Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:20]([CH3:21])[CH2:19][C:5]2[NH:6][C:7]([CH2:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[O:11])=[N:8][C:4]=2[CH2:3]1.[C:22](O)(=[O:25])[C:23]#[CH:24].N1(C(N2C=CN=C2)=O)C=CN=C1>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]([C:9]2[CH:24]=[CH:23][C:22](=[O:25])[N:6]3[C:5]4[CH2:19][CH:20]([CH3:21])[CH:2]([CH3:1])[CH2:3][C:4]=4[NH:8][C:7]=23)=[O:11])=[CH:17][CH:16]=1
Reactant: C#CC(=O)O
Reactant: CC1Cc2nc(CC(=O)c3ccc(F)cc3)[nH]c2CC1C
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC1Cc2[nH]c3c(C(=O)c4ccc(F)cc4)ccc(=O)n3c2CC1C

Procedure:
The compounds are prepared as described in example 10 with 200 mg (0.70 mmol) of 2-(5,6-Dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-1-(4-fluorophenyl)ethanone (example XIV), 73.3 mg (1.05 mmol) of propiolic acid and 204 mg (1.26 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[CH:10][C:9]([O:22]C)=[C:8]([NH:24]C(=O)C)[CH:7]=2)#[N:2].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:24][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][C:9]=1[OH:22]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cc1NC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(N)c(O)cc2c1Nc1ccc(Cl)cc1Cl
Temperature: 200 °C
Yield: 30.1 %

Procedure:
An amount of 200 mg (0.50 mmol) of N-[3-cyano-4-(2,4-dichloroanilino)-6-methoxy-7-quinolinyl]acetamide, was stirred with pyridine hydrochloride (1.4 g, 12.5 mmol), and heated at 200° C. for 2 hours. The mixture was cooled to room temperature, stilled with ethyl acetate and saturated sodium bicarbonate solution, and filtered. The layers were separated, and the organic layer was subsequently washed with saturated brine solution, dried over sodium sulfate, and evaporated to a yellow oil. Purification was carried out by preparative thin layer chromatography (5% methanol in ethyl acetate), to yield a yellow solid (52 mg, 30% yield), mp 265° C. decomp.; 1H NMR (DMSO-d6) δ 10.26 (bs, 1H), 8.93 (s, 1H), 8.34 (s, 1H), 7.66 (d, J=2 Hz, 1H), 7.35 (dd, J=9Hz, J=2Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=9 Hz, 1H), 6.99 (s, 1H), 5.90 (s, 2H); HRMS (EI) m/z 344.0897 (M+1). Analysis for C16H10Cl2N4O.0.5CH3OH: Found: C, 54.43; H, 3.12; N, 15.34. Calcd: C, 54.74; H, 3.32; N, 15.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.65 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=431.2.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:29](Cl)=[O:30])[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>CC1C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:29]([N:2]([CH3:3])[CH3:1])=[O:30])[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: CNC
Reactant: COc1ccc(C2(C(=O)Cl)CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C(=O)N(C)C)CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (<0° C.) mixture of 49.5 parts of N-methylmethanamine solution 40%, 93 parts of sodium carbonate and 1000 parts of water is added dropwise a solution of 124 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carbonyl chloride in 675 parts of methylbenzene. Upon completion, stirring is continued overnight at room temperature. The layers are separated and the organic phase is washed with water, dried, filtered and evaporated, yielding 128 parts (100%) of 8-(4-methoxyphenyl)-N,N-dimethyl-1,4-dioxaspiro[4,5]decane-8-carboxamide as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]([O:40][CH2:41]Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:15])=[C:12]([S:17][C:18]3[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(OC)nc(Sc2nccc(-c3ccc(F)cc3)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(F)cc3)c2C(=O)OCOC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of 0.70 g (0.0019 mol) of 4-(4-fluorophenyl)-2-(4,6-dimethoxypyrimidin-2-ylthio)nicotinic acid and 0.50 g (0.0036 mol) of potassium carbonate in 10 ml of N,N-dimethylformamide was stirred at room temperature for 1 hour. Thereafter, 0.34 g (0.0022 mol) of chloromethyl pivalate was further added to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into water, and extracted with 50 ml of ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 0.81 g of a yellowish thick syrup-like aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)#[CH:23].C(N(C(C)C)CC)(C)C>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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1[C:23]#[C:22][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C#Cc2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (50 mg, 0.120 mmol), 2-(4-ethynylphenyl)propan-2-ol (28.2 mg, 0.176 mmol), Pd(Ph3P)4 (13.58 mg, 0.012 mmol), copper(I) iodide (2.237 mg, 0.012 mmol) and diisopropylethylamine (0.062 ml, 0.360 mmol) in dioxane (2 ml) was charged in a reaction tube. Then the tube was sealed and N2 was bubbled through for 5 min. The mixture was heated at 80 C for 2 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS m/e=458.35 (M+H)+ (Rt 1.70/4.0 min); 1H NMR δ (ppm) (CD3OD): 7.83 (s, 1H), 7.58-7.54 (m, 4H), 5.13 (septet, 1H, J=5 Hz)), 4.34 (ddd 1H, J=12, 5, 2 Hz), 3.89 (dd, 1H, J=12, 2 Hz), 3.64 (dd, 1H, J=12, 6 Hz)), 3.61 (dd, 1H, J=12, 5 Hz), 3.37 (t, 1H, J=11 Hz), 3.19-3.15 (m, 1H), 2.77-2.73 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz), 1.55 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)[CH3:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCOc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1NN(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 41.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2-ethoxyphenylboronic acid (Combiblock; 1.12 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. overnight. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 20-25% ethyl acetate/hexanes, to give N′-(2-ethoxy-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (751 mg, 38%) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][N:5]([CH2:44][C:45]([O:47]C)=[O:46])[C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:9]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:8]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:45]([CH2:44][N:5]([C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:9]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:8]=1)[CH2:4][C:3]([OH:49])=[O:2])([OH:47])=[O:46]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)OC)CC(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)O)CC(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 59.3 %

