Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:15]([F:22])=[CH:16][C:17]([O:21][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:24][CH:25]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(O)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Oc2ccccc2)cc1F

Procedure:
In analogy to example 278.4 (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetamide (example 293.2) was reacted with phenyl boronic acid to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-phenoxy-phenyl)-2-ethoxy-acetamide. Light yellow solid. MS 423.1 ([M+H]+)
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.[Cl:12][C:13]1[CH:27]=[CH:26][C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][NH:21][C:15]=2[CH:14]=1>CCOCC.C(N(CC)CC)C>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][N:21]([C:1]([Cl:4])=[O:2])[C:15]=2[CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
13 parts of phosgene in 45 parts of toluene was stirred for 2 hours at 5°-10° C., and then 70 parts of ether was added. This was followed by the addition of a solution of 18.9 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine and 7.2 parts of triethylamine in 140 parts of ether. After the addition was complete, the mixture was stirred for 2 hours, and then was filtered. The solvent was then evaporated from the filtrate. The resulting residue was then dissolved in 200 parts by volume of hot hexane, and this mixture was then filtered and cooled.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C@H:4]1[CH2:6][O:5]1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CCO.O>[N:9]([CH2:6][C@@H:4]([OH:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NC[C@@H](O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
To a solution of (S)-2-(2,2,2-trifluoroethyl)oxirane (2.00 g, 16.0 mmol) in a mixture of EtOH (16 mL) and H2O (4 mL) were added NaN3 (2.06 g, 32.0 mmol) and NH4Cl (1.70 g, 32.0 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with H2O (50 mL), extracted with Et2O (2×75 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give (S)-1-azido-4,4,4-trifluorobutan-2-ol as an oil (2.26 g, 83% yield). NMR: 400 MHz (CDCl3) 4.17 ppm, 1H, ddd, J=6.81, 3.74, 3.52 Hz; 3.48 ppm, 1H, m; 3.37 ppm, 1H, m; 2.35 ppm, 2H, m.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([OH:13])=O)[C:4](=[O:15])[CH:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:18]=2)=[O:13])[C:4](=[O:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1Br
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br

Procedure:
571 mg (2.01 mmol) of 2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and 426 mg (2.21 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 562 mg (61% of theory)
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30].[NH4+].[Cl-]>ClCCl>[CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:28]([O:29][CH3:30])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(COC2CCCCC2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(COC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Methyl 2-(cyclohexyloxymethyl)piperidine-4-carboxylate (2.13 g, 8.34 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.034 mL, 11.68 mmol) and methyl carbonochloridate (0.788 mL, 10.01 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M NH4Cl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Dimethyl 2-(cyclohexyloxymethyl)piperidine-1,4-dicarboxylate (2.54 g, 97%) was isolated. MS m/z 314 (M+H)+
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCCCC1
Yield: 72.4 %

Procedure:
Using the general method of Example 92, cyclohexanecarbonyl chloride (94 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide as a white powder, m.p. 188-190° C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30; Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (EI) calcd for C22H30N6O (M+) 394.2481 found 394.2475.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]=[CH:21][N:20]=1)=[O:18].[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28])[CH:22]=[CH:21][N:20]=1)=[O:18])(=[O:36])[CH3:35]
Reactant: CCOC(=O)n1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-ethoxycarbonyl-2-[4-[(tert-butyldimethylsilyloxy)methyl]pyridine-2-carbonyl]indole (step 5) and acetyl chloride.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[ClH:20]>C(Cl)(Cl)Cl>[Cl:20][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: Cl
Reactant: CCOC(=O)c1cc2cccc(OCC3CO3)c2o1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
There was dissolved 2.6 g (0.01 mole) of 7-(2,3-epoxypropoxy)-2-ethoxycarbonylbenzofuran obtained in Reference Example 9 in 15 ml of chloroform, and thereto 2 ml of concentrated hydrochloric acid was added. Thereafter, the mixture was vigorously stirred at room temperature for 15 minutes. After the chloroform layer was washed with water, the layer was dried with magnesium sulfate, and then the solvent was distilled away from the reaction mixture under reduced pressure. The resultant residue was purified by silica-gel column-chromatography (eluent:n-hexane:methylene chloride=1:1) to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+].O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:24]([CH3:27])([CH3:25])[CH3:23])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
[Reference: European Patent Application 87-109919.8 example 85a, page 148 line 22]To a solution of 4'-methyl[1,1'-biphenyl]-2-carboxylic acid (25.0 g, 0.118 mol) in dichloromethane (120 mL) at 0° C. was added oxalyl chloride (2.0 M solution in methylene chloride (470 mL, 0.236 mol) over 30 minutes. The solution was warmed to 25° C., stirred for three hours and concentrated in vacuo to remove excess oxalyl chloride. The remaining residue was suspended in diethyl ether (300 mL), cooled to 0° C. and potassium t-butoxide (26.44 g, 0.236 mol) was added over 15 minutes keeping the temperature of the mixture between 15°-25° C. The mixture was allowed to warm to 25° C. and was stirred for one hour, poured into water (200 mL), and extracted with diethyl ether. The ether extract was then washed with aqueous sodium bicarbonate (saturated solution), dried (magnesium sulfate) and concentrated in vacuo to an amber oil. Subsequent distillation (124°-130° C., 0.6 mm Hg) yielded the title compound as a colorless liquid (27.7 g, 92%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[H-].[Li+].[Al].[Li].[H-].[Al+3].[H-].[H-]>O1CCOCC1.C(Cl)Cl.O>[CH3:1][NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CNc1c(-c2ccccc2)sc2ccccc12
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1c(-c2ccccc2)sc2ccccc12
Reaction time: 0.25 h

