Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([N:21]([CH2:35][CH3:36])[C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:24]([C:23]3[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:22]=3[N:21]([CH2:35][CH3:36])[CH2:19][CH3:20])=[O:25])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 501.4 (M+H+; 100%)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]([F:13])[F:12])[S:8][CH:7]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[F:13][CH:11]([F:12])[C:9]1[S:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1csc(C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1csc(C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][S-:20].[Na+]>CS(C)=O.O>[CH3:19][S:20][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[S-]
Reactant: Clc1onc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1onc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.7 %

Procedure:
To a stirred solution of 5-chloro-3,4-diphenylisoxazole (Step 1) (1.75 g, 6.84 mmol) in DMSO (30 mL) was added sodium thiomethoxide (0.58 g, 8.21 mmol). After stirring for 30 hours at room temperature, the reaction was diluted with water and extracted twice with Et2O . The combined ethereal phases were washed with NaHCO3 saturated solution, KHSO4 solution (0.25N), and brine, dried over MgSO4, filtered and concentrated in vacuo yielding 5-methylthio-3,4-diphenylisoxazole (1.53 g, 84%): mp 83°-86° C. 1H NMR (CDCl3 /300 MHz) 7.50-7.18 (m, 10H), 2.63 (s, 3H). FABLRMS m/z 268 (M+H). FABHRMS m/z 268.0781 (M+H C16H14NOS requires 268.0796). Anal. Calc'd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C, 71.71; H, 4.95; N, 5.17.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:14][CH2:13][CH2:12][N:10]3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][C:11]1[N:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: c1ccc(-c2cn3c(n2)CCC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1c(-c2ccccc2)nc2n1CCC2
Yield: 73 %

Procedure:
To a solution of 2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (3.38 g, 18.3 mmol) in dry CH2Cl2 (113 mL) slowly add bromine (1.0 mL, 20.2 mmol) and stir the mixture at room temperature for 1.5 hours. Add a saturated aqueous solution of NaHCO3 (100 mL) and extract with CH2Cl2 (3×100 mL). Wash the combined organic layers with NaHSO3 (40%, 30 mL), dry (MgSO4) and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, eluent: CH2Cl2 to CH2Cl2/MeOH 20:1) to yield a red solid, 3.54 g, 73% yield. MS(ES+): m/z=263.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].N1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)c1cc(NC(=O)CCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: COC(=O)c1cc(N2CCCC2=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
Subsequently, 5-(4-chloro-butyrylamino)-2-nitro-benzoic acid methyl ester (50 mg) was dissolved in N,N-dimethylformamide (5 ml). Morpholine (70 mg) and potassium carbonate (44 mg) were added to the solution at room temperature, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (45 mg, yield 100%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[C:38]([F:41])([F:40])[F:39]>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[C:27]([C:38]([F:40])([F:41])[F:39])[CH:28]=3)[CH2:37][CH2:36]2)=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: COc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Reactant: COc1ccc(N2CCNCC2)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(NC(=O)CN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(4-methoxy-2-nitro-phenyl)-acetamide (6.7 g; 19.6 mmol) is dissolved in 200 ml ethanol in the presence of 6.3 g sodium carbonate. 1-(4-Methoxy-3-trifluoromethyl-phenyl)-piperazine hydrochloride (5.8 g; 19.6 mmol) is added to the resulting suspension and the mixture is stirred overnight at room temperature. The mixture is evaporated to dryness under vacuum and the residue is taken up with water and ethylacetate. The organic phase is separated and washed twice with water. After drying over magnesium sulfate, evaporation of the solvent leaves a residue which is triturated with ethylether.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:10]2[N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2[nH]c3c(F)cccc3c2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(c3cccc(F)c3n2S(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
A suspension of 200 mg (6-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 17) in 5 ml dichloromethane was treated with 106 mg methane sulfonyl chloride, followed by 118 mg triethylamine. The reaction mixture was stirred overnight. Concentration and chromatography (silica gel; ethyl acetate) yielded the title compound as a slightly yellowish solid (17 mg; 7%). MS (m/e): 509.0 (M+CH3COO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:23])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 601.3 [(M+H)+]; mp 239° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)=[C:10]2[Cl:28].[CH:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)=[O:30]>C1COCC1>[Cl:28][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:29]([OH:30])[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C#N)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.25 mL. 3.12 mmol) was added dropwise by syringe to a solution of 4-((6-bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)benzonitrile (1.211 g, 3.125 mmol, Intermediate 8: step d) in dry THF (15 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 4-formylbenzonitrile (498.8 mg, 3.804 mmol) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes and then removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The combined organic phase was dried (Na2SO4), filtered, and concentrated. Crude product was purified by flash column chromatography (silica gel, 100% EtOAc, followed by 0-5% MeOH-DCM), to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13-8.11 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63-7.59 (m, 2H), 7.56-7.51 (m, 5H), 7.38-7.34 (m, 2H), 6.03 (d, J=3.2 Hz, 1H), 4.33 (s, 2H), 4.05 (s, 3H); MS m/e 440.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[O:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:11]1[C:12](OC)=[O:13]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[C@H:11]([OH:10])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1

