Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1c(-c2ccc(Cl)cc2)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (11.8 g, 32.7 mmol), prepared as described in example 1B, in toluene (200 ml) was added Pd(PPh3)4 (2.26 g, 1.96 mmol). After 5 min, 2N aqueous sodium carbonate (65 ml, 130 mmol) solution was added, followed by 4-chlorophenylboronic acid (7.16 g, 45.8 mmol). The reaction was stirred at 100° C. for 6 h. After this time, the solution was cooled RT and the reaction mixture was diluted with ethyl acetate. The resultant solution was washed with water, saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified using silica gel column chromatography eluting with a gradient of 10-20% Ethyl acetate/Hexane to give the title compounds, 2-benzyl-6-(benzyloxy)-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one which were obtained as a mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:2])[CH2:4][CH2:5][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CO
Reactant: COc1ccc(CN)cc1
Product: COC(=O)CCNCc1ccc(OC)cc1

Procedure:
A solution of p-methoxybenzyl amine (690 mg, 722 μL, 8.01 mmol) in dry methanol (5 ml), under nitrogen was cooled to 0° and treated dropwise with a solution of metacrylate (951 μL, 1.0 g, 7.28 mmol) in MeOH (1.0 ml) added over 2 min. After 15.5 h the clear solution was distilled at atmospheric pressure to remove MeOH. The high boiling residue (>170°) formed 3-(4-Methoxy-benzylamino)-propionic acid methyl ester (1.88 g, Quantitative) 1H (300 MHz, CDCl3) 1.78 (bs, 1H), 2.45 and 2.53 (t, J=3.0 Hz, 2H), 2.77 and 2.87 (t, J=3.0 Hz, 2H), 3.46 and 3.67 (s, 3H), 3.64 and 3.73 (s, 3H), 3.88 (m, 2H), 6.78 and 6.85 (m, 2H), 7.17 and 7.23 (m, 2H).
Reaction SMILES: Br[CH:2]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[CH3:17][SH:18].[OH-].[Na+]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][CH2:6][CH:2]([S:18][CH3:17])[C:3]([OH:5])=[O:4])=[CH:10][CH:11]=1
Reactant: CS
Reactant: COc1ccc(CSCC(Br)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSCC(SC)C(=O)O)cc1

Procedure:
A solution of 2-bromo-3-(4-methoxybenzylmercapto)propanoic acid (15 g.), methylmercaptan (3 g.) and sodium hydroxide (4.6 g.) in 95% ethanol (25 ml.) is refluxed for twelve hours. The sodium bromide is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(4-methoxybenzylmercapto)-2-(methylthio)propanoic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.CN1C[CH2:21][CH2:20][C:19]1=O.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)/C=C/C)CCC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2](/[CH:19]=[CH:20]/[CH3:21])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: CN1CCCC1=O
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C/C=C/[Sn](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C/C=C/c1cnc2nc(O)n(C(CC)CC)c2n1
Temperature: 120 °C
Yield: 15 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv) and (Ph3P)4Pd (0.15 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5-10 min, and N-methylpyrrolidone (11.7 volume equivalents), triethyl amine (2.0 equiv), and (E)-tributyl(prop-1-enyl)stannane (2.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and cap and heated to 120° C. in a microwave for 20 min. The reaction was then diluted with EtOAc, washed with three times with water and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (15%) as a foam. LCMS m/z (APCI)=247.1 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49](O)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[F:53][C:54]([F:68])([F:67])[C:55]1[CH:56]=[C:57]([N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:58]=[CH:59][CH:60]=1>CN(C=O)C>[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([N:64]4[CH2:63][CH2:62][N:61]([C:57]5[CH:58]=[CH:59][CH:60]=[C:55]([C:54]([F:67])([F:68])[F:53])[CH:56]=5)[CH2:66][CH2:65]4)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (240 mg; 0.75 mmol) and N-methylmorpholine (206 μl; 189 mg; 1.87 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.63 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (140 μl; 172 mg; 0.75 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 198 mg (62%).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].[Cl-].[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:8]1([NH:7][C:1](=[O:6])[C:2](=[N:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3](=[O:4])[CH3:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)Nc1ccccc1
Yield: 47.6 %

