Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(NC)NC(=O)CC1C(Cl)=CC=CC=1Cl.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:31]=[C:30]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[N:29]=[C:28]([NH:41][C:42](NC(C)C)=O)[N:27]=2)=[CH:21][CH:20]=1)#[N:18]>CN(C=O)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][C:30]1[N:29]=[C:28]([NH:41][CH3:42])[N:27]=[C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=2)[N:31]=1
Reactant: CC(C)NC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Agent: CNC(N)NC(=O)Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: CNc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 104 °C
Yield: 30.3 %

Procedure:
A mixture of N-[amino(methylamino)methyl]-2,6-dichloro-benzeneacetamide (4.15 g) and intermediate 6 (3.05 g) in DMF (25 ml) was stirred and refluxed for 20 hours. The solvent was evaporated, the residue dissolved in DMF (25 ml) and heated at 80° C. for 16 hours and at 100-108° C. for another 66 hours. The reaction mixture was cooled, quenched with water, extracted with diethyl ether, and washed with dilute NaOH, water, brine, and dried over K2CO3. The solvent was evaporated, and the residue was purified by flash column chromatography, and recrystallized from 2-propanol, and finally from methanol, yielding 0.78 g (12.6%) of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-(methyl-amino)-1,3,5-triazin-2-yl]amino]benzonitrile (compound 7, mp. 229-230° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and cyclopropanecarbonyl chloride (68 μL, 0.75 mmol). The resulting suspension was stirred for 18 h at ambient temperature before it was extracted with a mixture of aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (226 mg, 95%) as a light yellow solid. MS: m/e=417.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:15][C:14]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cc(Oc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
The product from Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol) and K2CO3 (0.78 g, 5.6 mmol) in DMF (10 ml) was heated at 110° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound. The residue was treated with i-Pr2O and insoluble material was filtered off. The filtrate was evaporated and purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title product as pale yellow oil (0.51 g, 43%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]>O1CCCC1.C(OCC)(=O)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([O:3][CH2:2][C:1]([OH:5])=[O:4])=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(O)CO
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)COC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of glycolic acid (760 mg) and triethylamine (1.1 g) in tetrahydrofuran (20 ml) was added p-nitrobenzyl chloroformate (2.26 g) with ice-cooling and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to give p-nitrobenzyloxycarbonyloxyacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc(N)nc(N2CCC(c3ccc(F)cc3)CC2)c1C#N

Procedure:
In analogy to the procedure described in example 20b, the 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with the 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diiso-propylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid; MS: [M+H]+=344.
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[CH2:27](N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[S:7]([O:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:2]1[CH:1]=[CH:6][C:5]([CH3:27])=[CH:4][CH:3]=1)(=[O:8])=[O:9]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reaction time: 24 h
Yield: 97.8 %

Procedure:
Toluene sulphonyl chloride (0.513 g, 2.69 mmol) was added to a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.390 g, 1.79 mmol), triethylamine (0.50 mL, 3.59 mmol) and DMAP (cat.) in dichloromethane (11 mL). The reaction mixture was stirred for 24 h then diluted with dichloromethane (25 ml) and washed sequentially with water (25 mL) and 0.2M HCl (25 mL). The organic phase was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/5), to give the title compound as a colourless solid (0.650 g, 97%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[CH2:16][CH2:15][CH2:14][N:5]1[C@@H](C(Cl)(Cl)Cl)[O:7][C:8]2=O.[NH3:17]>CO>[CH3:1][O:2][CH2:3][C@@:4]1([C:8]([NH2:17])=[O:7])[CH2:16][CH2:15][CH2:14][NH:5]1
Reactant: N
Reactant: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Solvent: CO
Product: COC[C@@]1(C(N)=O)CCCN1
Reaction time: 48 h

Procedure:
A mixture of (3R,7aR)-7a-methoxymethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (0.6 g) and 7M ammonia in methanol (6 ml) is stood at room temperature for 2 days in a sealed vessel. The reaction mixture is then evaporated to give the title compound as a pale yellow oil which is used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:2]=12.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:2]=12
Reactant: OC1CCCCc2cccnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CCCCc2cccnc21
Yield: 82.7 %

Procedure:
To a stirred solution of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (41.70 g, 0.255 mol) in CH2Cl2 (300 mL) at 0° C. was added triethylamine (72 mL, 0.517 mol) followed by methanesulfonyl chloride (30 mL, 0.388 mol). The resultant mixture was stirred at room temperature over night. The mixture was poured into water (200 mL) and the phases were separated. The organic phase was washed with brine (2×150 mL), dried (Na2SO4), and concentrated to give 50.87 g of crude methanesulfonic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[N:15]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Br
Yield: 94.6 %

