Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:13][CH2:12][CH2:11]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:61]=[CH:60][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:53][CH:52]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47](=O)[NH:48][N:49]=1>CN(C=O)C>[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:52]=[CH:53][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:60][CH:61]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47]([N:10]2[CH2:13][CH2:12][CH2:11]2)=[N:48][N:49]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Reactant: C1CNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(N4CCC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
DIPEA (38.44 mg, 51.81 μL, 0.2974 mmol), azetidine (8.490 mg, 0.1487 mmol) and bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (76.27 mg, 0.1636 mmol) were added to a solution of 4-(5-amino-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-N,N-dimethylbenzamide (50 mg, 0.1487 mmol) in DMF (485.1 μL) and the resulting solution stirred at room temperature for 2 h. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were concentrated in vacuo and triturated with dichloromethane/ diethyl ether to give the product (8.6 mg, 15% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 6H), 4.25 (t, 4H), 7.52 (dd, 2H), 7.65 (br s, 1H), 8.04-8.06 (m, 2H) and 8.83 (s, 1H) ppm; MS (ES+) 366.21
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O>>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared according to General Procedure D by the reaction of 4-[4-(4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 5) with trifluoroacetic acid, followed by reaction of the resulting amine with isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.2 Hz), 1.95-2.01 (m, 4H), 2.98-3.09 (m, 2H), 3.19 (s, 3H), 4.07-4.12 (m, 2H), 4.78-4.82 (m, 1H), 4.93-4.97 (m, 1H), 7.92-7.94 (m, 2H), 8.17-8.19 (m, 2H), 8.41 (s, 1H), 8.54 (s, 1H), 10.49 (s, 1H). Mass spectrum MH+=459.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:16][C@H:10]3[CH2:11][N:12](C)[CH2:13][CH2:14][C@@H:9]3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[BH4-].[Na+].CO>C(O)C.O.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:16][C@H:10]3[CH2:11][NH:12][CH2:13][CH2:14][C@@H:9]3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: CN1CC[C@@H]2CC(=O)c3cc(N)ccc3C[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)C=C[C@H]1CCNC[C@@H]1C2
Reaction time: 1 h

Procedure:
The starting material can be produced as follows. A solution of 13.2 g of trans-8-amino-1,2,3,4,4a,5,11,11a-octahydro-2-methyl-6H-benzo[5,6]cyclohepta[1,2-c]pyridin-6-one in 132 ml of ethanol is mixed at 40° with a solution of 1.45 g of sodium borohydride in 4 ml of water and 0.1 ml of water and 0.1 ml of conc. caustic soda and the resulting mixture is stirred for 1 hour at 70°. After addition of 10 ml of methanol, the reaction mixture is boiled for 10 minutes and evaporated to dryness and the residue is dissolved in water and chloroform. After separation of the organic phase, the aqueous phase is extracted with chloroform and the combined organic extracts are washed with water, dried over potassium carbonate and evaporated. The crude product is employed as such in the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[C:4]=12.[BH4-].[Na+].[CH3:19][C:20]([CH3:22])=O>>[CH3:19][CH:20]([NH:16][CH:15]1[C:4]2=[C:3]([CH3:2])[C:11]3[C:6]([N:5]2[CH2:12][CH2:13][CH2:14]1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH3:22]
Reactant: CC(C)=O
Reactant: Cc1c2n(c3ccccc13)CCCC2N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1c2n(c3ccccc13)CCCC2NC(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Molecular sieves (20 g, 4 Å type) were added to a solution of 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-amine hydrochloride (8 g, 40 mmol, described in Example 20, Step 2) in acetone (200 mL). The reaction mixture was stirred at 25° C. for 14 hours. The sieves were removed by filtration and benzene (25 mL) was added to the filtrate. The mixture was evaporated and the residue dissolved in methanol (100 mL). Sodium borohydride (2 g, 52.6 mmol) was added portionwise and the reaction mixture stirred at 25° C. overnight. After evaporation of the mixture in vacuo, the residue was partitioned between water (60 mL) and ether (100 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel (120 g). Elution with 2% methanol in chloroform afforded 6 g (62%) of the title base as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[C:32](#N)[CH3:33].Cl[Si](C)(C)C.C(I)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:32][CH3:33])[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: CC#N
