Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH3:63])=[C:55]([C:64]([F:67])([F:66])[F:65])[CH:54]=3)[N:49]=[C:48]([C:68]#[N:69])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:68]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH3:63])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:64]([F:67])([F:65])[F:66])[CH:54]=2)[N:49]=1)#[N:69]
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 50.1 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (51.1 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide (30.2 mg).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C>[C:1]1([S:7][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: c1ccc(SCc2ccccn2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Thiophenol 2(2) (2.77 g, 0.025 mol), cesium carbonate (24.65 g, 0.075 mol) and catalytical amount of cesium fluoride were added successively to a solution of 2-chloromethylpyridine 6(1) (1.13 g, 0.017 mol) in absolute DMF (28 ml). The reaction mixture was stirred at 50-60° C. for 2 h in argon current and left for night at 20° C. Solvent was removed in vacuo, the residue was dissolved in water, the reaction product was extracted with CH2Cl2, dried over MgSO4, solvent was evaporated in vacuo. It gave 2-phenylsulphanylmethylpyridine 6(2), 3.2 g, (95%).
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])(=O)=O)=CC=1.C[O-].[Na+]>CO>[N:12]1[CH2:14][C:13]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=NOS(=O)(=O)c1ccc(C)cc1)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1cncc(C2=NC2)c1

Procedure:
The process of claim 5 wherein 1-(3-pyridinyl)-ethanone-O-[(4-methylphenyl)-sulfonyl]-oxime is reacted with methanol and sodium methylate to form 3-(2H-azirin-3-yl)-pyridine, reacting the latter without isolating it with oxalic acid to obtain β,β-dimethyloxy-3-pyridine-ethanamine, reacting the latter without isolating it with formamide to obtain N-[β,β-dimethoxy-2-(3-pyridinyl)-ethyl]-formamide and subjecting the latter without isolating it to cyclization by heating to obtain a compound of formula I.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[N:33][C:22]=4[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:19]=3[CH:18]=[N:17][C:16]=2[C:37]#[N:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]1([S:24]([N:23]2[C:19]3[CH:18]=[N:17][C:16]([C:37]#[N:38])=[C:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:20]=3[C:21]3[CH:36]=[CH:35][CH:34]=[N:33][C:22]2=3)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc2c(c1CC1CCNCC1)c1cccnc1n2S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-(9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.38 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (2 mL) and the resultant mixture stirred for 1 h then concentrated in vacuo. The residue was purified by flash chromatography (silica, 5 g column, SPE-NH2, 0-8% methanol in DCM) to give title compound as an off white solid (150 mg, 80%). LCMS (Method G): RT=3.07 min, M+H+=432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:28])=[C:17]([C@@:19]2([CH3:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH2:20]2)[CH:18]=1>>[F:28][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:18][C:17]=1[C@@:19]1([CH3:27])[NH:25][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: Cl
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COCCC(=O)N1

Procedure:
Starting from 5-chloro-pyridine-2-carboxylic acid and (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 5-chloro-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a white solid. MS (ISP): m/z=378.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)[C:10]([O:12][C:13](C)(C)C)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[Br-].[K+].Cl>CO>[N:1]1([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 4.17 h

