Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19](Cl)[Cl:20])([CH3:17])[CH3:16]>C1COCC1>[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[P:19]([Cl:20])[O:1][CH2:2][CH2:3][C:4]#[N:5])([CH3:17])[CH3:16]
Reactant: CC(C)N(C(C)C)P(Cl)Cl
Reactant: N#CCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Reaction time: 0.42 h

Procedure:
FIG. 15 illustrates the synthesis of bifunctional diphosphitylating, triphosphitylating, and tetraphosphitylating reagents (66, 69, 72). For the preparation of 66, phosphorus trichloride (21, 875 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added to anhydrous THF. Diisopropylamine (1,400 μL, 10 mmol) was added dropwise in 10 min to the solution mixture and the mixture was stirred for 45 min at 0° C. to yield diisopropylphosphoramidodichloridite (29). Then 3-hydroxypropionitrile (22, 683 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise to the solution of 29 in anhydrous THF during 10 min period. The stirring was continued for 25 min at 0° C. to afford 2-cyanoethyl diisopropylphosphoramidochloridite (24). Water (180 μL, 10 mmol) and diisopropylethylamine (1,747 μL, 10 mmol) were added dropwise in 10 min period to the solution. The mixture was stirred for 10 min at 0° C. to yield 2-cyanoethyl diisopropylamine hydroxyphosphite (25). Then 29 (1 eq, 10 mmol) that was prepared at the same time in a separate reaction vessel, was added dropwise in 10 min period to the solution containing 25. The mixture was stirred for 25 min at 0° C. to yield diisopropylphosphoramidochloridite-O-2-cyanoethyl diisopropylphosphoramidite 66 (bifunctional diphosphitylating reagent). The reaction mixture containing diphosphitylating reagent 66 was immediately used in coupling reactions with polymer-bound p-acetoxybenzyl alcohol 78. Further stability studies on 66 using mass spectrometry methods showed that the compound remained stable after 2 months storage at −20° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11](Cl)[C:12](Cl)=[C:13](Cl)[C:14]=1Cl)[C:8]([OH:10])=[O:9].[CH2:20]([SH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:13]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:14]=1[S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Reactant: CCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1c(SCCCCCCCCCC)c(SCCCCCCCCCC)c(C(O)=NCCO)c(C(=O)O)c1SCCCCCCCCCC

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 5.30 g (30.4 millimols) of n-decanthiol, 6.30 g (45.6 millimols) of potassium carbonate and 20 ml of N,N-dimethylformamide are stirred at 25° C. for 7 hours. The mixture is acidified and extracted with methylene chloride. After recrystallisation from n-hexane at 0° C., 3.75 g (70% of theory) of the title compound are obtained; melting point 57°-8° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]3)=[CH:8][CH:9]=2)[C:4]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[N:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]3)=[CH:8][CH:9]=2)[C:4]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[N:3]1
Reactant: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cc(N3CC[C@@H](N)C3)ccc21
Temperature: 25 °C
Yield: 91.6 %

Procedure:
tert-Butyl {(3R)-1-[1-methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-yl}carbamate (0.200 g, 0.395 mmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature over night. The solvent and excess trifluoroacetic acid was evaporated and the residue was dissolved in ethyl acetate. The organic mixture was washed with saturated aqueous potassium carbonate. The solvent was evaporated to afford a pure (3R)-1-[1-methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-amine (15, 0.147 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:13].[N:14]([O-])=[O:15].[Na+].CCOCC>O>[ClH:13].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]=[O:15])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2ccc(O)cc21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1CCCc2cc(N=O)c(O)cc21
Temperature: 4 °C
Yield: 84 %

