Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]12([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]23[CH2:9][CH:10]4[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]4)[CH2:17]2)[CH2:15]3)=[CH:23][CH:22]=1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the method described in Example 16, the use of ethyl bromoacetate and p-(1-adamantyl)-phenol as starting materials gives 4-(1-adamantyl)-phenoxyacetic acid ethyl ester of melting point 89°-90° C (flakes; from etherpentane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[S:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>CC(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[S:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:19]=1
Reactant: CC1(C)OB(c2ccccc2F)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Temperature: 100 °C
Yield: 44.9 %

Procedure:
To a mixture of 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.639 g, 2.88 mmol), 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (1.150 g, 2.056 mmol) in 70% IPA/H2O (18 mL) was added potassium phosphate (1.309 g, 6.17 mmol), and AmPhos (0.073 g, 0.103 mmol). The reaction was heated at 100° C. for 5 min. The aq. layer was removed and the organic layer was evaporated. The residue was purified with prep HPLC to give 2-(3-(2-fluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.487 g, 0.923 mmol, 44.9%) as a light brown solid. MS (ESI, pos. ion) m/z: 528 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:9]=1[C:10]([O:12]C(C)(C)C)=[O:11])=[O:6]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COc1ccccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2-methoxybenzamido)-4-phenylbenzoate and stirred at room temperature for 3 minutes. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 65 mg of 2-(2-methoxybenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:9][C:8](=[O:45])[NH:7]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:49][C:47]1[CH:46]=[C:4]([CH:3]=[C:2]([F:1])[CH:48]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:9][C:8](=[O:45])[NH:7]1
Reactant: CC(C)[Si](Oc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3cccc(O)c3CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-(triisopropylsilyloxy)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step F (13), 200 mg, 0.3 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (118 mg, 0.45 mmol). The mixture was stirred at rt for 1 h. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 95 mg of the title compound (60% yield): 1H NMR (CD3OD, 500 MHz) δ 2.51-2.56 (1H, m), 2.68 (1H, d, J=20 Hz), 3.22 (1H, dd, J=5, 20 Hz), 3.35 (1H, m), 3.53 (1H, dd, J=5, 15 Hz), 3.80 (1H, d, J=15 Hz), 4.06-4.12 (1H, m), 4.21 (1H, m), 4.80-4.83 (1H, m), 4.91 (1H, s), 6.57 (1H, d, J=10 Hz), 6.66 (1H, d, J=5 Hz), 6.84-6.88 (3H, m), 6.98-7.01 (1H, m), 7.22 (2H, dd, J=10, Hz), 7.28-7.34 (4H, m), 7.46-7.50 (4H, m). MS (ESI) (M−H)− 525.17.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:23][C:24]1[C:29]([F:30])=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:28]3[CH:27]=[CH:26][C:25]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:24]([F:23])[C:29]=3[F:30])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (101 mg, 0.27 mmol, 1.00 equiv), ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate (prepared according to PCT Application WO2010/048207A2) (81 mg, 0.35 mmol, 1.30 equiv), N,N-dimethyl formamide (3.0 mL), potassium carbonate (113 mg, 0.82 mmol, 3.01 equiv). The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-Plate with Petroleum ether/EtOAc=6:1. This resulted in 0.10 g (73%) of ethyl 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C22H17ClF5NO3S, 506.1 (M+H). found 506.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: CCc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: CCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
2-(2,6-Difluorophenyl)-4-ethylbenzimidazole (4010) (0.70 g, 2.71 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (0.72 g, 3.48 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-ethylbenzimidazole (4011) (0.79 g, 2.06 mmol, 76% yield). M.p. 165-166° C. 1H-NMR (200 MHz, CD2Cl2): δ 7.53 (m, 1H, H4′), 7.32 (d, J=8.2 Hz, 1H, H5), 7.29-7.16 (m, 2H, H6,4″), 7.14-7.01 (m, 1H, H7), 7.07 (m, 2H, H3″,5″), 6.81 (m, 2H, H3″,5″), 5.33 (s, 2H, CH2), 3.07 (q, J=7.6 Hz, 2H, CH2), 1.35 (t, J=7.6 Hz, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[CH:17]([OH:18])[CH:16]([OH:19])[C:12]=2[C:11]2[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:17]=[O:18])[C:6]3[C:11]([C:12]=2[CH:16]=[O:19])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Cc1ccc2c3c4ccccc4c(c2c1)C(O)C3O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: Cc1ccc2c(C=O)c3ccccc3c(C=O)c2c1
Reaction time: 2.5 h