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCI
Product: CCN1CCc2ccccc2[C@@]1(c1ccccc1)[C@H](Oc1cc(OC)cc(OC)c1)C(=O)O
Temperature: 55 °C
Yield: 27.2 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in acetonitrile (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before ethyliodide (95 μl, 1.19 mmol) is added. Stirring at 55° C. is continued for another 16 h before water is added (about 200 μl). The solvent is removed under reduced pressure and the crude product is purified by prep. HPLC on Rp-C18 silica gel to furnish (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-ethyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (58 mg) as a white solid. LC-MS2: tR=4.20 min, [M+1]+=448.39, [M−1]−=446.34.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:26])C.[Li+].[OH-].Cl>>[Cl:12][C:11]1[N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7](=[O:26])[C:8]([NH:13][C@H:14]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9][CH:10]=1
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H](Cc2ccccc2)CN(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN(C)C[C@H](Cc1ccccc1)Nc1ncc(Cl)n(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [6-chloro-(S)-3-(1-dimethylaminomethyl-2-phenyl-ethylamino)-2oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (385 mg, 0.98 mmol) in THP (6 ml) is added 1N LiOH (1.27 ml, 1.27 mmol) and the reaction mixture is stirred at room temperature for 3 h. To the reaction mixture is added 1N HCl (1.27 ml, 1.27 mmol) and the reaction mixture is concentrated in vacuo, azeotroped with methanol and dried on high vacuum to give [6-chloro-(S)-3-(1-dimethylaminomethyl-2-phenylethylamino)-2-oxo-2H-pyrazin-1-yl)-acetic acid as a white solid which contains 1.3 eq LiCl. 1H NMR (CD3OD, 400 MHz): δ 7.30–7.15 (m, 5H); 6.86 (s, 1H); 4.80 (A of AB, d, J=16.7 Hz, 1H); 4.76–4.66 (m, 1H); 4.56 (B of AB, d, J=16.7 Hz, 1H); 3.45 (A of ABX, dd, J=13, 12.9 Hz, 1H); 3.25 (B of ABX, dd, J=13, 3.4 Hz, 1H); 3.00–2.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.Cl>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A 100-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (4.75 g, 14.52 mmol), dichloromethane (50 mL), pyridine (1.996 mL, 24.68 mmol), and cyclopropanecarbonyl chloride (1.976 mL, 21.77 mmol). The reaction mixture was stirred at rt for 2 h and then 1 M aqueous HCl solution (25 mL) was added. The organic layer was separated and concentrated under reduced pressure to afford (S)-tert-butyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (5.72 g, 99%) as a solid, which was used directly in next step. MS (ESI, pos. ion) m/z 395, 397 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:5]=2[N:6]=1.[H-].[Na+].FC(S(O[CH2:22][P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])(=O)=O)(F)F>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:22][P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])[C:5]=2[N:6]=1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: Nc1nc2c(O)cccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1cccc2sc(N)nc12)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-amino-4-hydroxybenzothiazole (1 mmole) and NaH (1.3 mmole) in DMF (5 mL) was stirred at 0° C. for 10 min, and then treated with diethylphosphonomethyl trifluoromethylsulfonate (1.2 mmole). After being stirred at room temperature for 8 h, the reaction was subjected to extraction and chromatography to give 2-amino-4-diethylphosphonomethyloxybenzothiazole as an oil.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[NH2:27][OH:28].CC(O)C>O>[OH:28][N:27]=[C:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH2:14][CH2:13]2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(OCCCN2CCC(CCCO)CC2)cc1
