Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON[C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]3[C:15](=[O:32])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]5=[O:31])=[CH:21][CH:20]=4)[CH2:17][CH2:18][C:13]=3[C:12]([C:33]([F:36])([F:35])[F:34])=[N:11]2)[CH:5]=1.[OH-:38].[Na+].OO>ClCCl>[O:32]=[C:15]1[C:14]2[N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([NH2:37])=[O:38])[N:11]=[C:12]([C:33]([F:34])([F:36])[F:35])[C:13]=2[CH2:18][CH2:17][N:16]1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]2=[O:31])=[CH:21][CH:20]=1
Reactant: N=C(NO)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 116, part A (0.05 g) was dissolved in dichloromethane (10 mL). To this was added sodium hydroxide (1N, 5 mL), hydrogen peroxide (3 mL), and tetrabutylammonium-hydroxide (0.01 g). The reaction mixture was stirred at rt for 24 h and concentrated, quenched with water (50 mL) and the organics extracted with ethylacetate (2×50 mL), dried (MgSO4) and concentrated. The crude was purified via prep HPLC to a colorless solid. ESI mass spectrum 494(M+H) and 492(M−H).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH:8]1[CH:12]=[N:11][N:10]=[N:9]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:8]1([CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[N:11][N:10]=[N:9]1
Reactant: c1nnn[nH]1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)n1cnnn1
Temperature: 18 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of methyl 2-bromopropionate (66.8 g), 1H-tetrazole (28.02 g), anhydrous potassium carbonate (110 g) and acetone (1000 cm3) was stirred together at the ambient temperature (ca. 18° C.) for 1 hour and then at reflux temperature for four hours. After keeping the mixture for a further 16 hours at the ambient temperature the insoluble component was removed by filtration and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residual oil (60 g) was subjected to distillation and the fraction having a boiling point range from 78°-93° C. at 0.35 to 2.5 mm Hg collected to yeild methyl 2-(1,2,3,4-2H-tetrazol-2-yl)propionate (A; 22.3 g). The undistillable residue was dissolved in dichloromethane and purified by elution through a short silica column. The collected eluate was concentrated by evaporation of the solvent under reduced pressure to yield methyl 2-(1,2,3,4-1H-tetrazol-1-yl)propionate (B; 35 g, 99% pure by gas/liquid chromatographic analysis).
Reaction SMILES: C1(C([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH2:20][CH2:21][CH:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1.[C@@H]12C[C@@H](CC1)[C@H](C(OCC)=O)N2>>[CH:10]12[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21]1)[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)C1C2C=CC(CC2)N1C(C)c1ccccc1
Agent: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Product: CCOC(=O)C1NC2CCC1CC2

Procedure:
Ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate is subjected to a reaction similar to the reaction (b) of Example 1, to give ethyl 2-azabicyclo[2.2.2]octane-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH:11]=O.[Br-].[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[PH4+].C([Li])CCC>C1COCC1.CCCCCC.O.CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH:11]=[CH:21][CH2:20][CH:15]1[O:16][CH2:17][CH2:18][CH2:19][O:14]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1=C(CC=O)C(C)(C)CCC1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [PH4+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CC1=C(CC=CCC2OCCCO2)C(C)(C)CCC1
Temperature: 25 °C

