Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([C:15](=O)[CH2:16]Br)[CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25]([NH2:27])=[S:26])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[S:26][CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([N:5]4[CH2:6][CH2:7][CH2:8][CH:4]4[C:1]([OH:3])=[O:2])[N:14]=3)[N:27]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:20]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(CBr)c1cccc(N2CCCC2C(=O)O)n1
Product: CCOc1ccc(-c2nc(-c3cccc(N4CCCC4C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxy-1-pyrrolidinyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxy-1-pyrrolidinyl)-2-pyridyl]thiazole.
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl {4-[acetyl(methyl)amino]phenyl}carbamate (200 mg, 0.589 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.103 ml, 0.589 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (47.3 mg, 18.3%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3cc(F)cc(F)c3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3cc(F)cc(F)c3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(3,5-difluorophenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(3,5-difluorophenyl)-4-[(4-aminophenyl)methyl-]piperazine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]Br)=[CH:4][C:3]=2[O:2]1.[CH2:17]([O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH3:18].[Li]>CN(C)C=O>[C:22]([CH:21]([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:25])(=[O:23])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCC=CCCc1ccc2c(c1)OCO2
Agent: [Li]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC=CCCc1ccc2c(c1)OCO2)C(C)=O
Reaction time: 48 h

Procedure:
A mixture of 28.3 g. (0.1 mole) of 6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide and 21 g. (0.15 mole) of lithium ethylacetoacetate in 200 ml. of dimethylformamide was heated under nitrogen with stirring at 55°-60° C. for 2 days. The reaction mixture was concentrated in vacuo and the residue partitioned between water and methylene dichloride. The methylene dichloride layer was washed with 5% aqueous sulfuric acid, water, 5% aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The ether solution was concentrated to afford ethyl 2-acetyl-8-(3,4-methylenedioxyphenyl)-5-octenoate as a yellow oil, used directly in the following reaction.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl>[CH2:3]([O:10][CH2:11][CH2:12][S:13]([NH2:2])(=[O:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)CCOCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 28% ammonium hydroxide (10 ml) was added dropwise 2-(benzyloxy)ethanesulfonyl chloride (4.1 g) in dichloromethane (10 ml) over 10 minutes under ice-cooling. The mixture was stirred at ambient temperature overnight. The organic layer was separated and the aqueous layer was extracted with dichloromethane/methanol (5/1). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=50/50) to give 2-(benzyloxy)ethanesulfonamide (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH:35]=[CH2:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: C=Cc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCC)C4)nc(N)n2)C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(CC)ccc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
(S)-Ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated via an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was lyophilized from 1:1 H2O:CH3CN to provide (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1]
Reactant: CC(C)(C)CCI
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: N
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
To a solution of methyl 2-methoxy-naphthoate (1.00 g, 4.6 mmol) and tert-butyl alcohol (0.43 mL, 4.6 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. under N2 was added anhydrous ammonia (˜20 mL), followed by the portionwise addition of potassium metal until a dark blue solution was maintained for >15 min. To the resulting mixture was added neohexyl iodide (0.5 g, 2.36 mmol), the mixture was stirred at −78° C. for 20 min, and then allowed to slowly warm to rt while evaporating the ammonia with a dry N2 stream. To the resulting suspension was added anhydrous tetrahydrofuran (10 mL), and the mixture was heated at 50° C. under N2 for 16 h. The reaction mixture was partitioned between saturated aq. NaHCO3 (20 mL) and ethyl acetate (3×20 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 19:1 hexanes:ethyl acetate to provide the title compound as a colorless gum (0.32 g, 23%). 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.23 (m, 4H), 5.06 (t, J=3.9 Hz, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 3.54-3.57 (m, 2H), 2.20-2.31 (m, 1H), 2.00-2.11 (m, 1H), 0.82-0.94 (m, 1H), 0.75 (s, 9H), 0.45-0.57 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].ClS([N:26]=[C:27]=[O:28])(=O)=O.C(O)(=O)C>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:27](=[O:28])[NH2:26])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid benzyl ester (3.5 g, 13.9 mmol) in THF (70 mL) at 5° C., was added NaH (60% in mineral oil, 557 mg, 13.9 mmol). The mixture was stirred at 5° C. for 30 min before slow dropwise addition of chlorosulfonyl isocyanate (2.42 mL, 27.9 mmol) maintaining the temperature between 5° C. and 10° C. The pale yellow solution was further stirred at RT for 3.5 h. Acetic acid (22.5 mL) was added (exothermic), and the resulting solution was stirred at RT for 1.5 h before addition of ice cubes and water (100 mL). The white thick suspension was stirred at RT for 30 min and the precipitate was filtered-off, taken up in MeOH and filtered-off again to afford the desired compound. 