28])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)s3)c3cncn3C)ccc2n1
Yield: 99 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (1.0 g, 1.87 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (170 mg, 3.44 mmol) generated the title compound of 18A as a yellow solid (919 mg, 65% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[F:17][C:18]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:18]=2[F:17])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3F)cc2)OC1(C)C
Product: CCOC(=O)c1c(-c2ccc(Oc3ccc(F)cc3F)cc2)c(C#N)c(CC)n1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in the final step of example E-227 using 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 38) and 2-[4-(2,4-difluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane. Purify the material by silica gel chromatography (Chromatotron™) eluting with hexane/ethyl acetate 4:1 to provide the final title compound, 4-cyano-5-ethyl-3-[4-(2,4-difluoro-phenoxy)-phenyl]-1-methyl-1H-pyrole-2-carboxylic acid ethyl ester, as a tan solid. Mass spectrum (m/e): 411.1 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.27-7.31 (2H, d), 7.07-7.14 (1H, m), 6.74-6.97 (4H, m), 4.04-4.11 (2H, dd), 3.84-3.88 (3H, s), 2.78-2.89 (2H, dd), 1.23-1.34 (3H, t), 1.00-1.06 (3H, t).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[C:20](N)=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1.N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[N:16]1[C:15]2[S:12](=[O:14])(=[O:13])[NH:11][C:9]3[C:8](=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cccnc21
Yield: 7.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, using 3-amino-pyridine-2-sulfonic acid quinolin-8-ylamide (Intermediate 303) (180 mg, 0.6 mmol), t-butyl nitrite (0.11 ml, 0.9 mmol), AcOH (1.8 ml) and THF(1.8 ml) gave the title compound (12 mg, 7%) after purification with prep HPLC (neutral conditions).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[O:19][C:20]3[CH:25]=[CH:24]C(F)=[CH:22][C:21]=3F)=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-:43]>C1COCC1.CO.O>[CH:37]1([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH:18]([O:19][CH:20]3[CH2:25][CH2:24][O:43][CH2:22][CH2:21]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:41])=[CH:9][CH:8]=4)=[CH:12][N:13]=3)=[O:40])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:38][CH2:39]1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 72.2 %

Procedure:
The compound of example B29 was obtained by similar method described in example B28 using 4-{2-[2-(4-Cyclopropanesulfonyl-phenyl)-2-(2,4-difluoro-phenoxy)-acetylamino]-thiazol-5-yloxy}-benzoic acid methyl ester (0.17 g, 0.29 mmol), LiOH (0.062 g, 1.48 mmol) in THF: MeOH: Water (1:1:1, 9 mL) to provide the title compound (0.117 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:9][N+:10]([O-])=O)[CH2:5]2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:10][CH2:9][C:6]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH:4]2[CH:7]1[CH:8]=[C:2]([CH3:1])[CH2:3]2
Reactant: CC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1=CC2C(C1)CC2(CN)CC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
Tert-butyl [3-methyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.12 g, 3.99 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (892.8 mg, 15.9 mmol) and ammonium chloride (211.5 mg, 3.99 mmol) were added, and the mixture was stirred for 4 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N solution of hydrochloric acid in ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (105.8 mg, 28%).
Reaction SMILES: C([Mg]Br)C.C[Si]([O:9][CH2:10][C:11]#[CH:12])(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:12]#[C:11][CH2:10][OH:9])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C#CCO[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−5° C.) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 130 ml, 130 mmol) in tetrahydrofuran was added O-trimethylsilylpropargyl alcohol slowly. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 2 hours, before cooling to −10° C. To this was then added a solution of (2S)-1-tert-butyloxycarbonyl-2-phenylpiperidin-3-one (Desc. 1; 30 g, 108 mmol) in tetrahydrofuran keeping the temperature below 5° C. The reaction was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (200 ml/200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and evaporated to an oil. This oil was dissolved in ethyl acetate (400 ml) and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 130 ml, 130 mmol) added. After stirring at room temperature for 2 hours, water (200 ml) was added, and the two layers separated. The aqueous phase was further extracted with ethyl acetate (200 ml), the organic layers dried (MgSO4) and evaporated to give the product as an oil (50 g) which was used crude for Description 3. 1H NMR (CDCl3) δ7.53-7.55 (2H, m), 7.19-7.35 (3H, m) 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m) 3.25 (1H, bs), 2.77-2.81 (1H, m) 2.77 (1H, bs), 2.12-2.20 (1H, m) 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), 1.39 (9H, s).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][O:3]1.C1(S(O)(=O)=O)C=CC=CC=1>CO.C(OCC)(=O)C>[N:8]1([C@@H:7]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C@H:5]([OH:6])[CH2:4][OH:3])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC1(C)OC[C@H]([C@@H](c2cccs2)n2ccc3ccccc32)O1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@@H](O)[C@H](c1cccs1)n1ccc2ccccc21
