Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[C:16]([F:22])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:1](=[O:3])[CH3:2])=[C:16]([F:22])[CH:15]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(Br)cc1F
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
Acetyl chloride (0.7 mL, 9.9 mmol) followed by triethylamine (2.8 mL, 19.9 mmol) were added to a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (2 g, 8.3 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 90 mins and then partitioned between 1 N HCl and EtOAc. The organic layers were brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a clear oil (1.5 g, 74%). MS (ESI): 246.10, 248.10 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH2:16].O>C(OC(O)C)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:16][CH2:15][CH:14]([OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NCC(O)c1ccccc1
Reactant: Clc1c(Br)cnc2ccccc12
Agent: CCOC(C)O
Solvent: O
Product: OC(CNc1c(Br)cnc2ccccc12)c1ccccc1

Procedure:
A solution of 4 g of 3-bromo-4-chloro-quinoline and 6 g of 2-hydroxy-2-phenyl-ethylamine was heated at 150° C. for 3 hours in 10 ml of ethoxyethanol. The mixture was cooled and poured into 150 ml of water. The product was extracted with two 50 ml portions of ether. The ether layer was dried over sodium sulfate, the solvent was evaporated and the residue was recrystallized from isopropanol. The yield was 3.0 g, mp 131°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCCc1ccccc1
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(NCCc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 96.3 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and β-phenethylamine (133 μL, 1.061 mmol) to give 383 mg of the title compound (96%): mp 246°~249° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.01 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.25 (m, 5H), 7.22 (d, 1H, J=1 Hz), 7.07 (d, 1H, J=1 Hz), 5.07 (dd, 1H, J=10, 5 Hz), 3.65 (dd, 1H, J=17, 10 Hz), 3.30 (dt, 2H, J=5.6, 7 Hz), 3.04 (dd, 1H, J=17, 5 Hz), 2.71 (t, 2H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:18](OC)=[O:19])=[O:15])[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:9]=[CH:8]2.[BH4-].[Na+]>C1COCC1.CCO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][OH:19])=[O:15])[N:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[N:9]=[CH:8]2
Reactant: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H](CO)CCN(C)C)cc21
Temperature: 60 °C
Yield: 96.3 %

Procedure:
A mixture of (S)-methyl 2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)-4-(dimethylamino)butanoate (30d; Example 120, Steps A-E) (0.370 g, 0.76 mmol) and NaBH4 (0.114 g, 3.04 mmol) in THF/EtOH (20 mL, 3:2) was heated to 60° C. for 7 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane. The slurry was chromatographed on Biotage eluting with 10% MeOH in dichloromethane with 1% triethylamine. The product was obtained as 0.337 g of viscous oil (97% yield). MS (ESI+) m/z 461 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.34 (d, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.13 (m, 1H), 7.02 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.33 (m, 1H), 4.22 (d, 2H), 3.64 (m, 2H) 2.37 (m, 1H), 2.17 (s, 6H), 2.10 (m, 1H), 1.82 (m, 1H), 1.07 (m, 2H), 0.93 (d, 6H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3]1.Cl.[F:15][C:16]1([F:27])[O:20][C:19]2[CH:21]=[CH:22][C:23]([NH:25]N)=[CH:24][C:18]=2[O:17]1.Cl>O>[F:27][C:16]1([F:15])[O:17][C:18]2=[CH:24][C:23]3[NH:25][C:2]4[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][C:3]=4[C:22]=3[CH:21]=[C:19]2[O:20]1
Reactant: NNc1ccc2c(c1)OC(F)(F)O2
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Agent: Cl
Solvent: O
Product: CC(C)C(=O)NC1CCc2[nH]c3cc4c(cc3c2C1)OC(F)(F)O4
Temperature: 25 °C
Yield: 42.8 %

Procedure:
Add N-(4oxo-cyclohexyl)-isobutyramide (933 mg, 5.09 mmol) to a suspension of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydrazine hydrochloride salt (1.14 g, 5.09 mmol), water (7 mL) and concentrated hydrochloric acid (3 mL). Heat the reaction to 90° C. for 12 h with stirring and cool to ambient temperature. Collect the resultant solid by vacuum filtration, rinse with water and place in a vacuum oven for 5 h to afford the subtitled compound (732 mg, 43%) as a tan solid. 1H NMR (300 MHz, CDCl3): δ 7.96 (br s, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 5.54 (br d, J=7.5 Hz, 1H), 4.40 (br s, 1H), 3.03 (dd, J=15.3, 5.1 Hz, 1H), 2.88-2.71 (m, 2H), 2.51 (dd, J=15.3, 7.0 Hz, 1H), 2.33 (pentet, J=6.9 Hz, 1H), 2.12-1.91 (m, 2H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[OH-].[NH4+].O>[CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc([C@@H]2CO2)cc1
Reaction time: 3 h
Yield: 32 %