Procedure:
A mixture of 24.5 g (0.15 mol) of 1-methyl-1,2,3,4-tetrahydro-7-hydroxyquinoline, 75 ml of water and 75 ml of concentrated hydrochloric acid was stirred and cooled in an ice bath to 5°. To this mixture was added dropwise during 40 minutes a solution of 12.42 g(0.18 mol) of sodium nitrite in 50 ml of water while maintaining the temperature between 3 to 5° C. It was occasionally necessary to add a few ml of ether to control foaming. When the addition was complete, the reaction mixture was stirred for 40 min in the ice bath. The solid was collected and rinsed with 2N hydrochloric acid and with ether. It was recrystallized from 700 ml of 2.4 N hydrochloric acid to give 28.7 g (84%) of crude product as brown needles.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:28]>O>[Br:28][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(Br)ccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (885 mg, 3 mmol) in 8 mL of aq HBr was added a solution of NaNO2 (228 mg, 3.3 mmol) in 2 mL of H2O at 0° C., then the mixture was stirred at 0° C. for 40 minutes. After that, the mixture was poured into a solution of CuBr (905 mg, 6.3 mmol) in 8 mL aq HBr at 0° C. The reaction was heated to 60° C. and stirred for 2 hours. After cooling, the mixture was based with 2M NaOH to pH=8-9 and extracted with EA, washed with H2O and brine, dried and concentrated to give black solid. MS (m/z): 261 (M+H)+
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][OH:5].[C:26](OCC(F)(F)F)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(C(C)=O)C>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][O:5][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCCC(=O)OCC(F)(F)F
Solvent: CCC(C)=O
Product: CCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A mixture of 1 g of 17α,21-dihydroxy-pregna-4-ene-3,20-dione and 10 ml of trifluoroethyl butanoate in 50 ml of methyl ethyl ketone was reacted at 45° C. in the presence of 5 g of Candida cylindracea lipase for 8-10 hours, adding at regular time intervals 1 g of lipase. After completion of the reaction, the lipase was filtered off, the filtrate was concentrated under vacuum, taking up the residue three times with solvent. The semi-solid residue was purified by chromatography on a silica gel column with a dichloromethane/methanol 99:1 mixture. The richer fraction was evaporated to obtain 0.89 g (2.14 mM) of 17α-hydroxy-21-butanoyloxy-pregna-4-ene-3,20-dione.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH2:46]>C1COCC1>[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH:46][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1F)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 2,4-difluoro-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 568.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 1H-indazole-5-carboxylic acid (6.0 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq) and EDCI (8.5 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (15 g, 4.0 eq) dropwise at 0° C. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (4.4 g, 58%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.56 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [Na].Cl.[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1.[CH2:29]=O>CO.C1COCC1>[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH3:29])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1
Reactant: C=O
Reactant: CS(=O)(=O)N1CC(CCl)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc21
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)N(S(C)(=O)=O)CC2CCl
Yield: 73 %

Procedure:
Sodium cyanoborohydnide (40 mg, 0.64 mmol) then 2N HCl (0.5 mL) were added to a solution of 30 (96 mg, 0.24 mmol) and formaldehyde (0.18 mL of a 40% w/v aq. solution, 2.4 mmol) in MeOH (15 mL) and THF (5 mL) and the mixture stirred at 20° C. for 45 min. The solvent was evaporated, the residue was diluted with water and extracted with CH2Cl2 (×2), and the extracts dried (Na2SO4) and evaporated. Dry column chromatography (eluting with 1:2 EtOAc:petroleum ether) gave 3-(chloromethyl)-1-(methanesulfonyl)-6-[N-methyl-N-(4-nitrobenzyl)amino]indoline (31) (73 mg, 73%), mp (benzene-petroleum ether) 138-139 C. 1H NMR (CDCl3) a 8.18 (d, J=8.8 Hz, 2 H, ArH o to NO2), 7.39 (d, J=8.8 Hz, 2 H, ArH m to NO2), 7.05 (d, J=8.4 Hz, 1 H, H-4), 6.82 (d, J=2.4 Hz, 1 H, H-7), 6.3 5 (dd, J=8.4 2.4 Hz, 1 H, H-5), 4.63 (s, 2 H, NCH2Ar), 4.04 (dd, J=10.8, 8.8 Hz, 1 H, CHHN), 3.93 (dd, J=10.8, 4.7 Hz, 1 H, CHHN), 3.71 (dd, J=10.4, 4.1 Hz, 1 H, CHHCl), 3.68-3.61 (m, 1 H, H-3), 3.55 (dd, J=10.4, 7.8 Hz, 1 H, CHHCl), 3.11 (s, 3 H, NCH3), 2.81 (s, 3 H, NSO2CH3). 13C NMR a 150.3, 147.1, 146.5, 143.5, 118.9 (C-6,8,9,1,4), 127.4, 123.9 (C-2 and 6, 3 and 5), 125.5, 107.7, 97.9 (C-4,5,7), 56.5, 54.7 (C-2, NCH2Ar), 46.9 (CH2Cl), 41.8 (C-3), 39.5 (NCH3), 34.5 (SO2CH3). Anal. Calculated for C18H20ClN3O4S): C, 52.8; H, 4.9; N, 10.3; Cl, 8.7. Found: C, 52.6; H 5.1; N, 10.1; Cl, 8.9%.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:34][C:25]1[C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][CH2:7]4)=[CH:12][CH:13]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=[C:27]([C:30]([F:32])([F:31])[F:33])[N:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1Nc1ccc(-c2ccc(C3CCC(CC(=O)O)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (332 g, 0.69 mmol) was dissolved in THF/MeOH (3:1, 4 mL) and to it was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the organic solvent was removed via rotary evaporation. The remaining crude was diluted with water and the pH was adjusted to 2 with 1M HCl. The resulting precipitate was collected by filtration and dried under vacuum to obtain the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 0.95-1.04 (m, 2 H) 1.44 (dd, J=12.51, 2.91Hz, 2 H) 1.67 (br. s., 1 H) 1.74-1.87 (m, 6 H) 2.47 (m, 1 H) 2.60 (s, 3 H) 7.25 (d, J=8.59 Hz, 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.56 (d, J=8.34 Hz, 2 H) 7.66 (d, J=8.34 Hz, 1 H) 7.97 (dd, J=8.72, 2.65 Hz, 1 H) 8.48 (d, J=2.27 Hz, 1 H) 8.67 (d, J=8.34 Hz, 1 H) 8.80 (s, 1 H); MS (M+H)+ 470.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:46]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:51]([CH:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:52])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1)C1CCCC1
Yield: 25.6 %