Procedure:
3.0 g (11.8 mmol) of 3-formamido-2-phenyl-benzo(b)thiophene and 1.08 g (28.4 mmol) of lithium hydride and aluminium are refluxed with stirring for 30 minutes in 60 milliliters of absolute dioxane. The cooled reaction mixture is mixed with water to decompose the excess lithium and aluminium hydride and, after the addition of approximately 100 milliliters of CH2Cl2, it is stirred for a further 15 minutes. After centrifuging with the addition of the hyflo, the organic phase is dried over K2CO3 and evaporated: 3-methylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product. It is dissolved in a little CHCl3 and converted into the hydrochloride by hydrochloric gas: 2.6 g (80% of theory) of colourless crystals in a mixture of ethanol and ether, decomposition from 198° C. (in sealed tubes).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][N:6]1[CH2:30][CH2:29][C:9]2([N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:12](=[O:21])[N:11]=[C:10]2[NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:8][CH2:7]1.[CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)=[CH2:35].P(C1C=C(S(O)(=O)=O)C=CC=1)(C1C=C(S(O)(=O)=O)C=CC=1)C1C=C(S(O)(=O)=O)C=CC=1.C(NC(C)C)(C)C>CC(O)=O.CC(O)=O.[Pd].CN(C=O)C.O>[CH:23]1([NH:22][C:10]2[C:9]3([CH2:29][CH2:30][N:6]([CH2:5][C:4]4[CH:3]=[C:2]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[CH:34]=[CH2:35])[CH:33]=[CH:32][CH:31]=4)[CH2:7][CH2:8]3)[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:12](=[O:21])[N:11]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCN(Cc3cccc(Br)c3)CC2)N1c1cccc(F)c1
Reactant: C=Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=S(=O)(O)c1cccc(P(c2cccc(S(=O)(=O)O)c2)c2cccc(S(=O)(=O)O)c2)c1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: C=Cc1ccccc1-c1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 100 °C