Procedure:
4.5 g (25.4 mmol) of acetoacetanilide, a solution of 3.46 g (89 mmol) of NaOH in 45 ml of water and 95 mmol of phenyldiazonium chloride were treated as described in preparation 8. The residue was crystallised from EtOH, yielding 3.4 g of the title compound. M.p.=96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:20])=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(N)=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.79 mmol) in 5 mL of dry tetrahydrofuran is added 1,1'-carbonyldiimidazole (167 mg, 1.03 mmol). The reaction solution is heated at reflux for 1 hour then cooled to room temperature. Aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxamide in 84% yield; mp=154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:10]2)=[CH:5][CH:4]=1.[NH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH:48][CH:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NC1CCOCC1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)C=O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)CNC4CCOCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 43a, 430 mg of 3-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionaldehyde and 79 mg of 4-aminotetrahydropyran are used to afford the title compound as a yellow oil. Rf=0.05 (EtOAc-heptane 1:1); Rt=4.65.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[C:19]1([C:16]2[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[O:18][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(-c2ocnc2-c2onc(-c3ccccc3)c2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(-c2ocnc2-c2onc(-c3ccccc3)c2-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
5-[5-(3-Methoxyphenyl)-4-oxazolyl]-3,4-diphenylisoxazole (25) (1.01 g, 2.56 mmol) was dissolved in dichloromethane (65 mL) and cooled to about 0° C. under N2. Boron tribromide solution (13 mL of 1 M in dichloromethane) was added dropwise and the solution stirred about 18 hours at room temperature. Methanol (10 mL) was added dropwise {caution: reacts vigorously}, and after being stirred about 10 minutes the solution was concentrated on to SiO2 and chromatographed (elution with 10% ethyl acetate/chloroform) to give the phenol 631 mg (68%), mp 199°-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:19].[OH-].[Na+]>>[CH2:13]([O:12][P:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:19])[CH:8]=1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: CCOP(=O)(Cc1ccnc(C#N)c1)OCC
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC

Procedure:
A mixture of 1.10 g of 2-cyano-4-(diethylphosphonomethyl)pyridine and 4.5 ml of concentrated sulfuric acid is heated at 90° for 5 minutes. The reaction mixture is poured onto ice and neutralized with 10% sodium hydroxide. The resulting precipitate is collected to afford 4-(di-ethylphosphonomethyl)-2-pyridinecarboxamide melting at 140°-142°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Si:28]([O:35][CH2:36][CH:37]=[O:38])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:37]([OH:38])[CH2:36][O:35][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CO[Si](C)(C)C(C)(C)C)nc3N21
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 4.00 g (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml toluene was added drop wise at −78° C. 10.86 ml of a 1.5M solution of tert-butyllithium in pentane. The mixture was stirred at this temperature for 30 min. To the resulting solution was added 5.017 g (tert-butyldimethylsilyloxy) acetaldehyde and the mixture was stirred at −78° C. for 30 min. The reaction was quenched by addition of 10% aqueous ammonium chloride. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to yield 2.34 g (4R,9aR)-6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as slightly yellow oil (MS: 464.4 (M+H+))
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29](=[O:32])[CH2:30]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([O:25][CH3:24])[CH:27]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: COc1cccc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cccc(OC)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-methoxyphenacyl bromide.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][CH2:8][O:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][O:3]1.CNN>ClCCl.C(OCC)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][CH2:8][O:9][NH2:10])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCON2C(=O)c3ccccc3C2=O)O1
Agent: CNN
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)OCC(CCON)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH:15]([CH3:17])[CH3:16].C(Br)CC(C)C.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]([OH:12])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CC(C)CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)CCBr
Product: CC(C)CCC(O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-t-butoxycarbonylsarcosinal (3.46 g) in dry tetrahydrofuran (100 ml) which was cooled to -78° C., was added dropwise a solution of isopentylmagnesium bromide prepared from isopentyl bromide (30.8 g) and magnesium (4.86 g) in dry tetrahydrofuran (200 ml). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred at the same temperature for 4 hours. After saturated aqueous ammonium chloride (200 ml) was added thereto, the resulting mixture was extracted with diethyl ether (300 ml×2). The combined extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silicagel column chromatography (20% ethyl acetate in n-hexane as eluent) to give 1-(N-t-butoxycarbonyl-N-methylamino)-2-hydroxy-5-methylhexane (3.96 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:22])[CH3:21])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.87 g, 6.93 mmol), tributyl(1-ethoxyvinyl)tin (3.00 g, 8.31 mmol), Pd(PPh3)4 (801 mg, 0.693 mmol), and LiCl (734 mg, 17.3 mmol) in 1,4-dioxane (50 ml) was heated to reflux for 7 hours. The mixture was filtered through a pad of Celite with ethyl acetate. The filtrate was washed with water (100 ml) and brine (100 ml), dried over MgSO4, and evaporated in vacuo. To the obtained residue were added 2N HCl (20 ml) and THF (60 ml). The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous NaHCO3 (60 ml) was added and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over MgSO4, and evaporated in vacuo. The resulting residue was chromatographed over slica gel with hexane/ethyl acetate (3:1) to give 1.51 g (94%) of the title compound as a white solid.
Reaction SMILES: O=C(Cl)[O:3][C:4]([Cl:7])(Cl)Cl.[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=2[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[C:21]([O:22][CH3:23])=[CH:20][C:14]2[CH2:15][CH2:16][N:17]([C:4]([Cl:7])=[O:3])[CH2:18][CH2:19][C:13]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCN(C(=O)Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.2 mL (10 mmol/1 eq.) of diphosgene in 20 mL of dichloromethane, at about 0° C., there are added, dropwise, a solution of 3.55 g (20 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 22 mL of dichloromethane, and then 4.2 mL (30 mmol/1.5 eq.) of triethylamine. Stirring overnight at ambient temperature and then concentration are carried out. The residue is taken up in dichloromethane, washed with water and dried over magnesium sulphate to yield, after concentration, the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N+:10]([C:13]1[C:14]([C:18](O)=O)=[N:15][NH:16][CH:17]=1)([O-:12])=[O:11].[OH-].[NH4+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([C:14]3[C:13]([N+:10]([O-:12])=[O:11])=[CH:17][NH:16][N:15]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid (4N) was treated with 4-nitro-pyrazole-3-carboxylic acid (826 mg) then heated at reflux temperature, under nitrogen. The reaction mixture was cooled to room temperature when the pH was adjusted to 8 by addition of ammonium hydroxide and the mixture was extracted with ethyl acetate. The extracts were evaporated to give 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole. (b) 5,6-dichloro-2-(4-nitro-1H-pyrazol -3-yl)-1H-benzoimidazole
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][S:19]SC>[Cu]>[CH3:17][C:10]1[C:11]([CH3:16])=[C:12]([S:19][CH3:18])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: Cc1c(N)ccc(Br)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1C
Temperature: 77.5 °C
Reaction time: 9 h

Procedure:
603 g (5.85 mol) of tert-butyl nitrite and 375 g of copper powder (5.9 mol) are initially charged in 3000 ml of dimethyl disulfide, and 761 g (3.75 mol) of 4-bromo-2,3-dimethylaniline are added dropwise at from 50 to 58° C. The mixture is subsequently stirred at from 75 to 80° C. for 9 hours. For work-up, the mixture is cooled, the residue is filtered off and the filtrate is washed with saturated aqueous NaHCO3 solution. For purification of the product, the organic phase is separated by distillation. Initially, the excess dimethyl disulfide is separated off at atmospheric pressure. 1870 g of dimethyl disulfide (purity>97% according to GC) are recovered. The residue is subsequently subjected to fractional distillation under reduced pressure (0.1 mbar).