Reaction time: 16 h
Yield: 73.2 %

Procedure:
1-[(S )-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole (160 mg, 0.51 mmol) was dissolved in methanol (10 mL) and benzenesulfonic acid (10 mg, 0.06 mmol) was added. The mixture was stirred for 16 hours then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 5% methanol/chloroform) to afford 102 mg (74%) of (2S,3R)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol that was carried directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:16].C([Li])(C)(C)C.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH4+].[Cl-]>CCOCC.CCCCC.C1COCC1>[C:11]([O:10][C:9]([NH:8][C:5]1[CH:4]=[C:3]([CH3:16])[C:2]([Cl:1])=[CH:7][C:6]=1[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(Cl)c(C)cc1NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 5.9 g of tert-butyl 4-chloro-3-methylphenylcarbamate in 60 ml of ether is cooled to −50° C., under a nitrogen atmosphere, 42 ml of a solution of tert-butyllithium in pentane are added dropwise, and the mixture is stirred for 2 hours while allowing the temperature to rise to −20° C. The reaction mixture is cooled to −70° C., a solution of 4.5 g of diethyl oxalate in 30 ml of THF is added dropwise and the resulting mixture is stirred for 1 hour while allowing the temperature to return to 20° C. The reaction mixture is poured into saturated NH4Cl solution, the phases are separated by settling, the aqueous phase is extracted with EtOAc, the combined organic phases are washed with 1N HCl and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with an iso ether/pentane mixture (50/50; v/v). 8 g of the expected product are obtained in the form of an oil which crystallizes, m.p.=111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:35][CH2:36][CH3:37])([O:38][CH2:39][CH3:40])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OCC)OCC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 30 °C
Yield: 86.4 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(diethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 119, 500 mg, 0.85 mmol) in THF (10 ml) and MeOH (2.5 ml), at room temperature, was treated with a solution of lithium hydroxide (102 mg, 4.27 mmol) in water (2.5 ml). The reaction was heated to 30° C. overnight and subsequently warmed to 40° C. for about 5 hours. The mixture was allowed to cool to room temperature whereupon the volatiles were removed under reduced pressure. The concentrate was diluted with 30 ml of water, acidified with a few drops of 6N HCl to provide a white precipitate. The precipitate was collected by vacuum filtration to give the title compound (410 mg, yield: 86%).
Reaction SMILES: [H-].[Li+].[Al+3].[Li+].[H-].[H-].[H-].[H-].[N:9]1[C:18]2[NH:17][C:16]3[CH:19]=[C:20]([C:23](OC)=[O:24])[CH:21]=[CH:22][C:15]=3[S:14][C:13]=2[N:12]=[CH:11][CH:10]=1.O.[OH-].[Na+]>O1CCCC1>[N:9]1[C:18]2[NH:17][C:16]3[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[CH:22][C:15]=3[S:14][C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)Nc1nccnc1S2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)Nc1nccnc1S2
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Into a solution of 40 g of lithium aluminum lithium hydride in tetrahydrofuran (1 l) was dropped a solution of 200 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate in tetrahydrofuran (2.5 l) while maintaining the mixture at a temperature not exceeding 15° C. After continuing the reaction at 15° C. or below for 1 hour, 40 ml of water, 40 ml of a 15% aqueous solution of sodium hydroxide and 120 ml of water were successively added and the resulting mixture was stirred for an additional 1 hour. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure to thereby give 125 g of the title compound as yellow crystals.
Reaction SMILES: C(C1C=CC2OC(C)(C)[C@@H](Br)[C@H](O)C=2C=1)#N.[H-].[Na+].[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[CH:27]3[O:29][CH:28]3[C:23]=2[CH:22]=1)#[N:20].[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>CS(C)=O.O>[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[C@@H:27]([OH:29])[C@H:28]([N:34]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[C:23]=2[CH:22]=1)#[N:20]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=C1CCCN1
Agent: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-bromo-4-hydroxy-2H-benzo[b]pyran (4 g, 14.2 mM) in dimethylsulphoxide (20 ml) was stirred and sodium hydride (60% dispersion in oil, 0.6 g, 15 mM) added. The suspension was stirred for 1 hour when a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran resulted. 2-Pyrrolidone (1.8 g, 21 mM) and further sodium hydride (0.8 g, 21 mM) were introduced and the mixture stirred at room temperature for an additional 16 hours. Water (40 ml) was slowly added to the mixture to induce crystallisation of the product after which it was cooled in ice and filtered under suction. Crystallisation from ethanol (20 ml) gave the title compound as a cream coloured solid in 60% yield. Recrystallisation from ethyl acetate afforded the pure product as needles, m.p. 226.5°-227.5° having an nmr spectrum and t.l.c. characteristics identical to those of the compound of Example 1.
