Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>C(O)C>[CH2:1]([N:7]([CH2:21][CH2:22][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Temperature: 80 °C
Yield: 80 %

Procedure:
In 30 ml of ethanol were dissolved 5.47 g of N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide and 2.85 g of piperidine, and the solution was heated in a pressure vessel at 80° C. for 3 hours. To the mixture obtained was added 100 ml of chloroform, and the resultant mixture was washed with 100 ml of water and dried with anhydrous magnesium sulfate. The chloroform was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: 3% methanol solution in chloroform) to obtain 3.6 g of N-hexyl-N-(2-piperidinoethyl)-5-isoquinolinesulfonamide [Compound (45)]. Compound (45) was analyzed to give the following data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)[CH2:16][CH2:15]1.[Cl-:32].[NH4+]>O1CCCC1.CCCCCC>[ClH:32].[ClH:32].[OH:13][C:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)[CH2:16][CH2:15]1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(CCC2COc3ccccc3O2)CC1
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cl
Product: OC1(c2ccccn2)CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 8 h

Procedure:
To the solution of 3.2 g of 2-bromopyridine in 50 ml of tetrahydrofuran is added 12.5 ml of 1.6 N n-butyl lithium in hexane, while stirring at -75°. After one hour the solution of 2.65 g of 2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan in 10 ml of tetrahydrofuran is added while stirring. After standing overnight at room temperature, the mixture is decomposed with 10 ml of saturated aqueous ammonium chloride. The organic solvent layer is separated, dried, evaporated and the residue strongly basified with aqueous ammonium hydroxide. The mixture is extracted with ethyl acetate, the extract washed with water, dried and evaporated. The residue is suspended in 10 ml of ethanol, the suspension neutralized with ethanolic hydrogen chloride and the precipitate recrystallized from ethanol-diethyl ether, to yield the 2-[2-(4-hydroxy-4-(2-pyridyl)-piperidino)-ethyl]-1,4-benzodioxan dihydrochloride, melting at 260°-262° with decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH2:37](N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH2:21][CH3:37])=[CH:36][CH:35]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)=[CH:5][CH:6]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1=Cc2cc(-c3ccncc3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccncc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 7—(4-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml)was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7—(4-pyridyl)-N-(4—((N-tetrahydropyran-4-yl-N-ethylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 147) (0.07 g) as pale brown crystals.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[ClH:22]>CO.CCOC(C)=O>[ClH:22].[NH2:20][C:19]([NH2:21])=[N:18]/[N:17]=[C:1](/[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)\[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: C/C(=N\N=C(N)N)c1ccc(C(=O)O)cc1
Temperature: 20 °C

Procedure:
4-Acetylbenzoic acid (L1) (1.041 g, 6.34 mmol), amino guanidine bicarbonate (1.12 g, 8.2 mmol, 1.3 eq) and c.HCl (0.7 ml, 7.0 mmol) in MeOH (30 mL) was refluxed for 1 h. The reaction mixture was diluted with EtOAc cooled to 20° C. and the resulting precipitate was filtered and recrytallized from MeOH/EtOAc to give L2 (887 mg, 55%), mp (MeOH/EtOAc)>300° C.; 1H NMR ([(CD3)2SO] δ7.97-7.89 (m, 4 H, ArH), 6.75 (br, 4 H, 2×NH2), 2.25 (s, 3 H, CH3), mass APCI+ 221.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])C1C=CC=CC=1.N[C@@H:41]1C[CH2:44][N:43]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42]1>>[CH2:46]([N:43]1[CH2:42][CH2:41][CH:1]([NH:8][C:9]([CH:11]2[CH2:23][N:21]3[C:22]4[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=4[CH:19]=[CH:20]3)[C:13](=[O:39])[CH2:12]2)=[O:10])[CH2:44]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NC1CCN(Cc2ccccc2)C1)C3
Yield: 30 %