Procedure:
To a suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (1.270 ml) was added triethylamine (0.062 ml, 0.444 mmol). A solution of cyclopentanecarbonyl chloride (0.024 g, 0.178 mmol) in dichloromethane (0.508 ml) was added dropwise and stirred. The reaction was quenched with water, extracted 2× with DCM, the organic extracts dried over MgSO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM with MeOH (0% to 10%) and collected fractions to obtain the title compound as a solid (30 mg, 25% yield). MS (ESI): 659 [M+H]+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]12[N:8]([C:16]([Cl:15])=[O:18])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CC2CCC(C1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1C2CCCC1CC2
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a cooled (10° C.) solution 8-aza-bicyclo[3.2.1]octane (295 mg, 2.00 mmol) and pyridine (486 μL, 6.02 mmol) in DCM (10 mL) was added triphosgene (595 mg, 2.00 mmol) portionwise. The reaction was allowed to reach room temperature and stirred overnight. The mixture was quenched with HCl (1M aqueous, 10 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with HCl (1M aqueous), brine, dried (MgSO4) and concentrated in vacuo, to give the title compound (244 mg, 70%). 1H NMR (400 MHz, CDCl3): 1.46-1.70 (4H, m), 1.72-1.92 (5H, m), 2.04-2.11 (2H, m), 4.39-4.44 (2H, m).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CO>[NH2:20][C:21]1[CH:22]=[C:23]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: CO
Product: Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 70 °C

Procedure:
N4-(3,4-Ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.18 mmol) was dissolved in dry MeOH (1 ml), to it was added 3-aminoaniline (163 mg, 1.2 mmol) and the mixture was refluxed for 4 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3—Acetone, 9:1) to give N2-(3-aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.66 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=2.1 Hz), 7.09 (t, 1H, J=2.1 Hz), 6.80-6.90, (m, 1H), 6.69 (d, 1H, J=8.1 Hz), 6.57 (m, 1H), 6.20 (m, 1H), 6.60 (m, 1H), 4.10 (m, 4H); LCMS purity: 90.7%; MS (m/e): 354.13 (M+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:34])[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:36][S:37](O)(=[O:39])=[O:38]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:34])[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[C:29]([S:37]([Cl:36])(=[O:39])=[O:38])=[C:28]([CH3:33])[CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(C)c1S(=O)(=O)Cl
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a cooled solution of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 16, 4.6 g, 9.1 mmol) in 3 mL of CH2Cl2 was added drop-wise ClSO3H (3 mL, 5 eq., 45.5 mmol)) at 0° C. During the reaction small aliquots of the reaction mixture were taken out as samples, treated with ice, extracted with ethyl acetate, and the ethyl acetate layers were analyzed by thin layer chromatography (TLC). TLC analysis showed that the reaction was complete after 30 min. Then the resulting thick reaction mixture was poured onto the crushed ice with vigorous stirring to give a yellow gummy material mostly in the bottom of the flask. This mixture was extracted with CH2Cl2, the organic layers were dried over anhydrous MgSO4, and concentrated under reduced pressure to give Intermediate 17 (2.2 g, 40%) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:21]([F:22])([F:23])[F:24])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.102) (0.40 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white foam (0.37 g), which was subsequently deprotected.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]=[O:46])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]([OH:46])[CH:19]([CH2:18][C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[C:20]([O:22][CH3:23])=[O:21])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CCc1cccs1
Reactant: CCCCc1nc2cccc(C=O)c2n1Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCc1nc2cccc(C(O)C(Cc3cccs3)C(=O)OC)c2n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A solution of n-butyl lithium (0.4 mL of 2.5M in hexane, 1 mmol) in dry tetrahydrofuran (5 mL) at -78° C. under argon was treated with diisopropylamine (108 mg, 1.06 mmol). This mixture was stirred 10 minutes at -78° C. and methyl 3-(2-thienyl)propanoate (156 mg, 0.92 mmol) was added in tetrahydrofuran. After being stirred an additional 30 minutes at -78° C., a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxaldehyde (200 mg, 0.61 mmol) in tetrahydrofuran (1.5 mL) was added. This mixture was stirred at -78° C. for 15 minutes and the reaction was quenched with saturated ammonium chloride. The product was extracted into ethyl acetate, washed with water, dried and concentrated product was flash chromatographed over silica gel with 5-10% of methanol in ethyl acetate to provide 0.17 g (56%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-benzimidazol-7-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate as an oil.