Procedure:
A mixture of isomers of 2-methyl-11,12-dihydroxy-9,10-ethano-anthracene weighing 2.1 g. is dissolved in 45 ml. of glacial acetic acid and is treated at room temperature with 7.45 g. of lead tetraacetate until a starch-iodide test is positive. After 2-3 hours at room temperature followed by cooling there is deposited orange crystals, which are collected by filtration and recrystallized from methylene chloride-methanol giving 1.1 g. of orange crystals melting at 162°-164° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:14])=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.CCN(C(C)C)C(C)C>C1COCC1>[C:10]([C:9]1[C:8]([F:13])=[CH:7][C:6]([F:14])=[C:5]([C:3](=[O:4])[CH2:2][N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C@H:17]2[CH2:16][OH:15])[CH:12]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: N#Cc1cc(C(=O)CBr)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cc(C#N)c(F)cc2F)[C@H](CO)C1
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A suspension of 5-(bromoacetyl)-2,4-difluorobenzonitrile (2.5 g, 9.6 mmol), tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.1 g, 9.6 mmol) and DIEA (1.90 g, 14.4 mmol) in 50 mL of THF was stirred at 20° C. for 10 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(OC(C)C)(C)C>CN(C)C=O>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([O:15][CH2:14][C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(OCc2ccc(F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CC(C)(C)n1ncc(OCc2ccc(OCc3ccc(F)cc3)nc2)c(Cl)c1=O
Temperature: 0 °C
Yield: 77.7 %

Procedure:
To a solution of 2.3 g of 6-(4-fluorobenzyloxy)-3-pyridine methanol in 20 ml of N,N-dimethylformamide was added under stirring at 0° C. 0.5 g of 55% sodium hydride (in mineral oil). After stirring for 30 minutes at room temperature, thereto was added 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone. The reaction mixture was stirred at room temperature for additional 8 hours, poured into 50 ml of ice water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 4.1 g of a crude product. The crude product was added with isopropyl ether and recrystallized therefrom to obtain 3.2 g of 2-t-butyl-4-chloro-5-[{6-(4-fluorobenzyloxy)-3-pyridyl}-methyloxy]-3(2H)-pyridazinone, m.p. 121.0°~124.0° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:4]=1.[N:14]#[C:15][NH2:16]>CCO>[NH:2]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:4]=1)[C:15]([NH2:16])=[NH:14]
Reactant: N#CN
Reactant: N#CCCCCn1ncc(N)n1
Agent: Cl
Solvent: CCO
Product: N#CCCCCn1ncc(NC(=N)N)n1
Reaction time: 2 h

Procedure:
A solution 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile hydrochloride (2.01 g.) in EtOH (15 ml.) was treated with cyanamide (0.42 g.) and the solution heated under reflux for 4.5 hours. A further 0.1 g. of cyanamide was added and heating under reflux was continued for 2 hours. The solution was evaporated and the residue basified with ammonia and continuously extracted for 24 hours with EtOAc to give a yellow oil which was purified by medium pressure chromatography using chloroform/MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.1 v/v/v as eluant to give 5-(4-guanidino-1,2,3-triazol-2-yl)valeronitrile as a colourless oil (0.45 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20](/[C:24](/[F:36])=[CH:25]/[C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20](/[C:24](/[F:36])=[CH:25]/[C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(/C=C(\F)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(/C(F)=C/c4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a stirred solution of (Z)-methyl 4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoate (50 mg, 0.09 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at room temperature overnight and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give (Z)-4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoic acid (25 mg, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 12.94 (brs, 1H, exchangeable by D2O), 10.18 (s, 1H, exchangeable by D2O), 9.40 (s, 1H), 8.54-8.49 (m, 2H), 7.82-7.74 (m, 3H), 7.41-7.31 (m, 5H), 6.90-6.78 (m, 2H), 3.80 (s, 6H). LC-MS: 529 [M+H]+, 527 [M−H]−, tR=1.71 min. HPLC: 96.85% at 214 nm, 95.49% at 254 nm, tR=5.08 min.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[Cl-].[CH2:7]([S:16][C:17]1[S:21][S:20][C:19](=[N+:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>C(O)C>[S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[CH2:7]([S:16][C:17]1[S:21][S:20][C:19](=[N+:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=S(=O)(O)O
Agent: O=C(CSc1cc(=[N+]2CCOCC2)ss1)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: O=S(=O)([O-])O
Temperature: 10 °C

