Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:11]#[N:12])[C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6])#[N:2].CC(C)([O-])C.[K+].[CH:19]1([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[C:32]([F:34])[CH:33]=[C:28]3[C:27]([C:35](=[NH:37])[NH2:36])=[N:26]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(C)(C)C>[NH2:2][C:1]1[C:3]2[C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[NH:12][C:11]=2[N:37]=[C:35]([C:27]2[C:28]3[C:29](=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[N:26]=2)[N:36]=1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Reactant: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(N)c21

Procedure:
30 ml of tert-butanol, 1.068 g (6.429 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 15 ml of tert-butanol and 901 mg (8.037 mmol) of potassium tert-butoxide were added to 1.400 g (5.358 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide, and the mixture was heated under reflux for 24 h. The reaction mixture was concentrated on a rotary evaporator, triturated with 60 ml of water/ethanol (v/v=5:1), filtered off with suction and dried under high vacuum. This gave 1.296 g (57% of theory) of the target compound.
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(C)=O>[CH2:41]([O:29][C:25]1[C:26]2[O:28][C@H:10]3[C@@:9]45[CH2:20][CH2:19][C@:16]6([CH2:17][C@@H:18]4[C@:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:34])[O:6][CH2:7][O:8]5)[C@@:11]43[CH2:12][CH2:13][N:14]([CH2:30][CH:31]3[CH2:32][CH2:33]3)[C@@H:15]6[CH2:21][C:22]([C:27]=24)=[CH:23][CH:24]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a suspension of compound 3 (1.0 g, 2.15 mMol) and K2CO3 (0.88 g, 6.45 mMol) in acetone (10 ml) was added benzyl bromide (0.31 mL, 2.15 mMol). The resulting suspension was stirred at ambient temperature for 24 h. All volatiles were removed by vacuum distillation. The crude product was purified by column chromatography on silica to give 0.66 g of the title compound 7 (54.5% yield) in a purity of 96.9% as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13]
Reactant: O=C(Nc1ccccc1Br)Nc1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of N-(2-hydroxy-3-nitrophenyl)-N'-(2-bromophenyl)urea (300 mg, 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHCO3 then extracted with ethyl acetate (3×). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z 323 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35](F)[CH:36]=2)(=[O:30])=[O:29])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:36]=2)(=[O:30])=[O:29])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(F)c1)C2
Reactant: C1CCNCC1
Agent: CN1CCCC1
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CCCCC3)c1)C2
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A mixture of (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (100 mg, 0.185 mmol) and piperidine (47 mg, 0.56 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. for 6 hours. The mixture was cooled and the reaction mixture was purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to give (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (35 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=605; 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=3.0 Hz), 8.27 (d, 1H, J=2.0 Hz), 8.05 (d, 1H, J=3.0 Hz), 7.65 (d, 1H, J=3.0 Hz), 7.54-7.41 (m, 2H), 7.31-7.30 (m, 2H). 7.19-7.14 (m, 2H), 6.53 (d, 1H, J=2.0 Hz), 5.51 (dd, 1H, J=12.0, 2.0 Hz), 4.21 (d, 1H, J=17.0 Hz), 3.90-3.86 (m, 1H), 3.27-3.25 (m, 4H), 2.91-2.81 (m, 3H), 2.61-2.52 (m, 2H), 1.75-1.56 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH3:21].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:21])=[N:18][N:19]=[C:20]1[CH2:23][OH:24]
Reactant: C=O
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 4, 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone is heated with paraformaldehyde in xylene at 125° C. to give 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 193.5°-195° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=2[O:25][CH3:26])[CH2:17]1>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([OH:10])[CH2:11][NH:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=3[O:25][CH3:26])[CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1OC)CC(N)C2
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CC(NCC(O)c1cccc(C(F)(F)F)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of m-trifluoromethylphenylglyoxal and 2-amino-4,5-dimethyoxyindane in toluene is refluxed for 2 hours, using a Dean-Stark trap to remove the formed water. The solution is concentrated in vacuo and the residue is dissolved in methyl alcohol. The resulting solution is cooled in ice, sodium borohydride is added in portions and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo, the residue is partitioned between water and methylene chloride and the layers are separated. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 1-(3-trifluoromethylphenyl)-2-(4,5-dimethoxyindan-2-yl)aminoethanol. Under anhydrous conditions, tetrahydrofuran, triethylamine and carbonyldiimidazole are added to the above compound and the mixture is stirred at room temperature for 20 hours. The reaction mixture is quenched with water and extracted with diethyl ether. The diethyl ether extracts are combined, washed with 2N hydrochloric acid, saturated sodium chloride, dried over magnesium sulfate. The solution is evaporated in vacuo to give a mixture of (R*,R*) and (R*,S*)-5-(3-trifluoromethylphenyl)-3-(2,3-dihydro-4,5-dimethoxy-1H-inden-2-yl)-2-oxazolidinone. This mixture is separated into the individual (R*,R*) and (R*,S*) racemates by chromatographic techniques described in Example 1. Each racemate is treated with boron tribromide and the individual products are reacted with diethyl dibromomalonate, as described in Example 1, to give (R*,R*) and (R*,S*)-7-[[2-(3-trifluoromethylphenyl)-2-hydroxyethyl]amino]-7,8-dihydro-6H-indeno[4,5-d]-1,3-dioxole-2,2-dicarboxylic acid diethyl esters. These products are then hydrolyzed with 2.5N sodium hydroxide, as described in Example 3, to give the desired products.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5]1[N:6]([CH3:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][N:3]=[C:4]([Br:14])[C:5]1[N:6]([CH3:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNN=Cc1ncc([N+](=O)[O-])n1C
Solvent: ClC(Cl)Cl
Product: CNN=C(Br)c1ncc([N+](=O)[O-])n1C

