Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:29]
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
Compound 64 (60 mg, 0.13 mmol), iron powder (364 mg, 6.50 mmol) and ammonium chloride (35 mg, 0.65 mmol) were added to ethanol (1.0 mL) and water (1.0 mL) at room temperature, stirred at 50° C. for 1 hour and then the reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 69 (11 mg, 22%).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([S:19][CH3:20])[N:16]=[C:17](Cl)[C:12]=2[C:11](=[O:21])[CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.[NH2:35][NH2:36]>O1CCOCC1>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([S:19][CH3:20])[N:16]=[C:17]([NH:35][NH2:36])[C:12]=2[C:11](=[O:21])[CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(NN)c2C1=O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Ethyl 8-benzyl-4-chloro-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate from step-1 (48 g, 0.122 mol) in 1,4-dioxane (300 mL), and triethylamine (20.5 mL, 0.147 mol) was added hydrazine hydrate (6.73 g, 0.134.6 mol). The reaction mixture was stirred at room temperature for 5-6 h. After completion of the reaction, dioxane was evaporated under vacuo, and water (250 mL) was added to the reaction mixture and was extracted with dichloromethane (200 mL×3). The combined dichloromethane layer was washed with water (500 mL) followed by brine (500 mL). The dichloromethane layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude ethyl 8-benzyl-4-hydrazinyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate as an oil that was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[Cl:16].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:31]2[CH:39]=[C:38]3[C:34]([C:35]([NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])=[N:36][N:37]3[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:33][CH:32]=2)O1.C(OCC)(=O)C>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:3]1[CH:4]=[C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[C:31]1[CH:39]=[C:38]2[C:34]([C:35]([NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])=[N:36][N:37]2[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:45])[CH3:46])=[CH:33][CH:32]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Clc1cc(OCc2ccccc2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Yield: 56 %

Procedure:
1.95 g of 1-bromo-2-chloro-4-(phenylmethoxy)benzene, described previously, 1.11 g of sodium carbonate in 36 cm3 of water and 347 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 56, in 180 cm3 of dioxane. The medium is then refluxed for 2 hours and the mixture is allowed to return to room temperature, 200 cm3 of ethyl acetate and 100 cm3 of water are added and the resulting mixture is filtered through a sinter funnel packed with Celite. The combined organic phases are washed with 100 cm3 of distilled water and then with 100 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 1.34 g of N-[6-[2-chloro-4-(phenylmethoxy)phenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH2:10][C@H:9]2[CH3:22])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1>>[ClH:1].[CH2:28]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:27]1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:20])[CH2:10][C@H:9]2[CH3:22])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: C[C@@H]1CN(CCCC(=O)O)C(=O)C=CN1c1ccc(Cl)c(C(F)(F)F)c1
Agent: O[C@@H]1CNCCC12CC2
Product: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)C=CN1c1ccc(Cl)c(C(F)(F)F)c1
Product: Cl

Procedure:
In analogy to the procedure described for example 15, 4-[(R)-4-(4-chloro-3-trifluoromethyl-phenyl)-3-methyl-7-oxo-2,3,4,7-tetrahydro-[1,4]diazepin-1-yl]-butyric acid (46% ee) (intermediate 35) and (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave the title compound in 69% yield as light yellow oil. MS: 544.19 (M+HCOO−, Cl).
Reaction SMILES: C([N:4]1[CH2:17][C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:9]2[CH2:8][N:7]3[CH2:6][CH2:5]1)(=O)C.[OH-].[K+].O>CO>[CH:12]1[CH:13]=[CH:14][C:15]2[CH2:17][NH:4][CH2:5][CH2:6][N:7]3[C:16]=2[C:11]=1[CH:10]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:9]1[CH2:8]3
Reactant: CC(=O)N1CCN2CC3CCCCCC3c3cccc(c32)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1cc2c3c(c1)C1CCCCCC1CN3CCNC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
The compound from example 7 (0.5 g, 1.67 mmol) was dissolved in methanol (5 mL). To the mixture was added KOH (0.99 g and 16.7 mmol) and water (5 mL). The reaction mixture was heated to 100° C. and held for 4 hours. Methanol was then added (10 mL) and the mixture was held for an additional 20 hours (16 mL). At 24 hours, KOH (0.47 g, 8.3 mmol) and methanol (16 mL) were added. After 48 hours, the reaction mixture was cooled to room temperature. The methanol was removed, and the reaction mixture was transferred to separatory funnel with methylene chloride and water. The reaction mixture was extracted with methylene chloride (3×). The combined extracts were dried with magnesium sulfate, filtered and concentrated to dryness to give 430 mg of yellow oil. Further purification (20% ammonia(2M solution in ethanol)/ethyl acetate) yielded 0.273 g of desired product (63%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[NH:24])[NH:22]O)[CH:16]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13]([NH:14][C:15]1[CH:16]=[C:17]([C:21]2[N:24]=[C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])[O:5][N:22]=2)[CH:18]=[CH:19][CH:20]=1)=[O:25])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(CCC(=O)O)n2)c1
Temperature: 120 °C