Procedure:
A mixed solution of the compound (2.55 g, 6.85 mmol) obtained in step 6 and 1N aqueous sodium hydroxide solution (10.27 mL, 10.27 mmol) in ethanol (10 mL) and THF (10 ml) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration, and washed with diethyl ether and hexane to give 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (2.23 g, 6.48 mmol, 95%) as a white powder.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH2:23]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]#[CH:25].C(N(CC)C(C)C)(C)C.C(OCC)C>O1CCCC1.[Cu]I.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>[CH2:27]([O:26][CH2:23][C:24]#[C:25][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOCc1ccccc1
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnnc1C(=NOCc1csc(C#CCOCc2ccccc2)n1)c1ccccc1
Yield: 64.8 %

Procedure:
A solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-methanimine (190 mg, 0.50 mmol), benzyl propargyl ether (149 mg, 1.00 mmol), copper(I) iodide (9.5 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.02 mmol), N,N-diisopropylethylamine (258 mg, 2.0 mmol) in degassed tetrahydrofuran (2.5 mL) was stirred under an Argon atmosphere at 50° C. for 14 h. After the addition of diethylether (2 mL) the suspension was filtered over a pad of silica gel and the filtrate was concentrated in vacuo. Purification on silica gel afforded N-({2-[3-(benzyloxy)prop-1-yn-1-yl]-1,3-thiazol-4-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine as a thick oil (144 mg, yield 62%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C1C=CC=CC=1>[Cl:20][C:18]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOC(=O)Cl
Reaction time: 2 h

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.2 g) and triethylamine (7.0 ml) are dissolved, and the resulting solution is dropwise added to a solution of phosgene (0.05 mol) in benzene (52.5 ml) at 5°C. The mixture is stirred at the same temperature for 2 hours and allowed to stand at room temmperature over night to give a solution of ethyl 2-chlorocarbonyloxyimino-2-cyanoacetate.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[OH:67]>ClCCl.CO>[Br:1][C:65]1[CH:64]=[CH:63][C:62]([OH:67])=[C:61]([O:60][CH2:59][CH2:58][CH2:57][O:56][CH3:55])[CH:66]=1
Reactant: COCCCOc1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(Br)ccc1O

Procedure:
6.9 g of tetrabutylammonium tribromide are added in portions at room temperature to a solution of 2.6 g of 2-(3-methoxypropoxy)-phenol in 60 ml of dichloromethane and 40 ml of methanol. The reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation and the residue is purified by means of FC (700 g of silica gel, dichloromethane/diethyl ether 98:2) to yield the title compound: Rf (dichloromethane/diethyl ether 97: 3)=0.50; HPLC Rt =14.3 minutes; FAB-MS (M+H)+ =262.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1.[N:19]1C=CC=CC=1.[C:25]([O:28]C(=O)C)(=O)[CH3:26].N>C(Cl)(Cl)Cl.CO>[C:25]([C:2]1[N:3]=[C:4]([NH2:19])[C:5]2[CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[N:18]=1)(=[O:28])[CH3:26]
Reactant: c1ccncc1
Reactant: CCCN1CCC[C@H]2Cc3nc(N)ncc3C[C@@H]21
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN1CCC[C@H]2Cc3nc(C(C)=O)nc(N)c3C[C@@H]21

Procedure:
A solution was prepared containing 0.75 g of trans-(±)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline in 20 ml. of pyridine and 0.34 g. of acetic anhydride was added thereto in dropwise fashion. The reaction mixture was heated to reflux temperature under a nitrogen blanket overnight. TLC at this point in time indicated that starting material was still present; therefore, about 1.5 ml. more acetic anhydride were added and the reaction mixture again heated to reflux temperature under a nitrogen blanket. TLC, using a 9:1 chloroform/methanol solvent system containing ammonia, indicated that the reaction had gone largely toward completion but that some starting material was still present. The reaction mixture was therefore concentrated in vacuo and the resulting residue triturated in hot ethyl acetate. On cooling, crystals formed which were isolated by filtration. Thirty-four hundredths grams of trans-(±)-2-acetyl amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained; molecular ion at 288; nmr and infrared spectra were in conformance with the proposed structure.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([OH:25])=O)[C:21]([OH:22])=[C:16]2[CH:15]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CC(O)=O>CN(C=O)C>[Br:13][C:14]1[S:26][C:17]2=[N:18][CH:19]=[C:20]([C:23]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=3)=[O:25])[C:21]([OH:22])=[C:16]2[CH:15]=1
Reactant: O=C(O)c1cnc2sc(Br)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(Br)cc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (1.00 g) in CHCl3 (26 mL) is added bromine (0.23 mL) dropwise. The reaction is stirred at rt for 2 h. The reaction mixture is poured into 2N HCl (30 mL), and the aqueous layer is extracted with CHCl3 (3×30 mL). The combined organic layers are washed with H2O (100 mL), dried with MgSO4, filtered and concentrated in vacuo to yield 0.840 g (62%) of the bromide as a yellow solid. This material (0.757 g) is suspended in 10% aqueous NaOH (7 mL) and heated to reflux. The reaction is stirred at reflux for 1 h. The reaction mixture is cooled to rt, and H2O (26 mL) is added. Conc. HCl is added until a precipitate forms. The precipitate is filtered off to yield 0.597 (87%) of the acid as a brown solid. Carbonyldiimidazole (0.530 g) is added to a solution of 2-bromo-4-hydroxy-thieno-[2,3-b]pyridine-5-carboxylic acid (0.597 g) in DMF (20 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([Cl:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+]>[OH-].[Na+]>[Cl:8][C:7]1[C:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[C:5]([Cl:10])[C:6]=1[O:24][C:21]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 52.4 gm of 2,3,4,5-tetrachloro-1-nitro-benzene, 122 gm of phenol and 60 gm of potassium carbonate was heated for 11/2 hours at 160° C. Thereafter, the still hot reaction mixture was stirred into 1.2 liters of 2 N sodium hydroxide, and the precipitated product was collected by suction filtration and recrystallized from 300 ml of ethyl acetate. 70.5 gm (93.8% of theory) of the title compound, m.p. 164° C., were obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[CH3:12][O:6][C:5](=[O:7])[C@H:2]([CH2:3][SH:4])[NH2:1]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H](N)CS
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. slurry in methanol of L-cysteine (1.23 g, 9.1 mmol) was added thionyl chloride (0.75 mL, 10.3 mmol). The cold bath was removed and the reaction mixture was stirred for 15 minutes and then overnight at 45° C. The reaction mixture was cooled to ambient temperature and concentrated to a white solid. The white solid was azeotroped with methanol to give cysteine methyl ester hydrochloride.
Reaction SMILES: [OH-].[Li+].IC1C=C(C=CC=1)C[O:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([I:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=2)=[C:14]([I:28])[CH:13]=1.Cl.CO>C1COCC1>[I:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]([OH:29])=[O:8])[CH:13]=[C:14]([I:28])[C:15]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=1
Reactant: O=C(CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1)OCc1cccc(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1
Reaction time: 14 h
Yield: 94.6 %