Procedure:
The hydrazones formed in this manner are in turn allowed to react with N-bromosuccinimide at about room temperature in a suitable solvent, such as chloroform, to yield 1-methyl-5-nitroimidazole-2-carbonyl bromide alkyl or hydroxy-alkyl hydrazones. The reaction with N-bromosuccinimide is applicable to any of the substituted hydrazones to yield the bromo-substituted hydrazones. As a specific example, when 1-methyl-5-nitroimidazole-2-carboxaldehyde methyl hydrazone is allowed to react with N-bromosuccinimide at room temperature in chloroform solvent, there is obtained 1-methyl-5-nitroimidazole-2-carbonyl bromide methyl hydrazone.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[O:40]=[C:41]1[NH:45][CH2:44][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([N:45]2[CH2:44][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42][C:41]2=[O:40])=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: COC(=O)C1CNC(=O)C1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(I)cc1C)C(=O)OC(C)(C)C
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(N2CC(C(=O)OC)CC2=O)cc1C)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
Using the compound (650 mg, 1.00 mmol) of Example 293, step A and methyl 5-oxopyrrolidine-3-carboxylate (215 mg, 1.50 mmol), and according to the method of Example 298, step A, the title compound (480 mg, yield 72%) was obtained as a brown oil (480 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>ClCCl>[CH2:21]([NH:25][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH2:22][CH2:23][CH3:24]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 12 h
Yield: 71.8 %

Procedure:
In 100 ml of dichloromethane was dissolved 2.28 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.38 g of anhydrous potassium carbonate and 1.46 g of n-butylamine, and the mixture thus obtained was stirred at a temperature of 20° C. to 25° C. for 12 hours. The reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the dichloromethane was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 1.90 g of N-n-butyl-5-isoquinolinesulfonamide, i.e., Compound (27) in a yield of 72%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Br:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[Br:10]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: Fc1ccc(CN2CCOCC2)cc1Br

