Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)N2CCCC2)CC1

Procedure:
In 50 ml of toluene was dissolved 8.1 g (0.05 mole) of 1-methyl-4-chlorocarbonylpiperazine at room temperature and a solution of 10.7 g (0.15 mole) of pyrrolidine in 50 ml of toluene was dropped to the above solution at 0° C. over a period of 30 minutes. The mixture was refluxed for 1 hour to complete the reaction. The reaction mixture was cooled, and the precipitated yellow crystal (pyrrolidine hydrochloride) was removed by filtration. The filtrate was dried with anhydrous sodium sulfate and toluene as the solvent was removed by distillation under reduced pressure to obtain crude 1-methyl-4-(pyrrolidinocarbonyl)piperazine as the distillation residue. The crude product was purified by distillation under reduced pressure to obtain 6.6 g of a pure product having a boiling point of 109.5 to 110.0° C. at 0.5-0.6 mm Hg obs. The yield was 66.9%. The elementary analysis values are as follows:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][I:19])=[CH:12][CH:11]=1>CC(C)=O>[CH3:1][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][I:19])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(CCCI)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Temperature: 70 °C
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (4.14 g, 30.0 mmol), iodomethane (3.74 mL, 60.0 mmol), and 3-(4-hydroxyphenyl)-1-iodopropane (1.58 g, 6.0 mmol) were added to acetone (25 mL) at rt. The mixture was heated to 70° C. for 8 h. The resulting solution was gravity filtered to remove salts and the filtrate was concentrated in vacuo to afford 3-(4-methoxyphenyl)-1-iodopropane (1.22 g, 73%).
Reaction SMILES: [C:1]([C:4](=[N:10][NH:11][C:12]1[CH2:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1)[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])([OH:3])=[O:2].[N+](=[CH2:31])=[N-]>>[CH3:31][O:2][C:1]([C:4](=[N:10][NH:11][C:12]1[CH2:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1)[CH2:5][CH2:6][N:7]([CH3:8])[CH3:9])=[O:3]
Reactant: CN(C)CCC(=NNC1=Nc2ccccc2C(c2ccccc2)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCN(C)C)=NNC1=Nc2ccccc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 2-[[1-carboxy-3-(dimethylamino)propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 2-[[1-(methoxycarbonyl)-3-(dimethylamino)-propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O1CCCC1>CO>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
To a mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g) in methanol (10.0 ml) were added conc. hydrochloric acid (0.52 g) and tetrahydrofuran (5.0 g) and the mixture was stirred for 2 hours and 10 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate and then the resulting mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated, washed with ethyl acetate (x2) and then concentrated. The concentrate was adjusted to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1)=[N+:25]=[N-:26]
Reactant: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
0.950 g (2.59 mmol) of 4-chloro-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine (III) is placed in 20 mL of dimethylformamide and 0.900 g (13.84 mmol) of sodium azide is added. The reaction mixture is stirred for 4 hours at 100° C. It is then concentrated by evaporation, the residue is cooled in the ice bath and combined with water. The precipitate formed is suction filtered, washed, and dried. 0.920 g of product IV (76%) is obtained and used further in the crude state.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([CH:17]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:19]=2[O:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)(=O)C>[CH2:5]([CH:17]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[C:25]([OH:28])[C:26]([N+:1]([O-:4])=[O:2])=[CH:27][C:19]=2[O:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCC1Oc2ccc(O)cc2NC1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC1Oc2cc([N+](=O)[O-])c(O)cc2NC1=O

Procedure:
Fumic nitric acid (δ1.52, 1.4 ml, 0.0336 mole) in acetic acid (16 ml) was added dropwise under stirring at 15° C. to 2-n-dodecyl-6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (11.2 g, 0.0336 mole) in acetic acid. The 2-n-dodecyl-6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (5.6 g, 44%) separated as orange prisms and was used as such.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[C:4]([CH3:18])[N:3]=1.C1CCN2C(=NCCC2)CC1>O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[CH:12][C:13](=[O:14])[N:8]([CH2:9][CH3:10])[C:6]=2[N:7]=1
Reactant: CCNc1nc(N)nc(C)c1/C=C/C(=O)OCC
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)ccc2c(C)nc(N)nc21
Temperature: 165 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and the mixture was heated to 165° C. and stirred for 24 h. After that, the mixture was cooled to 70° C. followed by the addition of H2O (20 mL) to precipitate crystal and stirred for 1 h at room temperature. The crystal was collected and washed with H2O and acetone and dried under vacuum to afford 2.70 g (73.5% yield of 2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellowish brown solid. LC/MS: Calculated for C10H12N4O (204.2). Found: 205.31 (MH+); HPLC analytical purity: 98.5%.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([O:16]C)=[O:15])[C:11](=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)CC1SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)CC1SCc1ccccc1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of methyl (4-benzylthio-2-oxo-azetidin-1-yl)acetate (2.5 g, 9.4 mmol) in methanol (80 ml) was added, dropwise at 0° C., a solution of 1 N sodium hydroxide (9.9 ml, 9.9 mmol). The reaction was stirred for 1 hr and evaporated to dryness. Water (50 ml) was added and the solution acidified to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts were dried (MgSO4), evaporated and the residue purified by recrystallisation (hexane/ether) to give (4-benzylthio-2-oxo-azetidin-1-yl)acetic acid as a white solid (1.3 g, 55%), mp 110-110° C. 1H NMR δ (CDCl3) 2.99 (1H, dd, J=6.87, 17.5 Hz, H3a), 3.27, 4.06 (each 1H, d, J=18.40 Hz, NCH2), 3.39 (1H, dd, J=5, 15.4 Hz, H3b), 3.77 (2H, s, SCH2), 4.91 (1H, m, H4), 7.27 (5H, m, Ph-H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:25])[N:16]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:12]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:11]=1.[CH3:32]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:32][N:9]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(Cl)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=c1[nH]c2c(-c3ccncc3)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a vial containing crude 2-(2-amino-5-chlorophenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (0.015 mmol) was added anhydrous methanol (2.5 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and p-toluene sulfonic acid (1 mg) and the reaction mixture was stirred under Ar at room temperature for 4 h (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (1.2 mg, 18% yield on two steps), as a yellow solid. TFA salt. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.18 (s, 1H), 8.83 (br m, 2H), 8.71 (s, 1H), 8.07 (br m, 2H), 7.76 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 4.76-4.72 (m, 1H), 4.26-4.23 (m, 2H), 3.66 (app t, J=11.5 Hz, 2H), 2.90-2.87 (m, 2H), 1.91 (br d, J=12.8 Hz, 2H); MS (EI) m/z 448.3 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:5])[CH3:2].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:12])=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C)[nH]n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A mixture of 5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (4.45 g, 28.9 mmol) and N-chlorosuccinimide (5.01 g, 37.5 mmol) in dimethylformamide (60 mL) was stirred for 24 hours at ambient temperature. The reaction was then concentrated down and purified by eluting through a silica gel column with a 0 to 100% ethyl acetate/heptane gradient to afford the title compound (5.2 g, 96% yield) as a white solid. MS (ESI) [m/e, (M+H)+]=189.3. 1H NMR (400 MHz, chloroform-d) δ ppm 9.39 (br. s., 1H), 4.44 (q, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:48]>>[ClH:48].