Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]([CH3:12])([CH3:11])[C:9](=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.B#B.CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]([CH3:12])([CH3:11])[CH2:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3c(Cl)nc(Cl)nc32)cc1
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CC(C)(C)c3c(Cl)nc(Cl)nc32)cc1

Procedure:
To a solution of 2,4-dichloro-7-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (270 mg, 0.77 mol) in tetrahydrofuran (10 mL) was added diborane (1 M in tetrahydrofuran, 3.85 mL, 3.85 mmol) dropwise under nitrogen. The mixture was refluxed overnight. After cooling, methanol (2 mL) was added dropwise to decompose the excessive diborane. The solvent was removed and the residue was purified by silica gel column chromatography to afford the product
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24]O)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: O=C1CCCN1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN2CCCC2=O)(c2ccccc2)OC1=O

Procedure:
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following an analogous procedure using pyrrolidin-2-one in Step 2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[NH2:13]
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2c(c1)C(=O)NCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a suspension of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.1 g, 50 mmol) in conc. HCl (100 mL) in an ice-H2O bath was added a solution of NaNO2 (3.45 g, 50 mmol) in H2O dropwise at such a rate that the reaction mixture never rose above 5° C. A solution of SnCl2.2H2O(22.5 g, 0.1 mol) in conc. HCl (150 mL) was added dropwise after 30 min. The resulting mixture was stirred for another 2 h at 0° C. The precipitate was collected by suction, washed with ether to afford 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.3 g), which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N+:25]([O-:30])[C:26]([Cl:29])=[CH:27][CH:28]=1>CS(C)=O>[Cl:29][C:26]1[N+:25]([O-:30])=[N:24][C:23]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:28][CH:27]=1
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Reactant: Cc1cccc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cccc(C)c1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
268 mg (2.20 mmol) of 2,6-dimethylphenol, 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, 270 mg (2.41 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 370 mg (2.24 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours and allowed to stand for 2 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 350 mg (1.39 mmol, Yield: 63.1%) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.Cl[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>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.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:28]2[C:29]([C:30]#[N:31])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:9]=1)[CH3:2]
Reactant: N#Cc1ccccc1Cl
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:47]1[CH:52]=[CH:51]C=[CH:49][CH:48]=1)=O>ClCCl>[C:32]1([C:35]2[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=2)[CH:33]=[CH:34][C:29]([S:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=1
Reactant: CSCc1ccc(N)c(Br)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: CSCc1ccc(N)c(-c2cccc(Cl)c2)c1

Procedure:
2-bromo-4-(methylthiomethyl)aniline and 3-chlorobenzene boronic acid can be combined to form 2-(3-chlorophenyl)-4-(methylthiomethyl)aniline,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([OH:22])=O)=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:22])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: NC1(c2ccccc2)CCC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1-phenylcyclobutanamine hydrochloride (0.041 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.18 (s, 1H), 8.42 (d, J=4.58 Hz, 1H), 8.14-8.22 (m, 2H), 7.97 (s, 1H), 7.88 (dd, J=16.02, 7.48 Hz, 2H), 7.82 (d, J=8.54 Hz, 1H), 7.66 (dd, J=8.24, 5.80 Hz, 2H), 7.59 (t, J=7.63 Hz, 1H), 7.52 (d, J=7.63 Hz, 2H), 7.31-7.40 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.77 (d, J=4.58 Hz, 3H), 2.62-2.71 (m, 2H), 2.53-2.60 (m, 2H), 2.02-2.11 (m, 1H), 1.83-1.92 (m, 1H). LCMS: retention time: 3.370 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 535 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:15][CH2:14]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:48][CH3:49].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]5[CH2:31][CH2:32][C@H:33]([N:36]6[CH2:41][CH2:40][N:39]([CH2:42][CH:43]7[CH2:45][CH2:44]7)[CH2:38][CH2:37]6)[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 2) (0.14 g, 0.45 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 2 (0.14 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative 1) to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 25%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.37 g (8.49 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyridine (14) in 30 mL of dioxane-degassed water 1:1 were added 311 mg (0.34 mmol) of Pd2dba3 followed by 288 mg (0.68 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.42 g (25.46 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 150 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 3:1 gave the expected product as a white solid: yield 1.19 g (65%). 1H-NMR (CDCl3) δ 6.89 (s, 1H), 5.75 (s, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 2.05 (s, 6H); 13C-NMR (CDCl3) δ 148.80, 145.03, 143.12, 135.51, 128.43, 122.32, 106.01, 18.48, 15.95, 12.80.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2-Fluorophenylacetic acid (2.96 g, 19.24 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (2.1 ml, 24.05 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (3.0 g, 16.03 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (3.21 g, 24.05 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (4.0 g, 81% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.97(s,1H), 8.01(d, J=1.7 Hz, 1H), 7.58(dd, J=8.8,2.3.1 Hz, 1H), 7.35(m,1H), 7.23(d, J=7.3 Hz, 1H), 7.17(m, 2H), 6.92(d, J=8.9 Hz, 1H),4.33(s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1.[C-:24]#[N:25].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([C:24]#[N:25])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(S(C)(=O)=O)nc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the product from step (iv) (0.13 g) and sodium cyanide (0.054 g) in dimethylsulphoxide (3 ml) was stirred at room temperature for 72 h then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 2:1 ethyl acetate in isohexane. Yield 0.035 g
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C.C1(C)C(C)=CC=CC=1.N12CCN(CC1)CC2>[C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)=[O:22])(=[O:19])=[O:18]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: Cc1ccccc1C
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 100 ml of dry acetonitrile, and then 0.1 g of 1,4-diazabicyclo[2,2,2]octane was added thereto. To this mixture was added dropwise a solution of 28.5 g of 2-biphenylylsulfonyl isocyanate in 30 ml of xylene over an hour. During this addition, the reaction was accompanied by slight heat generation, and therefore cooling was applied as necessary. After the addition, the reaction was continued at room temperature for 5 hours and then at 40° C. for 5 hours. After allowing the mixture to cool to room temperature, the precipitated colorless crystals were filtered, washed with ether and dried to obtain 33.9 g of N-2-biphenylylsulfonyl-N'-(4-methoxy-6-methyl-1,3,5-triazin-2yl) urea; m.pt. 190°-193° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17]>>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O=C1CNCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(=O)C1
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperazin-2-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-2-one as a white solid (166 mg, 100%). 1H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 8.09 (s, 1H), 3.78 (s, 3H), 3.44-3.30 (m, 6H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:19]([CH:21]=O)=O>C(#N)C>[N:10]12[CH:21]3[N:7]([CH2:6][CH2:5][N:4]4[CH:19]3[N:1]([CH2:12][CH2:11]1)[CH2:2][CH2:3]4)[CH2:8][CH2:9]2
Reactant: CCNCCNCCNCCN
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C1CN2CCN3CCN4CCN1C2C43

