Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[C:16]2[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:29]>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:16]3[CH:8]=[C:9]([CH3:29])[S:10][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCCl)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cccc(OCCCCl)c1
Yield: 99.1 %

Procedure:
A mixture of methyl 2-[3-(3-chloropropoxy)phenyl]acetate (4.95 g, 0.02 moles) and a solution of 1N sodium hydroxide (0.02 moles) was stirred at room temperature for 24 hours. After acidification the acid separated as white powder (4.53 g, 97% yield)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>O>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CSc1nccc(-c2cccnc2Oc2ccc(Cl)nc2)n1
Temperature: 120 °C

Procedure:
A mixture of cesium carbonate (5.03 g, 15.4 mmol), 6-chloropyridin-3-ol (1.00 g, 7.72 mmol), and 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (1.83 g, 7.72 mmol) was sealed and heated to 120° C. overnight. The reaction was cooled slightly and poured slowly into a rapidly stirring solution of 250 mL water. A tan precipitate resulted which was collected by filtration through a 0.45 micron filter. The solid was washed 3× with water, then dried in vacuo overnight to give 4-(2-(6-chloropyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine as a tan solid. MS m/z=331 [M+H]+. Calc'd for C15H11ClN4OS: 330.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[C@@H:13]3[C@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1.OS(C(F)(F)F)(=O)=O>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:9]3[CH2:10][CH2:11][CH2:12][CH:13]3[C:14](=[O:15])[C:4]=2[CH:3]=1
Reactant: O=C1[C@H]2CCC[C@H]2N1c1ccc(F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1c2cc(F)ccc2NC2CCCC12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A 500-mL, three-necked, round-bottomed flask was charged with cis-6-(4-fluorophenyl)-6-azabicyclo[3.2.0]heptan-7-one (racemic 17DP) (26.5 g, 129 mmol) and 250 mL of dichloroethane. The reaction mixture was cooled at 5° C. while triflic acid was added via syringe over 10 min. The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to room temperature with an ice-water bath and then quenched with saturated sodium bicarbonate to adjust the pH to 10. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated to give 26.5 g of a 90:10 mixture of the title compound as a brown semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[Cl:19].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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]>[Cl:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccccc2F)c(Cl)c1
Yield: 82.9 %

Procedure:
2-Fluorophenylboronic acid (0.405 g, 2.89 mmol) and 4-bromo-3-chlorophenol (0.500 g, 2.41 mmol) were dissolved in dioxane (10 mL). A solution of caesium carbonate (2.35 g, 7.21 mmol) in water (2 mL) was added and the reaction mixture was degassed. Tetrakis(triphenylphosphine)palladium (0) (0.280 g, 0.242 mmol) was added and reaction was further degassed before heating the reaction at 100° C. for 18 hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc and washed with water and dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/Heptane 2:3 to give the title compound (0.445 g, 69%) as dark solid
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]([C:24]4[CH2:31][C:27]5([CH2:30][CH2:29][CH2:28]5)[O:26][N:25]=4)=[C:16]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:28]1[C:27]2([CH2:31][C:24]([C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:16]=3[NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:25][O:26]2)[CH2:30][CH2:29]1
Reactant: COc1ccc(Cn2ncc3c(NC4CCOCC4)c(C4=NOC5(CCC5)C4)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: c1nc2[nH]ncc2c(NC2CCOCC2)c1C1=NOC2(CCC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Methoxybenzyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.8 gm, 4 mmol) (example 9) was dissolved in trifluoroacetic acid (4.56 gm, 40 mmol) and the reaction mixture was stirred for about 4 hours at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and sodium bicarbonate solution was added drop wise. It was extracted with ethyl acetate, organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccn2)c(N)c1N=O
Yield: 53 %

Procedure:
By the method of Preparation 8(a), 5-amino-3-methyl-1-(2-pyridyl)pyrazole (2.21 g, 12.7 mmol) was treated with sodium nitrite in aqueous acetic acid. The precipitated solid was triturated with methanol (250 ml), and the mother liquors were concentrated under reduced pressure to give the title compound as a red-brown solid (1.37 g, 53%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH:11]([NH2:13])[CH3:12])[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[K+]>CO>[C:1]([NH:4][CH:5]([CH:11]([NH2:13])[CH3:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(C)N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC(C(=O)O)C(C)N
Temperature: 23 °C
Yield: 95 %

