Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[C:13](=O)[O:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S1C=CC(C(C2C=CSC=2)[C@@H](O)C)=C1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][O:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: C[C@H](O)C(c1ccsc1)c1ccsc1
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.336 g (1 mmol) of cis-1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4,6-trione in 3.3 ml of tetrahydrofuran are placed in an apparatus standing under argon. There is then added dropwise within 15 minutes at room temperature a solution of 0.15 ml (1.1 mmol) of triethylamine and 0.224 g (1 mmol) of [S]-1,1-di-(3-thienyl)-2-propanol ([α]36520 =-77.4° (1% in ethanol)) in 3.3 ml of tetrahydrofuran. The solution is then stirred at room temperature for 1.5 hours. To this solution there are added at 40°-50° C. while gassing with argon 1.9 ml of a 1.04 molar lithium borohydride solution in tetrahydrofuran (2 mmol) and the mixture is stirred at 40°-45° C. for 2 hours. After cooling 3 ml of 3N HCl are added dropwise thereto at 10°-15° C. The mixture obtained is then stirred at 70° C. for 30 minutes and susequently extracted in 2 separating funnels with 100 ml of ether each time. The organic phases are washed four times with 50 ml of water each time, combined, dried over sodium sulphate and concentrated. The residue is chromatographed on 150 g of silica gel with 600 ml of n-hexane/ether (4:6, v/v) and 800 ml of toluene/acetone/glacial acetic acid (92:5:3, v/v). There is obtained (3aS,6aR)-1,3-dibenzyl-dihydro-1H-furo[3,4-d]imidazole-2,4(3H,3aH)-dione with [α]D20 =+49.3° (1% in CHCl3), which corresponds to an optical purity of 79.5% e.e.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C@@H:10]([CH3:22])[CH2:9]3.[CH:23](OC)=[O:24].C[O-].[Na+].O[C@@]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C)C(=C(C)C(=O)C(=CO)C1)CC3>O1CCCC1.CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[C:14](=[CH:23][OH:24])[CH2:15]1)[C@@H:10]([CH3:22])[CH2:9]3
Reactant: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reactant: COC=O
Agent: CC1=C2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3CC[C@]4(C)O)[C@@]2(C)CC(=CO)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC(=CO)C(=O)C=C12

Procedure:
17β-Hydroxy-2-hydroxymethylene-6α-methylandrost-4-en-3-one was prepared from 286 g. of 17β-hydroxy-6α-methylandrost-4-en-3-one (6α-methyltestosterone), 410 ml. of methyl formate, 140 g. of sodium methoxide, 40 ml. of methanol and 3 l. of tetrahydrofuran according to the procedure of Example 1, part (c). The total product, obtained nearly quantitative yield as an amber glass was used directly in the next reaction.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:12]1(=[O:14])[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]=[CH:3][CH:2]=[C:1]3[CH2:11]1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-Naphthylacetic acid (100 g, 530 mmol) was dissolved in dichloromethane (15 ml). Thionyl chloride (158 g, 1.32 mol) was added under ice-cooling and the mixture was heated under reflux for 1 hr. The solvent was evaporated and 1,2-dichloroethane (500 ml) was added to the obtained residue for dissolution. Aluminum chloride (150 g, 1.12 mol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, dried over magnesium sulfate and concentrated to give acenaphthen-1-one (80 g) as yellow crystals.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:20]([N:10]2[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]2[CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:21])[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1C(=O)c1cccc(Cl)c1

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 73 and 3-chlorobenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:20])[C:13]=2[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.NC[C@H]1CC[C@H](O)CC1.[NH:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][N:55]=2)[C:50]([CH:57]=O)=[CH:49]1.N1CCC[C@H]1C(O)=O>CC(O)C>[NH:48]1[C:56]2=[N:55][CH:54]=[CH:53][CH:52]=[C:51]2[C:50]([CH:57]=[C:11]2[O:10][C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)=[C:13]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:12]2=[O:20])=[CH:49]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)OC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OCC1=O
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: NC[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)CCl
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of isopropyl 2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and trans-4-aminomethylcyclohexanol (0.056 mg, 0.49 mmol) in 2-propanol (1.0 mL) was stirred at ambient temperature for 20 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and L-proline (0.0050 g, 0.044 mmol) were added then the mixture was refluxed for further 1.5 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford isopropyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.0076 g, y. 4%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C([CH2:14][C:15]([O-])=[O:16])(C)=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:7]([C:3]1[C:2]([O:1][C:15](=[O:16])[CH3:14])=[CH:6][S:5][CH:4]=1)=[O:8]
Reactant: COC(=O)C1CSCC1=O
Reactant: C=C(C)CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cscc1OC(C)=O
Temperature: -25 °C

