Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=3[Cl:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 100 %

Procedure:
Combine 4-(3-amino-phenoxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 35, 0.40 g, 1.31 mmol), 1,4-dioxane (20 mL), triethylamine (0.22 mL, 1.57 mmol) and 2-chloro-4-fluoro-benzoyl chloride (0.30 g, 1.57 mmol) with stirring. After 4 hr., partition between 4:1 hexane:ethyl acetate (100 mL) and 0.5M aqueous sodium hydroxide solution (100 mL). Separate the organic layer, dry over sodium sulfate, filter and concentrate to obtain of the title compound (0.60 g, 100%): 1H NMR (CDCl3): 7.9 (bs, 1H), 7.8 (dd, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.2 (dd, 1H), 7.1 (m, 1H), 7.0 (dd, 1H), 6.7 (dd, 1H), 4.7 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Removal of the BOC group in the product from Step A (13.78 g, 27.67 mmol) was accomplished with trifluoroacetic acid (100 ml) in dichloromethane (200 mL) at room temperature. After stirring for 2 h, the reaction was concentrated and neutralized with 25% MeOH and 2.5% ammonium hydroxide in dichloromethane. Solvents were removed under reduced pressure and the resulting crude material was purified on a 65i Biotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane. The isolated material was further purified by recrystallization from 5:1 EtOAc/CH2Cl2 at 60° C. The crystalline product was washed with cold 2:1EtOAc/hexanes to give the title compound as a light brown solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>S1(CCCC1)(=O)=O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O=S1(=O)CCCC1
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.13 h

Procedure:
21 g of anthraquinone are introduced into 100 ml of 98 % HNO3 at 20° and the mixture is stirred at this temperature for 8 minutes. 50 ml of sulpholan are then added, the temperature rising to 53°. 40 ml of 98 % HNO3 are distilled off at 35°/10 mm, a further 50 ml of sulpholan are added, the reaction mixture is filtered at 40° and the precipitate is washed with a small quantity of sulpholan and then with water. After drying, 13.9 g of 1-nitro-anthraquinone are obtained, having the following composition:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].[CH3:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:22]=1.[BH4-].[Na+]>O1CCCC1.CO>[NH2:17][C:13]1[CH:12]=[C:11]([CH:9]([OH:10])[CH2:8][N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:28]=3[CH:29]=[CH:30][C:21]([CH3:20])=[N:22]4)[CH2:32][CH2:33]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(N3CCNCC3)cccc2n1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CC(O)c4cccc(N)c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 55 %

Procedure:
Sodium carbonate (1.5 eq) and 2-bromo-1-(3-nitrophenyl)ethanone (1.5 eq) were added to a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) in tetrahydrofuran at room temperature under an inert atmosphere, and the reaction was left under stirring for 1 h. The solution was then diluted with MeOH, NaBH4 (2 eq) was added and the reaction was left under stirring for 1 h. The solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (SCX) using as eluant a gradient from MeOH to MeOH:CH2Cl2 (1:1) and then 2M NH3 in MeOH affording an intermediate which was reduced following a similar procedure to D6 to give the title compound in 55% yield.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.Cl.[N:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:7]([C:4]1[C:3]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][CH:17]=[N:16]3)[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: N#Cc1csc(N)c1-c1cnccn1
Agent: Cl
Product: N#Cc1csc(NC(=O)Cc2cccc3ncccc23)c1-c1cnccn1