Procedure:
A solution of 0.90 g (1.3 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine methyl ester and 1.0 ml (6 mmol) of 6N NaOH in 80 ml of methanol and 35 ml of dioxane was stirred at reflux for 6 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was removed by filtration. Recrystallization from ethyl acetate-hexane gave 0.51 g (59% yield, mp 84°-87° ) of N-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][Mg]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:34][C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:23])[CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][C:17]=1[NH:24][C:25](=[O:41])[CH2:26][CH:27]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=2[O:34][C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: I[Mg]CCCC1CCCCC1
Product: CC(C)(C)c1ccc(C(O)CCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using 3-cyclohexylpropylmagnesium iodide and N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:12]=2)=[O:10])=[CH:3][CH:2]=1.C(O)(C)C.[H][H]>[Ni].O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[CH:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ccc(Cn2cc(C(=O)C(=O)Nc3ccncc3)c3ccccc32)cc1
Reaction time: 3 h

Procedure:
A mixture of 200 mg of Raney nickel in 50 ml of dioxane is treated with a suspension of 320 mg (0.8 mmol) of N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxyl-amide in a solvent mixture of 150 ml of dioxane and 20 ml of isopropanol. Hydrogen is passed into this suspension with shaking at a gas pressure of 5 bar and the temperature is kept at 30-35° C. After about 3 hours, a further 400 mg of Raney nickel are added and the hydrogenation is continued at 35° C. and 5 bar for a further 8 hours with vigorous shaking. The catalyst is filtered off under an N2 atmosphere, the filtrate is concentrated to dryness in vacuo and the residue is dried in vacuo at 40° C.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[F:9][C:10]([F:25])([S:21](F)(=[O:23])=[O:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[OH-].[K+]>O>[F:25][C:10]([F:9])([S:21]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:23])=[O:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (202 g, 1.52 mol, obtained from Sinochem Corp.), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (465 g, 1.52 mol, obtained from 3M Company) and water (500 g) were combined in a 3-liter, 3-necked round bottom flask. The flask was equipped with a magnetic stirrer, cold water condenser, thermocouple and an addition funnel. Aqueous potassium hydroxide (45 percent by weight, 211.5 g, 1.7 mol, obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase. Unreacted 2,2,3,3-tetrafluoropropan-1-ol and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride were removed from the liquid fluorochemical product phase by atmospheric distillation.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([Cl:14])[CH:4]=1.[C-:15]#[N:16].[K+].C(O)C>O>[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(CBr)cc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(CC#N)cc1Cl
Yield: 16 %