Procedure:
Five grams of ethyl 2-acetamido-3-aminobutyrate were dispersed in 10 ml of cold methanol, after which 1.51 g of potassium hydroxide in 15 ml of methanol were added. The mixture was stirred in an ice bath and then allowed to warm to 23° C. over a period of 18 hours. The solvent was removed at reduced pressure, and the residue was dissolved in a minimum of warm water and adjusted to a pH of 6.5 with hydrochloric acid. Upon cooling, crystals of 2-acetamido-3-aminobutyric acid were formed in a 95% yield.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:20]C=O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:13]2[N:14]([CH3:17])[CH:15]=[N:16][C:12]=2[CH:11]=1.C(=O)(O)[O-].[Na+]>CO.O>[CH3:2][C:3]1[CH:4]=[C:5]([NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:13]2[N:14]([CH3:17])[CH:15]=[N:16][C:12]=2[CH:11]=1
Reactant: Cc1cc(NC=O)ccc1Oc1ccc2c(c1)ncn2C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(N)ccc1Oc1ccc2c(c1)ncn2C
Temperature: 25 °C

Procedure:
To a solution of concentrated aqueous HCl (10 mL) in methanol (10 mL) was added N-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)formamide (1.70 g, 6.04 mmol). After heating to reflux for 2 hours, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was neutralized with sodium bicarbonate and extracted with dichloromethane. The organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([CH2:18][C:19](O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[CH2:18]([C:19]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:11]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Product: O=[N+]([O-])c1ccc2[nH]c(Cc3ccccc3)nc2c1
Temperature: 25 °C
Yield: 33 %

Procedure:
A misture of 4-nitro-o-phenylene diamine (1.54 g) and phenylacetic acid (2.04 g) in 5N aqueous HCl (16 ml) were heated at 110° C. under nitrogen for 22 hours. The mixture was cooled to room temperature and the accumulated black solid collected by filtration. This crude residue was then adsorbed onto silica and chromatographed to give the title compound (0.84 g) as a purple foam; δH CDCl3 9.70 (1H, bs), 8.15 (1H, d), 7.30 (7H, m), 4.30 (2H, s); m/z (M+1)+254.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COCCN
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 443 (M+H+, 100).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[O:34]=[S:33]1(=[O:35])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:30])(=[O:31])[N:15]1[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1

Procedure:
A solution of N-Boc-p-phenylenediamine (0.68 g, 3.26 mmol) and Et3N (0.51 mL, 7.19 mmol) in dry DCM (29 mL) was added to a refluxing solution of 1,2-benzenedisulfonyl dichloride (0.90 g, 3.27 mmol) in DCM (135 mL). After the addition was complete, the reaction solution was maintained at reflux for an additional 2 h. The heat was removed and after 16 h at rt, the solvent was removed under reduced pressure. The residue of the crude reaction mixture was dissolved in DCM and washed with saturated NaHCO3, brine, and dried. After filtration and concentration under reduced pressure yielding tert-butyl (4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)phenyl)carbamate, 1.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58]>CN(C)C=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
The Boc-Gly-Phe-Leu-OH obtained in Example 18 (2.4 g) and N-hydroxysuccinimide (656 mg) were dissolved in N,N-dimethylformamide (50 ml), cooled to 4° C., and then added with N,N′-dicyclohexylcarbodiimide (1.17 g), and stirred for 2 hours. To this solution, a N,N-dimethylformamide solution (40 ml) in which tosylate of H-Gly-OBzl (1.9 g) and triethylamine (0.79 ml) had been dissolved was added, and the mixture was allowed to react with stirring at room temperature for 16 hours. This reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=50:1 solution) to give the title compound (2.0 g).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:10]([O:18][C@H:19]([C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+].[Cl-].[NH4+].Cl.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:51][N:50]=[N:49][N:17]=3)[CH2:15][C@@:9]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:10]([O:18][C@H:19]([C:29]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:30]=1)[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc([C@H](COCc2ccccc2)O[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Yield: 52.8 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-phenylmethoxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 157; 0.7105 g, 1.07 mmol), sodium azide (0.2087 g, 3.21 mmol) and ammonium chloride (0.172 g, 3.21 mmol) in dimethylformamide (10 ml) were heated at 120° C. for 18 hours. A further 3.0 eq of sodium azide and 3.0 eq of triethylamine hydrochloride were added and the mixture heated for a further 18 hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 5% methanol/dichloromethane to give the title compound (400 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:4]([C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])=[C:13]=[O:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1N=C=O