Procedure:
To a solution of 0.020 g (0.039 mmol) 8-(3-bromobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (5-3) in 0.5 mL degassed DMF:H2O (4:1) was added 0.006 g (0.039 mmol) (2-vinylphenyl) boronic acid and 0.003 g (0.006 mmol) 3,3′,3″-Phosphinidynetris (benzene sulfonic acid) and 0.001 g (0.002 mmol) palladium II acetate and 16 μL (0.117 mmol) diisopropylamine. The reaction was heated in the microwave at 100° C. for 10 mins. Purification by preparative HPLC (5-95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 PRO YMC 20×150 mm) afforded 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-[(2′-vinyl-1,1′-biphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one as a white solid. NMR 1H NMR (CD3OD) δ 7.65 (dd, J=6.8 Hz, 2.2 Hz, 1H), 7.43 (dt, J=7.96 Hz, 6.32 Hz, 1H), 7.34 (m, 3H) 7.17 (m, 7H), 6.61 (dd, J=17.49 Hz, 10.99 Hz, 1H), 5.70 (d, J=17.58, 1H), 5.15 (d, J=10.99 Hz, 1H), 3.75 (m, 1H), 3.46 (s, 1H), 2.78 (m, 2H), 2.14 (m, 6H), 1.93 (m, 2H), 1.74 (m, 2H), 1.63 (m, 1H), 1.34 (m, 4H), 1.17 (m, 1H). High resolution mass spec (FT/ICR) calc M+H=537.3024 found 537.3038.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NCC1CCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCC1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
668.5 mg of the 2-azidomethyl-1-benzylpyrrolidine crude product obtained was dissolved in 5 mL of ethanol, to which 160 mg of 10% palladium carbon was added, and stirred at room temperature under an atmosphere of hydrogen gas for 5 hours. The 10% palladium carbon was celite-filtered, and the filtered product was washed with methanol. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform to chloroform:methanol=30:1 to chloroform:methanol=15:1) to obtain 539.7 mg of the title compound crude product as a light yellow oil. Without further purification, this was used as the feed material for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methoxyphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 20, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: C[O-].[Na+:3].[C:4]([CH2:6][N:7]([CH3:12])[C:8](=[O:11])[O:9][CH3:10])#[N:5].[CH:13](OCC)=[O:14]>O1CCCC1>[C:4](/[C:6](/[N:7]([C:8]([O:9][CH3:10])=[O:11])[CH3:12])=[CH:13]\[O-:14])#[N:5].[Na+:3]
Reactant: COC(=O)N(C)CC#N
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C)/C(C#N)=C/[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.46 g (0.01 mmol) of sodium methoxide is added under argon to tetrahydrofuran (solution A). Then 1.00 g (0.01 mmol) of methyl cyanomethyl(methyl)carbamate from Example 9A is added to 1.73 g (0.02 mmol) of ethyl formate. Solution A is slowly added dropwise to this mixture. The mixture is stirred at RT overnight. The solvent is concentrated in vacuo in a rotary evaporator, and diethyl ether is added to the residue. The crystals which have separated out are filtered off with suction and dried under high vacuum.
Reaction SMILES: [O-]P(OP([O-])[O-])[O-].CC(C1C=[C:16]([O:18]C)[CH:15]=[C:14]([C:20]2[C:25]([O:26]P3OC4C(=CC=CC=4)C4C(=CC=CC=4)O3)=[C:24](C(C)(C)C)[CH:23]=[C:22](OC)[CH:21]=2)C=1OP1OC2C(=CC=CC=2)C2C(=CC=CC=2)O1)(C)C.C=CCC([OH:71])CC=C.C(=O)=O>>[CH:21]([CH2:22][CH2:23][CH2:24][CH:25]1[O:26][CH:16]([OH:18])[CH2:15][CH2:14][CH2:20]1)=[O:71]
Reactant: COc1cc(-c2cc(OC)cc(C(C)(C)C)c2Op2oc3ccccc3c3ccccc3o2)c(Op2oc3ccccc3c3ccccc3o2)c(C(C)(C)C)c1
Reactant: C=CCC(O)CC=C
Agent: O=C=O
Agent: [O-]P([O-])OP([O-])[O-]
Product: O=CCCCC1CCCC(O)O1
Temperature: -60 °C

Procedure:
To a 300 mL stainless steel autoclave with two sapphire windows containing Rh(acac)(CO)2 (1.5 mg, 6×10-3 mmol) and a diphosphite ligand, BIPHEPHOS or MCP-1, (1.2×10-2 mmol) was added 1,6-heptadien-4-ol (112 mg, 1.0 mmol). The air was replaced by CO and CO (7 atm) was introduced followed by H2 (7 atm). The reaction vessel was cooled to -60° C. and CO2 (85 atm) was introduced. The mixture was allowed to stir at 65° C. and 100 atm overnight. The autoclave was cooled to 0° C. and all the gasses were carefully released. The reaction mixture was then concentrated under vacuum and the residue was chromatographed on silica gel using hexane/AcOEt as the eluant to give 6-(3-formylpropyl)-2-hydroxytetrahydropyran in nearly quantitative yield: 1H NMR (CDCl3) (two diastereomers) δ 1.14-2.02 (m, 10 H), 2.43 (t, J=6.8 Hz, 2 H), 3.16 (br s, 1 H), [3.36-3.44 (m), 3.88-3.96 (m)] (1 H), [4.66 (d, J=9.1 Hz), 5.26 (br s)] (1 H), 9.74 (s, 1 H); 13C NMR (CDCl3) δ [17.50, 18.04], 21.95, [30.26, 30.99], [32.55, 32.03], [35.01, 35.18], [43.13, 43.52], [72.96, 75.64], [91.36, 96.21], [201.90, 202.74]; IR (neat, cm-1) 3420, 2942, 2867, 2723, 1724, 1458, 1440, 1412, 1390, 1352, 1184, 1116, 1066, 1035, 977.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37](OC)[O:38]C)[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].ClC([SiH3])(Cl)Cl>C(#N)C>[CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]=[O:38])[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1