Reactant: NO
Solvent: CC(C)O
Solvent: O
Solvent: CS(C)=O
Product: NC(=NO)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a dimethylsulfoxide (200 mL) solution of 18.7 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile was added 8.92 mL of a 50% hydroxylamine aqueous solution at room temperature, which was then stirred at the same temperature for 5 hours and 30 minutes. Thereto was added 8.92 mL of a 50% hydroxylamine aqueous solution at room temperature, which was stirred at the same temperature for 15 hours and 50 minutes. To the reaction mixture were added 2-propanol and water, which was then stirred at room temperature for one hour. The precipitate was collected by filtration and washed with water to provide 17.5 g of N′-hydroxy-4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4].C(OC(=O)C)C.[N:22]12CN3CN(CN(C3)C1)C2.C(O)C.[ClH:35]>>[ClH:35].[NH2:22][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (60.00 g 1.00 equiv; 210.50 mmoles (mmol)) in ethylacetate (EA) (450 mL; 4.60 moles (mol)), add 1,3,5,7-tetraazatricyclo-[3.3.1.13,7]decane (Methenamine, 1.10 equiv; 231.55 mmol; 32.46 g) and stir at RT overnight. Remove the solvent in vacuo and triturate the solid with methyl-t-butylether (MTBE), filter and dry in vacuo. Add ethanol (450 mL; 7.73 mol) followed by hydrogen chloride (36.5 wt/wt % in water) (150 mL; 8.30 equiv; 1.75 mol) and stir the mixture overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50° C. for 1 week to give the title compound (54.23 g; 100% yield) as a white solid with some amount of ammonium salt. 1H NMR (300 MHz, DMSO): 8.69-8.59 (m, 4H), 8.07-8.01 (m, 1H), 4.95 (d, J=5.2 Hz, 2H). Use the solid as is.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49].C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:50][C:48](=[O:49])[CH2:47][NH:46][C:21]([N:7]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:6]1=[O:33])=[O:22]
Reactant: NCC(N)=O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCC(N)=O)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (197 mg, 0.315 mmol; Example 6A) was reacted with glycinamide hydrochloride (104 mg, 0.945 mmol) and N,N-diisopropylethylamine (122 mg, 0.945 mmol) in acetonitrile (2.5 ml) to give the target compound (72 mg, 39% of theory).
Reaction SMILES: [Cl-].[C:2]([O:7][CH3:8])(=[O:6])[C:3]([O-])=[O:4].[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:3](=[O:4])[C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1
Yield: 100.6 %

Procedure:
With stirring, 6.7 g of monomethyl oxalate chloride are added dropwise at 0° to 5° C. to a solution of 6.4 g of 4-chloroaniline and 7.9 g pyridine in 150 ml of dry methylene chloride. When the addition is complete, the suspension is stirred for 30 minutes at room temperature, then diluted with 100 ml of methylene chloride, washed twice with 3N hydrochloric acid and once with saturated sodium bicarbonate solution, dried and concentrated. The residual oil crystallises on trituration, affording 10.4 g of crystalline title compound with a melting point of 162°-164° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN1CCCN(C)C1=O.[CH3:22][O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34][CH3:35])=[O:33])[CH2:27]1)=[O:25].Br[CH2:37][CH2:38][Cl:39]>O1CCCC1.CCCCCC>[CH3:35][O:34][C:32]([C:28]1([CH2:37][CH2:38][Cl:39])[CH2:29][CH2:30][CH2:31][CH:26]([C:24]([O:23][CH3:22])=[O:25])[CH2:27]1)=[O:33]
Reactant: ClCCBr
Reactant: COC(=O)C1CCCC(C(=O)OC)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1CCCC(CCCl)(C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 18.6 %

Procedure:
