Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[CH:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[CH:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Reactant: Cc1noc(C)c1CCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1 H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1 H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 395 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[C:16](=[CH:9]/[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)/[C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C=O)cn1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cn1
Yield: 95.7 %

Procedure:
6-Methoxy-3-pyridinecarboxaldehyde (411 mg) was condensed with 3,4-dimethoxybenzyl cyanide (532 mg) through Method A (production step 2), to thereby yield the target product (yield: 850 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)([OH:22])=[O:21].O>C1COCC1>[OH:28][CH:27]([C:26]1[CH:25]=[CH:24][C:23]([C:20]([OH:22])=[O:21])=[CH:30][CH:29]=1)[C:13]#[C:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCSc2ccc(C#CC(O)c3ccc(C(=O)O)cc3)cc21
Reaction time: 0.5 h

Procedure:
2 g (9.9 mmol) of (4,4-dimethylthiochroman-6- yl)acetylene and 25 ml of THF were introduced into a three-necked flask under a stream of nitrogen, 4 ml (9.9 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -50° C. and stirring was carried out for 30 min. A solution of 743 mg (4.9 mmol) of 4-carboxybenzaldehyde in 25 ml of THF was then added and stirring was carried out at room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was recrystallized from diisopropyl ether. After filtration, 730 mg (42%) of the expected acid, with a melting point of 168°-169° C., were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH2:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[OH-].[K+]>CO>[NH:15]1[CH2:16][CH:17]=[C:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:20]1
Reactant: O=C1CCNCC1
Reactant: NC(=O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 40.6 %

Procedure:
A mixture of 1H-indole-5-carboxamide (1.8 g), 4-piperidone hydrochloride monohydrate (3.4 g), and potassium hydroxide (11 g) in methanol (100 ml) was heated at reflux for 16 h. The mixture was cooled, and partitioned between ethyl acetate (200 ml) and saturated potassium carbonate (200 ml). The aqueous phase was separated, and extracted with ethyl acetate (100 ml. The organic extracts were combined, dried and the solvent evaporated in vacuo to give a semi-solid which was triturated with absolute ethanol (10 ml), and washed with ether (3×20 ml). The resultant solid was dried in vacuo to give the title compound, (1.1 g) m.p. 225°-230°.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](F)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[C:9]([F:10])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)c(F)c1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1c(F)cc(C#N)c(F)c1F

Procedure:
Using 2,3,4,5-tetrafluorobenzonitrile (876 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 922 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2ccccc2Cl)cc1
Temperature: 45 °C

Procedure:
A solution of 2-chlorobenzaldehyde (70 g.) and 4-methoxyaniline (61.5g.) in toluene (750 ml.) was refluxed under a Dean and Stark separator until no more water collected (ca. 1 hour). The toluene was evaporated in vacuo, and the residue was dissolved in methanol (1.5 l.). The methanolic solution was treated at room temperature with sodium borohydride (60 g.) added portionwise so that, with gentle cooling, the temperature was maintained at 40-50° C. The solution was then refluxed for 15 minutes, diluted with water (1.5 l.), and the aqueous mixture extracted with ether (3 × 200ml.). The combined ethereal extracts were washed with water (2 × 100 ml.), dried (K2CO3), and evaporated to give N-(4-methoxyphenyl)-2-chlorobenzylamine as a brown oil, Infra Red ν max 3400, 1618 cm.-1, which was used directly in the next stage.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:17])[CH2:15][Cl:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[C:22](O)(=[O:24])[CH3:23]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([O:17][C:22](=[O:24])[CH3:23])[CH2:15][Cl:16])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1C(=O)CCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC(CCl)c1ccsc1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
1.5 g (0.005 mole) of N-t-butyl-3-(chloroacetyl)-2-thiophenesulfonamide synthesized in Example 6 was dissolved in the combined solution of 1 ml of acetic acid and 10 ml of tetrahydrofuran and then 0.31 g (0.005 mole) of sodium cyanoborohydride was added slowly thereto. The reaction solution was stirred at normal temperature for 30 minutes and then subjected to a vacuum evaporator to remove the solvent. To the residue was added 10 ml of water and then the resulting solution was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and filtered. To the filtrate were added acetic anhydride, pyridine and N,N-dimethylaminopyridine and the mixture was stirred at normal temperature for 24 hours and then washed with 5% aqueous hydrochloric acid solution. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was subjected to column chromatography on silica gel to obtain 5 g (Yield: 84%) of the title compound. 1H NMR(CDCl3, δ): 1.3(s, 9H), 2.15(s, 3H), 3.57-3.9(m, 2H), 5.23(s, 1H), 6.5(m, 1H), 7.13(d, 1H), 7.5 (d, 1H)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:18])=[O:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>FC(F)(F)C(O)=O.O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][S:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[N+:1]([O-:4])=[O:2])(=[O:17])=[O:18]
Reactant: COC(=O)CCS(=O)(=O)CCOCCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCS(=O)(=O)CCOCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated nitric acid (3.25 ml) was added dropwise over a half hour period to a stirred cooled (ice/salt) solution of methyl 3-[2-[2-phenylethoxy]ethylsulphonyl]propanoate (15.12 g) (prepared from the acid, which was itself prepared by the procedure outlined in Example 1b)) in trifluoroacetic acid. The reaction was allowed to warm to room temperature, stirred overnight, diluted with water and extracted several times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to yield the crude mixture of isomeric methyl 3-[2-[2-[nitrophenyl]ethoxy]ethylsulphonyl propanoates. The subtitled compound was separated from the other isomers by normal phase preparative HPLC using 1:1 hexane:ethyl acetate as eluant.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:3][C:2]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc2ccccc2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)c1ccc2c(Br)c(OC)ccc2c1
Temperature: 5 °C
Yield: 11 %

