Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.S(Cl)([Cl:14])=O>N1C=CC=CC=1>[Cl:14][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCCC(C)CCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCl
Temperature: -3 °C

Procedure:
275 ml (1.46 mol) of 3,7-dimethyl-1-octanol were placed in a 1 l four-neck round-bottom flask fitted with dropping funnel, low-temperature condenser and magnetic stirrer bar and cooled to −3° C. 0.7 ml of pyridine were then added and 129 ml (1.77 mol, 1.2 eq) of thionyl chloride were added dropwise at such a rate that the temperautre did not exceed 15° C. (75 minutes). The HCl gas formed was trapped in Ca(OH)2/water in a wash bottle. The mixture was then heated to 130° C. over a period of 40 minutes. After two hours at this temperature, the mixture was cooled to 50° C., volatile constituents were distilled off by application of a vacuum of 100 mbar. The residue was then cooled to room temperature, diluted with 200 ml of n-hexane and washed first twice with 50 ml each time of 10% strength of NaOH solution in water, then with 50 ml of water and finally with 50 ml of saturated aqueous NaHCO3 solution. The solution was dried over Na2SO4, the solvent was removed by distillation on a rotary evaporator. The residue was purified by distillation under reduced pressure (13 mbar, 86-87° C.). This gave 178.9 g (1.01 mol, 69%) of 1-chloro-3,7-dimethyloctane as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:18]([NH:28][C@H:29]([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)C2
Yield: 75.8 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while cooled on ice. To the obtained mixture, carbobenzyloxy-L-alanine (2.3 g, 10.5 mmol), a hydrochloric acid salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as WSC.HCl) (2.3 g, 11.0 mmol), and 1-hydroxybenzotriazol (hereinafter referred to as HOBT) (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The obtained residue was extracted with chloroform, washed with 1N-HCl and saturated aqueous NaCl solution, and dried. The solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol =20:1) to obtain 3.3 g of the title compound as colorless powdery crystals (76.0%)
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=3)[C:9]2=[O:23])=CC=1.O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=2)[C:9](=[O:23])[NH:8][CH2:17]1
Reactant: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.0 g) was dissolved in CH3CN (100 ml) and H2O (50 ml) and cooled to 0° C. CAN (9.64 g) was added and the reaction was stirred at 0° C. for 30 min, then warmed to RT and stirred for 6 h. The mixture was extracted with CH2Cl2 (2×300 ml) washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The crude material was recrystallized in CH2Cl2/EtOAc (1:1) to give 4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one as a white solid.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12>O1CCCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
60% Sodium hydride in mineral oil (1.013 g, 25.34 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (8.5 g, 21.12 mmol) in tetrahydrofuran (150 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (6.18 g, 23.23 mmol) in tetrahydrofuran (20 mL) was added dropwise over a period of 5 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was quenched with 1M citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (7.15 g, 53.6%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17](=O)[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]1)=O)=[CH:14][CH:13]=[CH:12][CH:11]=2>O1CCCC1>[F:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH:23]2[CH2:22][CH2:21][N:20]([CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=3[CH3:7])[CH2:25][CH2:24]2)=[CH:32][CH:31]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(=O)N1CCC(Oc2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1[nH]c2ccccc2c1CCN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
By following the manipulative procedure described in Example 2(d), 5.5 g of lithium aluminum hydride in 160 ml. of tetrahydrofuran and 12.0 g of 1-(2-methylindol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine in 120 ml. of tetrahydrofuran are reacted to produce a white solid. The solid is recrystallized from an ethanol and water mixture (charcoal treatment) to give a white powder of 3-{2-[4-(p-fluorophenoxy)piperidyl]ethyl}-2-methylindole, m.p. 97°-99° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:27][CH2:28]2)[N:3]=1
Reactant: COc1ccccc1C1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(2-methoxy-phenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=413.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[NH4+].O>C(OCC)(=O)C>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (50 ml), 1-(4-methoxycarbonyl-phenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (10.0 g) and ammonium acetate (9.9 g) were charged in 500-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 90 to 100 ° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, water (250 ml) and ethyl acetate (250 ml) were added, the mixture was stirred, and an ethyl acetate layer was separated. The ethyl acetate layer was further washed with water (250 ml) and a saturated saline solution (100 ml). The ethyl acetate layer was concentrated in vacuo to make 50 ml, and n-heptane (250 ml) was added to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The crystals were filtered at room temperature and washed with a solution (50 ml) consisting of n-heptane and ethyl acetate (5:1). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (100 ml) to give 1-amino-1-(4-methoxycarbonyl-phenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (6.56 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[O:21]1[C:9]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: C1CCCCCC2(CCCCC1)CO2
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a dry flask under nitrogen is added 3.1 g (64.6 mmol) of 50% sodium hydride in mineral oil. The sodium hydride is washed twice with hexanes, is suspended in 80 ml of dry dimethyl sulfoxide and then 14.3 g (65.0 mmol) of trimethylsulfoxonium iodide is added. The mixture is stirred at room temperature for several hours and then 11.8 g (64.7 mmol) of cyclododecanone is introduced. The mixture is allowed to stir overnight at room temperature and then is heated for 1 hour at 50° C. The mixture is cooled to room temperature, is dissolved in 500 ml of cold water and is extracted seven times with ethyl ether. The combined organic layers are washed once with water, dried over magnesium sulfate and subjected to evaporation in vacuo. The residue is chromatographed on silica gel using 20% ethyl acetate/hexanes as the mobile phase to give 10 g (78%) of the title compound as a colorless oil: NMR (CDCl3) δ 1.2-1.8 (m, 18 H), 2.05 (s, 1H), 2.4 (t, 2 H, J=5.0 Hz), 2.45 (d, 2H), 2.58 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:1]4[CH:25]=[CH:29][CH:28]=[CH:27]4)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[NH:5][C:6](=[O:22])[C:7]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Yield: 6.8 %