Procedure:
Commercially available 2,6,6-trimethyl-1-cyclohexene-1-acetaldehyde is chain-extended by Wittig reaction with commercially available 2-(1,3-dioxan-2-yl)ethyl triphenylphosphonium bromide as follows: To a stirred suspension of the phosphonium salt (20.4 g) in THF (30 ml) is added HMPA (30 ml). The mixture is cooled to -70° under nitrogen and n-butyllithium (17.5 ml of 2.5M solution in hexane) is added dropwise. After 30 minutes the aldehyde (6.65 g in 10 ml THF) is added and the mixture is allowed to warm slowly to room temperature. Water and hexane are added, the organic phase is evaporated and the residue chromatographed with 40% dichloromethane in hexane to provide crude (mostly cis) 2-[4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenyl]-1, 3-dioxane as a colorless oil (5.26 g). This material is hydrogenated in ethanol over a 5% Pd/BaSO4 catalyst for 18 hr under 40 psi hydrogen. Filtration and evaporation provide crude 2-[4 -(2,6,6-trimethyl-1-cyclohexen-1-yl)butyl]-1,3-dioxane as a colorless oil. This is hydrolyzed with acid in refluxing 1:1 dioxane-water to provide 5-(2,6,6-trimethyl-1-cyclohexen-1-yl)pentanal as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1ccc(C)c(-n2cnc3ccc(O)nc32)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,5-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:14])[CH:4]=[CH:5][C:6](=[O:13])[CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[K+]>O1CCCC1>[CH3:1][CH2:2][CH:3]([OH:14])[CH:4]=[CH:5][CH:6]([OH:13])[CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12]
Reactant: CCC=CCCC(=O)C=CC(=O)CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC=CCCC(O)C=CC(O)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tricyclo[6.2.2.0]dodeca-4,9-diene-3,6-dione (2.55 g) was combined with toluene (500 ml) and 1M diisobutylaluminum hydride in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 3 hours. The solution was cooled in an ice bath and 30% potassium hydroxide solution was added. The resulting mixture was stirred for 30 minutes and the layers separated. The aqueous layer was extracted with ether (2×100 ml) and the combined organic layers were concentrated on a rotary evaporator. The residue was recrystallized from hexane/ethyl acetate to provide the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 19 (400 mg, 0.86 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (237 mg, 1.03 mmol) using Method D to give the title compound.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[OH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1>CC(C)=O>[CH3:3][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)n1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Iodomethane (10 ml) and cesium carbonate (4.89 g) were added to an acetone (20 ml) solution containing ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (2.51 g) obtained in the 2nd step under ice cooling in a nitrogen atmosphere, followed by stirring at 80° C. for 0.5 hours. An insoluble precipitate was removed by filtration and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A white solid of ethyl 3-methoxy-5-nitro-1H-indazol-1-carboxylate (1.24 g) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]([F:45])([F:44])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]2[CH2:34]OS(=O)(=O)[N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:25][CH:24]=1>CN(C=O)C.CCOCC>[Br:1][C:2]1[S:3][C:4]([N:7]([CH2:34][C@@H:30]([NH:31][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:44])[F:45])=[CH:28][CH:27]=2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1cnc(Br)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl 2-bromothiazol-5-ylcarbamate (0.75 g, 2.69 mmol), DMF (26.9 mL, 2.69 mmol), and cesium carbonate (1.75 g, 5.37 mmol). The mixture was warmed to 50° C. and 1,1-dimethylethyl 4-((4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.13 g, 2.96 mmol, Scheme 1) was added slowly in 10 mL DMF. After 1 hour, the mixture was cooled, diluted with ether (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, evaporated onto a plug of silica gel and purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 20% to 100% EtOAc in hexane, to provide the product (1.42 g, 91% yield) as a white amorphous solid. LCMS (API-ES) m/z (%): 582 (100%, M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.3 %

Procedure:
A solution of 3-benzylimidazolidin-2,4-dione (5.7 g, JACS 1965, 3414) in DMF (10 ml) was added under N2 to a stirred suspension of anhy. K2CO3 (4.1 g) in DMF (10 ml), followed by the addition of a solution of p-nitrobenzyl bromide (6.45 g, Aldrich) in DMF (10 ml). After additions were complete, the mixture was stirred at room temperature for 72 hours, then poured into ice-water and extracted with ethyl acetate (×3). The combined extracts were washed with water (×2) and brine, dried over MgSO4 and evaporated to give a yellow oil which was flash chromatographed through a silica column using chloroform to give the desired product as a pale yellow solid (7.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:23])=[CH:4][CH:3]=1.[C]=O>CO.[Pd]>[OH:23][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]([O:18][CH3:19])=[O:17])=[CH:3][CH:4]=2)[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]1[CH2:11][CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(O)C(c1ccc(Br)cc1)C2
Agent: [Pd]
Agent: [C]=O
Solvent: CO
Product: COC(=O)c1ccc(C2CC3CCC(C2O)N3C(=O)OC(C)(C)C)cc1

Procedure:
(eee) In an analogous manner to that described in Example 12 (c)-(d), cleavage of the N-methyl group from (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-2-ol, obtained analogously to the 4-chlorophenyl derivative [J.Org.Chem. 35, 802 (1970)], was effected by firstly synthesizing (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-2-(2,2,2-trichloro-ethoxycarbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate by reaction with 2,2,2-trichloroethyl chloroformate and subsequently reacting with zinc in glacial acetic acid to give (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol. Subsequent introduction of the BOC group analogously to Example 1 (f) gave tert-butyl (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-2-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylate, palladium-catalyzed carbonylation of which with carbon monoxide in methanol analogously to Example 22 (d) yielded tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxy-3-(4-methoxycarbonyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. Subsequent reduction with lithium borohydride analogously to Example 22 (e) gave tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxymethyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, reaction of which with trityl chloride analogously to Example 22 (h) gave tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxy-3-(4-trityloxymethyl)-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. Further reaction with 2-bromomethyl-naphthalene analogously to Example 1 (9) gave tert-butyl (1RS,2RS,3RS,5SR)-2-(naphthalen-2-ylmethoxy)-3-(4-trityloxymethyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. In an analogous manner to that described in Example 86 (u) (b), by cleavage of the trityl group with a mixture of trifluoroacetic acid and trifluoroacetic anhydride there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, alkylation of which with benzyl 3-bromopropyl ether analogously to Example 44 (e) gave tert-butyl (1RS,2RS,3RS,5SR)-3-[4-(2-benzyloxy-propoxy-methyl)-phenyl]-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo-[3.2.1]octane-8-carboxylate as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl>CS(C)=O.O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1cccc(F)c1
Reaction time: 0.3 h
Yield: 94 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 150 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of potassium carbonate, 20 g (0.12 mole) of potassium iodide and 36.3 g (0.25 mole) of 3-fluorobenzyl chloride. The reaction mixture was heated with rapid stirring to 100° over 0.3 hours, held at 100° for 1.8 hours and poured with rapid stirring into 1.5 l of cold water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over magnesium sulfate overnight and filtered. The filtrate was concentrated to dryness to give 46 g (94%) of a light green semi-solid. The crude product was washed with 125 ml of ether, filtered and air dried to give 13.5 g (28%) of a white solid, m.p. 103°-105°.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7]>>[CH2:6]([N:8]([CH:2]([CH3:1])[C:3]#[CH:4])[CH2:9][CH2:10][OH:11])[CH3:7]
Reactant: C#CC(C)O
Reactant: CCNCCO
Product: C#CC(C)N(CC)CCO

