Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)#[N:2].C(N)CC.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.Cl[C:41]1[N:46]2[N:47]=[CH:48][CH:49]=[C:45]2[N:44]=[C:43]([CH3:50])[CH:42]=1>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([C:41]2[N:46]3[N:47]=[CH:48][CH:49]=[C:45]3[N:44]=[C:43]([CH3:50])[CH:42]=2)[CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1cc(Cl)n2nccc2n1
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCO
Solvent: CCCN
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)c1cc(C)nc2ccnn12

Procedure:
2.5 g (10.0 mmol) of N-(2'-cyanobiphenyl-4-yl)methyl-N-propyl amine (prepared from n-propylamine and 4-bromomethyl-2'-cyanobiphenyl by the method described in EP 490 820) and 1.8 g (10.7 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) were heated with reflux in 20 ml dry ethanol for 4 h. The mixture was concentrated to halve of the volume in vacuo and cooled with ice, while the remaining starting amine crystallized. It was filtered with suction, and the rest of the solvent was removed. The title compound was obtained from the residue after column chromatography (silica gel, acetone/hexane 1:9 and 2:3) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[CH2:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][CH2:6][Cl:7])[O:10][CH2:8][CH3:9]
Reactant: CCO
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OCCCl
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74%) of the intermediate ethyl chloroethyl carbonate as a crude product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([NH:13][CH2:14][C:15]2([OH:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCl.C(=O)(O)[O-].[Na+]>[Si:1]([O:8][CH2:9][C:10]1([N:13]([CH2:14][C:15]2([OH:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[C:40](=[O:41])[CH2:39][Cl:38])[CH2:11][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNC2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CN(C(=O)CCl)C2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirring solution of tert-butyl 4-(((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate (1.688 mmol) and N,N-diisopropylethylamine (4.22 mmol) in anhydrous dichloromethane (30 mL) cooled to 0° C. was added neat chloroacetyl chloride (2.53 mmol). After 30 min, the reaction was diluted with saturated aq sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and were evaporated onto silica. Purification of the solid by flash chromatography (30% ethyl acetate in hexanes) afforded the title product (742 mg, 85% yield) as a light orange oil. MS(ES)+ m/e 491.4 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([CH3:29])[CH:22]=[C:23](Br)[CH:24]=2)[N:19]=1.[Cl-].[NH4+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O>CCCCCC.O1CCCC1.O.[Cl-].[Zn+2].[Cl-].CO.C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([CH3:29])[CH:22]=[C:23]([C:8]3[N:7]([CH3:6])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH:24]=2)[N:19]=1
Reactant: COc1ccc2cc(Br)cc(C)c2n1
Reactant: Cn1cnc2ccccc21
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: COc1ccc2cc(-c3nc4ccccc4n3C)cc(C)c2n1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
n-Butyllithium (3.55 cm3 of a 1.55M solution in hexane) was added dropwise to a stirred solution of 1-methyl-benzimidazole (0.6 g) in tetrahydrofuran (THF) (10 cm3) at -50° under nitrogen. After 1 hour a solution of anhydrous zinc chloride (1.5 g) in THF (10 cm3) was added and the mixture allowed to warm to room temperature. 2-Methoxy-6-bromo-8-methylquinoline (1.25 g) and tetrakis (triphenylphosphine)palladium (O) (0.05 g) were added and the mixture heated under reflux for 4 hours. Saturated ammonium chloride solution (10 cm3) was added to the cooled mixture, followed by a solution of ethylenediamine tetraacetic acid disodium salt (12.0 g) in water (200 cm3). Ethyl acetate (200 cm3 and methanol (20 cm3) were added and the phase separated. The aqueous layer was further extracted with methanol:dichloromethane; 1:20 by volume (2×200 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to afford a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:100 by volume. Combination and evaporation of appropriate fractions gave the title compound (1.05 g) which was characterised spectroscopically and used in Example 4 without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][N:24]([CH3:26])[CH3:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][N:24]([CH3:26])[CH3:25])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: Cc1nc2c(OCc3ccccc3N)cccn2c1CN(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1COc1cccn2c(CN(C)C)c(C)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
Acetic anhydride (0.43 g) was added dropwise to a solution of 8-(2-aminobenzyloxy)-3-dimethylaminomethyl-2-methylimidazo[1,2 a]pyridine (1 g) in methylene chloride (13 ml) with ice cooling. After being stirred for 5 hours at room temperature the reaction solution was washed successively with aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (20 g) with a mixture of methylene chloride and methanol (50:1-20:1) as an eluent to give 8-(2-acetamidobenzyloxy)-3-dimethylaminomethyl-2-methylimidazo[1,2-a]pyridine (0.88 g)
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(O)C.[OH-].[Na+]>[N+:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: OC(CCl)CCc1cccnc1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 25 °C