Procedure:
In the same manner as Step B in Example 1-D-26, using 4-fluoro-3-bromo-benzaldehyde (270 mg) and morpholine (0.23 ml), reductive amination was carried out, to obtain a crude product of 2-fluoro-5-morpholin-4-ylmethyl-bromobenzene as a colorless oil (344 mg). In the same manner as Example 1-D-08, bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (92 mg) and using a crude product (66 mg) of 2-fluoro-5-morpholin-4-ylmethyl-bromobenzene obtained in the above step instead of 4-bromobenzoic acid methyl ester, a crude product of 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained. Using a crude product (90 mg) of 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-ylamine was obtained as a colorless powder (5.4 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=1)[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), 4-trifluoromethoxyaniline (404 μL, 3.01 mmol) and potassium carbonate (416 mg, 3.01 mmol) in DMSO (15.0 mL) were heated in a sealed tube within a microwave reactor at 120° C. for 10 min. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-40% EtOAc/hexanes as eluent) afforded the title compound i-1a. m/z (ES) 324 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.81 (s, 1H), 8.60 (d, 1H, J=1.9 Hz), 7.58 (dd, 1H, J=1.8, 9.1 Hz), 7.29 (m, 4H), 7.16 (d, 1H, J=8.9 Hz).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][SH:5].[OH-].[K+].Br[CH2:12][CH2:13][OH:14]>C(O)C>[NH2:1][CH:2]([CH2:3][CH2:4][S:5][CH2:12][CH2:13][OH:14])[C:6]([OH:8])=[O:7]
Reactant: OCCBr
Reactant: NC(CCS)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(CCSCCO)C(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To D,L-homocysteine (6.69 g, 49.4 mmol) was added 2N aqueous potassium hydroxide (32 mL) and the resulting solution was cooled to 0° C. 2-Bromoethanol (4.2 mL, 59.3 mmol) in ethanol (56 mL) was then added dropwise and the reaction mixture was allowed to warm to 25° C. After 18 h the reaction mixture was acidified to pH 5 and concentrated to give 2-(amino)4-[(2-hydroxyethyl)sulfanyl]butanoic acid (WO 9808823 ) as a white paste. To this material was added water (110 mL) and dioxane (110 mL) and triethylanine (20.7 mL, 148 mmol) and to the resulting solution was added 4-(2-butynyloxy)phenylsulfonyl chloride (14.2 g, 54.3 mmol). After 20h the reaction mixture was acidified to pH 1 with 1N aqueous hydrochloric acid and extracted with dichloromethane (3+). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)4-[(2-hydroxyethyl)sulfanyl]butanoic acid as an oil (20.8 g). Electrospray Mass Spec 385.8 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:54])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:54][CH:46]([CH3:45])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)Cc4ccccc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (1,1,3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-methyl-2-phenylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methyl-2-phenylethyl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.43 min, MH+ 412.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:27])[NH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[H-].[Na+]>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:27])[N:19]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: BrCCCCBr
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reaction time: 5 h

Procedure:
15 g of 1,4-dibromobutane was added to a mixture of 5.0 g of compound 1 and 1.0 g of sodium hydride in dimethylformamide. After stirring the resulting mixture for 5 hours, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). M.p. colourless oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CCCNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C1C=CC(C)=CC=1)(=O)=O.[Br-:33].[Li+].CCOCC.Cl>CC(C)=O>[Br:33][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCOCC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To 2 mmol of product 2 in acetone was added lithium bromide (7 mmol) and the solution was stirred at room temperature for 4 hours. Ether (20 ml) and dilute HCl was added, and the organic layer washed successively with water and brine, dried (MgSO4), and evaporated under reduced pressure. The product 3 was isolated as an oil in 85% yield by column chromotography (hexane/ethyl acetate 4:1). TLC (hexane/ethyl acetate 3:1) Rf=0.8. 1H-NMR 1.2-1.65 (m, 20H, CH2), 1.48 (s, 9H, (t-butyl) CH3), 3.41 (t, 2H, C(15)H2), 3.50 (t, 2H, C(4)H2), 3.94 (s, 3H, C(2)H2).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=[C:9]2[C:8]1=[O:22])[CH3:6].[Cl-].[NH4+].CN(C)C=O>O>[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[CH:17]=[C:18]([C:20]3[NH:21][N:3]=[N:2][N:1]=3)[CH:19]=[C:9]2[C:8]1=[O:22])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(=O)c2cc(C#N)cn2c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc(-c3nnn[nH]3)cn2c2ccccc21
Reaction time: 12 h
Yield: 48 %

Procedure:
0.48 g (7.4 mmole) of sodium azide were added to a suspension of 1.3 g (5.5 mmole) of the product of Step B, 0.425 g (8.0 mmole) of ammonium chloride and 50 ml of dimethylformamide and the mixture was stirred at 130°-140° C. for 12 hours and was then cooled. 200 ml of water were added thereto and the mixture was filtered. The recovered product was crystallized from a methanol-ethyl acetate mixture to obtain 0.74 g (48% yield) of 5-ethyl-2-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-4(5H)-one in the form of off-white crystals melting at 295°-297° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[CH2:3]1.I[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:9][CH:10]=2)[N:5]([CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)N(C(C)C)C(=O)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(C(C)C)C(=O)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.282 g (1.17 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-7-ethynyl quinoline (Compound 30) and 0.52 g (1.9 mmol) of ethyl 4-iodobenzoate in 2.5 ml of diethylamine which was degassed under argon for 30 min, was added 0.049 g (0.26 mmol) of copper(I) iodide and then 0.159 g (0.23 mmol) of bis(triphenylphosphine)palladium(II) chloride. The reaction was stirred at room temperature for 4 h. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a solid.