Procedure:
A mixture of 3-(4-morpholinyl)-5-nitro-benzoic acid, 1,1-dimethylethyl ester (Example 87b; 0.77 g, 2.5 mmol), 1,8-diazabicyclo[5,4,0]undec-7-ene (0.56 mL, 3.75 mL), and potassium bromide (1.09 g, 12.5 mmol) in methanol (25 mL) is stirred at 90° C. for 250 min. The cooled mixture is then added to hydrochloric acid (50 mL of 0.1 M) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium hydro-carbonate (2×25 mL), water (2×25 mL) and brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate—hexane to afford the title compound as yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[C:25]([F:28])([F:27])[F:26]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Fc1cccc2c1CCNC2C(F)(F)F
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(F)cccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[NH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[N:12]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a stirred mixture of sodium hydride (12.5 g, 520 mmol, 60% in mineral oil) in anhydrous THF (300 mL) at 0° C. was added dropwise 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (40.0 g, 262 mmol) dissolved in anhydrous THF (200 mL). The reaction mixture was stirred at 0° C. for 15 min them SEMCl (52.5 g, 315 mmol) was added dropwise. The mixture was then stirred at RT for 1 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 42 g (56.4%) of 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine as an orange oil. A high-pressure tube charged with 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (2.23 g, 7.90 mmol), tributyl(1-ethoxyvinyl)stannane (3.7 g, 10.27 mmol), and Pd(PPh3)2Cl2 (200 mg) in degassed DMF (20 mL) under N2 was sealed and heated at 100° C. for 16 h. The reaction mixture was cooled, diluted with EtOAc, and filtered through a pad of Celite® to remove Pd solid. The filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was dissolved in anhydrous THF (0.3 M), and 2N HCl (5.0 eq.) was added. The reaction mixture was stirred at RT under N2 for 16 h, poured into 10% aq. NaOH solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 1.5 g (66%) of 1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanone as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.66 (d, J=3.2 Hz, 1H), 6.89 (d, J=4.8 Hz, 1H), 5.60 (s, 2H), 3.49 (t, J=8.0 Hz, 2H), 2.88 (s, 3H), 0.901 (t, J=8.0 Hz, 2H), −0.053 (s, 9H); MS (ESI) m/z: 291 [M+].
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]([OH:16])[CH2:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>C(O)C>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:31])[CH2:4][CH:5]([OH:16])[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCCSCCCN(CC)CC(O)CNc1ccc(C#N)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Product: CCCS(=O)CCCN(CC)CC(O)CNc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of 4-[[3-[ethyl[3-(propylthio)propyl]amino]-2-hydroxy-propyl]amino]-benzonitrile (2.0 g, 5.9 mmol) and toluene-4-sulfonic acid (2.3 g, 11.9 mmol) in ethanol (50 ml) was stirred 1/2 h at room temperature. The mixture was cooled to -10 ° C. and solid 3-chloroperbenzoic acid was added during 1/2 h. The solution was stirred for 1 h at room temperature. Solid calcium hydroxide (1.2 g, 16.4 mmol) was added, followed by stirring for 15 minutes. Filtration and evaporation gave an oily residue. Purification by column chromatography on silica gel yielded 1.0 g of the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 70.7 %

Procedure:
3-Iodo-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.00 g, 3.45 mmol) and cesium carbonate (1.69 g, 5.17 mmol) were combined in dry DMF (35 mL). p-Methoxybenzyl chloride (0.702 mL, 5.17 mmol) was added to this mixture, and the mixture was stirred at room temperature for 22 hours. Water (200 mL) was then added to the reaction mixture, resulting in a precipitate, which was collected by filtration. The solids were triturated with 3:1 EtOAc/Et2O (50 mL) to give 3-iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (1 g, 71%) as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](Br)=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH:5]([N:1]=[N+:2]=[N-:3])=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCC=CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC=CN=[N+]=[N-]
Temperature: 80 °C
Yield: 56.4 %

Procedure:
To do this, sodium azide (2.781 g, 43 mmol) was dissolved in 170 ml of dimethylformamide (DMF). 5 ml of undecenyl bromide (36 mmol) were added, with stirring, to the reaction medium, which was subsequently heated at 80° C. for 24 hours. The mixture was left to cool to ambient temperature, and then 100 ml of water were added portionwise. An extraction with ethanol (3×100 ml) was subsequently carried out, and the organic phase was then washed with water (3×100 ml) and dried over sodium sulfate (Na2SO4). Finally, the solvent was evaporated off and 2.58 g of undecenyl azide (20.3 mmol; yield 60%) were isolated in the form of a pale yellow-colored transparent oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.05 eq) was added to the reaction. Hydrogen gas was introduced via a balloon; and the reaction was stirred for 2 hours at room temperature. The mixture was filtered through Celite and washed with MeOH. The solvent was removed en vaccuo and the crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM with 0.5% NH3 to give diethyl 2-(2-(2-aminoethoxy)ethoxy)ethylphosphonate as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[C:8]([C:10]1[C:14]([S:15][C:16]([F:19])([F:18])[F:17])=[C:13]([CH2:20][F:21])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]>OO>[C:8]([C:10]1[C:14]([S:15]([C:16]([F:18])([F:17])[F:19])=[O:4])=[C:13]([CH2:20][F:21])[N:12]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:11]=1)#[N:9]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1SC(F)(F)F
Agent: OO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CF)c1S(=O)C(F)(F)F
Reaction time: 6 h
Yield: 32 %

