Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>O>[N:7]1[CH:8]=[CH:9][N:10]=[CH:11][C:6]=1[CH2:5][NH:4][C:15](=[O:16])[CH2:14][CH2:13][Cl:12]
Reactant: NCc1cnccn1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCl)NCc1cnccn1
Yield: 56.7 %

Procedure:
To an aqueous solution of sodium hydroxide (2.31 g) in water (30 ml) was added 2-aminomethylpyrazine hydrochloride (7.0 g) under ice cooling, to which 3-chloropropionylchloride (5.05 g) and solution of sodium hydroxide (2.31 g) in water (30 ml) were simultaneously added dropwise over 30 minutes under stirring. The mixture was stirred for 1 hour at room temperature, followed by extraction with ethyl acetate-THF (1:1, 100 ml×2). The aqueous layer was subjected to salting out with sodium chloride, followed by extraction with ethyl acetate-THF (1:1, 100 ml×2). The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure. The concentrate was subjected to column chromatography [carrier: silica gel, 200 g; developing agent: ethyl acetate→ethyl acetate-ethanol (4:1)]. The eluent was concentrated and the resulting solid was washed with hexane to give the title compound (4.50 g) as colorless solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:12][C:5]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1CBr
Yield: 86.6 %

Procedure:
A mixture of methyl 5-chloro-2-methyl-3-nitrobenzoate (6 g, 26.2 mmol), NBS (5.1 g, 28.8 mmol), and BPO (0.63 g, 2.6 mmol) in CCl4 (50 mL) was heated to reflux overnight. Water (200 mL) was added and CCl4 was removed under reduced pressure. The residue was extracted with DCM (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude title compound (7 g, yield 87%) as a brown oil which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:26](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]2[CH:13]=[N:26][NH:1][C:2]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 equiv.) in chloroform (13 mL per 1 mmol), potassium acetate (1.05 equiv.) and acetic anhydride (2 equiv.) were added and reaction mixture stirred at room temperature for 12 h. After this time, tert-butyl nitrite (4 equiv.) and 18-crown-6 (0.35 equiv.) were added and the reaction stirred again at 65° C. for 3 h. On completion, the reaction mixture was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to afford the title compound (yield 90-95%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][CH2:15][O:16][C@H:17]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:19]([C@@H:20]([OH:46])[CH2:21][C@@H:22]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:23]3[CH2:24][C@@H:25]3[O:30][C@@:29]4([O:36][CH2:35][C@H:33]([CH3:34])[CH2:32][CH2:31]4)[C@@H:27]([CH3:28])[C@@H:26]32)[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][CH2:15][O:16][C@H:17]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:19]([C:20](=[O:46])[CH2:21][C@@H:22]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:23]3[CH2:24][C@@H:25]3[O:30][C@@:29]4([O:36][CH2:35][C@H:33]([CH3:34])[CH2:32][CH2:31]4)[C@@H:27]([CH3:28])[C@@H:26]32)[CH2:18]1)[CH3:13]
Reactant: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
Pyridinium chlorochromate (1.98 g, 9.20 mmol) was added to a mixture of (3β,5α,6α,25R)-3-ethoxy methoxy-6-hydroxyspirostane (0.90 g, 1.8 mmol) and celite (8.0 g) in anhydrous dichloremethane at 0° C. The reaction mixture was gradually warmed to ambient temperature over 1 hour and allowed to stir for an additional 5 hours. The reaction mixture was then filtered through a plug of silica gel using ether as the eluent. The combined ether fractions were concentrated in vacuo to afford 0.80 g (91%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OCc2ccccc2)c1