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and 2-Ethylaminoethanol were converted to yield 2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol as colorless oil, MS: 141 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12](C)C=O>O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CN(C)C=O
Reactant: Nc1ccc(I)cc1CO
Solvent: O
Product: N#Cc1ccc(N)c(CO)c1
Temperature: 25 °C

Procedure:
2-Amino-5-iodobenzyl alcohol (12 g.) and cuprous cuyanide (5.4 g.) in dry dimethylformamide (10 ml.) were heated on a steam-bath for 30 hours, then cooled to ambient temperature and poured into a solution of ferric chloride (10 g.) in water (100 ml.). This mixture was exhaustively extracted with ether (14×60 ml.), the extracts were combined and dried, and the solvent was evaporated. The residue was chromatographed on a column of "Merck 7734" silica, and elution with ether yielded the required 4-amino-3-hydroxymethylbenzonitrile as a buff-coloured solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 14 h
Yield: 37.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (240 mg, 0.834 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 14 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (115 mg, 37.8%) as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([NH:28]C(=O)OC(C)(C)C)[CH:22]=3)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:28][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[C:19]([C:17]([NH:16][CH2:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]4[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=4)[C:11]=3[F:36])=[O:18])[NH:20]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(N)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-6-yl)carbamate (0.046 g, 0.081 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by column chromatography (dichloromethane/methanol) to give the title compound (0.037 g, 74%) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 9.35 (br. s., 2H), 9.04 (s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.44-7.54 (m, 3H), 7.38 (t, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 6.88 (d, 1H), 4.55 (d, 2H). MS: m/z 548 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15]3=[N:16][C:17]([Sn](C)(C)C)=[CH:18][N:19]=[C:14]3[NH:13][CH2:12][C:11]2=[O:24])[CH2:5][CH2:4]1.Br[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:11](=[O:24])[CH2:12][NH:13][C:14]3[N:19]=[CH:18][C:17]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=4)=[N:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc([Sn](C)(C)C)nc32)CC1
Reactant: Cc1cc(C#N)ncc1Br
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Temperature: 100 °C

Procedure:
1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol), triethylamine (0.687 mL, 4.93 mmol), tri-ortho-toylphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 mL) were combined in a sealed reaction vessel. Nitrogen was bubbled through the reaction for 5 min and reaction was heated at 100° C. for 3 h. Reaction is filtered, concentrated and purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). Fractions were combined and concentrated to afford the crude title compound used directly for next step (0.607 g, 1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([NH:16][CH2:17][CH:18]([OH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.C(O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C(O)=O.C([O-])(=O)C([O-])=O>>[CH3:3][CH:4]([NH:16][CH2:17][CH:18]([OH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OC)cc1OC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [BH4-]
Product: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 ml of ethanol are added to the α-(α-methyl-3,4-dimethoxyphenethylimino)-2-methoxyacetophenone solution obtained in paragraph (2). After ice-cooling, 1.53 g of sodium borohydride is added gradually to the solution, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is treated in the same manner as described in Example 1-(3), whereby α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-methoxybenzylalcohol [the mixture of two diastereoisomers] is obtained as a crude oil. Said benzylalcohol [i.e., the mixture of two diastereoisomers] is treated with oxalic acid to convert it into its oxalate, and the oxalate is recrystallized from 70% aqueous ethanol. The crystalline precipitates are collected by filtration (the filtrate is hereinafter referred to as "mother liquor"). 4.5 g of α-[(α-methyl-3,4-dimethoxyphenethylamino)methyl]-2-methoxybenzylalcohol 1/2 oxalate [the diastereoisomer of M.p. 199°-200° C. (decomp.)] are thereby obtained.