Procedure:
A 320 g. portion of methyl tetrahydro-4-oxo-3-thiophenecarboxylate [Hromatka et al., Monat. Chemie, 104, 1520 (1973)] is dissolved in 650 ml. of isopropenylacetate, 2.0 g. of p-toluenesulfonic acid is added and the mixture is refluxed overnight. The mixture is concentrated, dissolved in 750 ml. of methylene chloride, cooled to -25° C. and 160 ml. of sulfuryl chloride is added over a one hour period. The methylene chloride is distilled off giving 4-acetoxy-3-thiophenecarboxylic acid methyl ester.
Reaction SMILES: [C:1](=[N:5][C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][C:9]([CH2:14][CH3:15])=[C:8]([N:16]=[C:17]([CH2:19][CH3:20])[CH3:18])[C:7]=1[CH3:21])([CH2:3][CH3:4])[CH3:2]>[Pt].CC(C)=O>[CH:17]([NH:16][C:8]1[C:9]([CH2:14][CH3:15])=[CH:10][C:11]([CH2:12][CH3:13])=[C:6]([NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])[C:7]=1[CH3:21])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)=Nc1c(CC)cc(CC)c(N=C(C)CC)c1C
Agent: [Pt]
Solvent: CC(C)=O
Product: CCc1cc(CC)c(NC(C)CC)c(C)c1NC(C)CC
Reaction time: 12 h