1H-NMR (400 MHz, DMSO): δ (ppm) 8.64 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.90 (m, 2H), 7.50 (d, 2H), 7.42 (t, 2H), 7.36-7.30 (m, 3H), 5.38 (s, 2H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[I:6][C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][S:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butylamine (300 mg) was added to a stirred, cooled (ice-bath) solution of 3-iodobenzenesulfonyl chloride (Bromidge et al, J. Med. Chem., 1999, 42(2), 202-205) and triethylamine (420 mg) in dichloromethane (7 ml). The mixture was then stirred for 2 h at room temperature, diluted with dichloromethane (10 ml) and washed with 2M hydrochloric acid (5 ml). The mixture was separated on a hydrophobic frit and the organic phase was evaporated to give the title compound (1.26 g). LCMS ES+ve 340 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:18]([NH:22][C:23]([C:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH:44]([F:46])[F:45])[CH:41]=4)[NH:36][N:35]=3)[N:32]=2)[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:26]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([NH:22][C:23]([C:25]1[C:33]2[C:28](=[N:29][CH:30]=[C:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH:44]([F:45])[F:46])[CH:41]=4)[N:36]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]4)=[O:4])[N:35]=3)[N:32]=2)[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:26]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CN1CCN(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
To a stirred solution of 2-chloro-1-(4-methylpiperazin-1-yl)ethanone (138.2 mg, 782 mmol) in DMF (32.0 mL) under Ar, potassium carbonate (328.5 mg, 2.38 mmol) was added at 25° C. After 1 h, N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 151 μmol) in DMF (8.00 mL) was added and the reaction was stirred at 70° C. After 18 h, the reaction was cooled to 25° C. and quenched with water (350 mL). The product was extracted with ethyl acetate (2×250 mL). The organics were combined, dried over sodium sulfate, and the solvent removed to give a yellow oil. The solid was dried in vacuo (200 mTorr, 25° C.) to give a yellow solid. The solid was purified by chromatography (silica, 115 g Analogix column, 3-10% ethyl acetate in hexanes, gradient over 0.5 h) to give a yellow oil. The product was concentrated to a yellow oil and dried in vacuo to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (41.7 mg, 62.2 μmol, 41.2%) as a yellow solid. MS (M)'=671; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.60 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.40 (dd, J=2.3, 8.8 Hz, 1H), 7.21 (t, J=74.4 Hz, 1H), 5.73 (s, 2H), 5.67 (s 2H), 3.61 (br. s, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.45 (br. s, 2H), 2.45 (br. s, 2H), 2.32 (m, 2H), 2.33 (s, 3H), 1.52 (s, 9H), 0.86 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:18]3[N:17]=[C:16]([CH3:19])[N:15]=[C:14]([NH:20][CH2:21]CCC(N)=O)[C:13]=3[N:12]([CH3:27])[CH:11]=2)=[C:5]([CH3:28])[CH:4]=1.B.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:10][CH2:11][NH:12][CH2:13][CH2:21][NH:20][C:14]2[C:13]3[N:12]([CH3:27])[CH:11]=[C:10]([C:6]4[C:5]([CH3:28])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])[C:18]=3[N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(C)c(-c2cn(C)c3c(NCCCC(N)=O)nc(C)nc23)c(C)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(CCNCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Dissolve 2-(4-methoxyphenyl)-N-(2-{[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolo[2,3-e]pyrimidin-4-yl]aminoethyl)acetamide in anhydrous THF (5 mL) and stir under N2. Add borane-dimethylsulfide complex (0.2 mL, 10.0 M in THF) and heat to reflux for 14 h. Quench by addition of N,N′-dimethyl-1,2-ethylenediamine (0.21 mL) in MeOH (5 mL) and stir for 1 h at ambient temperature. Concentrate under reduced pressure and purify the residue by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt)
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:18])([CH3:17])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[N-:26]=[N+:27]=[N-].[Na+]>O.Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([CH3:17])([CH3:18])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:10][CH:11]=1)=[N+:26]=[N-:27]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.75 h

Procedure:
A solution of NaNO2 (0.69 g, 10.0 mmol) in 10 mL water was added dropwise to a solution of 2-[4-(4-aminophenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (1.4 g, 5.0 mmol) in 30 mL 4M HCl at 0-5° C. After stirring the mixture at this temperature for 45 min, a solution of NaN3 (0.53 g, 8.0 mmol) in 10 mL water was added dropwise to the mixture at the same temperature. Stirring was continued for 1 h below 5° C. and then at room temperature overnight. The precipitate formed was filtered off, washed with water and air-dried. The yellow product was recrystallized from dichloromethane/1-propanol. Yield: 1.25 g (82%). Mp: 184° C. IR (neat) 3056, 2990, 2235, 2122, 2091, 1601, 1568 cm−1; 1H NMR (400 MHz, DMSO) δ 7.90 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 1.86 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.1, 176.6, 145.0, 130.61, 123.4, 120.30, 112.35, 111.4, 111.3, 101.60, 100.30, 55.20, 24.90; Anal. Calcd for C16H10N6O: C, 63.57; H, 3.33; N, 27.80. Found: C, 63.51H, 3.44; N, 27.20. UV-Vis (CH2Cl2): λmax=384 nm ε=2.9×104 L·mol−1 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O.O1CCOCC1>[F:15][C:16]1[N:17]=[CH:18][C:19]([N:4]2[C@@H:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([CH3:14])([CH3:1])[O:6][C:5]2=[O:7])=[CH:20][CH:21]=1
Reactant: Fc1ccc(I)cn1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(F)nc2)[C@H]1c1ccccc1
Yield: 72.6 %

Procedure:
To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.750 g, 3.92 mmol), 2-fluoro-5-iodopyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.749 g, 7.84 mmol), and dioxane (15.69 mL). Tribasic potassium phosphate (4.16 g, 19.61 mmol) was then added to the mixture. The vessel was purged with nitrogen followed by the addition of N,N′-dimethylethylenediamine (0.844 mL, 7.84 mmol) and copper (I) iodide (0.747 g, 3.92 mmol). The vessel was heated to reflux overnight providing an orange suspension. To the mixture was added water (˜10 mL), and the resulting slurry was filtered through Celite® brand filter aid. The yellow filtrate was transferred to a separatory funnel, diluted with water and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The residue was purified with a 50 g SNAP column (Biotage) ramping EtOAc in heptane (0-35%, then isocratic at 35%) to elute (S)-3-(6-fluoropyridin-3-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.815 g, 2.85 mmol, 72.6% yield) which was obtained as a white solid upon drying. 1H NMR (400 MHz, CDCl3) δ=8.21 (ddd, J=3.0, 6.8, 9.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.41-7.34 (m, 3H), 7.20-7.16 (m, 2H), 6.88 (ddd, J=0.6, 3.5, 8.9 Hz, 1H), 5.00 (s, 1H), 1.71 (s, 3H), 1.04 (s, 3H). m/z (ESI) 287.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(F)c1cc(N)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
3-(2-fluoropropan-2-yl)isoxazol-5-amine (11.26 g, 78.19 mmol) described in Example 42A in THF (300 mL) was treated with potassium carbonate (21.58 g, 156 mmol) and p-chlorophenyl chloroformate (14.94 g, 78.19 mmol). After stirring at rt for 1 h, additional p-chlorophenyl chloroformate (7.5 g, 39.26 mmol) was introduced, and the reaction mixture was stirred at rt overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into ethyl acetate, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (eluting with 10 to 50% ethyl acetate in hexanes) to give 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (16.51 g, 71%) as a cream solid. 1H NMR (300 MHz, CDCl3) δ 7.87 (brs, 1H), 7.36-7.41 (m, 2H), 7.13-7.17 (m, 2H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: NCC1C=NC=CC=1.[CH3:9][N:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[N:11]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34](O)=[O:35])=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34]([NH:16][CH2:15][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=4)=[O:35])=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 80 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with (1-methyl-1H-pyrazol-4-yl)methylamine to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 80% yield: mp 168-170° C.; 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.40-7.33 (m, 2H), 7.06-6.98 (m, 2H), 6.86 (s, 1H), 6.02 (t, J=5.0 Hz, 1H), 4.95 (s, 2H), 4.41 (d, J=5.0 Hz, 2H), 3.87 (s, 3H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6 (d, JC-F=247.1 Hz), 162.2, 150.4, 140.0, 138.7, 134.3, 132.3, 131.2 (d, JC-F=3.3 Hz), 130.3 (d, JC-F=8.3 Hz), 129.5, 125.9, 120.2, 118.1, 115.7 (d, JC-F=21.7 Hz), 48.9, 38.9, 34.4, 15.9; MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][C:30]1[CH:39]=[CH:38][C:33]2[N:34]=[C:35]([NH2:37])[S:36][C:32]=2[CH:31]=1>>[CH3:26][C:23]1[C:22]([CH2:27][NH:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([CH3:29])[CH:39]=[CH:38][C:33]=3[N:34]=2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Cc1ccc2nc(N)sc2c1
Product: Cc1ccc2nc(NCc3c(C)noc3-c3ccc(-c4ccc(C5(C(=O)O)CC5)cc4)cc3)sc2c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-methyl-benzothiazol-2-ylamine.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[N-:15]=[N+:16]=[N-:17].[Na+]>O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(-n2nnnc2S)cc1
Temperature: 80 °C
Yield: 55 %

Procedure:
20 g of 4-carboethoxyphenyl isothiocyanate and 6.5 g of sodium azide are added to water and heated at 80° C. After 2 hours of reaction, the reaction mixture is filtered, cooled and acidified with hydrochloric acid to give crystals of 1-(4-carboethoxyphenyl)-5-mercaptotetrazole. To the crystals are added 5 equivalents of sodium hydroxide (1N NaOH in water) and the mixture is heated at 80° C. for 5 hours. After cooling, the reaction mixture is acidified with hydrochloric acid to cause crude crystals of Compound III-4 to separate out. The crystals are recrystallized from methanol. Yield: 55%, m.p. about 195° C. (decomposed).