Procedure:
The title compound was synthesized from 5-amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile (30.5 mg, 0.15 mmol) and 2-(quinolin-5-yl)acetic acid hydrochloride (36 mg, 0.16 mmol) according to protocol A. The product was purified by HPLC method [4], retention time=1.393 min; MS (ESI) 372.1 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.30 (d, J=1.5 Hz, 1H), 9.06 (dd, J=4.8, 1.3 Hz, 1H), 8.99 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.09 (dd, J=8.6, 7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.86 (dd, J=8.6, 4.9 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: O=[C:2]1[C:7]([O:8]B(O)O)=[CH:6][CH2:5][CH2:4][CH2:3]1.Br[C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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.O>[CH3:18][N:17]1[C:13]([C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:14][N:15]=[CH:16]1
Reactant: O=C1CCCC=C1OB(O)O
Reactant: Cn1cncc1Br
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cncc1C1=CCCCC1=O
Yield: 8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using (6-oxocyclohex-1-en-1-yl)boric acid (J. Org. Chem. 2011, 76, 3946-3959; 790 mg, 5.65 mmol), 5-bromo-1-methyl-1H-imidazole (910 mg, 5.65 mmol), tetrakis(triphenylphosphine)palladium (0) (326 mg, 0.282 mmol), cesium carbonate (4.00 g, 12.3 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (80 mg, 8%) as a brown oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)=[CH:33][CH:32]=4)[CH:27]=3)[CH:23]=[N:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([CH2:37][NH:38][CH3:39])=[CH:35][CH:36]=4)[CH:27]=3)[CH:23]=[N:22][CH:21]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cncc(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2cc(-c3cncc(-c4ccc(S(=O)(=O)C(C)C)cc4)n3)on2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl N-[[4-[5-[6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-methyl-carbamate (85 mg, 0.1549 mmol) in DCM (5 mL) and the reaction was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The reaction mixture was passed through a 2 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (45.6 mg, 66% Yield). 1H NMR (400.0 MHz, DMSO) d H NMR (400.0 MHz, DMSO) δ 9.67 (s, 1H), 9.46 (s, 1H), 8.72 (d, 2H), 8.21 (d, 2H), 8.19 (s, 1H), 8.11 (d, 2H), 7.67 (d, 2H), 3.87 (s, 2H), 3.69 (sept, 1H), 2.43 (s, 3H) and 1.35 (d, 6H) ppm; MS (ES+) 449.2; LCMS Retention time: 1.09 min.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:20].ClC(OCC)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:10])=[CH:17][C:18]=1[Cl:19]
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccccc2)cc1Cl
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,5-dichloro-β-phenyl-cinnamic acid (isomer ratio A:B=1.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.CN(C)/[CH:20]=[CH:21]/[C:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])=O>C(O)C>[OH:34][C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=1[C:22]1[N:1]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]2)[N:2]=[CH:20][CH:21]=1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of crude tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 858, 5.7 g, 0.030 mol) in ethanol (66 mL) at 0° C. was added acetic acid (6.6 mL) dropwise. Then (2E)-3-(dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one, (Preparation 859, 6.4 g, 24.68 m mol) was added portionwise and allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and neutralised with aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate (150 mL). The combined organic layer was washed with water (100 mL), saturated aqueous sodium chloride solution (50 mL) and dried over anhydrous sodium sulphate. After concentration of organic layer in vacuo, the crude product was washed with 20% v/v ethyl acetate in hexane to get the title compound as a white solid (7.4 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)=[CH:4][CH:3]=1.[CH3:22][N:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](Cl)=[O:25]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([O:18][C:24](=[O:25])[N:23]([CH3:22])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=3)=[CH:20][CH:21]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(O)ccc12
Product: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(4-fluorobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and N-methyl-N-phenylcarbamoyl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:16][C:15](=[O:17])[NH:14][C:8]1=[N:9]2.C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:14][C:15](=[O:17])[CH2:16][N:7]1[CH2:6]2
Reactant: COCc1cccc2c1CN1CC(=O)NC1=N2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COCc1c(Br)ccc2c1CN1CC(=O)NC1=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 1.87 g. (0.01 mole) of 6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one in 40 ml. of glacial acetic acid is added dropwise at room temperature 1.60 g. (0.01 mole) of bromine. The mixture is stirred at room temperature for one hour, water (50 ml.) is added and the volume concentrated (10-15 ml.) in vacuo. Additional water (50 ml.) is added, the solution made basic with ammonium hydroxice, warmed and the insoluble material filtered under suction. The colorless solid is washed with water, dried and crystallized from 50 ml. of 5% hydrochloric acid yielding the title product as a colorless solid. Purification is effected by crystallization from methanol/ether to yield the title product.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:14])[NH:7][CH:6]=1.[C-:17]#[N:18].[Na+]>C(O)C>[CH3:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5]([CH2:4][C:17]#[N:18])=[CH:6][NH:7]2
Reactant: [C-]#N
Reactant: Cc1cccc2[nH]cc(C[N+](C)(C)C)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C