Procedure:
N,N′-di-sec-butylidene-[diethyl(methyl)-1,3-benzenediamine] (28 g) and Pt(S)/C (2.8 g) were added to acetone (30 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. The mixture was kept at 21° C. and 125 psi (8.62×105 Pa) of H2 for 12 hours, forming the corresponding N,N′-di-sec-butyl-[diethyl(methyl)-1,3-benzenediamine] quantitatively.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]([N+:20]([O-:22])=[O:21])=[C:6]([C:8]([C:18]#[N:19])([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:9]([OH:11])=[O:10])[N:7]=1.C.N[C:26]1NC(=O)C([N+]([O-])=O)=C(Cl)N=1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]([N+:20]([O-:22])=[O:21])=[C:6]([C:8]([C:18]#[N:19])([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH3:26])=[O:10])[N:7]=1
Reactant: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: N#CC(Cc1cccs1)(C(=O)O)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetic acid, methyl hydride (4.5 g, 60% suspension in oil washed with hexane) is suspended in dry DMF (50 mL) under an atmosphere of dry N2 and a solution of methyl 2-cyano- 3-(2-thienyl) propionate (U.S. Pat. No. 4,279,903) (22.0 g) in dry DMF (50 mL) is added dropwise when a dark blue solution is formed. A solution of freshly recrystallized 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone (8.57 g) in DMF (75 mL) is added in one portion. The reaction mixture is heated at 60° C. overnight and cooled and then is acidified to pH 5 with 1N HCl. It is poured into 1000 mL ethyl acetate and is extracted with water (4×300 mL). The organic layer is evaporated to near dryness and the residue is suspended in ether and collected by filtration. The crude product is washed with hexane until the washings are no longer green. The solid is dried under vacuum to give 2-Amino-α-cyano-1, 6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidine-acetic acid, methyl ester. ##STR14##
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13].I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[O:13]=[C:4]1[N:3]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](=[O:12])[O:5]1
Reactant: CCOC(=O)CI
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (851 mg, 60% dispersion in oil) in dry N,N-dimethylformamide (DMF) (15 ml) was cooled under argon in an ice bath. A solution of 1H-thieno[3,2-d][1,3]oxazine-2,4-dione (3 g) in DMF (10 ml) was added over ca 20 min. The reaction mixture was stirred for 30 min at room temperature, then recooled in an ice bath. Ethyl iodoacetate (4.55 g) was added and the mixture stirred at room temperature for ca 2 h. The solution was concentrated to about half volume and cooled in an ice bath. Water was added (ca 200 ml). After 10 min the precipitate was filtered off and washed with water and hexane and dried at 40° C. in vacuo overnight. The title compound was obtained as a white solid (3.62 g, 80%). 1H-NMR (CDCl3) δ 1.30 (3H, t), 4.28 (2H, q), 4.71 (2H, s), 6.77 (1H, d), 7.87 (1H, d). (APCI+) Found (M+1)=256, C10H9NO5S requires 255.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])[C:9]1=[O:23].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][C:19](=[O:21])[N:18]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:17]2=[O:22])[C:9]1=[O:23]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCN1C(=O)CC2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.192 g., 50% w/w oil dispersion) was added to a stirred solution of 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.5 g.) in dry N,N-dimethylformamide (DMF) (20 ml.) under a nitrogen atmosphere. The solution was stirred for 30 minutes and then chloromethyl pivaloate (0.60 g.) was added. The mixture was stirred for 20 hours and then poured into water (30 ml.) The mixture obtained was extracted with ethyl acetate (2×40 ml.). The combined extracts were washed with water (2×15 ml.) dried (MgSO4) and evaporated. The residue was dissolved in ethyl acetate (20 ml.). Chromatographic silica gel (10 g.) was added to the solution and then the solvent was evaporated. The residue was added to a column of silica gel (400 g.) made up in ethyl acetate/petrol (60-80 (1:1 v/v). This solvent mixture was used to elute the column. Evaporation of those combined fractions of eluate containing the major component [relative flow value 0.6, as judged by TLC (SiO2 : 50% v/v EtOAc/toluene)] gave 1'-(3,4-dichlorobenzyl)-1-pivaloyloxymethyl-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione as an oil which solidified slowly to give a solid (0.55 g.), m.p. 134°-135° C. (cyclohexane).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:23]#[N:24])[CH2:2][CH2:3][N:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60° C. (7 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H2O (2×50 ml), and saturated aqueous NaCl (50 ml), dried (Na2SO4) and concentrated in vacuo. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].C[Li].C([Li])(C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1.C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[SH:9])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Fc1ccc(S)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-fluoro-thiophenol (6.0 g, 28.9 mmol) in dry tetrahydrofuran (TBF, 25 mL) at −78° C. was slowly added methyl lithium (1M in cumene/TBF, 28.9 mL, 28.9 mmol). After 30 min at −78° C., tert-butyl lithium (1.7 M in THF, 39.9 mL, 63.8 mmol) was added and the reaction mixture was stirred 30 min at −78° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.77 g, 28.9 mmol) in THE (20 mL) was added and the reaction mixture was allowed to warm to rt and stirred overnight. Water (50 mL) and ethyl acetate (25 mL) were added, and organic phase was discarded. The aqueous phase was extracted with ethyl acetate (50 mL) and saturated aqueous ammonium chloride (25 mL). The organic phase was washed with saturated aqueous ammonium chloride (25 mL) and dried over magnesium sulfate, and evaporated to afford the crude product. The crude product was purified by flash chromatography on silica gel (eluent: An increasing amount (0-20%) of ethyl acetate in heptane). Yield: 4.67 g (49%).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 178.4 %