Procedure:
The compound of Example 3b was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using (R)-3-amino-1-benzylpyrrolidine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.52 mmol/g) and purification by RP-HPLC provided 10.5 mg (30%) of the title compound as a white powder. MS (M+H)+=602.5.
Reaction SMILES: [C:1](Cl)(=[O:3])C.CO.CC(C)=[O:9].[CH3:11][O:12][N:13]=[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]1=NO>O>[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:14](=[N:13][O:12][CH3:11])[C:15]([O:3][CH3:1])=[O:9]
Reactant: CC(=O)Cl
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: CC(C)=O
Solvent: O
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10.5 g of acetyl chloride (0.133 mol) are added dropwise to a mixture of 100 ml of methanol and 100 ml of acetone. 10 g (0.052 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are dissolved in this mixture, and the reaction mixture is then stirred at room temperature for 12 hours. The mixture is poured into water and the product is extracted with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution and dried over sodium sulphate, and the solvent is distilled off under reduced pressure. This gives 9 g of crude product which, according to HPLC, contains 17.7% methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 61.8% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38.
Reaction SMILES: O=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(=O)[nH]c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a solution of 20.0 g (0.105 mole) of ethyl β-amino-cinnamate in 40 ml. of chlorobenzene under ice cooling was added a solution of 11.6 g (0.112 mole) of chorocarbonylsulfenyl chloride in 10 ml. of chlorobenzene. The reaction mixture was heated at 110° C. for 2 hours, cooled to triturated with petroleum ether. The precipitate was heated with hot benzene, cooled and filtered to give 14.4 g (55%) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate as yellow needles. A mixture of 3.0 g (0.012 mole) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate and 14 ml. of phosphorus oxychloride was held at reflux for 24 hours and cooled. The reaction mixture was poured into ice water. The solid precipitate was extracted into ether. The ether solution was dried and concentrated under reduced pressure. The residue was recrystallized from hexane to give 2.2 g (68%) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, m.p. 56°-57° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(Oc3ccccc3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCCC1)c1c[nH]c2ncc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide from Step 3 in dichloromethane (0.7 mL) was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was stirred with THF (1 mL), water (0.5 mL), and Et3N (0.5 mL) for 2 h then concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by SiO2 column chromatography (0% to 80% EtOAc/hexanes) then triturated with Et2O to provide 0.022 g (22%, 2 steps) of 2-phenoxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide as a white solid. MS: (M+H)+=337; mp=255.0-257.0.
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:49]Cl>>[CH3:57][O:56][C:52]1[CH:51]=[C:48]([CH:47]=[C:46]([O:45][CH3:44])[C:53]=1[O:54][CH3:55])[CH2:49][N:34]1[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[N:33]1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1Cc1cc(OC)c(OC)c(OC)c1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 3,4,5-trimethoxy benzyl chloride (purchased from Aldrich). 1H-NMR δ 6.98 (s, 1H), 6.21 (s, 2H), 5.44 (s, 2H), 4.41 (q, 2H), 3.81 (s, 3H), 3.76 (s, 6H), 1.40 (t, 3H), 0.22 (s, 9). Calculated mass for C19H28N2O5Si, 392.18, observed, 393.0 (M+1), 415.1 (M+Na).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=[N:4][N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(O)C.C(=O)(O)[O-].[Na+]>[C:11]1([C:8]2[C:7]3[C:2]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:3][N:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nncc2onc(-c3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CNc2nncc3onc(-c4ccccc4)c23)CC1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
The compound prepared in Example 82 (202 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.266 g) and triethylamine (0.607 mL) were combined in ethanol (1.5 mL) and heated at 80° C. for 17 hours. The reaction mixture cooled to room temperature, diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1 to 2:1) to obtain the title compound (316 mg) having the following physical data.
Reaction SMILES: [I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][N+](C)(C)C)[CH3:3].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:3]
Reactant: CCn1cccc1C[N+](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CC#N
Product: CCn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 81.3 %