Procedure:
A solution of concentrated sulphuric acid (d=1.83; 0.2 cc) in ethanol (5 cc) is added to a solution of N-(5-phenacylthio-1,2-dithiol-3-ylidene)-morpholinium chloride (0.75 g) in ethanol (20 cc) under reflux. After cooling to a temperature of about 10° C., the insoluble product formed is filtered off and washed with ethanol (4 cc). After drying, N-(5-phenacylthio-1,2-dithiol-3-ylidene)-morpholinium hydrogensulphate (0.8 g), melting at 192° C., is obtained.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC(C)C)(C)C.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 83 °C
Yield: 94.9 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Diisopropyl ether (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 20 hours while agitating at an internal temperature of 83° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure, and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of isopropyl ether that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.9 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 94% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]([C:8]2[CH:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:6][CH2:5][CH2:4][CH2:3]1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[CH3:1][C:2]1([CH3:27])[C:7]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[F:26])=[CH:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCCC2(C)C)c1
Reaction time: 4.5 h
Yield: 90.2 %

Procedure:
To a stirred solution of T14.3 (0.300 g, 0.814 mmol) in THF (0.0587 g, 0.814 mmol) at 0° C. was added LAH in THF (1.63 mL, 1.63 mmol, 1.0M). The reaction was stirred for 4.5 hours and then 1N NaOH(aq) was added to quench the mixture. The reaction was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-20% EtOAc in hexanes) to yield T14.4 as a colorless oil (0.250 g, 90.2% yield).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Product: Clc1cnc2[nH]cc(Cc3cnc(NC4CCCCC4)nc3)c2c1

Procedure:
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amine P-3001 is prepared in one step from 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine 37 and cyclohexanamine 62 as shown in Scheme 9.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([C@H:12]2[C@@H:16]([OH:17])[C@H:15]([O:18]CC3C=CC=CC=3)[C@:14]([CH2:29][O:30]CC3C=CC=CC=3)([CH:26]([F:28])[F:27])[O:13]2)[C:8](=[O:38])[N:7]=1.N1C=CC=CC=1.CO>ClCCl>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([C@H:12]2[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@@:14]([CH:26]([F:28])[F:27])([CH2:29][OH:30])[O:13]2)[C:8](=[O:38])[N:7]=1
Reactant: Nc1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccn([C@@H]2O[C@@](CO)(C(F)F)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
BCl3 (3.7 mL, 3.7 mmol) was added to a solution of compound 37 (0.175 g, 0.37 mmol) in dichloromethane (10 mL) cooled to −78° C. The reaction was stirred at −78° C. for 3 h, then warmed to 25° C. and stirred for a further 12 h. The reaction mixture was cooled to 0° C. and then pyridine was added into the mixture, followed by methanol. The reaction mixture was evaporated to dryness under reduced pressure. Purification by prep-HPLC afforded the product 38 (0.052 g, 41%) as a white solid. LC-MS (M+H)+=294.1
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:42]([CH2:47][CH:48]1[CH2:50][O:49]1)[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)C>[CH2:31]([N:42]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:47][CH:48]([OH:49])[CH2:50][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: CCCCCCCCCCCN(CC1CO1)S(C)(=O)=O
Solvent: CCO
Product: CCCCCCCCCCCN(CC(O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1)S(C)(=O)=O

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 6.11 g (20 mmol) of N-undecyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2c), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]\[C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])([O-])=O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]\[C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:23])[CH3:22]
Reactant: COC(=O)c1sccc1/C=C\c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1sccc1/C=C\c1cccc(NC(C)=O)c1
Yield: 91.3 %

Procedure:
Substantially the same procedure as in Reference Example 14 was repeated using methyl (Z)-3-(3-nitrostyryl)-2-thiophenecarboxylate obtained in Reference Example 13 (3.51 g, 12.1 mmol), and also using acetic anhydride (3.43 ml, 36.3 mmol) instead of trimethylacetyl chloride, to give methyl (Z)-3-(3-acetamidostyryl)-2-thiophenecarboxylate (3.33 g, 2 steps, 91.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=2)=[CH:4][CH:3]=1.B.CSC>O1CCCC1>[NH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: N#Cc1cccc(-c2ccc(Br)cc2)n1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1cccc(-c2ccc(Br)cc2)n1

Procedure:
To a refluxing solution of 1.6 g of 2-(p-bromophenyl)-6-cyano pyridine in 8 ml of tetrahydrofuran is added slowly a solution of 0.92 ml of borane-dimethylsulfide in 6 ml. of tetrahydrofuran. Dimethyl sulfide is simultaneously removed by distillation through a 10 cm vigreux column. The mixture is refluxed for 15 minutes after the addition is complete, cooled to 30°, and 6 ml of 6N hydrochloric acid is added. After hydrogen evolution has ceased, the reaction is refluxed for 30 minutes, cooled to 0°, saturated with solid sodium carbonate and extracted with 4×50 ml aliquots of methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed through 10.0 g of silica gel with 1:1 methanol-ethyl acetate as eluent to yield 2-aminomethyl-6-(p-bromophenyl)pyridine melting at 71°-75°.