Procedure:
A solution of (±)-α-(chloromethyl)-3-pyridinepropanol (0.80 g) in ethanol (10 ml) was added to a refluxing solution of 3'-nitrobiphenyl-4-ol (1.40 g) in ethanol (20 ml) and aqueous sodium hydroxide (1.4 M, 5 ml) over 30 minutes. The solution was heated at reflux for a further hour and then was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with chloroform:ethanol (49:1 to 24:1) to give a yellow solid after trituration with ether (0.332 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([O:32][CH2:33][CH:34]=[O:35])=[CH:28][CH:29]=3)[NH:24][C:23]=2[C:22]([C:36]([NH2:38])=[O:37])=[N:21][CH:20]=1.[CH3:39][Mg]Br>O1CCCC1>[OH:35][CH:34]([CH3:39])[CH2:33][O:32][C:27]1[CH:26]=[C:25]2[C:30]([C:31]3[C:19]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([N:8]5[C:17](=[O:18])[C:16]6[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=6)[N:10]=[CH:9]5)[C:2]=4[CH3:1])=[CH:20][N:21]=[C:22]([C:36]([NH2:38])=[O:37])[C:23]=3[NH:24]2)=[CH:29][CH:28]=1
Reactant: C[Mg]Br
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC=O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.7 %

Procedure:
To a solution of 4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-(2-oxoethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (178 mg, 85% purity, 0.300 mmol) in tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (0.707 mL, 2.121 mmol). The mixture was stirred at rt for 20 min. Additional methylmagnesium bromide (0.50 mL, 1.50 mmol) was added. The mixture was stirred at room temperature for another 20 min and then the reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were combined and concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (7.6 mg, 0.014 mmol, 4.9% yield) as a yellow solid. LCMS (M+H)+=520.21. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 4.01 (m, 1H), 3.92-3.84 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([C:15]([O:17]CC)=[O:16])([C:10]([O:12]CC)=[O:11])[O:9][C:5]=2[CH:4]=1)=O.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:50]>ClCCCl>[Cl:32][C:28]1[CH:27]=[C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH2:1][C:3]2[CH:21]=[CH:20][C:6]3[O:7][C:8]([C:15]([O-:17])=[O:16])([C:10]([O-:12])=[O:11])[O:9][C:5]=3[CH:4]=2)[CH:31]=[CH:30][CH:29]=1.[Na+:50].[Na+:50]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C=O)cc2O1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C([O-])C1(C(=O)[O-])Oc2ccc(CNCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
One equivalent of the above aldehyde, one equivalent of 2-amino-1-(3-chlorophenyl)ethanol, one equivalent of acetic acid, and 1.5 equivalents of sodium triacetoxyborohydride in 1,2-dichloroethane is stirred at room temperature for 1 hour. The solvent is evaporated in vacuo. The residue dissolved in 2.5N sodium hydroxide in ethyl alcohol, heated at reflux temperature for one hour, and evaporated in vacuo. The residue is passed through an ion exchange column to give the title compound.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:31])=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl.C(N(CC)CC)C>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[C:20]([CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc(=O)[nH]c2)c1C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (40 mg, 0.09 mmol) in dioxane (1 mL) was added 4M HCl and the reaction was stirred at 90° C. for 3 hours. To the mixture at room temperature, 0.5 mL of triethyl amine was added and the reaction was concentrated under reduced pressure. The crude residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (50-100%). ESI-MS m/z calc. 439.4. found 440.3 (M+1)+. Retention times: 1.53 minutes. H NMR (400 MHz, DMSO) 8.79 (s, 1H), 7.76 (s, 1H), 7.56-7.53 (m, 2H), 7.44-7.32 (m, 3H), 6.35 (d, J=9.4 Hz, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 1.50-1.48 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1oc(=O)oc1CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(=O)oc1CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 2.0 g of 4-chlorobenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.9 g of the captioned compound as colorless crystals.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:17]([CH2:18]O)[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C>C(Cl)Cl>[C:1]([NH:9][C:10]1[S:11][CH2:18][CH:17]2[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:14][C:13]2([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[N:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=S)NC1(c2cccs2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: O=C(NC1=NC2(c3cccs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a 0° C. solution of racemic benzyl 3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-(2-thienyl)pyrrolidine-1-carboxylate (30 g, 60.5 mmol) in methylene chloride (300 mL) is added a methylene chloride solution (20 mL) of 1-chloro-N,N,2-trimethylpropenylamine (9.61 mL, 72.6 mmol). The resulting solution is stirred at 0° C. for 30 minutes and then warmed to room temperature. The solution is quenched with saturated sodium bicarbonate solution, the organic layer is isolated, dried over sodium sulfate and concentrated. The crude mixture is purified over silica gel eluting with 5% to 50% ethyl acetate in hexanes gradient to give the title compound (24 g, 83%). ES/MS (m/e): 478 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:8]1[N:9]=[C:10]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:11]=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(Cl)n1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCNCC2)n1