[ClH:48].[CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:11]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10% Hydrogenchloride dioxane solution (30 ml) is added to N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester (2.25 g) and the mixture is stirred at room temperature for two hours. The reaction mixture is concentrated under reduced pressure to remove solvent and ether is added to the residue to give L phenylalanyl-L phenylalanyl-L-histidine methyl ester dihydrochloride (2.15 g) as white powder. The product (2.15 g) thus obtained is dissolved in dimethylformamide (15 ml), and pivaloyl chloride (0.48 g) is added thereto. Triethylamine (2.24 ml) is added dropwise to the mixture under ice-cooling and the mixture is stirred at room temperature overnight. Ethyl acetate is added to the reaction mixture and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and water, dried, and then concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chroroform:methanol=12:1) and triturated with ether to give N-pivaloyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester (0.98 g). Yield ;44.8%
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[NH:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14.2 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (11.37 g, 37 mmol) in 50 mL of DMF was added into the solution of 1-(benzyloxy carbonyl)pyrazolidine-3-carboxylic acid (12.04 g, 48.1 mmol) and Hunig's base (25.8 ml, 148 mmol) in 70 ml of DMF. The reaction was stirred at 25° C. for 5 hrs. The reaction was diluted with ethyl acetate, and the resulting solution was washed with aqueous NH4Cl (2×200 ml). The aqueous solution was extracted with ethyl acetate (5×100 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica Gel chromatography and then recrystallization from ethyl acetate and hexane to yield (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.834 g, 5.27 mmol, 14% yield). MS (ES+) m/z 538.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2
Reactant: O=[N+]([O-])c1ccncc1Nc1ccc2[nH]ccc2c1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccncc1Nc1ccc2[nH]ccc2c1
Reaction time: 6 h

Procedure:
A mixture of N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N5 -oxide (7.8 g) in 500 ml ethanol containing platinum oxide (1.25 g) was hydrogenated at 50 psi for six hours and thereafter filtered and concentrated. The product was purified by flash chromatography (silica, 20% methanol in dichloromethane) to give 6 g solid, m.p. 83°-90°. Three grams were distilled twice via Kugelrohr (240°-250° @ 0.01 mm Hg) to give 2.4 g solid, 138°-140°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([O:12][C:13](Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:14])[N:26]([CH2:25][CH2:24][Cl:23])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: ClCCNc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Nc1cccc(OC(=O)N(CCCl)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 22.9 g of chloroformic acid-3-methoxycarbonylaminophenylester in 50 ml acetic acid ester is added dropwise together with a solution of 30.5 g potassium carbonate in 150 ml water at a temperature of 10° to 15° C. into a solution of 23 g N-(2-chloroethyl)-aniline hydrochloride in 50 ml water and 50 ml acetic acid ester. During the addition the solutions are stirred. The stirring is then continued for 30 minutes at 15° C. whereupon the organic phase is separated, diluted with about 100 ml acetic acid ester and washed at 0° C. successively with dilute sodium hydroxide, water, dilute hydrochloric acid and again water. After drying on magnesium sulfate the mass is concentrated by evaporation under a reduced pressure. The residue obtained is at first oily but soon crystallizes throughout and is then recrystallized from acetic acid ester/pentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:21])=O>>[Br:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=P(Br)(Br)Br