Procedure:
Succinic anhydride (14 mg, 0.14 mmol) and [3-(N-hydroxycarbamimidoyl)-phenyl]-carbamic acid tert-butyl ester (35 mg, 0.14 mmol) were dissolved in 0.25 mL DMF and heated at 120° C. for 2 h. The cooled solution was evaporated and dried to yield 3-[3-(3-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:18][CH2:17][C@H:16]([CH3:19])[CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:32])=[O:31]
Reactant: C[C@@H](CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-(-)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol (7.26 g, 24.8 mmol), triethylamine (3 ml, 30 mmol) in methylene chloride (DCM, 120 ml), methanesulfonyl chloride (3.13 g, 27.3 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 1 hour, then concentrated down to a crude mixture. Triethylamine hydrochloride salt was removed by filtration with DCM/ether as solvent. The crude oily mixture was purified with a flash chromatography column (SiO2, 90 g; eluted with DCM). The colorless oil, which is the methanesulfonate ester, weighed 6.48 g (70%), and was used directly in the following step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=N1.C1(N)C(N)=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:39][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1C1CC(=O)NS1(=O)=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)Nc2ccccc2N)ccc1C1CC(=O)NS1(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
A solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoic acid (200 mg, 0.448 mmol) in N,N-dimethylformamide (2.0 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.218 g, 0.493 mmol). After stirring for 10 minutes at 0° C., a solution of 1,2-benzenediamine (72.7 mg, 0.672 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.24 mmol) in DMF (1.0 mL) was cannulated into the reaction flask. The solution was stirred at 25° C. for 2 h. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and 1.0 M hydrochloric acid solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (196 mg, 82%). 1H NMR (400 MHz, CD3OD): δ 7.47 (d, 0.5H), 7.39–7.22 (m, 9H), 7.12 (d, 0.5H), 7.07 (s, 1H), 6.82 (d, 0.5H), 6.71 (d, 0.5H), 5.50 (t, 1H), 5.10 (s, 2H), 4.47 (m, 1H), 3.3 (m, 2H), 3.07 (m, 2H), 2.48 (s, 1.5H), 2.38 (s, 1.5H); MF=C27H28N4O6S; LCMS found for C27H29N4O6S (M+H)+: m/z=537.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([C:23]([O:25]C(C)(C)C)=[O:24])[C:16]([O:18]C(C)(C)C)=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(C(=O)O)C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Di-tert-butyl [2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (0.873 g, 2.08 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.60 g of product (white solid, 94%). 1H NMR (DMSO-d6) δ 13.10 (br s, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 4.83 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:3])=[O:22]
Reactant: OCCCCCCCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 7-bromoheptanol (1.95 g, 10 mmols) with cooing with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with ether (80 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of sodium hydrogencarbonate (120 ml). The aqueous layers were combined, then made acidic (pH=1) with 5% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.45 g (70%) of 7-bromoheptanoic acid was obtained as colorless needle-like crystals. WSC (891 mg, 4.7 mmols) and HOBt (628 mg, 4.1 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.06 g, 5 mmols) and 2,6-diisopropylaniline (738 mg, 4.2 mmols), and stirred at room temperature for 12 hour. The reaction mixture was extracted with ether. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated Then, the residue was purified through silica gel colt chromatography (developer:hexane/acetone=5/1), and the resulting crystals ware recrystallized from ether-hexane to obtain 466 mg (yield: 30%) of 7-bromo-N-(2, 6-diisopropylphenyl) heptanamide as colorless needle-like crystals.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[NH:14][N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1.ClC1C2C=NC3N(CC)N=CC=3C=2N2N=CN=C2N=1.C(O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[CH2:45]([OH:47])C>>[C:38]1([C:2]2[C:7]3[CH:8]=[N:9][C:10]4[NH:14][N:13]=[CH:12][C:11]=4[C:6]=3[N:5]3[N:15]=[C:16]([O:47][CH3:45])[N:17]=[C:4]3[N:3]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Clc1nc2ncnn2c2c1cnc1[nH]ncc12
Reactant: CCO
Reactant: OCc1ccccc1
Agent: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Product: COc1nc2nc(-c3ccccc3)c3cnc4[nH]ncc4c3n2n1