Procedure:
Ethyl pyruvate (1,64 g, 14,1 mmol) in dichloromethane (5 mL), was added to a mixture of 1-bromo-2-methoxynaphthalene (2,23 g, 9,41 mmol) and aluminium chloride (1,88 g, 14,1 mmol) in dichloromethane (20 mL) at 5° C. over 30 minutes. The mixture was stirred at 5° C. for a further 1,5 hours and poured on to ice. Ethyl 2-hydroxy-2-(5-bromo-6-methoxynaphth-2-yl)propionate was formed in 11% yield. 1HNMR δ (CDCl3) 1.24 (3H,t), 1.85 (3H,s), 4.00 (3H,s), 4.26 (2H,q), 7.2-8.2 (5H2 m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(N)c(CO)c1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-piperidine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and piperidine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].OCN([CH2:29][OH:30])C>C(Cl)Cl.N1C=CC=CC=1>[OH:4][CH2:5][CH:10]([CH2:29][OH:30])[NH:11][S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17]
Reactant: CN(CO)CO
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)NC(CO)CO)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.8 g, 2.51 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of bis(hydroxymethyl)methylamine (0.44 g, 4.8 mmol) in pyridine (20 ml). The mixture was stirred for 2 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, chloroform/MeOH 19/1) Yield: 0.35 g=29% 13C (100 MHz, DMSO-d6) δ 150.17, 147.50, 138.39, 132.09, 130.34, 129.29, 129.10, 126.02, 123.25, 122.75, 122.51, 115.22, 60.36, 57.07, 40.94
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20]Br.C(=O)(O)[O-].[Na+].O>C(O)C>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:1]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]2[CH:20]=1
Reactant: Nc1nccc2ccccc12
Reactant: Cc1ccccc1C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Yield: 81.9 %

Procedure:
A mixture of 3.0 g of 1-aminoisoquinoline, 6.7 g of 2'-methyl-2-bromoacetophenone and 17.5 g of sodium bicarbonate in 50 ml of ethanol was refluxed for 2 hours. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from dichloromethane/petroleum ether to give 4.4 g of the title compound as pale brown prisms.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].O>CN(C=O)C>[CH2:23]([N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:9]1=[O:18])[C:22]#[CH:21]
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reaction time: 0.33 h
Yield: 45 %

Procedure:
4,5-Diphenyloxazol-2-one (500 mg, 2.11 mmol) was dissolved in DMF (4 ml) and sodium hydride (153 mg, 2.55 mmol) was added under nitrogen and with ice cooling over 20 minutes. After stirring for 20 minutes, propargyl bromide (210 μl, 2.79 mmol) was added. After stirring for 15 minutes with ice cooling and stirring at room temperature for 2 hours, water (20 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(2-propynyl)-4,5-diphenyl-oxazol-2-one.
Reaction SMILES: N1C=CC=CC=1.N([C@@H:10]1[C@@H:14]([CH2:15][OH:16])[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11]1)=[N+]=[N-].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([O:16][CH2:15][C@H:14]1[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11][CH2:10]1)(=[O:28])[CH3:27]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CC[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reaction time: 8 h