Procedure:
3.1 g (11.2 mmol) of ethyl 4-(bromomethyl)-2-chlorobenzoate are added dropwise to a solution composed of 0.94 g (14.3 mmol) of potassium cyanide, 3.75 ml of water and 8.8 ml of ethanol, heated under reflux. After refluxing for 3 hours, the medium is poured over 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with a dilute HCl solution and then with water saturated with NaCl. The oil obtained after concentration of the organic phase is purified by flash chromatography on silica (hexane-ethyl acetate 1:0 to 1:1 gradient). 0.4 g of a brown solid is obtained (Yield=16%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.O>C(O)C>[CH:16]1([NH:19][C:11]([C:8]2[CH:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(-c2cccs2)on1
Solvent: O
Solvent: CCO
Product: O=C(NC1CC1)c1cc(-c2cccs2)on1
Temperature: 80 °C
Yield: 64 %

Procedure:
To a solution of ethyl 5-(thiophen-2-yl)isoxazole-3-carboxylate (220 mg, 1 mmol) in absolute ethanol (5 mL) was added cyclopropylamine (285 mg, 5 mmol). The reaction was sealed and heated to 80° C. for 24 hours. The reaction was allowed to cool to room temperature and water (1 mL) was added. The product was collected by vacuum filtration as a white crystalline solid (150 mg, 64% yield). δH (400 MHz, d6 DMSO): 8.85 (1H, d), 7.83 (1H, d), 7.76 (1H, d), 7.24 (1H, d), 7.18 (1H, s), 2.83 (1H, m), 0.58-0.71 (4H, m).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 66.7 %

Procedure:
A mixture of 2.05 g of 2-(R)-hydroxy-4-methylpentanoic acid, 2.01 g of benzyl alcohol and 0.251 g of p-toluenesulfonic acid monohydrate in 40 ml of benzene was heated to reflux for 1.5 hours. The reaction mixture, after being allowed to cool, was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to yield the title compound as a colorless oil (2.30 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:11][C:10](=[O:12])[NH:9][CH2:8]2)[C:3]1=[O:13].[H-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:11][C:10](=[O:12])[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[C:3]1=[O:13]
Reactant: ClCc1ccccc1
Reactant: CN1C(=O)CC2(CNC(=O)C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 1.82 g (10 mmol) 2-methyl-2,7diazaspiro[4.4]nonane-1,3,8-trione in 20 ml N,N-dimethylformamide was added gradually under a nitrogen atmosphere to 0.050 g (10.4 mmol) of 50% oil suspension of sodium hydride which had been previously washed twice with toluene and covered with 10 ml N,N-dimethylformamide. After stirring one hour there was added 1.40 g (11 mmol) of benzyl chloride and stirring was continued overnight at room temperature. After concentrating to a small volume in vacuo, the residue was diluted with 40 ml water and extracted twice with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate, and evaporated to give a solid. Crystallization from toluene-hexane afforded 1.74 g of 2-methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 157°-158° C. 2-Methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane Dihydrochloride
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH3:61])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:70])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (76.4 mg, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][N:24]=3)=[O:22])=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C1COCC1>[ClH:32].[C:29]([C:27]1[CH:26]=[CH:25][N:24]=[C:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][C:16]=2[F:31])=[O:22])[CH:28]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(C#N)ccn3)c(F)c2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1ccnc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of (S)-2-{4-[(4-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (73 mg, 171 μmol, Eq: 1.00) in THF (3 ml) was added 4M−HCl in dioxane (0.642 ml, 2.52 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 5 h. To the cooled mixture was then added ethyl acetate and the suspension was filtered off and dried under high vacuo to give the target compound as a white solid (53 mg, 85%). MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[C:27]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([Cl:47])[CH:38]=5)[O:34][N:33]=4)[CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:48])[CH:24]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:47][C:39]1[CH:38]=[C:37]([C:35]2[O:34][N:33]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[N:25]([CH3:48])[CH:24]=[C:23]4[CH2:22][CH2:21][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:36]=2)[CH:42]=[CH:41][C:40]=1[O:43][CH:44]([CH3:45])[CH3:46]
Reactant: CCOC(=O)CO
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 136.4 %

Procedure:
To a stirred solution of ethyl hydroxyacetate (23 mg) in DMF (5 mL) was added NaH (18 mg). The reaction mixture was stirred at 20° C. for 15 mins. Then a solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl 4-methylbenzenesulfonate (D127) (25 mg) in DMF was added dropwise. The mixture was stirred at room temperature for 24 h. The reaction was quenched with water, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, 2 M hydrochloric acid and brine, dried over sodium sulphate and evaporated to give the crude product ethyl ({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}oxy)acetate (D104) (30 mg), used directly in the next step. MS (ES): C26H28ClN3O5 requires 497; found 498.2 (M+H+).