Procedure:
Trimethyl-(4-methyl-1H-indol-3-ylmethyl)-ammonium iodide (2.6 g, 7.5 mmol) is suspended in ethanol (53 mL) and sodium cyanide (736 mg, 15 mmol), is added to the reaction. The reaction is stirred and heated to reflux overnight. After 16 hours the reaction is cooled to room temperature and evaporated in vacuo. The resulting oil is taken up in dichloromethane and washed with water 3×, dried (Na2SO4), filtered and evaporated in vacuo. The resulting material is purified on silica with hexanes/dichloromethane as the eluent (1.0 g, 5 mmol, 71%) LC/MS (M++1): 171.3.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(C)(C)C)cc(C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Water, 20 mL, was added to a mixture of 12.0 g (58.0 mmol) of 1-nitro-4-tert-butyl-2,6-dimethylbenzene dissolved in 160 mL of ethanol. To the stirring solution of 1-nitro-4-tert-butyl-2,6-dimethylbenzene was added CaCl2, 4.8 g (43.2 mmol), dissolved in 20 mL of water, followed by the addition of zinc powder, 50.0 g (76.5 mmol). The reaction was stirred overnight at 65° C., then cooled to ambient temperature and filtered. The filtrate was extracted three times with ether, and the organic layer was dried over MgSO4. Removal of the solvent gave 9.58 g (93%) of a brown oil. 1H NMR (300 MHz, CDCl3): δ=6.90, s, 2H, 3.40, broad singlet, 2H, 2.11, s, 6H, 1.21, s, 9H.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:17]3[N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N:29]=1)=[O:5])C>CCO.[OH-].[Na+]>[S:25]([C:21]1[CH:20]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3[CH:11]=[CH:10][C:9]4[N:29]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=4[C:17]=3[N:16]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])(=[O:27])[NH2:26]
Reactant: CCOC(=O)c1nc2ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc3c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc4nc(C(=O)O)sc4c3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.5 %

Procedure:
8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid ethyl ester (494 mg, 1.15 mmol) was suspended in a mixture of EtOH (30 ml) and 1N sodium hydroxide (20 ml). The mixture was stirred at room temperature for 12 h. EtOH was removed in vacuo and the residual crude mixture was neutralised with 1N HCl (20 ml). The resulting solid was filtered and dried under vacuo to afford 0.473 g of a brownish solid. MS (ES+) 402, (ES−) 400. δH (d6 DMSO) 7.37 (2H, s), 7.50 (1H, d), 7.60 (1H, t), 8.06 (2H, s), 8.16 (1H, d), 8.62 (1H, s), 9.50 (1H, s), 10.52 (1H, s), 14.80 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[O:11][CH:12]=2)=[CH:4][CH:3]=1.[N+:21]([O-:26])([N+]([O-])=O)=[O:22]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[O:11][C:12]=2[N+:21]([O-:26])=[O:22])=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2coc3c2ccc2ccccc23)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClCCl
Product: O=[N+]([O-])c1oc2c(ccc3ccccc32)c1-c1ccc(Br)cc1