Procedure:
General procedure K was used to convert 3-hydroxybenzaldehyde (8.2 mmols) and benzyl bromide (12.3 mmols) to 1 (8.2 mmols, quant.)1H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 7.51-7.44 (m, 4H), 7.44-7.39 (m, 1H), 7.38-7.33 (m, 1H), 7.26 (ddd, J=1.8, 3.5, 4.2, 1H), 5.13 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 192.08, 159.29, 137.81, 136.29, 130.13, 128.68, 128.22, 127.56, 123.70, 122.20, 113.22, 77.31, 77.06, 76.80, 70.20.
Reaction SMILES: [N:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:33]([F:36])([F:35])[F:34])[CH:16]=1>>[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=[C:10]4/[C:11](=[O:12])[N:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[C:8](=[O:13])[S:9]/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:33]([F:34])([F:36])[F:35])[CH:16]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: O=C1CSC(=O)N1N1CCOCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-morpholin-4-yl-1,3-thiazolidine-2,4-dione was prepared from 3-morpholin-4-yl-thiazolidine-2,4-dione and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][OH:31])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:35])([F:34])[F:33])[CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][O:31][S:44]([CH3:43])(=[O:46])=[O:45])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:34])([F:33])[F:35])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-[5-(6-hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 (330 mg, 0.67 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (62 μL, 0.80 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:15. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methylmethanesulfonate 18 was obtained (246 mg, 65% yield) as a pale yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[Si:29]([O:36][C:37]1[CH:38]=[C:39]([CH:68]=[CH:69][CH:70]=1)[C:40]([NH:42][NH:43][C:44](=[O:67])[C@H:45]([NH:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]#[N:64])=[C:59](Cl)[C:58]=1C)[C@@H:46]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH3:47])=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[CH2:71]([Cl:73])Cl>>[Si:49]([O:48][C@@H:46]([CH3:47])[C@@H:45]([NH:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]#[N:64])=[C:71]([Cl:73])[C:62]=1[CH3:61])[C:44]1[O:67][C:40]([C:39]2[CH:68]=[CH:69][CH:70]=[C:37]([O:36][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[CH:38]=2)=[N:42][N:43]=1)([C:52]([CH3:55])([CH3:53])[CH3:54])([CH3:50])[CH3:51]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: ClCCl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (100 mg, 0.3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (3 mL) followed by addition of solid iodine (76 mg, 0.30 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (0.17 mL, 1.2 mmol). This mixture was allowed to stir at room temperature for an additional ten min. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (95 mg, 0.15 mmol) was taken up in methylene chloride (5 mL) and slowly added to the heavily stirred reaction mixture. After a period of 20 min, the solid polymer was filtered out and washed with additional methylene chloride (20 mL). The organic filtrate was then washed with 10% sodium thiosulfate/water (2×10 mL), brine (1×20 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown oil/solid, which was purified via silica gel chromatography eluted with 20% EtOAc/hexanes to provide the title compound as a white solid (63 mg, 68%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.52 (m, 1H), 7.38 (m, 1H), 7.33 (m, 2H), 6.99 (m, 1H), 6.46 (d, J=8.6 Hz, 1H), 5.37 (d, J=8.8 Hz, 1H), 4.80 (dd, J=1.8, 8.8 Hz, 1H), 4.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), 0.06 (s, 3H), −0.20 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH:6][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2cc(Br)cc(Br)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1c[nH]c2cc(Br)cc(Br)c12)NC(=O)OCc1ccccc1

Procedure:
Mix DL-4,6-dibromotryptophan ethyl ester (1.20 g, 3.07 mmol), triethylamine (341 mg, 3.38 mmol) and methylene chloride (50 mL). Add benzyl chloroformate (692 mg, 4.06 mmol) and stir for 12 hours. Dilute with methylene chloride, wash with 1M hydrochloric acid (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([NH2:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(OCC)C>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][NH:12][C:30]([C:20]34[CH2:29][CH:24]5[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]5)[CH2:27]3)[CH2:21]4)=[O:31])=[CH:4][C:5]=2[O:6]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NCCc1ccc2c(c1)OCO2)C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
Dissolve 0.5 g. of homopiperonylamine in 5 ml. of ethyl ether and 2.5 ml. of triethylamine. The mixture is cooled in an ice-bath and a solution of 0.6 g. of 1-adamantane carboxylic acid chloride in 10 ml. of ethyl ether added dropwise. Stir the mixture for an additional 3 hours. Add water and extract the mixture with ethyl acetate. Wash the ethyl acetate extract with 2N hydrochloric acid, saturated sodium bicarbonate solution, and water. Dry over anhydrous sodium sulfate, filter and evaporate the filtrate to a residue. Crystallize the residue from ethyl acetate to obtain the product of this step, m.p. 146°-148°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:30]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1)#[N:31]>C(O)(C)(C)C.ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:42][S:39]([C:35]3[CH:36]=[C:37]([CH3:38])[C:32]([C:30]#[N:31])=[CH:33][C:34]=3[CH3:43])(=[O:40])=[O:41])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Cc1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(C)cc1C#N
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-c]pyridine-2-carboxylic acid (2.5 g, 9.5 mmol, prepared as described in Example 1 Step C) in t-butanol (70 mL) and dichloromethane (70 mL) was added 4-(dimethylamino)pyridine (3.47 g, 28.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol). The reaction mixture was stirred for 15 min after which time 4-cyano-2,5-dimethylbenzenesulfonamide (1.85 g, 8.85 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), the organic phase was collected and dried over magnesium sulfate and then concentrated under reduced pressure to afford a solid. The solid was isolated by filtration, rinsed with diethyl ether, and recrystallized from hexane/ethyl acetate to afford 1.5 g of the title compound, a compound of the present invention, as a solid, m.p. 228-229° C. 1H NMR (CDCl3) δ 9.97 (br s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 2.71 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Chloro-4-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell, et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4-fluoro-2-nitroaniline (500 mg, 3.2 mmol) in dry DMF (10 mL) under N2 was added dropwise a solution of N-chlorosuccinimide (426 mg, 3.2 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. The solution was then poured into 100 mL H2O and the resulting cloudy suspension extracted with 4×25 mL ethyl acetate. The combined organic phases were washed with 4×25 mL H2O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a brown crystalline solid which was purified further by flash chromatography (2:1 hexanes:ethyl acetate) to yield 424 mg of an orange crystalline solid (69.5%) 1H NMR (CDCl3) δ6.46 (br s, 2H, NH2), 7.42 (dd, JH5-3 =3 Hz, JH3-F =7.2 Hz, H-4), 7.85 (dd, JH5-3 =3 Hz, JH5-F =8.7 Hz, H-5)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:3])[CH3:2].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)=[O:18])(=[O:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CCOC(C)=O)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2.3 g of the sulfonyl isocyanate from Example 7 in 25 ml dry acetonitrile was added 1.2 g of 2-amino-4,6-dimethoxypyrimidine. The reaction mixture was warmed to 50° C. for 11/4 hour and then stirred at room temperature for 2 days. Filtration of the insoluble solids and washing with 1-chlorobutane followed by drying afforded 1.8 g of 2-[2-(acetyloxy)ethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide as a light yellow solid, m.p. 160°-162° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][N:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: COc1ccccc1CBr
Product: COc1ccccc1CN(Cc1ccco1)S(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 35 %