Procedure:
7.50 g (49.3 mmol) 2-methyl-4-nitro-aniline are combined with 7.20 ml (59.2 mmol) diphosgene in 200 ml of toluene and refluxed for 2 h with stirring. The reaction mixture is evaporated down i. vac., the residue is twice taken up in toluene and evaporated down completely i. vac. The residue is further reacted without any further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:28]=[CH:27][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([N+:24]([O-])=O)[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:28]=[CH:27][C:13]3[NH:14][C:15]([C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)=[N:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-2-nitro-phenylamine (500 mg, 1.3 mmol) in 4:1 ethyl acetate/methanol (50 ml) was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was filtered through Celite, washed with methanol, and the combined filtrate and washings were concentrated to give the crude 4-[5-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine as an orange solid that was used in the next step without any purification.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[NH:14][C:13]=12.C(=O)(O)[O-].[Na+]>CO.O>[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17]([OH:18])=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[N:14][C:13]=12
Reactant: Cc1nn2c(=O)cc(-c3ccncc3)[nH]c2c1Cc1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 3-(2,3-dichlorobenzyl)-2-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (100 mg, 0.225 mmol), sodium bicarbonate (0.5 g) in methanol/water (20 mL/10 mL) was stirred at room temperature overnight. Then the mixture was concentrated. The residue was purified by silica gel column to give the titled product (75 mg, 87%); LC/MS: MS (ES+) m/e 385 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.15 (s, 3H), 4.14 (s, 2H), 6.11 (s, 1H), 6.97-7.00 (m, 1H), 7.25 (t, J=8.1 Hz, 1H), 7.48-7.50 (m, 1H), 7.82-7.82 (m, 2H), 8.71-8.74 (m, 2H), 12.20 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11](=[O:19])[CH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18].Cl>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]1[CH:16]=[CH:15][S:14][C:13]=1[CH:12]([C:3]([O:6][CH3:7])=[O:8])[C:11]([O:10][CH3:9])=[O:19]
Reactant: COC(=O)OC
Reactant: COC(=O)Cc1sccc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C(=O)OC)c1sccc1C
Temperature: 80 °C
Yield: 88 %

Procedure:
Under argon, 14.7 g of sodium hydride (60% in mineral oil) were added to 311 ml (332 g, 3.685 mol) of dimethyl carbonate, and the mixture was heated at 80° C. At this temperature, a solution of 41 g (0.217 mol) of methyl(3-methylthiophen-2-yl)acetate in 50 ml of toluene was slowly added dropwise, and the mixture was stirred under reflux overnight. For work-up, the mixture was diluted with about 200 ml of methanol and poured into ice-water and acidified with dilute hydrochloric acid. Extraction with dichloromethane, drying of the organic phase over sodium sulphate, filtration and removal of the solvent gave 43.6 g of dimethyl 2-(3-methylthiophen-2-yl)malonate. Yield: 88%. 1H-NMR (DMSO): δ=7.42 (d, 1H), 6.89 (d, 1H), 5.27 (s, 1H), 3.69 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([NH:10][C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH:19]([OH:22])CO)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][CH:12]=1)(=[O:9])[CH3:8]>O1CCCC1>[C:7]([NH:10][C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH:19]=[O:22])[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][CH:12]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1cnc(-c2ccccc2)n(CC(O)CO)c1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution (11.2 ml) of sodium periodate (897 mg, 4.19 mmol) was added to a solution of 3-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-1,2-propanediol (1.06 g, 3.50 mmol) in tetrahydrofuran (100 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated as such, and after water was added, the product was extracted 3 times with ethyl acetate, and it was washed with saturated saline. After dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure whereby the title compound (800 mg, 84%) was obtained as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1=CCNCC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CC=CCC1
Yield: 69.6 %

Procedure:
900 mg (5 mmol) of 4-nitrophenylisocyanate is dissolved, under an argon atmosphere, in a 100 ml three-necked flask in 17 ml of dry DMF. 0.45 ml (5 mmol) of 1,2,3,6-tetrahydropyridine is added to this solution in one go, and agitation is maintained for 15 hours. The reaction mixture is then concentrated to dryness under vacuum and the evaporation residue placed on a silica gel column. After elution with a heptane/ethyl acetate mixture: 4/6, the pure fractions are collected and concentrated under reduced pressure in order to produce 860 mg (70%) of a bright yellow powder. Melting point: 169-170° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:22][C:23](Cl)=[O:24].Cl.[OH-].[K+]>ClCCl.O>[CH2:1]([N:8]1[CH:9]([CH3:13])[CH2:10][CH2:11][O:12][CH2:22][C:23]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCOCC(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 3-benzylamino-butan-1-ol (0.50 g, 2.8 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dichloromethane was added chloroacetylchloride (0.26 mL, 3.3 mmol) at 0° C. and stirred for one hour. The reaction mixture was poured into 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 2-propanol (20 mL) and potassium hydroxide (0.66 g, 10 mmol) was added to the mixture at room temperature. After stirring for 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residual material was purified by flash column chromatography on silica gel (hexane/ethyl acetate=100/0 to 1/1 as an eluant) to afford 4-benzyl-5-methyl-[1,4]oxazepan-3-one (0.32 g, 1.4 mmol, 52%) as yellow viscous oil.