Procedure:
A 30 wt % aqueous solution of hydrogen peroxide (50 μL) was added to a trifluoroacetic acid solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole (205 mg) prepared as described in Example 30. The reaction mixture was stirred for 6 h whereupon solvent was evaporated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/DCM) to afford the title compound as a white solid (66.5 mg, 32%). MS (ES): M/Z [M−H] 452. 1H NMR: (400 MHz, DMSO-d6): 5.48-5.75 (m, 2H) and 8.41 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −62.05 (s, 3F), −73.68 (d, 3F) and −82.41 (m, 1F).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:30][NH:31][CH3:32]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:23])([F:25])[F:24])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([N:31]([CH3:32])[CH3:30])=[O:5]
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F

Procedure:
By the reaction in the same manner as in Example 60 using 2-fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (201 mg), thionyl chloride (0.06 ml) and aqueous dimethylamine solution (50%, 5 ml), the title compound (90 mg) was obtained as a colorless amorphous compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cccs6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (60 mg, 0.3137 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 76% yield (0.110 g, 0.1951 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C@@H:6]1[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[O:11][C@H:8](OC)[C@:7]1([CH3:25])[OH:24].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.C(#N)C>ClCCl>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:8]3[O:11][C@H:12]([CH2:13][O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[C@@H:6]([O:5][CH2:4][C:3]4[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:2]=4[Cl:1])[C@@:7]3([CH3:25])[OH:24])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound from Step C (9.42 g, 19 mmol) in anhydrous dichloromethane (285 mL) at 0° C. was added HBr (5.7 M in acetic acid, 20 mL, 114 mmol) dropwise. The resulting solution was stirred at 0° C. for 1 h and then at room temperature for 3h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×40 mL). The oily residue was dissolved in anhydrous acetonitrile (50 mL) and added to a solution of sodium salt of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Chem. Soc., 131 (1960)] in acetonitrile [generated in situ from 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (8.76 g, 57 mmol) in anhydrous acetonitrile (1000 mL), and NaH (60% in mineral oil, 2.28 g, 57 mmol), after 4 h of vigorous stirring at room temperature]. The combined mixture was stirred at room temperature for 24 h, and then evaporated to dryness. The residue was suspended in water (250 mL) and extracted with EtOAc (2×500 mL). The combined extracts were washed with brine (300 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (10 cm×10 cm) using ethyl acetate/hexane (1:3 and 1:2) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (5.05 g) as a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[CH2:9][CH2:10][N:11]([CH2:13][CH:14]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=O)[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]1[CH3:41])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O:44][CH:45]([O:53][CH3:54])[CH2:46][N:47]([CH3:52])[S:48]([NH2:51])(=[O:50])=[O:49].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:28]1([C:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:34]([NH:51][S:48]([N:47]([CH2:46][CH:45]([O:44][CH3:43])[O:53][CH3:54])[CH3:52])(=[O:50])=[O:49])=[O:36])=[CH:22][C:21]=3[N:19]3[C:18]=2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]([CH3:41])[CH:14]([CH2:13][N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH3:42])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:20]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)CC1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2N1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)C(=O)OC(C)(C)C)N(C)c1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (0.06M) and EDC (3 eq) was added. The mixture was warmed to 40° C. Within 5 min the clear yellow solution turned dark brown. The mixture was stirred overnight. After dilution with DCM the solution was extracted with 1N HCl, sat. aq. NaHCO3 and brine. After drying the organic phase over Na2SO4 the solution was discoloured with activated charcoal. All volatiles were evaporated in vacuo leaving tert-butyl {2-[({13-cyclohexyl-10-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-amino)carbonyl]-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-6-yl}methyl)(methyl)amino]ethyl}methylcarbamate as a glassy brownish solid (MS (ES+) m/z 755 (m+H)+). The material was dissolved in DCM (0.03M) and water was added. To the biphasic system TFA was added and then the vigorously stirred mixture was warmed to 40° C. After 2 h the acetal was completely cleaved, while some N-Boc-protected material was still around. More TFA was added until a monophasic system was obtained. Heating was continued for 3 h. Then all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. The residual sticky material was digested with Et2O leaving a dark red powder. This material was used without further purification in the next reaction. (ES+) m/z 609 (M+H)+.