Procedure:
1,4,7,10-Tetraazadodecane (1.1.4) trihydrobromide in acetonitrile with potassium carbonate was reacted with glyoxal to form 1,4,7,10-tetraazatetracyclo-[5,5,2,04,13,010,14] tetradecane (1.1.23). Following separation the pure product was obtained by low pressure distillation. This was dissolved in acetonitrile and benzylbromide was added to form 1,7-dibenzylonium-1,4,7,10-tetraaza-tetracyclo[5,5,2,04,13,010,14] tetradecane (1.1.24). Following recrystallization from ethanol this was reacted with sodium borohydride. HCl was added, followed by water and NaOH, and the product extracted with chloroform. Following evaporation of solvent the solids were dissolved in methanol and HBr was added to obtain 1,7-dibenzyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane (1.1.25) as the hydrobromide salt. This was dissolved in water and reduced using H2 and a Pd-C catalyst to remove the benzyl groups. Purification of the title compound was by crystallization of the hydrobromide salt. The base form was obtained by low pressure distillation following addition of base. 1.1.26 1,4,7,10,13-Pentaazabicyclo [8.5.2] heptadecane.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12]C(Cl)=C(Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1C=C[S:23]C=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][S:23][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1ccsc1
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccsc1
Yield: 52 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-3-yl)propan-2-one (6.53 g, 37.4 mmol) with acetic acid (4.3 mL, 4.5 g, 75 mmol) and triethylamine (10.4 mL, 7.57 g, 74.8 mmol). Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product, a golden-yellow oil (3.85 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.77 (s, 2H) 4.70 (s, 2H) 6.98 (dd, J=4.8, 1.3 Hz, 1H) 7.14 (dd, J=1.8, 1.0 Hz, 1H) 7.32 (dd, J=4.9, 2.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1)[CH3:2].[Br:12]Br>C(O)C.O>[Br:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cn2ccccc2n1
Reactant: BrBr
Solvent: O
Solvent: CCO
Product: CCc1nc2ccccn2c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 2-ethyl-imidazo[1,2-a]pyridine (2.17 g, 14.9 mmol) in ethanol (25 mL) was added bromine (2.0 g, 12.5 mmol) in water (5 mL) dropwise at rt. After stirring at rt for 4 h, ethanol was evaporated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with methylene chloride (3×). The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes afforded the title compound (1.88 g) as a viscous oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[Si](N=C=O)(N=C=O)(N=C=O)[N:18]=[C:19]=[O:20]>C1C=CC=CC=1>[CH3:1][N:2]([CH:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:19]([NH2:18])=[O:20]
Reactant: O=C=N[Si](N=C=O)(N=C=O)N=C=O
Reactant: CNC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CN(C(N)=O)C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 9-methylaminoxanthen (5 g.) in dry benzene (10 ml.) was added slowly to a stirred solution of silicon tetraisocyanate (1.16 g.) in benzene (10 ml.). The resulting solution was refluxed for 45 minutes and then evaporated to dryness in vacuo. The residue was refluxed for 30 minutes with 90% isopropanol (20ml.), filtered and the filtrate evaporated to dryness. The residue was washed with cold acetone and recrystallised from ethanol to give N-methyl-N-9-xanthenylurea, m.p. 199°-202°C.