Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(C)=O>[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:25]([OH:3])=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)=O
Reactant: O=Cc1sccc1-c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)c1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
8N Jones' reagent (ca. 10 ml) was added dropwise to a solution of 3-phenylthiophen-2-aldehyde (5) (0.58 g, 3.1 mmol) in 32 ml of acetone, until an orange colour persisted. The mixture was stirred at room temperature for 18 hrs. Isopropanol (5 ml) was added to remove the excess Jones' reagent and the mixture was then filtered, the organic solvents were evaporated under vacuum and extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was then chromatographed using 95/5 chloroform/methanol, thus giving the compound (6) (0.44 g, 1.36 mmol, 46% yield) (M. Pt. 200–202° C.). 1H-NMR (CDCl3) ä 6.87–7.37 (m, 5H, Ph-H) 7.05 (d J=5.0 Hz, 1H, th-H4), 7.53 (d J=5.0 Hz, 1H, th-H5).
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]([O:28][P:29]([O-:33])[O:30][CH2:31][CH3:32])[CH3:27].C(N(CC)CC)C>CN(C)C=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>[CH2:26]([O:28][P:29]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:33])[O:30][CH2:31][CH3:32])[CH3:27].[CH2:26]([O:28][P:29]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:30])[OH:33])[CH3:27]
Reactant: O=S(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)C(F)(F)F
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(O)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Product: CCOP(=O)(OCC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1

Procedure:
Procedure H is followed, introducing 70 mg (1 eq; 0.190 mmol) of trifluoromethanesulfonic acid 3-((E)-styryl)-1H-indazol-5-yl ester in solution in 3 ml of dimethylformamide, 26.7 μl (1.09 eq; 0.207 mmol) of diethylphosphite, 8.9 mg (0.04 eq-0.0076 mmol) of tetrakis(triphenylphosphine)palladium(0) and 28.8 μl (1.09 eq; 0.207 mmol) of triethylamine. The additions made are successively 27 μl of diethylphosphite, 29 μl of triethylamine, 10 mg of tetrakis(triphenylphosphine)palladium(0), then 50 μl of diethylphosphite, 50 μl of triethylamine, 20 mg of tetrakis(triphenylphosphine)palladium(0) and, finally, 27 μl of diethylphosphite, 29 μl of triethylamine and 9 mg of tetrakis(triphenylphosphine) palladium(0). 22 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid diethyl ester are isolated, along with 8.7 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid monoethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][C:27]4[CH2:28][CH2:29][CH2:30][CH:25]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=5)[C:26]=4[N:17]=3)=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccc(NC(N)=S)cc2)o1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of [4-(2,4-dimethyl-oxazol-5-yl)-phenyl]-thiourea (124 mg, 0.50 mmol) and 2-bromo-6-phenyl-cyclohexanone (139 mg, 0.55 mmol) in ethanol (5 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (170 mg, 85%) as a light brown solid. MS ISP (m/e): 402.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.37 (br s, 1H, NH), 7.53 (d, 2H), 7.42 (d, 2H), 7.30 (t, 2H), 7.20 (t, 1H), 7.12 (d, 1H), 4.05 (m, 1H), 2.72 (m, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 2.12 (m, 1H), 1.70-1.88 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S>O>[CH2:13]([O:9][C:8](=[O:10])[C@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[NH2:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](CCCCO)C(=O)O
Reactant: BrCc1ccccc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCCO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Dissolve 6-hydroxynorleucine (14.7 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl bromide (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give O-benzyl-6-hydroxynorleucine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH3:26])[CH:22]=2)[CH2:17][C@H:16]1[OH:38])(C)(C)C.O=C1CCC(=O)N1O[C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][C:51]=1[F:62])=[O:49].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[F:36])[CH2:29][CH2:28][NH:27][C:25](=[N:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][C@@H:16]([OH:38])[C@@H:15]2[NH:14][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[CH:52][C:51]=2[F:62])=[O:49])=[CH:19][CH:20]=1)[CH3:26]
Reactant: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C2)NCCc1ccc(F)c(F)c1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1F)[C@H](O)C2)NCCc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
Add 5 mL of trifluoroacetic acid to (R)-(6-(1-((3,4-difluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)carbamic acid tert-butyl ester (180 mg, 4.04 mmol) and stir for 30 minutes. Remove solvent under reduced pressure. Dissolve the residue in 15 mL of CH2Cl2. Then add 3-fluorobiphenyl-4-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (150 mg, 4.79 mmol) and triethylamine (0.6 mL, 4.0 mmol) to the solution and stir for 12 hours. Pour the mixture into methylene chloride, wash with water, dry with Na2SO4, and then concentrate. Purify the residue by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give 35 mg of the title compound as a white solid in 16% yield: 1H NMR (CD3OD) δ 7.88 (2H, t, J=8.0 Hz), 7.7 (2H, d, J=8.4 Hz), 7.60 (2H, dd, J=8.0, 1.2 Hz), 7.47-7.55 (3H, m), 7.43-7.47 (1H, m), 7.21-7.32 (2H, m), 7.18 (1H, d, J=8.0 Hz), 7.11-7.14 (1H, m), 6.71 (2H, dd, J=10.0, 1.2 Hz), 5.47 (1H, d, J=6.8 Hz), 4.69 (2H, s), 4.54 (1H, q, J=7.2 Hz), 4.54 (1H, q, J=6.4 Hz), 3.29 (1H, q, J=7.2 Hz), 3.07 (3H, s), 2.88 (1H, q, J=7.8 Hz), 1.99 (3H, s); MS 544 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7]O)[CH2:3][CH2:2]1.O=S(Cl)[Cl:11]>>[Cl-:11].[CH:1]1([CH2:4][NH2+:5][CH2:6][CH2:7][Cl:11])[CH2:3][CH2:2]1
Reactant: OCCNCC1CC1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]CC1CC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].NC(N)=[S:13]>O.C(O)C>[C:1]([O:6][CH2:7][CH:8]1[S:13][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NC(N)=S
Reactant: C=C(C)C(=O)OCC1CO1
Solvent: CCO
Solvent: O
Product: C=C(C)C(=O)OCC1CS1