Procedure:
By substituting the 5-chloro-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 15 for the 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]Triazolo[1,5-a]pyrimidine and benzyl alcohol for the ethanol in the procedure of Example 4, 5-phenyl-methoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1>CS(C)=O.[Cl-].[Na+].O>[CH3:13][O:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
Sodium cyanide (1.25 g, 25.4 mmol) was added to a solution of 5-(chloromethyl)-2-methoxypyridine (1.00 g, 6.34 mmol) in DMSO (10 ml) and stirred for 18 h at room temperature. After completion of reaction, the reaction mixture was diluted with brine and the compound was extracted with DCM (3×35 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by column chromatography using 100-200 silica gel, 10% ethyl acetate in petroleum ether as eluent to afford 0.6 g (63.8%) of 2-(6-methoxypyridin-3-yl)acetonitrile as white color solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])=[O:4].[OH-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH2:19][CH2:18][Br:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])=[O:4]
Reactant: BrCCCBr
Reactant: COC(=O)C1C(=O)Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A solution of 2-oxo-indan-1-carboxylic acid methyl ester (3.8 g) and NaOH (1 M in water, 20 mL) in ethanol (30 mL) is added dropwise to a solution of 1,3-dibromopropane (10 mL) in ethanol (20 mL) at room temperature. The solution is warmed to 40° C. and stirred at this temperature for 2 d. Then, the solution is concentrated under reduced pressure and ethyl acetate is added to the residue. The resulting mixture is washed with water and brine and dried (MgSO4). After removing the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 20:1->9:1) to give the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[N:2].[NH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15].[OH-].[Na+:19]>C(#N)C.O>[Na:19][CH:13]([S:14]([OH:17])(=[O:16])=[O:15])[NH:12][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:11]
Reactant: [Na+]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCS(=O)(=O)O
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)NC([Na])S(=O)(=O)O)cc1
Reaction time: 96 h
Yield: 55.1 %

Procedure:
To a stirred solution of 4-cyanophenyl isocyanate (0.400 g, 2.78 mmol) in 5 mL of acetonitrile was added a solution of aminomethylsulfonic acid (0.308 g, 2.77 mmol) and sodium hydroxide (0.111 g, 2.78 mmol) in 1.5 mL of water. The reaction mixture was stirred for 4 days, then concentrated in vacuo. The residue was slurried in water, and filtered. The filtrate was concentrated in vacuo, slurried in acetonitrile and filtered to afford 0.67 g (99%) of crude product. The crude product was purified by recrystallization from ethanol/water to afford 0.423 g (62%) of the desired urea. Analytical results are given below.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2]1
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -55 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (2.6 g, 10.0 mmol) in THF (30 mL) was slowly added LDA (6.7 mL, 12.0 mmol, 1.8 M solution in heptane-/tetrahydrofuran/ethylbenzene) at −78° C. and the mixture was slowly warmed to −55° C. over 1 h. To this mixture, 1-bromo-3-methyl-2-butene (1.55 g, 10.5 mmol) was slowly added and the reaction was warmed to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl and extracted with diethyl ether, and the combined extracts were washed with brine, dried and concentrated. The product (2.75 g, 85%) was purified by CombiFlash eluted with hexane/ethyl acetate.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB(/[CH:26]=[CH:27]/[CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1/[CH:26]=[CH:27]/[CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 57.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (180 mg, 0.48 mmol) was reacted with (E)-tert-butyl 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidin-4-ylcarbamate (100 mg, 0.32 mmol) to afford the desired product (86 mg, 57%) as a brown solid: ESI MS m/z 470 [C25H31N3O4S+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[S:16][CH2:20][CH:19]=[CH2:18])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Agent: [K]
Solvent: CCO
Product: C=CCSc1nnsc1-c1ccc(C(C)(C)C)cc1

Procedure:
A solution of 1.45 g of 5-[4-(1,1-dimethylethyl)-phenyl-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 3.0 g of allyl bromide. The solvent was removed in vacuo, the residue taken up in ether, filtered and concentrated in vacuo. The residual oil was dissolved in a small amount of dichloromethane and purified on thick layer silica gel plates, eluting with the same solvent. The active fraction gave 1.225 g of the desired compound as a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.39 (s, 9H, t-butyl); 3.98 (bd, 2H, SCH2); 5.05 (bd, 1H, CH=); 5.20 (bd, 1H, =CH); 5.87 (m, 1H, CH2CH=); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (neat): 1640(w); 1615(w); 1525(w); 1480(w); 1475(w); 1450(w); 1410(w); 1370(w); 1270(w); 930(s); 820(s).