Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH3:26][CH:27](I)[CH3:28]>CN(C)C=O>[CH3:26][CH:27]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[CH3:28]
Reactant: CC(C)I
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 0.90 g (2.0 mmoles) of 2-(4-hydroxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole dihydrobromide of Example 10 in 20 ml of dry dimethylformamide cooled in an ice bath was treated with 267 mg (6.67 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. A solution of 374 mg. (2.22 mmoles) of 2-propyl iodide in 2 ml of dimethylformamide was added dropwise and the reaction mixture heated at 100° C. for 4 hours. Another 35 mg (0.88 mmole) of 60% sodium hydride suspension was added at room temperature, followed by 113 mg (0.67 mmole) of 2-propyl iodide and the mixture heated at 100° C. for an additional 3 hours. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fraction eluting with 2% methanol in chloroform, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 148°-150° C. Anal. Calcd. for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.38; H, 6.58; N, 13.26.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:24][C:23]([F:26])([F:25])[CH2:22]3)=[C:17]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[N:16]=2)=[O:14])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH3:32]I.[H-].[Na+]>>[CH:1]1([CH2:4][C@H:5]([N:12]([CH3:32])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][C:23]([F:25])([F:26])[CH2:24]3)=[C:17]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[N:16]=2)=[O:14])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc([C@H](CC2CC2)N(C)C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
In analogy to the procure described in Example 16 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide was reacted with methyl iodide (CAN 74-88-4) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=448.2 [MH]+.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23](=[O:24])[C:22]3[C:17](=[C:18]([O:28][CH2:29][CH2:30][CH3:31])[CH:19]=[C:20]4[CH2:27][CH2:26][CH2:25][C:21]4=3)[NH:16][CH:15]=2)=[CH:10][CH:9]=1.[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>C(OCC)(=O)C.O>[Cl:38][CH2:37][CH2:36][CH2:35][N:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:23](=[O:24])[C:22]2[C:17]1=[C:18]([O:28][CH2:29][CH2:30][CH3:31])[CH:19]=[C:20]1[CH2:27][CH2:26][CH2:25][C:21]1=2
Reactant: ClCCCBr
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CCCCl)c13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
To a DMF solution (6 ml) of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (1.26 g, 3.60 mmol) was added sodium hydride (60% oil base, 189 mg, 4.33 mmol). The mixture was stirred at room temperature for 10 minutes. To the resulting mixture was added 1-bromo-3-chloropropane (1.70 g, 10.8 mmol), followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture and the resulting reaction mixture was then subjected to separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice. After being dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=20:1→12:1). The purified product was concentrated under reduced pressure, giving a yellow oily substance of 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (365 mg, yield: 92%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1.C(S)C.B(F)(F)F.CCOCC>CO>[OH:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH:14]=1
Reactant: Cn1cc(-c2nccc(-c3ccccc3)n2)cc(OCc2ccccc2)c1=O
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(-c2nccc(-c3ccccc3)n2)cc(O)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
To a solution of 3-(benzyloxy)-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one (21 mg, 0.057 mmol) was added ethanethiol (31.8 mg, 0.512 mmol) followed by BF3.OEt2 (73 mg, 0.512 mmol). The resulting solution was stirred at room temperature for 18 h, diluted with MeOH and concentrated. Purification by preparative HPLC (5-50% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 7.3 mg 3-hydroxy-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one (46%) as a light purple solid. 1H NMR (500 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.84 (d, J=5.3 Hz, 1H); 8.44 (s, 1H); 8.33 (s, 2 H); 7.90 (d, J=5.3 Hz, 1H); 7.72 (s, 1H); 7.59 (s, 3H); 3.65 (s, 3H). High resolution mass spec (FT/ICR) calc (M+H)+=280.1081 found 280.1080.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[S:7][CH2:8][CH2:9][C:10]([OH:12])=O)([O:3][CH3:4])=[O:2].C(=O)([O-])O.[Na+]>>[CH3:4][O:3][C:1]([C:5]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:6]=1[S:7][CH2:8][CH2:9][C:10]2=[O:12])=[O:2]
Reactant: COC(=O)c1ccccc1SCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cccc2c1SCCC2=O
Temperature: 0 °C
Reaction time: 21 h
Yield: 43.2 %

Procedure:
β(2-Carbomethoxythiophenoxy)propionic acid (6.00 g, 0.025 mol) (I. W. Still and M. J. Thomas J. Org. Chem 1968, 2733) was added slowly to ice cooled conc. sulphuric acid (75 ml) with stirring. After 21 h, the reaction mixture was poured into ice water and then made alkaline using solid sodium hydrogen carbonate. The resultant suspension was then extracted with CH2Cl2 (3x). The combined organic layers were then dried (Na2SO4), and evaporated under reduced pressure to give an orange oil which was dried in vacuo and crystallised on standing to give methylthiochroman-4-one-8-carboxylate (2.40 g, 43%)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]([CH2:28][C:29]3[C:34]([CH3:35])=[C:33]([O:36][CH3:37])[C:32]([CH3:38])=[CH:31][N:30]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])=[CH:16][N:15]([CH2:28][C:29]3[C:34]([CH3:35])=[C:33]([O:36][CH3:37])[C:32]([CH3:38])=[CH:31][N:30]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCN(C(C)C)C(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1c(C)cnc(Cn2cc(C#CCN(C(C)C)C(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by cleaving the pivaloyl protecting group of N-[4-chloro-5-(3-diisopropylamino-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide with ZnCl2 according to the General Procedure B. tR: 4.71 min. 1H-NMR (CDCl3) δ 8.24 (s, 1H), 7.05 (s, 1H), 5.30 (s, 2H), 4.96 (s, 1H), 3.76 (s, 3H), 3.68 (s, 2H), 3.27 (7, 2H), 2.27 (s, 2H), 2.20 (s, 2H), 1.15 (d, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O.Cl>C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was successively added pH3 HCl (5.2 mL), then PdC (350 mg) in ethyl acetate (3 mL). The mixture was vigorously stirred overnight under H2 (1 atm). The catalyst was filtered off through Celite and the filtrate was concentrated to dryness. The crude residue obtained was partitioned between DCM (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted DCM (2×25 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue obtained was purified by silica gel column chromatography using a gradient 50-100% ethyl acetate in hexanes to give 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%)
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12](=[N:18]O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH2:7]([C:8]1[O:9][N:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)C(N)=NO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
2-phenyl acetyl chloride (1.0 mL; 7.57 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.308 g (35%) of the title compound as a white solid.