Procedure:
Glycidyl methacrylate corresponding to the formula: ##STR10## is reacted with thiourea corresponding to the formula: ##STR11## at ambient temperature in a mixture of water and ethanol. The reaction gives 2,3-epithiopropyl methacrylate corresponding to the formula: ##STR12##
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][C:11]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.NN>[Pd].C(O)C>[NH2:23][C:11]1[CH:12]=[C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH:7]([OH:26])[CH2:6][NH:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1N

Procedure:
6-[4-(3-t-Butylamino-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone was reduced over 10% palladium on charcoal with excess hydrazine hydrate in ethanol to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH:3]([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8]1)[C:4]([OH:6])=[O:5].C(N[C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][SH:25])(=O)C>CO>[C:11]([NH:7][SH:25]([CH2:24][CH2:23][C:26]([OH:28])=[O:27])[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([NH:7][CH:3]([CH:2]([CH3:1])[CH2:17][CH3:18])[C:4]([OH:6])=[O:5])=[O:12])(=[O:12])[CH3:10]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CCC(C)C(C(=O)O)n1sc2ccccc2c1=O
Solvent: CO
Product: CCC(C)C(NC(=O)c1ccccc1S[SH](CCC(=O)O)NC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.58 g (2.2 mmol) of [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid in 20 mL of methanol was treated with 0.36 g (2.2 mmol) of N-acetyl-L-cysteine and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was triturated with 100 mL of 60° C. water. The water was decanted and the solid was dissolved in 50 mL of ethyl acetate. The organic solution was dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a white, solid foam, mp 85-90° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]C)[N:7]=1.[CH:12]1([CH:15]2[NH:20][C:19](=O)[CH:18]([CH2:22]C)[NH:17][C:16]2=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([CH:10]2[CH2:11][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Cl:1][C:19]1[C:18]([CH3:22])=[N:17][CH:16]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:20]=1
Reactant: CCC1NC(=O)C(C2CC2)NC1=O
Reactant: CCc1cnc(CC)c(Cl)n1
Product: Cc1cnc(C2CC2)c(Cl)n1
Product: Cc1ncc(C2CC2)nc1Cl

Procedure:
Following the procedure for the preparation of 3-chloro-2,5-diethylpyrazine but substituting 3-cyclopropyl-6-ethylpiperazine-2,5-dione and making non-critical variations provided 3-chloro-2-cyclopropyl-5-methylpyrazine (A) and 3-chloro-5-cyclopropyl-2-methylpyrazine (B) as oils. Analytical data for 3-chloro-2-cyclopropyl-5-ethylpyrazine (A): 1H NMR (CDCl3) δ 1.06-1.10, 1.28-1.33, 2.42-2.51, 2.73-2.81, 8.18; Analytical data for 3-chloro-5-cyclopropyl-2-ethylpyrazine (B): 1H NMR (CDCl3) δ 1.04-1.08, 1.24-1.39, 1.97-2.06, 2.88-2.95, 8.31.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>ClCCl>[CH2:25]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O[C@@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of oxalyl chloride (6.28 mL, 72.4 mmol) in dichloromethane (75 mL) at −60° C. under nitrogen is added a solution of DMSO (10.7 mL, 151 mmol) in dichloromethane (75 mL) dropwise and stirred at −60° C. for 15 min. (1R,2S)-2-(dibenzylamino)cyclopentanol (17.0 g, 60 mmol) in dichloromethane (75 mL) is added and the reaction is stirred at −60° C. for 30 min. TEA (46 mL, 330 mmol) is added and the reaction is allowed to warm to room temperature and stirred for 1 h. Water is added (100 mL) and the reaction is stirred overnight. The dichloromethane layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an orange oil (13.96 g, 83%). ES/MS m/z 280 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH2:15].[C:16]1([CH3:26])C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CO>[CH2:16]1[O:15][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)([CH3:2])[O:3][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: O
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C2(C)OCCO2)cc1