Procedure:
To a pyridine (50 ml) solution of 3'-azido-3'-deoxythymidine (5.0 g, 18.7 mmole) 1 was added acetic anhydride dropwise in an ice-water bath. The mixture was allowed to stand overnight in the refrigerator. The solution was then poured into CHCl3 (20 ml), washed with H2O (200 ml×2), with a saturated solution of sodium bicarbonate and then H2O (200 ml×2). The organic layer was then dried (MgSO4). After removing the solvent, a syrup (6.5 g) was obtained.
Reaction SMILES: [H-].[Na+].N1C=NC=N1.Br[CH2:9][CH2:10][N:11]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].O>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH:10]=[CH2:9])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Agent: c1nc[nH]n1
Solvent: O
Solvent: CN(C)C=O
Product: C=CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.04 g (1.00 mmol)) in DMF (5.0 ml), 1,2,4-triazole (0.08 g (1.16 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, N-(2-bromoethyl)-4′-chloro-2′-nitro-p-toluenesulfonanilide (0.35 g (0.81 mmol)) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.052 g (18%) of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:26]1([CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[CH2:32][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CCN(CC2CCCCN2)CC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(piperidin-1-ylmethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C28H33Cl2N5O2 (542.51); mass spectrum: (M−H)−=542/544/546 (chlorine isotope).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([F:14])([F:13])([F:12])([F:11])[F:10].Cl.Cl.[NH:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1
Reactant: FS(F)(F)(F)(F)c1ccccc1CBr
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2S(F)(F)(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2-(bromomethyl)-1-(pentafluorosulfanyl)benzene (213 mg) in DMF (5 mL) were added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (210 mg) and potassium carbonate (362 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (164 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]Cl)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:36])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([SH:35])=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:36])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 81B and 12C. MS m/z 503 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>CC(N(C)C)=O>[N:9]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C1CNC1
Reactant: Clc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Brc1ccc(N2CCC2)nc1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Sigma-Aldrich, Buchs, Switzerland, 196 mg, 1.018 mmol), azetidine (Sigma-Aldrich, Buchs, Switzerland, 0.213 ml, 3.06 mmol) and pyridine (0.124 ml, 1.528 mmol) in DMA (2.5 ml) was heated under microwave irradiation at 150° C. for 10 min and 170° C. for 10 min. The reaction was not completed. Again azetidine (0.106 ml) was added and the RM was heated under microwave irradiation at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 1.97 min (Method A); M+H=213, 215 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.12 (s, 1H), 7.70-7.60 (m, 1H), 6.37-6.29 (m, 1H), 3.96-3.86 (m, 4H), 2.34-2.24 (m, 2H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([C:36]1[C:37]([N:45]2[CH2:50][CH2:49][CH:48]([N:51]3[CH2:56][CH2:55][N:54]([S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:52]3)[CH2:47][CH2:46]2)=[CH:38][C:39]([O:43][CH3:44])=[C:40]([CH:42]=1)[NH2:41])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[C:36]([CH2:34][CH3:35])[C:37]([N:45]4[CH2:46][CH2:47][CH:48]([N:51]5[CH2:52][CH2:53][N:54]([S:57]([CH3:60])(=[O:59])=[O:58])[CH2:55][CH2:56]5)[CH2:49][CH2:50]4)=[CH:38][C:39]=3[O:43][CH3:44])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCc1cc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 175 °C
Yield: 34.3 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (0.050 g, 0.11 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (0.043 g, 0.11 mmol) and para-toluenesulfonic acid (0.049 g, 0.26 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 20 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.031 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.36 (br. s., 1H), 8.50 (s, 1H), 8.26 (d, J=5.22 Hz, 1H), 8.12 (d, J=2.11 Hz, 1H), 7.80 (dd, J=8.80, 2.02 Hz, 1H), 7.71 (d, J=9.07 Hz, 1H), 7.53 (s, 1H), 7.36-7.50 (m, 2H), 7.30 (d, J=8.80 Hz, 1H), 7.14-7.25 (m, 2H), 6.91-7.00 (m, 1H), 6.83 (s, 1H), 6.58 (d, J=5.22 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.08-3.15 (m, 4H), 3.00-3.07 (m, 2H), 2.88 (s, 3H), 2.67-2.76 (m, 2H), 2.61-2.66 (m, 4H), 2.56 (q, J=7.51 Hz, 2H), 2.38-2.46 (m, 1H), 1.80-1.91 (m, 2H), 1.50-1.68 (m, 2H), 1.11 (t, J=7.51 Hz, 3H). MS (M−H, ES−) 820.