Procedure:
In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D20 =+91.9° (c=0.1; DMF).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH3:24]>CN(C)C=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:23][CH3:24])=[O:8]
Reactant: CCI
Reactant: O=C(O)Cc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
24.8 g of 2-(furan-2-yl)acetic acid was dissolved in 590 mL of N,N-dimethylformamide and mixed with 32.6 g (0.236 mol) of potassium carbonate and 6.42 g (19.7 mmol) cesium carbonate successively. The reaction mixture was further mixed with 19 mL (0.24 mol) of iodoethane under cooling with ice and stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 17.0 g of the desired product as a brown liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[CH2:3]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:50][CH2:49][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:47]1>CN(C=O)C>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([N:46]3[CH2:50][CH2:49][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[CH2:47]3)=[O:14])[CH:8]=2)[CH2:3]1
Reactant: CN1CCc2cc(C(=O)O)ccc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCc2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.1 g (4.8 mmol) 2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (as hydrochloride) are dissolved in 12 ml DMF, mixed with 2.1 ml (19.3 mmol) NMM and 1.8 g (4.8 mmol) HATU and stirred for five minutes at RT. Then 0.9 g (4.8 mmol) tert. Butyl (R)-pyrrolidin-3-yl-carbamate are added and the mixture is stirred for 16 hours. Then the mixture is poured onto water and extracted with DCM. The organic phase is separated using a phase separation cartridge and evaporated to dryness i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 9:1 to 8:2).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[CH:4]1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[O:35][CH2:36][CH2:37][F:38]>C(Cl)Cl>[CH3:2][N:3]1[C:7]2=[N:8][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:35][CH2:36][CH2:37][F:38])=[O:39])[CH2:22][C:21]2=[O:26])=[CH:4]1
Reactant: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Reactant: O=C(Cl)OCCF
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(N2CCN(C(=O)OCCF)CC2=O)c2ccc(OCc3ccccn3)nc21
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 1-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one, hydrochloride (0.15 g, 0.40 mmol) and triethylamine (0.121 g, 1.20 mmol) in DCM (15 mL) is added dropwise 2-fluoroethyl carbonochloridate (0.076 g, 0.602 mmol) at room temperature, and the reaction mixture is stirred for 3 h. The reaction is quenched with a saturated solution of sodium bicarbonate (20 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on neutral alumina, eluting with 1% MeOH in DCM to give a product, which on triturating in Et2O, affords the title compound (0.07 g, 0.164 mmol) as an off-white solid. MS (m/z): 428 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 3.77 (m, 4H), 4.17 (bs, 2H), 4.28 (t, 1H), 4.35 (t, 1H), 4.58 (t, 1H), 4.71 (t, 1H), 5.49 (s, 2H), 6.66 (d, 1H), 7.30-7.34 (m, 2H), 7.50 (d, 1H), 7.77-7.83 (m, 2H), 8.56 (d, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:13]2[N:14]=[C:15](O)[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[N:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:2][CH:3]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)Oc1ccc(-c2cc3ncccc3c(Cl)n2)cc1