Procedure:
3.0 g (99 mmol) of 6-amino-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione and 1.3 g (99 mmol) of 2,5-dimethoxytetrahydrofuran were refluxed in 70 ml of acetic acid for 30 minutes. The mixture was then diluted with water, and the precipitate was filtered off with suction to yield 2.4 g (69%) of the product. Melting point 197° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyridin-4-yl)propanoate (218 mg) in THF (3.0 mL) and methanol (1.5 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (175 mg) as a white amorphous solid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[C:9]1([C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O1CCCC1.O>[O:24]=[C:23]([CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=1)[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)CCc1cccc(-c2ccccc2)c1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)CCc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.3 mL (0.044 mole) of acetonitrile in 50 mL of tetrahydrofuran was cooled to about -80° C., and 17.7 mL (0.044 mole) of n-butyllithium (2.5M in hexanes) was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes. After this time a solution of 10.3 grams (0.040 mole) of ethyl 3-(3-phenylphenyl)propanoate in 100 mL of tetrahydrofuran was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for one hour. After this time the reaction mixture was allowed to warm to ambient temperature, then was cooled to about 0° C., and 30 mL of aqueous 6N hydrochloric acid was added dropwise. Upon completion of addition, the reaction mixture was allowed to Warm to ambient temperature where it was stirred for 30 minutes. The mixture was poured into 200 mL of water, and then it was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. NMR analysis of the residual oil indicated that it was impure. The oil was dissolved in 10:1 methylene chloride and acetone, and the solution was passed through a column of basic alumina that was deactivated to Level III with water. The eluate was concentrated under reduced pressure, yielding 5.9 grams of 3-oxo-5-(3-phenylphenyl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:19]([NH:26][CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:19]([N:26]([CH2:1][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCNCc1ccccc1
Reactant: COC(=O)c1[nH]cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a stirred suspension of Intermediate 1C (3.20 g, 20.76 mmol) in dry THF (180 mL) was added anhydrous Na2SO4 (14.48 g, 192 mmol) and N-benzylethanolamine (3.70 g, 24.47 mmol). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (6.37 g, 28.5 mmol) was added portion-wise and the resulting mixture was stirred under nitrogen for 48 hours. The resulting mixture was quenched with water and neutralized with saturated NaHCO3 solution. The mixture was extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude mixture was purified using normal phase chromatography eluting with a 10-30% methanol/DCM gradient to provide Intermediate 1D as a white solid (5.80 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].II>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Sc1ccccc1Br
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Brc1ccccc1SSc1ccccc1Br
Yield: 86.3 %