Procedure:
Under anhydrous conditions, a solution of (2S)-2-{3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-ureido}-3-phenyl-propionic acid benzyl ester (0.78 g, 1.3 mmol), sodium iodide (0.491 g, 3.27 mmol), and trichloromethylsilane (0.308 mL, 2.62 mmol) in acetonitrile (20 mL) was stirred at ambient temperature for 15 minutes. The reaction mixture was quenched with water and partitioned with methylene chloride. The organic phase was washed with Na2S2O3 dilute solution and dried (Na2SO4). Removal of solvent afforded the crude product which was used directly in the next step without characterization.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.CC(C)=O.Cl.O.C(=O)(O)[O-]>>[OH:24][CH2:23][CH2:22][C:14]1[N:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:13]=1
Reactant: OCCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Reaction time: 17 h

Procedure:
2-[6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]ethanol was dissolved in acetone (60 mL, 900 mmol), and 5.0 M hydrogen chloride in water (20 mL, 98 mmol) was added and stirred for 17 hours. LCMS and HPLC analysis showed nearly complete conversion to M+H 305. Aqueous bicarbonate was added and the reaction mixture was stirred, then concentrated. This mixture was extracted with EtOAc. The EtOAc was dried (Na2SO4), and evaporated in vacuo to give 1.3 g light yellow viscous oil (used in the next reaction without purification). 1H NMR (300 MHz, CDCl3): δ6.80 (s, 1H); 5.60 (m, 1H, OCH); 4.06 (t, 2H, OCH2); 3.04 (t, 2H, CH2); 2.61 (m, 2H); 2.45 (m, 2H); 2.25 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(Cl)Cl.C1COCC1>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:20])[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:22][CH3:23]
Reactant: CNOC
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(C(=O)N(C)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 979.1 %

Procedure:
To a stirred solution of pyridine (33.1 mL, 40.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (26.0 g, 26.7 mmol) in anhydrous CH2Cl2 (300 mL) at 0° C. was added dropwise 2-phenylbutyryl chloride (37.4 g, 20.5 mmol) dissolved in THF (100 mL). The reaction mixture was stirred overnight at RT. H2O (300 mL) was added, and the mixture was extracted with CH2Cl2 (2×200 mL). The combined extracts were washed successively with 5% aqueous HCl (300 mL), 5% aqueous NaHCO3 (300 mL), H2O (300 mL), and brine (300 mL). The mixture was dried over Na2SO4, filtered, and concentrated to afford 41.6 g (98%) of 14 as a colorless oil which was used without further purification. 1HNMR (400 MHz, CDCl3): δ 0.87 (t, J=7.3 Hz, 3H), 1.74 (h, J=7.1 Hz, 1H), 2.08 (h, J=7.1 Hz, 1H), 3.14 (s, 3H), 3.46 (s, 3H), 3.88 (br s, 1H), 7.19-7.33 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][CH3:19])[CH:15]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CNc1cc(-c2cc3ccccc3[nH]2)ccc1OC
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
In acetone (50 mL) was placed 5-(1H-indol-2-yl)-2-methoxy-phenylamine (2.38 g, 10 mmol). To this was added potassium carbonate (5.53 g, 40 mmol), and to the vigorously stirred mixture was added methyl iodide (1.55 g, 11 mmol). The mixture warmed to 40° C. and stirred for 48 hours. The mixture cooled to room temperature and was filtered free of inorganics. The resulting solution was evaporated in vacuo to give a solid which was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, dried over magnesium sulfate, and evaporated in vacuo to give a tan solid. This solid was purified by flash chromatography over silica gel (5% ethyl acetate/methylene chloride). Evaporation of the appropriate fractions gave 0.68 g of pure compound. MS: M+1=253.1. 1H NMR (DMSO-d6) δ 2.79 (d, J=5.3 Hz, 3H), 3.80 (s, 3H), 5.08-5.12 (m, 1H), 6.69 (s, 1H), 6.83-7.05 (m, 5H), 7.33 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 11.28 (s, 1H) ppm.