Procedure:
ethyl 4-acetyl-benzoate (9.61 g, a product of the firm Wako Pure Chemical Ind.) was dissolved in toluene (200 ml) under an argon atmosphere whereto ethylene glycol (20 ml) and p-toluenesulfonic acid hydrate (200 mg) were added, whereupon the mixture was refluxed with heating for 24 hours while dehydrating on a Dean-Stark apparatus. After cooling down to room temerature, the toluene layer was washed with water (100 ml×twice) and with saturated aqueous sodium chloride solution (100 ml) succeedingly, followed by drying and concentrating to dryness under reduced pressure, whereby the above-identified compound was obtained (12.76 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:13]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([I:22])[C:19]([CH3:23])=[CH:18][N:17]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.[Cl-].[NH4+]>[CH3:10][O:11][C:12]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:13]=1[CH2:14][N:15]([C:16]1[CH:21]=[C:20]([I:22])[C:19]([CH3:23])=[CH:18][N:17]=1)[C:33]([CH:30]1[CH2:32][CH2:31]1)=[O:34]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)C2CC2)c2cc(I)c(C)cn2)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of DIEA (1.8 mL, 10.4 mmol) in DCM (50 mL) at 0° C. was added N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (2.0 g, 5.2 mmol) and cyclopropanecarbonyl chloride (0.66 mL, 7.3 mmol). The reaction mixture was allowed to stir at 0° C. for 2 h and then diluted with DCM and aqueous ammonium chloride. The aqueous solution was removed and the organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give N-(2,4-dimethoxybenzyl)-N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.8 g, 78%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C=C(N2CCCCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.90 g, 2.4 mmol) and piperidine (4 ml) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[I:23])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1nccc(I)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Yield: 93.7 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (90 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 h. Concentrate the solution in vacuo to afford crude 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (65 mg, 92%) as light yellow oil. The crude product was used directly for next step. MH+ 365.9.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 74475.7 %

Procedure:
Alcohol Compound 40 (48.8 g, 0.16 mmol) was added to a mixture of NaH (4.0 g, 0.17 mol) in dry THF (500 mL). After 5 min, MeI (10 mL, 0.17 mol) was added and, after another 3 hours, the mixture was quenched with H2O (150 mL), extracted into diethyl ether (500 mL), dried (MgSO4) and concentrated. Purification of the residue by silica-gel column chromatography [eluent: hexane/ethyl acetate, 90/10, v/v] yielded 1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 41) (37 g, 74%) as a yellow oil.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=1[Cl:17]>CS(C)=O>[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[Cl:17]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.5 %

Procedure:
Compound (1) (0.67 g, 5.5 mmol) and EDC (1.1 g, 5. 7 mmol) was dissolved in dimethyl sulfoxide (DMSO) (10 mL). N,N-dimethyl 1,2-ethylenediamine [compound (2)] (7.5 mL, 5.7 mmol) was added and the mixture was stirred at room temperature for 5 hours, whereafter the reaction mixture was freeze dried. The residue was subjected to column chromatography [silicon dioxide (SiO2) plates chromatographed in chloroform (CHCl3)-methanol (30:1, v/v)+triethylamine (Et3N) (1:1, v/v). This procedure gave quantitative yield (1.1 g) of compound (3) as a syrup.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Yield: 39.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.24 mmol) prepared in Example 104a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (45 mg, 56%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)(N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+]539.2447, observed 539.2449.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=[C:5]2[CH3:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.N1CCCCC1.CCOC(C)=O>O1CCOCC1.[Cu]I>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[C:5]4[CH3:19])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(N2CCC(C)CC2)nc2ccc(I)cc12
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 293 mg (0.8 mmol) of 6-iodo-4-methyl-2-(4-methylpiperidin-1-yl)quinoline, 184 mg (0.8 mmol, 93% purity) 5-(4-chlorophenyl)-2-ethynylpyridine, and 158 μL (1.6 mmol) of piperidine in 4 mL of 1,4-dioxane is evacuated three times and gassed with argon. After the addition of 3 mg (0.016 mmol) of CuI and 13 mg (0.016 mmol) of PdCl2(dppf)-DCM complex, the reaction mixture is stirred for 4 hours at RT. It is combined with 10 mL of EtOAc, and the precipitate is filtered off, washed with a little EtOAc and MeOH, and dried in the air. Yield: 240 mg (66% of theoretical); C29H26ClN3 (M=451.990); calc.: molpeak (M+H)+: 452/454 (Cl); found: molpeak (M+H)+: 452/454 (Cl); HPLC-MS: 6.1 min (method B).