Procedure:
A solution of 2 g. of the product of step B in 50 ml. of dichloromethane is treated with 2.0 g. of dinitrogen tetraoxide, and the mixture is stirred at about 20° C. for about 18 hours. The mixture is evaporated, and the residue obtained is recrystallized from aqueous ethanol to provide yellow crystals of 3-(4'-bromophenyl)-2-nitronaphtho-[1,2-b]furan, m.p. 230°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29]C)=[O:28])[CH2:22]3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:31])=[CH:7][CH:8]=2)[N:3]=1.O[Li].O>C1COCC1.O>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=[O:28])[CH2:22]3)=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:31])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)C1CCCC(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCN(C(=O)NC3CCCC(C(=O)O)C3)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-cyclohexanecarboxylic acid, methyl ester (150 mg, 0.33 mmol) in THF (20 mL) and water (6 mL) was added LiOH.H2O (28.0 mg). The reaction mixture was stirred at rt overnight, and then solvent was evaporated in vacuo. The resulting residue was acidified to pH 4, the precipitate was collected by filtration and dried to afford the title product. LC-MS: 432 (M++1). 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.25 (m, 2H), 1.75 (m, 3H), 1.95 (m, 1H), 2.25 (m, 1H), 3.10 (m, 4H), 3.50 (m, 5H), 6.25 (s, 1H), 6.40 (d, 1H), 7.25 (m, 1H), 7.50 (s, 1H), 780 (d, 1H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[O:16][CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH:14]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[O:16][CH3:17]
Reactant: COCOc1ccc(C=CC(C)=O)cc1OC
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)C=Cc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.7 %

Procedure:
1-(4-Methoxymethyloxy-3-methoxyphenyl)-1-buten-3-one (35j, 1.00 g, 4.2 mmol) and benzaldehyde (1b, 0.46 ml, 4.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.30 g, 7.5 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 1.35 g (99%) of an oil which was used without purification. The oil (36j, 1.30 g, 4.0 mmol) was stirred in methanol (50 ml) for 15 min at 60° C. Concentrated hydrochloric acid (3 drops) was added and the solution stirred for 18 hr at 60° C. The methanol was evaporated and the resulting residue extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a semi-solid. The crude semi-solid was chromatographed on silica gel with ethyl acetate/hexane to give 0.41 g (36%) of a yellow oil; 1H NMR δ 3.92 (s, 3H), 6.08 (s, 1H), 6.91 (d, 1H, J=16.1 Hz), 6.93 (d, 1H, J=8.2 Hz), 7.07 (d, 1H, J=15.9 Hz), 7.10 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 7.38 (m, 3H), 7.59 (m, 2H), 7.67 (d, 1H, J=15.9 Hz), 7.71 (d, 1H, J=15.9 Hz); 13C NMR: δ 56.0, 109.8, 114.9, 123.4, 125.3, 127.3, 128.3, 128.8, 130.3, 134.9, 142.8, 143.5, 146.8, 148.3, 188.7.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[C:13]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc2ccccc2nc1-c1ccccc1
Yield: 95.7 %

Procedure:
2-Chloro-3-methylquinoline (5.43 g, 30.6 mmol), phenylboronic acid (4.47 g, 36.7 mmol), Pd(II) acetate (0.17 g, 0.76 mmol), and triphenylphosphine (0.80 g, 3.06 mmol) were dissolved in 100 mL DME. To the stirred solution was added K2CO3 (11.4 g dissolved into 41 mL H2O). The entire mixture was allowed to stir at reflux for 18 hours under N2 atmosphere. The cooled mixture was then removed of water, enriched with 150 mL of ethyl acetate, extracted three times from brine, dried over anhydrous sodium sulfate, filtered and evaporated of solvent. The crude liquid was then purified on a silica gel column using 20% ethyl acetate/hexanes. The purest fractions were combined to give 2-phenyl-3-methylquinoline (6.42 g, 95.8% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Cn1nc(-c2ccccc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of ethyl 2-(5-amino-3-phenyl-pyrazol-1-yl)acetate (49 g, 0.17 mol) in pyridine (200 mL) was added acetic anhydride (17.4 g, 0.17 mol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2 and water. The layers were separated and the organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo. CH2Cl2 was added to the residue and the solid was collected by filtration, yielding the title compound as a solid (22 g). The mother liquors were concentrated in vacuo and washed with cold CH2Cl2 to yield a second batch of 15 g.