Procedure:
A solution of (3-Chloro-benzyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester I-4e (68 mg, 0.19 mmol) and piperazine (99 mg, 1.15 mmol) in Ethanol (2 mL) were refluxed overnight. The reaction mixture was cooled and poured into 0.1M NaOH and extracted into ethyl acetate. The organic layer was washed with H2O, brine, dried (Na2SO4), and concentrated to give the title compound I-4f (38 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:13])=[CH:4][N:3]=1.O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)[C:5]([CH3:13])=[CH:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1cnc(Cl)nc1NCCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3C)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)amino]-1-propanol (Example 339, 1.77 g, 8.81 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 970 mg, 8.81 mmol) in THF (33 mL) were added PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol). The reaction mixture was vigorously stirred at rt for 24 h, after which additional amounts of PPh3 (2.31 g, 8.81 mmol) and ADDP (2.22 g, 8.81 mmol) were added. After an additional 24 h, the reaction mixture was diluted with hexanes, filtered through Celite®, and the filtrate concentrated under reduced pressure. The residue was then purified by silica gel chromatography (2:1 to 1:1 hexanes/EtOAc) to give the product (1.70 g, 99%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.75-1.80 (m, 1H), 2.02 (s, 3H), 2.12-2.18 (m, 2H), 2.38-2.46 (m, 2H), 2.72 (dd, 1H), 2.84-2.2.92 (m, 2H), 3.52-3.55 (m, 1H), 3.73 (q, 2H), 4.13 (t, 2H), 4.18 (q, 2H), 6.70 (d, 1H), 6.77 (s, 1H), 7.08 (d, 1H), 7.78 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Yield: 99.7 %

Procedure:
By reaction of 17 g (82 mmol) of methyl 3-tert-butyl-4-hydroxybenzoate with 10.7 ml (82 mmol) of benzyl bromide in a manner analogous to Example 1(a), 24.4 g (100%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [S:1]([OH:5])(O)(=O)=O.S1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:13]=2)[CH2:8][CH2:7]1.S1CCN(C2C3C(=C(OC)C=CC=3)C=C(N3CCNCC3)N=2)CC1.OO.O.O.O.Cl.C(O)(C)C>S(=O)(=O)(O)O>[O:5]=[S:1]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[N:13]=2)[CH2:8][CH2:7]1
Reactant: COc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: OO
Solvent: CC(C)O
Solvent: O
Product: COc1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Yield: 36 %

Procedure:
1-(1-Oxido--thiomorpholino)-3-piperazino-5-methoxy-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-methoxy-isoquinoline hemisulfate by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. of its hydrochloride trihydrate: 151°-153°C (decomposition; from isopropanol). Yield: 36% of theory.
Reaction SMILES: [CH3:1][C@:2]1([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.I[Si](C)(C)C.Cl>C(Cl)Cl.CO>[CH3:1][C@:2]1([NH2:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: C[C@]1(NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@]1(N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To a solution of (S)-benzyl 3-methyl-1-(4-nitrophenyl)piperidin-3-ylcarbamate (525 mg, 1.421 mmol) in CH2Cl2 (5 ml) cooled at 0° C. was added iodotrimethylsilane (0.290 mL, 2.132 mmol) dropwise. After addition, the orange colored solution was stirred at 0° C. for 15 min, then at rt for 1 hr. The reaction was quenched by addition of 4.3 mmol of HCl (1.1 mL of 4N HCl in dioxane) in MeOH (5 mL). The mixture was then concentrated and the dark reddish residue was partitioned between ether and water. The ether layer was extracted with 0.2 N aqueous HCl. The combined acidic aqueous solution was extracted with ether (1×), then basified at 0° C. with 1N aqueous NaOH to pH=10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the desired product, (S)-3-methyl-1-(4-nitrophenyl)piperidin-3-amine (277 mg, 1.177 mmol, 83% yield) as a dark reddish oil. Anal. Calcd. for C12H17N3O2 m/z 235.2, found: 236.0 (M+H)+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (d, J=9.34 Hz, 2H), 6.83 (d, J=9.34 Hz, 2H), 3.62-3.50 (m, 1H), 3.32 (d, J=12.64 Hz, 1H), 3.18 (s, 1H), 3.12 (d, J=13.19 Hz, 1H), 1.82 (d, J=4.95 Hz, 1H), 1.75 (s, 1H), 1.69-1.54 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C:10](=[CH2:23])[C@H:9]3[CH3:24].[OH-:26].[Na+]>CO>[F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11]2([O:26][CH:12]2[C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C:10](=[CH2:23])[C@H:9]3[CH3:24]
Reactant: [OH-]
Reactant: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Agent: [Na+]
Solvent: CO
Product: C=C1[C@@H](C)[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](F)C[C@@H]23)[C@@]2(C)[C@H](C)CC(=O)C3OC132
Temperature: 0 °C
Reaction time: 24 h

Procedure:
344 mg of 16α-fluoro-1β,7α-dimethyl-6-methylenandrost-4-ene-3,17-dione (which can be prepared as described in Example 1) are dissolved in methanol (20 ml) and the solution cooled to 0°-5° C. Ice cold 36% hydrogen peroxide (2 ml) and 2% sodium hydroxide (1 ml) are added and the mixture stirred for further 24 hrs at 0°-5° C. Then the mixture is poured into ice water, the product filtered off, washed with water and dried to yield 16α-fluoro-4,5-epoxy-1β,7α-dimethyl-6-methylenandrostane-3,17-dione (306 mg).