Procedure:
A 500-mL flask, equipped with a temperature probe, a mechanical stirrer, a vacuum adapter, and a dip tube, was charged with (R,R)-Co(salen) (6.57 g, 0.0109 mol, 0.63 mol %), styrene oxide (209.0 g, 199.0 mL, 1.74 mol), and water (5.0 g, 5.0 mL, 0.28 mol, 16 mol %). A slight vacuum was applied to the flask to draw air into the reaction mixture through the dip tube (subsurface), agitation was initiated, and p-nitrobenzoic acid (3.64 g, 0.0218 mol, 1.25 mol %) was added in one portion. An exotherm was noted that ceased after about 3 h. When the internal temperature remained constant, additional water (5.0 g, 5.0 mL, 0.28 mol, 16 mol %) was added. An exotherm was again observed that ceased after about 1 h. This cycle was repeated two more times (2×5.0 g water). A final portion of water (42.6 g, 42.6 mL, 2.37 mol, 136 mol %) was added after the last exotherm had ceased. After stirring a total of 24 h, the reaction was deemed complete by HPLC. The reaction mixture was a brown solution with suspended orange solids. Ammonium hydroxide (3.0 mL, 28%, 0.049 mol, 2.8 mol %) was added, and the reaction mixture was stirred at room temperature for 2 h. A dark brown solution was obtained. Air flow through the reaction mixture was stopped, and the reaction mixture was washed with water (2×200 mL). The organic layer was fractionally distilled to give (R)-styrene oxide (67.0 g, 64% yield, 99.3% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[NH2:36][C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:38]=1[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][N:50]=1>C1COCC1>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:39]2[C:38]([C:49]3[CH:54]=[CH:53][N:52]=[CH:51][N:50]=3)=[C:37]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:12])[O:41][N:40]=2)=[CH:43][CH:44]=1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Reactant: CC(C(=O)O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C(=O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1)c1ccccc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In 5 mL of THF, 0.144 g of 2-(2-chlorophenyl)propionic acid and 0.126 g of CDI were dissolved and stirred at room temperature for an hour. Then 5 mL of THF solution containing 0.237 g of DBU and 0.1 g of 5-amino-3 (4-fluorophenyl)-4-4-pyrimidinyl isoxazole was added and stirred at room temperature for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and water was added to the residue which was then extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, removed of the solvent by distillation under reduced pressure, and the residue was purified on 20 g silica gel chromatography (eluent, chloroform:methanol=50:1). Washing the residue with ether, 0.118 g (yield: 72%) of the title compound was obtained.
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[O:19])[CH3:18]>O1CCCC1>[C:17]([NH:20][C:21]1[S:22][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:23]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)NC(N)=S
Reactant: COC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: C1CCOC1
Product: COC(=O)c1sc(NC(C)=O)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (1.25 g, 4.4 mmol) in 20 mL of tetrahydrofuran was added 1-acetylthiourea (0.52 g, 4.4 mmol). The resulting mixture was stirred at 65° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl acetate left the title compound as a white solid (0.4 g, 30%). MS (ESI) 302.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([CH3:30])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccn4)CC3)n1-2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the compound from example 1 (100 mg, 0.26 mmol) in dichloromethane (3 mL) was added formaldehyde (37% aqueous solution, 142 μL, 1.75 mmol) followed by sodium triacetoxyborohydride (55 mg, 0.26 mmol). The solution was stirred for 5 hours at room temperature, then sodium triacetoxyborohydride (20 mg, 0.09 mmol) was added. After 10 minutes, saturated sodium hydrogen carbonate solution was added and the mixture was stirred vigorously for 5 minutes. The phases were separated and the organic phase evaporated in vacuo to give the crude residue which was azeotroped twice with ethyl acetate and then diethyl ether to furnish the desired product, 63 mg (61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:10]3[C:9](=O)[NH:8][CH:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 2.52 g. (7.8 mmol) of the end product of Example 16 in 75 ml. dry THF was reduced with 3.12 ml. (31.2 mmol) of BMS according to the procedure described above in 6, Method B. The crude product from this reduction was then treated with 2.15 g. (9.4 mmol) of DDQ according to the oxidation procedure described above in Example 8. The crude oxidation product was chromatographed on a 29×20 cm column of silica gel packed in benzene and eluted first with 3% EtOAc in benzene and then 5% EtOAc in benzene. Recrystallization from CH3OH/H2O of the material isolated from the column yielded the analytically pure end product as colorless needles: mp 105°-107°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)[CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:40]1[CH:39]=[C:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:30]([OH:31])=[O:29])[CH:33]=2)[CH:43]=[CH:42][CH:41]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1
Yield: 98.2 %

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester (0.80 g, 2.04 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.15 g, 6.12 mmol, 3 eq.). When complete, the reaction was worked up as described leaving 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.73 g, 98% yield) as an orange oil that solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (119 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (177 mg, 79%). MS (ISP) 449.9 [(M+H)+]; mp 252-254° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24].Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3oc([N+](=O)[O-])c(C)c3c2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])oc2ccc(-c3ccc(CC(=O)O)cc3)cc12
Temperature: 0 °C