Reaction SMILES: CC1C([Li])C2C(C=1)=CC=CC=2.Cl[Si:13]1(Cl)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>CCOCC>[CH:15]1[C:14]2[SiH2:13][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cl[Si]1(Cl)c2ccccc2-c2ccccc21
Agent: [Li]C1C(C)=Cc2ccccc21
Solvent: CCOCC
Product: c1ccc2c(c1)[SiH2]c1ccccc1-2

Procedure:
Solid 2-Methylindenyl lithium (3.34 g, 24.52 mmol) was added to a stirred solution of 9,9-Dichloro,9-silafluorene (3.08 g, 12.26 mmol) in Et2O (ca. 25 mL) and the resultant mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was extracted into CH2Cl2 (ca. 75 mL), filtered and the solvent removed giving a white powder which was washed with pentane (ca 50 mL) and dried under vacuum leaving 9-Silafluorene, 9,9-bis-2-Methylindene as a white powder (3.80 g, 71%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=O)=[CH:10][CH:9]=1>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccc(Br)cc1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1ccc(CCN2CCOCC2)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a mixture of lithium aluminum hydride (3.35 g, 88.16 mmol, 2.00 equiv) in tetrahydrofuran (100 mL) maintained under nitrogen at −30° C. was added a solution of 2-(4-bromophenyl)-1-morpholinoethanone (12.5 g, 44.17 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) dropwise with stirring. The reaction mixture was stirred at −30° C. for 30 min and then at room temperature for 2 h. The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water. The solid was removed by filtration. The filtrate was extracted with 1×150 mL of ethyl acetate. The organic layer was collected then washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 11.5 g (97%) of 4-(4-bromophenethyl)morpholine as a white solid. LC-MS: (ES, m/z): 311 [M+CH3CN+H]+, 270 [M+H]+, 130, 102.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: Oc1ccccc1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: C1(N(C2C=CC=CC=2)[C:8]([NH:10][S:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])C=CC=CC=1.[NH:28]1[CH2:38][CH2:37][CH:31]([C:32]([O:34]CC)=[O:33])[CH2:30][CH2:29]1.CN(C)C=O>CCOCC.O1CCCC1>[C:32]([CH:31]1[CH2:30][CH2:29][N:28]([C:8]([NH:10][S:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])[CH2:38][CH2:37]1)([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(NS(=O)(=O)C=Cc1ccccc1)N(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)NS(=O)(=O)C=Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 g. of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide and 10.3 g. of ethyl isonipecotate in 20 ml. of N,N-dimethylformamide is maintained at ca. 90° C. for 40 minutes. The mixture is cooled to ambient temperature, diluted with ether, and then it is extracted with water. The water extract is acidified using concentrated hydrochloric acid, and then it is extracted with methylene chloride. The dried methylene chloride is evaporated to dryness in vacuo leaving a viscous oil. The oil is redissolved in a small volume of tetrahydrofuran, absorbed onto a column of silica gel, and then eluted from the column with an excess of the same solvent. The solvent is evaporated in vacuo, and the residue is dissolved in 50 ml. of 0.5N sodium hydroxide solution. After 1 hour it is re-precipitated by acidification, and recovered by vacuum filtration in the form of white crystals. It is then dissolved in a mixture of 100 ml. of acetone and 100 ml. of tetrahydrofuran, and the solution is concentrated slowly to effect precipitation of the product. The solid is filtered off, and then triturated with acetone to give pure N-([4-carboxypiperidino]carbonyl)-2-phenylethenesulfonamide, m.p. 179°-181° C.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:12]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[C:11]=1[CH3:29])=[O:9])[CH3:6].[N-:30]=[N+:31]=[N-].[Na+]>O.Cl>[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:12]([C:22]2[CH:23]=[CH:24][C:25]([N:28]=[N+:30]=[N-:31])=[CH:26][CH:27]=2)[C:11]=1[CH3:29])=[O:9])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(N)cc2)c1C
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(N=[N+]=[N-])cc2)c1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of NaNO2 (0.015 g, 0.216 mmol) in water (1.5 mL) was added to an ice-cold solution of Example 26 (0.075 g, 0.212 mmol) in HCl (3 mL, 37% w/v) over 10 minutes. A solution of NaN3 (0.138 g, 2.12 mmol) in water (0.5 mL) was added drop wise with stirring at 0° C. over 10 minutes, and the temperature of the mixture was allowed to rise to 25° C. After stirring for another 20 minutes at room temperature, the mixture was extracted with DCM (3×25 mL), and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 381 (M+H); IR: 2097 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25])[C:10](=[O:26])[NH:9][CH2:8]2)=[O:4].[I:27]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:27])=[CH:17][C:16]=1[F:25])[C:10](=[O:26])[NH:9][CH2:8]2)=[O:4]