Procedure:
200 mg 7-(3-fluoro-4-trifluormethoxy-phenyl)[1,6]-naphthyridine-5-ol (5.1) and 10 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 120° C. The reaction mixture was evaporated down, followed by co-evaporation with toluene (×3) and the residue purified via silica gel chromatography (ethyl acetate dichloromethane/methanol 4:1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[O:24]([C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)Oc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and phenyl chloroformate, there is obtained ethyl N-phenoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: 293 (100, M-phenolate radical), 265 (16), 167 (76);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Br:24])[C:22]=1[OH:23])[CH:18]=O.N1CCCCC1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:18]\[C:17]1[CH:16]=[C:15]([Br:14])[C:22]([OH:23])=[C:21]([Br:24])[CH:20]=1
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/c1cc(Br)c(O)c(Br)c1
Temperature: 95 °C
Yield: 99.6 %

Procedure:
6-Bromo-4H-isoquinoline-1,3-dione (0.12 g, 0.5 mmol), 3,5-dibromo-4-hydroxybenzaldehyde (0.14 g, 0.5 mmol), and piperidine (0.075 mL, 0.75 mmol) were dissolved in i-propanol (2 mL). After heating at 95° C. for 3 h, it is cooled, and the solid is filtered and washed with I-propanol, ether and hexane to yield 0.25 g (99.6%) solid; mp 167-168° C.; HRMS (ESI) m/z 499.8 (M−H)−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH2:14]Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][S:9]2(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCCCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1c1ccc(Br)cc1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
N-(4-Bromophenyl)-3-chloropropane-1-sulfonamide (1.0 g, 3.2 mmol) was dissolved in DMF, Cs2CO3 (1.56 g, 4.8 mmol) was added, and the mixture was stirred for 3 hours. The mixture was then diluted with ether, washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-60% ethyl acetate in hexane) to afford 0.65 g (74%) 2-(4-bromophenyl)isothiazolidine 1,1-dioxide.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C@H:24]([C@@H:41]([OH:43])[CH3:42])[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:26])[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[Si:10]([O:43][C@@H:41]([CH3:42])[C@@H:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([Cl:14])[CH:16]=1)[C:25]([NH:27][NH:28][C:29](=[O:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:26])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.7 %

Procedure:
Imidazole (3.77 g, 55.44 mol) and TBDMS-Cl (5.01 g, 33.24 mmol) were added sequentially to a pre-cooled (0° C.) solution of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-(methylsulfonyl)benzohydrazide (5 g, 11.08 mmol) in DMF (350 mL). The reaction mixture was allowed to warm to room temperature and stirred for 17 h, whereupon the solution was poured into H2O (90 mL). The white precipitate was filtered, washed with H2O (30 mL) and taken up in CH2Cl2 (170 mL) This organic layer was washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (4.3 g, 69%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.8 (br s, 1H), 8.08 (d, J=8.0 Hz, 2 H), 8.04 (d, J=9 Hz, 2 H), 7.53 (d, J=8 Hz, 1H), 6.99 (s, 1H), 6.85 (d, J=8 Hz, 1H), 6.22 (d, J=8 Hz, 1H), 4.43-4.38 (m, 1H), 4.27-4.22 (m, 1H), 1.37 (d, J=7 Hz, 3H), 0.86 (s, 9H), 0.11 (s, 3H) and 0.05 (s, 3H).
Reaction SMILES: [N:1]1([C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>[Ni].C1(C)C=CC=CC=1.CC(C)=O>[N:1]1([C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1
Agent: [Ni]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is obtained in a manner analogous to that described in Example 7 by hydrogenation of 4-(1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (Example 10) with Raney nickel. M.p. 243-245° C.; FAB-MS: (M+H)+ =342 (corresponds to C21H19N5); Rf value (toluene-acetone--4:6)=0.25.