Procedure:
(1-Ethylpyrrol-2-yl)methyltrimethylammonium iodide (20.0 g, 68.0 mmol) was suspended in acetonitrile (200 mL) and triphenylphosphine (22.0 g, 83.9 mmol) was added thereto, followed by stirring of the mixture at 80° C. for 9 hours. After cooling, the mixture was concentrated to about ½ under reduced pressure and ethyl acetate (100 mL) was added thereto. The precipitated crystal was collected by filtration, washed with ethyl acetate and dried under reduced pressure to obtain the title compound (27.5 g, yield: 81%).
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=O)[CH2:12][CH2:11][CH2:10][CH2:9]3.B.O1CCCC1.[ClH:26].[H][H]>O1CCCC1>[ClH:26].[NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][CH2:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: [H][H]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: c1cc2c3c(c4c(nc3c1)CCCC4)NCCO2
Reaction time: 2 h
Yield: 57.5 %

Procedure:
1,3,9,10,11,12-Hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.00 g) was suspended in dry tetrahydrofuran (100 ml) and 1M borane/tetrahydrofuran (16.0 ml) was added. After 2 hrs, an additional 30 ml of 1M borane/tetrahydrofuran was added, and the reaction mixture was stirred overnight. The reaction mixture was poured into 5% hydrochloric acid and stirred until hydrogen evolution ceased. The organic layer was separated and the aqueous phase was washed once with ethyl acetate. The aqueous phase was basified with 10% sodium hydroxide solution and precipitate was collected. The precipitate was treated with methanol/ether/hydrogen chloride. Recrystallized from methanol/ether gave 2.50 g (57.5%) of product, mp 300° C.(dec).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>C(OCC)C.C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:20])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Sodium hydride (5.2 g, 0.21 mol) was suspended in dry diethyl ether and cooled to 0° C. Diethyl carbonate (17.7 g, 0.15 mol) was added and the contents were stirred for ten minutes, at which time dropwise addition of p-bromoacetophenone (19.9 g, 0.1 mol) in diethyl ether (50 mL) and ethanol (0.2 mL) was initiated. Addition was continued for twenty minutes; the solution was refluxed for three hours, cooled to room temperature and poured onto cold 10% aqueous hydrochloric acid (250 mL). The aqueous solution was extracted twice with diethyl ether (750 mL) and the combined extracts were washed successively with water (250 mL), brine (250 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (4/1), to afford 20.2 g (74%) of the title compound as an oil. 1HNMR (60MHz, CDCl3): δ1.2 (t,3H), 3.9 (s, 2H), 4.1 (q, 2H), 7.55 (d, J=7 Hz, 2H), 7.75 (d, J=2 Hz, 2H).
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[NH4+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17].O>C(O)(=O)C>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:3][C:4]#[N:5])[C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17]
Reactant: N#C[S-]
Reactant: COc1ccc(OC)c(O)c1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(SC#N)c(OC)cc1O
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Bromine (8 g, 2.5 ml) in glacial acetic acid (10 ml) was added dropwise with vigorous stirring over 15 minutes to a mixture of ammonium thiocyanate (8 g), 2,5-dimethoxyphenol (7.7 g), and glacial acetic acid (50 ml) kept at 15°-20°. The mixture was left at room temperature for 30 minutes and then poured into water (400 ml). A solid separated which was filtered off, washed with water and dried in vacuo to give the thiocyanatophenol (7 g). RfE 0.36.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=3)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([NH2:18])=[CH:11][CH:10]=3
Reactant: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccc(N)cc2Sc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3,7-dinitro-phenothiazin-10-yl)-ethanone (2 g, 6.04 mmol), tin (II) chloride dihydrate (14.17 g, 62.8 mmol), and ethanol (50 cm3) was heated to reflux and stirred at this temperature for 5 hours. The mixture was then cooled to room temperature and poured over ice water. The pH was adjusted to 7 with 5% sodium hydrogen carbonate before the product was extracted with ethyl acetate (3×50 cm3). The extracts were washed with brine and dried over magnesium sulphate, filtered, and concentrated to give the title compound (1.64 g, 100%) as a purple blue solid; vmax (KBr)/cm−1: 3445 (NH), 3424 (NH), 3368 (NH), 3322 (NH), 3203 (NH), 3054 (CH), 2995 (CH), 1706 (C═O), 1650 (NO2), 1590 (NO2); δH (250 MHz; CDCl3): 2.01 (3H, s, CH3), 5.09-5.43 (4H, brd s, NH), 6.47-6.51 (2H, dd, J1.5, 8.25, ArH), 6.61 (2H, s, ArH), 7.11-7.15 (2H, d, J8, ArH); δC (62.9 MHz; CDCl3): 169.1 (C═O), 147.2 (ArC), 128.1 (ArC), 127.6 (ArC), 127.3 (ArC), 112.3 (ArC), 111.5 (ArC), 22.6 (CH3); m/z (ES) 293.9 (95%, [M+H, Na]+), 272.0 (20%, [M+H]+), 227.9 (100%, [M+H, −Ac]+).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=[O:11]>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(O)C(=NO)c1cnsc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cnsc1
Yield: 48.7 %