Reactant: ClI
Reactant: COC(=O)c1cc2c(cc1Nc1ccc([Si](C)(C)C)cc1F)C(=O)NC2
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of 6-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (284 mg, 0.76 mmol) in DCM (5 ml) at 0° C. was added a solution of iodine monochloride (246 mg, 1.52 mmol) in DCM (1.5 mL). The reaction mixture was stirred at 0° C. for 4 hours. The reaction was quenched by the addition of water (10 mL) then diluted with saturated aqueous sodium thiosulfate solution (10 mL). The resultant mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM) to yield the title compound as a brown solid (220 mg, 68%). LCMS (Method B): RT=3.65 min, 2M+H+=853.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([N+:26]([O-:28])=[O:27])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.C1COCC1>[CH3:1][O:2][CH2:3][C:4]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([N+:26]([O-:28])=[O:27])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)=[O:5]
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: COCC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
Methoxyacetyl chloride (24.2 mL, 264 mmol) was added dropwise over 10 min to a stirred suspension of the amine (3) (60.0 g, 203 mmol) in a mixture of DCM (300 mL), THF (450 mL) and DIPEA (53.1 mL, 305 mmol) under nitrogen at −5° C. After 10 min the reaction mixture was allowed to warm to RT during which time a dark solution formed. After 30 min a solution of NH3 (7M in MeOH, 30 mL) was added and stirring continued for 1 hr during which time a precipitate formed. The suspension was evaporated in vacuo and the residue was triturated with water (500 mL). The precipitate was collected by filtration, was washed with water (300 mL) and diethyl ether (500 mL) and then dried in vacuo at 60° C. to furnish the title compound (63) as a yellow solid (68 g, 88%): m/z 368 (M+H)+ (ES+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:19])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:10]([Cl:18])[CH:9]=1)([CH3:7])[CH3:6].CCN(CC)CC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][C:29]=1[O:37][CH3:38].O>C(Cl)Cl>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([C:4](=[O:19])[CH2:3][NH:2][C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([O:37][CH3:38])[CH:30]=2)=[S:36])[CH3:6])[CH:13]=[CH:12][C:11]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: COc1cc(N=C=S)ccc1F
Reactant: CC(C)(C(=O)CN)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(S(N)(=O)=O)c(Cl)c2)ccc1F
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 4-(4-amino-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide hydrochloride (7.8 g, 23.7 mmol) in DCM (150 mL) was added Et3N (9.9 mL, 71.1 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (4.35 g, 23.7 mmol). After stirring 2 h, DCM and water were added to the reaction mixture. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=1:1 to EtOAc/DCM=1:1) to give 2-chloro-4-(4-(3-(4-fluoro-3-methoxyphenyl)thioureido)-2-methyl-3-oxobutan-2-yl)benzenesulfonamide (8.6 g, 76%). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.15 (m, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.77 (m, 2H), 5.30 (s, 2H), 4.43 (d, J=4.4 Hz, 2H), 3.91 (s, 3H), 1.59 (s, 6H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH:33]1[CH:38]=[C:37]([CH2:39]Br)[C:36]([Cl:41])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].[H-].[Na+]>C(#N)C.O>[Cl:41][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][N:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)[C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Clc1ccccc1CBr
Reactant: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN1CCOCC1)N(Cc1ccccc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 126.9 %

Procedure:
A mixture of 0.11 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of O-chlorobenzyl bromide and 0.41 g of K2CO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na2SO4 and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](/[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)\[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: COc1cc(/C(C#N)=C/c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Solvent: CC(C)=O
Product: COc1cc(/C(C#N)=C\c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Yield: 7.2 %

Procedure:
1.38 g of (Z)-3-(3-nitro-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile was dissolved in 500 ml of acetone and the mixture was reacted in a photochemical apparatus (visible light) for 1 hour. The reaction mixture was concentrated and a quarter of it was purified on a silica gel plate to give 100 mg of the intended compound.