Procedure:
The monosilylated material (2) (90 g, 0.20 mol) was dissolved in 1 L of distilled methanol and the solution cooled to 0° C. under an inert atmosphere. Sodium borohydride (36 g, 0.98 mol) was added portionwise over 1.5 hour at 0–5° C. The mixture was allowed to warm to room temperature with stirring over 16 hours. The majority of the methanol (approx. 700 mL) was removed under reduced pressure and the resulting grey suspension was diluted with water (250 mL). Hydrochloric acid (1 M; 190 mL) was added dropwise at room temperature to provide a white suspension. Ethyl acetate (500 mL) was added and the suspension stirred for 30 minutes to provide homogeneous aqueous and organic phases. The aqueous layer was separated and further extracted with 2×500 mL of ethyl acetate. The organic layers were combined and washed with saturated, aqueous sodium bicarbonate (300 mL) and saturated, aqueous sodium chloride (300 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the crude product as a colourless foam (79 g). The foam was subjected to dry-flash chromatography to provide (3) (65 g, 72%) as a colourless foam. Rf 0.51 (methanol/ethyl acetate, 0.5:9.5). 1H NMR (300 MHz, DMSO-d6) δ: 7.76 (1H, d, J=7.9 Hz), 7.69–7.66 (4H, m), 7.45–7.39 (6H, m), 4.63–4.57 (2H, m), 4.39 (1H, d, J=5.2), 4.27 (1H, d, J=7.6), 3.85–3.58 (7H, m), 3.43–3.38 (1H, m), 1.85 (3H, s), 0.99 (9H, s). 13C NMR (300 MHz, DMSO-d6) δ: 171.2, 135.6, 135.5, 133.9, 133.8, 130.0, 128.1, 70.9, 69.5, 68.6, 66.7, 61.1, 53.4, 27.0, 22.9, 19.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][CH2:57][C:58]([NH:60][CH3:61])=[O:59]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][CH2:57][C:58](=[O:59])[NH:60][CH3:61])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CNC(=O)CCCc1ccccc1O
Product: CNC(=O)CCCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.40 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.23 g of 4-(2-hydroxyphenyl)-N-methylbutyramide are reacted. The title compound is obtained as a colourless resin. Rf=025 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.73.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21](Cl)[N:20]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[NH2:28][NH2:29]>CC(O)C.O>[NH2:26][C:25]1[C:22]2[C:21](=[N:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])(=[O:10])=[O:11])=[CH:18][CH:17]=3)=[CH:24][N:23]=2)[NH:29][N:28]=1
Reactant: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)cnc12
Temperature: 120 °C

Procedure:
2,3-Dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2yl)-phenyl]-benzenesulfonamide (1.0 g) was suspended in a mixture of 5 ml iPrOH and 5 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT. The precipitate was filtered off and washed with water to give the title compound as a yellow solid after drying under vacuum. Yield: 536 mg (54%).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[O:1]([C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCN(c2ccnc(Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(Oc2nccc(N3CCNCC3)n2)cc1
Yield: 64 %

Procedure:
2-Phenoxy-4-(4-formylpiperazino)pyrimidine (2.6 g) in methanol (27 ml) and 2N hydrochloric acid (6.9 ml) was left at room temperature for 24 hours and then heated on a steam bath for 30 minutes. The solvent was evaporated in vacuo and the residue re-crystallized twice from isopropanol to give 2-phenoxy-4-piperazinopyrimidine (1.5 g) characterized spectroscopically, and used directly.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:12]([CH3:14])[NH:13][C:8]=2[CH:7]=[C:6]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[N:5]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:3][C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:19][CH:20]=3)[CH:12]([CH3:14])[NH:13][C:8]=2[CH:7]=[C:6]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[N:5]=1
Reactant: CCOC(=O)Nc1cc2c(c(N)n1)N=C(c1ccc(O)cc1)C(C)N2
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Nc1cc2c(c(N)n1)N=C(c1ccc(OCc3ccccc3)cc1)C(C)N2
Reaction time: 0.2 h

Procedure:
To a stirred suspension of NaH (13.5 mg of 60% oil-dispersion, washed 1× hexane) in deoxygenated (N2) DMSO was added 14 (101 mg, 0.30 mmol). After stirring 0.2 hour, the nearly-clear amber solution was treated with benzyl chloride (36 mg, 0.29 mmol), stirred 18 hours under N2, and evaporated to dryness. The residue was triturated with de-oxygenated (N2) H2O (10 mL) to give a solid, which was purified by flash chromatography (45 g, CHCl3 --MeOH, 99:1) followed by recrystallization from EtOAc-hexane to afford 17 as a pale yellow solid: yield, 44 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method G)=2.61