Product: FC(F)(F)c1cc(Br)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-trifluoromethyl-1H-pyridin-2-one (example A.16 step 2) (7.38 g, 27 mmol) and phosphoryl bromide (25 g, 87 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a brown solid (8.92 g, 98%). MS (EI) 334.8 [(M)+], 336.7 [(M+2)+], 338.8 [(M+4)+] and 339.8 [(M+6)+]; mp 51-53° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[CH:15]=1)[C:7]2=[O:23].CC1C=CC=C2C=1NC(=O)NC2=O.BrCC1C=C(C=CC=1)C(OC)=O.[N:49]1([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:52]3[CH2:53][CH2:54][N:49]([C:55]4[N:56]=[CH:57][CH:58]=[CH:59][N:60]=4)[CH2:50][CH2:51]3)=[O:21])[CH:15]=1)[C:7]2=[O:23]
Reactant: Cc1cccc2c(=O)n(Cc3cccc(C(=O)O)c3)c(=O)[nH]c12
Reactant: c1cnc(N2CCNCC2)nc1
Agent: COC(=O)c1cccc(CBr)c1
Agent: Cc1cccc2c(=O)[nH]c(=O)[nH]c12
Product: Cc1cccc2c(=O)n(Cc3cccc(C(=O)N4CCN(c5ncccn5)CC4)c3)c(=O)[nH]c12

Procedure:
The compound was prepared from 8-methyl-3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 8-methylquinazoline-2,4(1H,3H)-dione and methyl 3-(bromomethyl)benzoate using a procedure similar to those used for Examples 222 and 223), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 10.81 (s, 1H), 8.36 (d, J=4.5 Hz, 2H), 7.83 (d, J=7.5 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.45-7.30 (m, 4H), 7.13 (t, J=7.7 Hz, 1H), 6.67 (t, J=4.7 Hz, 1H), 5.15 (s, 2H), 3.92-3.46 (m, 8H), 2.36 (s, 3H). MS: m/z 457.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=2)(=[O:44])=[O:43])[CH2:17][CH:16]=4)[C:10]1([CH3:34])[CH3:35])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC[C@@H](C)[C@H]2CC=C3C4=C(CC[C@@]32C)[C@@]2(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]2CC4)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (4.0 g) is dissolved in 80 ml of dry pyridine at 0° C. 3.04 g of p-toluenesulphonyl chloride is added and the mixture is stirred at 5° C. for 20 hours and at room temperature for 5 hours. After aqueous work-up and crystallisation from methanol, 3.01 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-p-toluenesulphonyloxy-5α-chola-8,14-diene is obtained.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[NH:13][C:14](OC(C)(C)C)=[O:15])(C)(C)C.O>C(O)(=O)C.C(OCC)(=O)C(OCC)=O>[C:21]1([C:11]2[C:12]3[NH:13][C:14](=[O:15])[C:6](=[O:5])[NH:7][C:8]=3[S:9][CH:10]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1scc(-c2ccccc2)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2scc(-c3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di-t butyl-4-phenylthiophene-2,3-dicarbamate (0.9 g crude oil from the preceding step) was dissolved in a mixture of 7 ml of acetic acid and 7 ml of diethyl oxalate and heated to reflux for three hours. While still hot, 7 ml of water was added, and the mixture stirred overnight at room temperature to precipitate 0.27 g of crude title compound. Three crystallisations from acetic acid combined with charcoal (Norit SU 18) and one from ethanol/acetic acid (1:1) produced 65 mg of pure title compound, m.p.>300° C. 1H-NMR (DMSO-D6, δ): 7.1 (s, 1H), 7.4 (m, 5H), 11.5 (br.s, 1H), 12.5 (br.s, 1H). MS: 244.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][C:6]1([CH2:9][O:8][CH2:7]1)[C:5]2=O.[OH-].[Na+].[CH2:18]1COCC1>[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][C:6]1([CH2:9][O:8][CH2:7]1)[C:5]2=[CH2:18]
Reactant: C1CCOC1
Reactant: O=C1c2cc(Br)ccc2OCC12COC2
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Product: C=C1c2cc(Br)ccc2OCC12COC2
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-4H-spiro[chromene-3,3′-oxetan]-4-one (143 mg, 0.531 mmol) in THF (2 mL) was added Tebbe reagent ((C5H5)2TiCH2ClAl(CH3)2, μ-Chloro[di(cyclopenta-2,4-dien-1-yl)]dimethyl(μ-methylene)titaniumaluminum, 0.5 M in toluene, 2 mL) under ice-water bath cooling. After the reaction mixture was stirred at the same temperature for 2 hours and then room temperature for 4 hours, 1M aqueous NaOH (1 mL) was added. After dilution with water and filtration with Celite, the insoluble material was washed with CHCl3. The aqueous phase was extracted with CHCl3 and combined organic layer was concentrated in vacuo. The residue was purified with silica-gel column chromatography to give 6-bromo-4-methylene-4H-spiro[chromene-3,3′-oxetane] (0.10 g).