Procedure:
To a mixture of 2-bromothiophenol (20.0 g, 106 mmol) and 2N sodium hydroxide solution (100 mL) in diethyl ether (400 mL) was added solid iodine (13.4 g, 53.0 mmol) in portions. The mixture was stirred at room temperature for 1 hour at which time the ether layer was separated. The aqueous layer was extracted with a fresh portion of ether and the combined ether layers were washed once with water, once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 17.2 g (43%) of intermediate product as a white solid: mp 95-97° C.; NMR (CDCl3) 7.52 (m, 4H), 7.25 (t, J=9.7 Hz, 2H), 7.06 (t, J=9.7 Hz, 2H); MS-FD m/e 380 (p+4, 20), 379 (p+3, 30), 378 (p+2, 85), 376 (p, 100), 374 (p−2, 75); IR.
Reaction SMILES: [Li+].[I-].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O>C(OCC)C>[CH3:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)=O
Reactant: CCCCC=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCC/C=C/C(C)=O

Procedure:
A solution of 7.73 g (58 mM) of anhydrous LiI and 1.47 ml (20 mM) of acetone in 35 ml of diethyl ether was heated to gentle reflux. To this solution was added dropwise a solution of 1.59 ml (15.0 mM) 1-pentanal in 5 ml diethyl ether over 10 minutes. The solution was then heated at reflux for 6 hours. After the solution was cooled to ambient temperature water was added and the layers separated. The ether phase was washed once with brine and dried over anhydrous MgSO4. The diethyl ether was removed by distillation at atmospheric pressure followed by distillation of the residue. There was obtained 0.52 g (27%) of a highly mobile colorless liquid. 1H NMR (CDCl3):6.80δ (dt,1H,JHH =7Hz, 16Hz), 6.01δ (d,1H,JHH =16Hz), 2.20δ (s,3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.C([O:15][C:16](=O)[CH:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[C:22]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:39][CH2:38]3)[CH:32]=[N:31][CH:30]=1)[CH3:18])(C)C>C1COCC1>[OH:15][CH2:16][CH:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[C:22]2[C:29]1[N:34]=[C:33]([O:35][C@H:36]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41][CH2:40][C:37]32[CH2:38][CH2:39]3)[CH:32]=[N:31][CH:30]=1)[CH3:18]
Reactant: CC(C)OC(=O)C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CO)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Yield: 65.5 %

Procedure:
Lithium aluminum hydride, 1.0 M solution in Et2O (109 μl, 0.109 mmol) was added to a solution of (4R)-tert-butyl 4-((6-(5-(1-isopropoxy-1-oxopropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (30 mg, 0.055 mmol) in THF (546 μl) at 0° C. for 1 h. The reaction was quenched with EtOAc and triturated with NH4Cl before it was filtered and concentrated to give (4R)-tert-butyl 4-((6-(5-(1-hydroxypropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (18 mg, 0.036 mmol, 66.8% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 494.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: COc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3nccc(Cl)c3s2)cn1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
To a solution of tributyltin derivative 6 (2.00 g, 4.36 mmol) (scheme 91) in toluene (10 mL) was added Ph(PPh3)4 (0.503 g, 0.436 mmol) followed by 5-bromo-2-methoxypyridine (0.62 mL, 4.8 mmol). Nitrogen gas was bubbled directly into the reaction mixture for 30 minutes before it was heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with hexanes. The material was then further purified by flash chromatography (eluent 20 to 50% ethyl acetate in hexanes) to afford the titled compound 418 as a fluffy white solid (0.752 g, 62% yield). MS (m/z): 277.0 (M+H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([NH2:4])=[O:3].Cl[C:10]([S:12]Cl)=[O:11]>C1(C)C=CC=CC=1>[O:11]=[C:10]1[S:12][N:4]=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[O:3]1
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)C(N)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nsc(=O)o1
Yield: 64.2 %

Procedure:
A mixture of 99.7 g (0.85 mol) of ethyl oxamate and 552 g (4.23 mol) of chlorocarbonylsulfenyl chloride, prepared in accordance with British Pat. No. 1,079,348, in toluene was held at reflux for 5.25 hours and then was concentrated under vacuum. Benzene was added to the residue, and the solution was extracted twice with water, twice with 5% NaHCO3, again with water, and was dried (CaSO4) and concentrated under vacuum. The residual oil was filtered to remove sulfur and was crystallized twice from methylcyclohexane to give 95.61 g (64%) of white solid, mp 49°-50.5 C.