Procedure:
Prepared as in Example 5-5 from 1-(bromomethyl)-2-methoxybenzene and 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b). Yield 35%. MS M+H calculated 402.3, found 402.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[NH2:17]>C(O)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(Br)cc34)cc2Cl)c1
Yield: 85.9 %

Procedure:
6-bromo-4-chloro-quinazoline (1.36 g) and 3-chloro-4(m-fluoro-benzyloxy)-aniline (1.42 g) were dissolved into 50 mL of isopropanol. The mixture was reacted under reflux for 3 h, and a lot of yellow solid was deposited. The precipitated solid was filtered, and the filter cake was washed with cold ethanol and dried at 60° C. under vacuum overnight to obtain the 6-bromo-4-aminoquinazoline product (2.20 g, 86%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#N)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.[C:30](=O)(O)[O-:31].[Na+].C(=O)(O)[O-:36].[Na+].ClCCl>ClCCl.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:31][CH3:30])=[O:36])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 20 °C
Yield: 97.7 %

Procedure:
Nitrile 6 (101 g) and methanol (1.01 L, 10 vol.) were charged to a 3-L flask equipped with stir bar and thermocouple. Concentrated H2SO4 (175 mL, 10.0 equiv.) was added drop wise to the solution over 15 minutes while maintaining a temperature below 60° C. Followed by 30% fuming sulfuric acid (124 mL) was added drop wise to the solution while maintaining a temperature below 60° C. The solution was then heated to reflux with a heating mantle and stirred overnight. When the reaction was deemed complete, it was cooled to 20° C. In a second flask (22 L), saturated sodium bicarbonate (10.7 L) and dichloromethane (1.1 L) were charged and cooled to 15° C. While maintaining a temperature below 20° C., the reaction mixture was added to the sodium bicarbonate/dichloromethane mixture. The quench was stirred for 15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (1×550 mL, 1×300 mL). The combined organics were dried with magnesium sulfate and concentrated to dryness to give 105 g of an orange solid (94% crude yield, 97.7% AUC by HPLC).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25]>ClCCCl>[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: Cn1cccc1CC#N
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added 24 g. (0.131 mole) ρ-isopropylbenzoyl chloride. The resulting mixture is added slowly and dropwise to a chilled solution (0° C.) of 15.7 g. (0.131 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane. After addition is complete, the mixture is stirred at room temperature for twenty minutes and heated at reflux for three minutes. The reaction mixture is then cooled and poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over magnesium sulfate; and the solvent evaporated. The product, 5-(ρ-isopropylbenzoyl)-1-methylpyrrole-2-acetonitrile, is isolated from the residual oil by column chromatography. The column is packed with acid washed alumina and eluted with benzene, ether and ethylacetate. The product is found in the first compound-bearing fraction which absorbs ultraviolet light at approximately 250 m. It is purified by recrystallization twice in ether:pentane (9 g.; 20% yield), M.P. 59°-64° C.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>O1CCOCC1>[CH:20]1([C:23]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Reactant: O=C(Cl)C1CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NN1CCN(C(=O)C2CC2)CC1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (500 mg) in 1N aqueous solution of sodium hydroxide (5 ml) and dioxane (5 ml) was added cyclopropanecarbonyl chloride (0.3 ml) at ambient temperature, and the solution was stirred at (he same temperature for 2 hours. After removal of the solvent in vacuo, the residue was dissolved into ethyl acetate and washed with brine (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was recrystallized from 20% ethanol-water to give N-(4-cyclopropanecarbonyl-1-piperazinyl)-p-fluorobenzamide (0.20 g).