Procedure:
A solution of 1.5 g. of, the product of step C in 25 ml. of acetic acid and 10 ml. of 6 N hydrochloric acid is heated at its reflux temperature for 45 minutes then poured into ice water. The precipitate is collected and recrystallized from an ethanol-N,N-dimethylformamide mixture to provide 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetic acid, m.p. 229°-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[C@@H:7]([CH3:10])[CH2:8][NH:9][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[C:11]([N:6]1[C@@H:7]([CH3:10])[CH2:8][N:9]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:4]2[CH:3]=[C:2]([Br:1])[CH:15]=[N:14][C:5]1=2)(=[O:13])[CH3:12]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N1c2ncc(Br)cc2NC[C@@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A reaction vial was charged with (S)-1-(7-bromo-3-methyl-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)ethanone (0.054 g, 0.2 mmol) and N,N-diisopropylethylamine (0.245 mL, 1.40 mmol) was added. Isopropyl chloroformate (1.0 M solution in toluene, 1.00 mL, 1.00 mmol) was added, and the reaction was heated at 50° C. overnight. The reaction was diluted with ethyl acetate (3 mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.070 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 356, 358 [M+H]+.
Reaction SMILES: COCC(O)C.CC(=O)CC(C)(O)C.C=CC1C=CC=CC=1.C(O)(=O)/C=C\C(O)=O.[C:31]1(C)[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](C)[C:32]=1[S:39]([O-:42])(=[O:41])=[O:40]>C(C(C)=O)C>[C:35]1([CH3:37])[CH:36]=[CH:31][C:32]([S:39]([OH:42])(=[O:40])=[O:41])=[CH:33][CH:34]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCC(C)=O
Solvent: CC(=O)CC(C)(C)O
Solvent: COCC(C)O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
A light-sensitive composition is prepared by blending together 210 g of methyl ethyl ketone, 94.5 g of propylene glycol mono methyl ether and 140 g of diacetone alcohol under moderate stirring and then adding 21 g of Scripset 540, a styrene/maleic acid half ester copolymer having an average molecular weight from about 10,000 to 50,000 available from Monsanto, and stirring until the copolymer is dissolved. 1.75 g of p-toluene sulfonic acid and 10.5 g of the condensation product of 3-methoxy-4-diazo diphenyl amine sulfate and 4,4'-bis-methoxy methyl diphenyl ether isolated as the mesitylene sulfonate are then added while under continued stirring. In a separate vessel, 122.5 g of a white dispersion (50% solids in propylene glycol mono methyl ether) and 42 g of a black dispersion (25% solids in methyl ethyl ketone) are blended. The first mixture is then added to the dispersion blend and the entire formulation is stirred for thirty minutes to insure complete mixing.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([OH:3])=[O:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH3:17][O:2][C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])=[O:3]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc2c1C(=O)NC2=O
Solvent: CCOCC
Product: COC(=O)c1cccc2c1C(=O)NC2=O

Procedure:
To a suspension of 3-carboxyphthalimide (10 g) in ether (50 ml), a solution of diazomethane in ether was added slowly until a faint yellow colouration persisted. Excess of diazomethane was destroyed with acetic acid and the reaction mixture was evaporated to yield the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].[Br:6][CH2:7][C:8](Br)=[O:9]>CCOCC.O>[Br:6][CH2:7][C:8]([N:2]([CH3:1])[CH:3]([CH3:5])[CH3:4])=[O:9]
Reactant: O=C(Br)CBr
Reactant: CNC(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)N(C)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 26 ml of methyl isopropylamine in 100 ml of ether was added to a solution of 10 ml of bromo acetyl bromide in 150 ml of ether cooled to −20° C. and the mixture was allowed to return to 20° C. The mixture was stirred for 30 minutes at 20° C. and diluted with water, decanted and extracted with ether. The extracts were dried and separated out by distillation to obtain 13 g of the expected product with a boiling point of 71° C. to 72° C. under 1 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([Cl:16])[CH:15]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:11]=[C:10]([Cl:9])[CH:15]=[C:14]([Cl:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cc(Cl)cc(Sc2ccc(Br)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 3,5-dichloroiodobenzene (0.72 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-3,5-dichloro-benzene (0.7 g). MS calcd. for C12H8BrCl2S [(M+H)+] 334, obsd. 334.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([C:17]#N)[CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[C:23]1([Mg]Br)[CH:28]=[CH:27]C=[CH:25][CH:24]=1>>[C:17]1([C:13]2([N:10]3[CH2:9][CH2:8][CH:7]([N:6]4[C:5]5[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=5[NH:3][C:2]4=[O:1])[CH2:12][CH2:11]3)[CH2:16][CH2:15][CH2:14]2)[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCC2)CC1
Yield: 48 %

Procedure:
This was prepared according to the procedure described in example 1 using 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cyclobutanecarbonitrile and phenylmagnesium bromide. Yield was 48%.