A solution of N,N-diisopropylamine (4.5 mL, 32 mmol) in tetrahydrofuran (25 mL) was cooled at −78° C. and treated with 1.6 M of n-butyllithium in hexane (19 mL). The reaction was warmed to 0° C., stirred for 5 minutes, then cooled back to −78° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL, 120 mmol) was added dropwise over 20 minutes, then a solution of cyclohexane-1,3-dicarboxylic acid dimethyl ester (5.0 g, 25 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture stirred for 1 hour at the same temperature. Then a solution of 1-bromo-2-chloroethane (2.9 mL, 35 mmol) in tetrahydrofuran (8 mL) was added dropwise. The reaction was allowed to return slowly to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with a small amount of water and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified with chromatography to give the intermediate 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester (1.22 g). A solution of N,N-diisopropylamine (0.91 mL, 6.50 mmol) in tetrahydrofuran (10 mL) was cooled at −78° C. and treated with 1.6 M of n-butyllithium in hexane (4.06 mL). The reaction was warmed to 0° C., stirred for 5 minutes, and then cooled back to −78° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.24 mL, 18.6 mmol) was added dropwise over 20 minutes, then a solution of 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester (1.22 g, 4.64 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred for 1 hour at the same temperature. The reaction was allowed to return slowly at room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The resulting residue was diluted with a small amount of water and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give crude product (3.05 g) containing DMPU. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:13]([CH:14]=[CH2:15])[O:16][C:26]1([CH3:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
983 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-5-cyclohexylpentene-3-ol was dissolved in 5 ml of dichloromethane, and 4 ml of 2,2-dimethoxypropane and 30 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature overnight. Then, 100 ml of ethyl acetate was added to the reaction mixture. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to obtain 967 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine as colorless oily substance.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][CH:16]=3)=[N:13][CH:14]=2)O1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[N:46]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C(Cl)Cl.CC(C)=O.C(Cl)Cl.C1COCC1>[CH:23]1[C:22]2[N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[N:13]=[CH:14][C:9]([C:36]5[CH:41]=[N:40][C:39]([C:42]6[O:43][C:44]7[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=7[N:46]=6)=[CH:38][CH:37]=5)=[CH:10][CH:11]=4)=[CH:16][CH:17]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3o2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)nc4)cn3)nc2c1
Yield: 80.7 %

Procedure:
Following the procedure for 19, 7 (0.868 g, 1.95 mmol), 11 (0.535 g, 1.95 mmol), tetrakis(triphenylphosphine)palladium(0) (112 mg, 97.2 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded 20 (0.81 g, 81%) as a white solid after flash chromatography (SiO2, 100% CH2Cl2 to 19:1 CH2Cl2-acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[O:7][C:6]=2[CH:12]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[CH2:24][C@H:23]([CH3:25])[NH:22][CH2:21][C@H:20]2[CH3:26])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:9][C:8]([N:22]2[CH2:21][C@H:20]([CH3:26])[N:19]([CH2:18][C:17]3[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:24][C@H:23]2[CH3:25])=[O:11])=[C:6]([OH:7])[CH:12]=1
Reactant: O=C1COc2ccc(Cl)cc2O1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Temperature: 95 °C
Yield: 63.3 %

Procedure:
To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.48 g, 2.6 mmol) in toluene (5 mL) was added 1-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine (0.59 g, 2.6 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.67 g).
Reaction SMILES: NCC1C=CC(S(=NC)(N(C)C)=O)=CC=1.[C:16]([CH2:18][N:19]=[S:20]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:25][CH:24]=1)([CH3:22])=[O:21])#[N:17]>>[C:16]([CH2:18][N:19]=[S:20]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([CH3:22])=[O:21])#[N:17]
Reactant: CS(=O)(=NCC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: CN=S(=O)(c1ccc(CN)cc1)N(C)C
Product: CS(=O)(=NCC#N)c1ccc(CN)cc1

Procedure:
The title compounds is prepared in analogy to preparation 60d, using 2-(4-(N-cyano-methyl-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 64a) as starting material. ESI mass spectrum: [M+H]+=224; r.t. HPLC: 0.22 min (X011_S03).