Reaction SMILES: S=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19].[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH2:25][CH2:26][CH2:27][N:28]=[C:2]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:8]4[C:9]=3[C:4](=[CH:5][CH:6]=[CH:7]4)[N:3]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: NCCCn1ccnc1
Reactant: N#CCCCCN1C(=S)c2cccc3cccc1c23
Solvent: CCO
Product: N#CCCCCN1C(=NCCCn2ccnc2)c2cccc3cccc1c23
Yield: 80.1 %

Procedure:
A mixture of 4.0 g of 2-thioxobenz[cd]indole-1(2H)-pentanenitrile (Cl), 1.88 g of 1H-imidazole-1-propanamine, 100 ml of ethyl alcohol, and 4.8 g of mercuric acetate is reacted as described in Example 3, giving 4.3 g of the desired product, mp. 76°-78.5° C.
Reaction SMILES: [NH2-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.N.[CH2:19](Br)[C:20]#[CH:21]>C1(C)C=CC=CC=1>[CH2:21]([N:8]1[C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Br:17])[CH:13]=2)[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 1.67 h
Yield: 63.9 %

Procedure:
Sodium amide (7.73 g, 0.198 mole) was carefully added to a suspension of 3,6-dibromocarbazole (54.7 g, 0.168 mole) in liquid ammonia (ca. 600 ml.) under argon atmosphere. After solution occurred, propargyl bromide (20.2 g, 0.170 mole) in toluene was added dropwise to the solution over 25 minute period. The reaction mixture was stirred for an additional 100 minutes, and the ammonia was allowed to evaporate. The resultant solid was washed with water and recrystallized from ethanol to give 39 g (63% yield) tan needles, mp 193°-194°. This solid gave an infrared spectrum with significant features at 3290, 2120, 870, 830, 800, and 790 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
To a suspension of 2-chloroisonicotinic acid (20 g, 0.127 mol), N,O-dimethyl-hydroxylamine HCl (19.8 g, 0.203 mol), 4-methylmorpholine (20.5 g, 0.203 mol) and DMAP (1.55 g, 0.013 mol) in dichloromethane (300 ml) at 0° C. was added EDCI HCl (29.2 g, 0.152 mol). The mixture was stirred at 0° C. for 10 min and at room temperature for 17 h. The mixture was poured into water/1M aqueous HCl and extracted with dichloromethane. The combined organic phases were washed with water, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (24.9 g) as a white solid. MS(m/e)=201.2 [M+H+].
Reaction SMILES: [H-].[Na+].CO[C:5](=O)[CH2:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:11]=2[CH:10]=1)=[O:8].C([O:25][C:26](=[O:29])CBr)C.C(O)(=O)C>O1CCCC1.O>[CH3:19][O:18][C:16]1[C:15]([O:20][CH3:21])=[CH:14][C:12]2[S:13][C:9]([C:7](=[O:8])[CH2:6][CH2:5][C:26]([OH:29])=[O:25])=[CH:10][C:11]=2[CH:17]=1
Reactant: COC(=O)CC(=O)c1cc2cc(OC)c(OC)cc2s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2cc(C(=O)CCC(=O)O)sc2cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.37 g) in dry tetrahydrofuran (15 ml) was stirred at room temperature under an atmosphere of nitrogen and treated dropwise over 10 min. with a solution of 3-(5,6-dimethoxybenzo[b]thien-2-yl)-3-oxo-propanoic acid methyl ester (5.0 g) in dry tetrahydrofuran (75 ml). After 30 min. ethylbromoacetate (4.0 ml) was added and the reaction mixture was stirred at room temperature for a further 45 min. and then warmed to 40° C. After 2 hours the suspension was cooled, treated with glacial acetic acid (2 ml) then poured into water (400 ml). The mixture was extracted with diethyl ether (2×100 ml), the organic extracts were combined, washed with water (50 ml), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in ethanol (25 ml), 5M hydrochloric acid (50 ml) was added and then the solution was heated at reflux for 10 hours. The resultant white suspension was cooled to room temperature and treated dropwise with 10M potassium hydroxide (30 ml). The reaction mixture was then stirred and heated at reflux under an atmosphere of nitrogen. After 1 hour the solution was cooled, diluted with water (100 ml) and extracted with ethyl acetate (50 ml). The aqueous layer was separated, stirred and acidified with 5M hydrochloric acid (10 ml). The resultant precipitate was filtered off, washed with water and dried at 65° C. under vacuum to give 4-(5,6-dimethoxy-benzo[b]thien-2-yl)-4-oxo-butanoic acid as a pale yellow solid (4.68 g). A portion crystallized from dichloromethane/methanol had m.p. 177°-178° C.