Procedure:
Dichloroacetyl chloride (3.58 g.) was added with stirring and ice-cooling to a suspension of 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (1.50 g.) in dry methylene chloride (40 ml.), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was concentrated to the volume of 10 ml. Petroleum ether (50 ml.) was added to the residue and the mixture was cooled in dry ice-acetone bath. Precipitates were collected by filtration and washed with petroleum ether to give 2-dichloroacetoxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (1.20 g.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[Cl:13])[N:4]1[C:14]([CH2:17][CH3:18])=[N:15][N:16]=[C:3]1[C:2]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[N:11]2
Reactant: CCc1nnc2c(Cl)nc3cc(Cl)c(Cl)cc3n12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(CC)CC)nc3cc(Cl)c(Cl)cc3n12
Reaction time: 0.25 h
Yield: 16 %

Procedure:
4,7,8-Trichloro-1-ethyl-[1,2,4]-triazolo[4,3-a]quinoxaline (2.9 g., 0.0096 mole) and 2.1 g. (0.0388 mole) of diethylamine in N,N-dimethylformamide (50 ml.) were stirred at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 15 minutes. The precipitate was separated by filtration, washed with water and air dried. Recrystallization (three times) from isopropanol then afforded 500 mg. (16% yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 147°-149° C. Mass spectrum: m/e, 337 (P); m/e, 339 (P+2).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16])=[O:3])[CH2:6][CH3:7]
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
27 g of propyl chloroformate were slowly added to a mixture of 41.2 g of m-amino-3-methoxy-crotonanilide, 300 ml of tetrahydrofuran and 22.2 g of triethylamine and the mixture was stirred for 16 hours at 20° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 40 g of m-(n-propyloxycarbonylamino)-3-methoxy-crotonanilide melting at 115° C. Crystallization from chloroform did not change the melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:23][CH2:22][CH2:21]1>C(O)C>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]1[C:23]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:22]=2[CH2:21][CH2:20][CH2:25]1
Reactant: O=C1C(Br)CCCC1c1ccccc1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2Cl)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (69 mg, 0.26 mmol) and of crude 6-bromo-2-(2-chloro-phenyl)-cyclohexanone (79 mg, 0.28 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (55 mg, 46%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.77 (s, 1H), 7.46 (s, 1H), 7.35 (m, 1H), 7.13 (m, 2H), 7.08 (d, 1H), 6.96 (m, 1H), 6.85 (s, 1H), 6.68 (d, 1H), 4.53 (m, 1H), 3.54 (s, 3H), 2.77 (m, 2H), 2.33 (s, 3H), 2.24 (m, 1H), 1.80-1.99 (m, 3H).