Procedure:
A 1.2 M solution of lithium hydroxide (275 ,L, 0.33 mmol) was added to a solution of 3-[3,5-diiodo-4-(3-iodo-benzyloxy)-phenyl]-propionic acid 3-iodo-benzyl ester (as prepared in Example 2, 213 mg, 0.25 mmol) in 2 mL THF. The biphasic solution was stirred for 14 hours, then 6 mL 0.5 M HCl was added and an oil formed. Methanol (0.5 mL) was added and the oil formed a solid, which was removed by filtration, yielding the title compound as an off-white powder (150 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 7.96 (s, 1H), 7.76-7.75 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 4.87 (s, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.4 Hz). HPLC (40-90), 17.23 min. LRMS (EI−) calc'd for [C16H13I3O3+CF3COO] 746.8, found 746.8.
Reaction SMILES: CN(/[CH:4]=[C:5]1/[CH2:6][C:7](=[O:21])[NH:8][C:9]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=2[C:11]/1=O)C.[C:22]([O:26][C:27](=[O:43])[NH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:42])=[C:36]([NH:38][C:39]([NH2:41])=[NH:40])[CH:37]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CCO.O.CCOC(C)=O>[C:22]([O:26][C:27](=[O:43])[NH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:42])=[C:36]([NH:38][C:39]2[N:41]=[CH:4][C:5]3[CH2:6][C:7](=[O:21])[NH:8][C:9]4[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:10]=4[C:11]=3[N:40]=2)[CH:37]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1NC(=N)N
Reactant: CN(C)/C=C1/CC(=O)Nc2cc(C(F)(F)F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
To a solution of (4Z)-4-[(dimethylamino)methylene]-8-(trifluoromethyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (1.05 g, 3.51 mmol) and tert-butyl[3-(5-{[amino(imino)methyl]amino}-6-methylpyridin-3-yl)propyl]carbamate (1.62 g, 5.27 mmol) in EtOH (50 mL) was added potassium carbonate (2.91 g, 21.1 mmol). The reaction mixture was allowed to stir at 80° C. overnight. The reaction mixture was diluted with water (100 mL) and EtOAc (50 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated to give tert-butyl[3-(6-methyl-5-{[6-oxo-9-(trifluoromethyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}pyridin-3-yl)propyl]carbamate (2.13 g, >99%) as a dark brown solid. LCMS (FA): Rt=1.79 min, m/z=543.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(S(C)(=O)=O)cc3)cc1-2
Yield: 40 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-(methylsulfonyl)phenylboronic acid were reacted to give 230 (0.072 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=2.3, 1H), 8.03 (d, J=8.4, 2H), 7.94 (s, 1H), 7.82 (d, J=8.4, 2H), 7.59-7.48 (m, 1H), 7.20 (d, J=8.4, 1H), 5.94-5.79 (m, 1H), 4.48 (t, J=4.9, 2H), 3.46 (dd, J=10.7, 5.8, 2H), 3.12 (s, 3H), 1.65 (d, J=6.6, 6H). MS (ESI(+)): m/z 467.1 (M+H)