Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[C:9]2[S:19][CH:20]=[CH:21][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH2:22]([Mg]Br)[CH3:23].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[CH:12]([CH2:22][CH3:23])[CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[C:9]2[S:19][CH:20]=[CH:21][C:8]1=2)=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)C)c2ccsc2c1=O
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sccc2N(C(=O)OC(C)C)C1CC
Temperature: -78 °C
Yield: 93 %

Procedure:
Mix 7-oxo-7H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.512 g, 1.66 mmol) and copper(I) iodide (0.695 g, 3.65 mmol) in THF (35 ml). Cool the mixture to −78° C. Inject ethyl magnesium bromide (3.0 M in diethyl ether, 1.66 ml) and stir for 1.5 h. Add another portion of ethyl magnesium bromide (3.0 M in diethyl ether, 3.30 ml) and keep the reaction at −78° C. for one more hour. Warm up to −20° C. overnight in a freezer. Pour the reaction mixture into saturated ammonium chloride solution (200 ml). Extract with ethyl acetate (3×200 ml). Combine all the organic layers, dry over Na2SO4, filter and concentrate to give 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.520 g, 93%) as a crude oil. MS (ES+): 340 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3]1=[O:25].Br[CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3](=[O:25])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCOP(=O)(CCCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Reactant: CCCCBr
Product: CCCCn1cnc2c1c(=O)n(CCCCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.008 mol of diethyl [5-(3-methyl-xanthin-1-yl)pentyl]phosphonate and 0.01 mol of 1-bromobutane analogously to Example 46.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:12]=1[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])(=O)C>CO.O1CCOCC1>[Cl:39][C:37]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[C:11]([OH:10])[CH:38]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (0.12 g) was added to a solution mixture of the obtained tert-butyl 2-(2-acetoxy-4-chlorobenzamido)-4-phenylbenzoate (0.13 g) in methanol (2.5 mL) and dioxane (2.5 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.11 of tert-butyl 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cccc(OCc2ccccc2)c1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(OCc2ccccc2)c1

Procedure:
(RS)-(3-Benzyloxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(3-benzyloxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.[ClH:15].[C:16](=[NH:21])(OCC)[CH3:17].C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:15].[ClH:15].[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:16](=[NH:21])[CH3:17])[S:3][C:4]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 25 °C
Reaction time: 240 h
Yield: 69 %

Procedure:
A suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)thiazole (205 mg), ethyl acetimidate hydrochloride (370 mg) and diisopropylethylamine (0.697 ml) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 10 days and evaporated under reduced pressure. To the residue was added hydrogen chloride in ethyl acetate (4N, 4 ml) and crystallized from methanol and ethyl acetate. The precipitate was collected by filtration and recrystallized from methanol and 2-propanol to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)acetamidine dihydrochloride (220 mg).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][CH:10]([NH:20]C(=O)OC(C)(C)C)[CH2:11][N:12]2[CH:17]3[CH2:18][CH2:19][CH:13]2[CH2:14][NH:15][CH2:16]3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH2:37]([N:41]=[C:42]=[O:43])[CH2:38][CH2:39][CH3:40]>CC#N>[NH2:20][CH:10]([CH2:9][CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:11][N:12]1[CH:13]2[CH2:19][CH2:18][CH:17]1[CH2:16][N:15]([C:42]([NH:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:43])[CH2:14]2
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C#N)cc1)CN1C2CCC1CNC2
Reactant: CCCCN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)N1CC2CCC(C1)N2CC(N)CCOc1ccc(C#N)cc1
Reaction time: 96 h

Procedure:
tert-Butyl 3-(4-cyanophenoxy)-1-(3,8-diazabicyclo[3.2.1]oct-8-ylmethyl)propylcarbamate (100.1 mg, 0.25 mmol; see Preparation M) was dissolved in MeCN (2.5 mL) and triethylamine (37.9 mg, 0.38 mmol). Butylisocyanate (29.7 mg, 0.3 mmol) was added and the reaction mixture was stirred at r.t for 4 days. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with HCl (2 mL) was added and the mixture was stirred for 6 h. The solvent was evaporated and the residue dissolved in MeCN (2 mL). The solution was added to ion-exchange solid phase extraction plug. The plug was then eluted with DCM/MeCN (4×2 mL of 4:1) (fraction 1) followed by DCM:MeOH:Et3N (4×2 mL of 8:1:1)(fraction 2). Evaporation of fraction 2 gave the title compound in quantitative yield.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[N:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ncc(I)cn1
Product: Nc1ncc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyrimidine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (270 mg, 67%). MS (ISP) 380.3 [(M+H)+]; mp 244-246° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:21][CH3:22].[OH-].[Na+]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:21][CH3:22])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCI
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) in DMF(10 mL) was carefully added sodium hydride (29.1 mg, 1.211 mmol). After 15 minutes stirring, iodoethane (0.077 mL, 0.951 mmol) was added and the mixture stirred at room temperature for 2 hr. Sodium hydroxide (1 mL, 1.000 mmol) was added and the mixture allowed to stir at room temperature for 1 h. The contents were concentrated in vacuo. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were then extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: hexanes to 100% EtOAc, then DCM to 20% MeOH:DCM). The final product was collected as 90 mg (45%). LCMS E-S (M+H)=232.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 4 H) 1.41 (t, J=7.33 Hz, 3 H) 2.35-2.45 (m, 1 H) 4.34-4.57 (m, 2 H) 7.62 (s, 1 H) 8.24 (s, 1 H) 13.83 (br. s., 1 H). Regiochemical assignment supported by 2D HNMR.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.Cl>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:24][CH2:23]1
Reactant: CCCCN=C=O
Reactant: COc1cc2ncnc(N3CCC(CN)CC3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)NCC1CCN(c2ncnc3cc(OC)c(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
n-Butylisocyanate (1.8 g.) was added to a stirred solution of 6,7-dimethoxy-4-[4-(aminomethyl)piperidino]- quinazoline (5 g.) in dry chloroform (100 ml.). The mixture was then stirred at room temperature for 3 hours, then left standing for 72 hours. An equal volume of 1 N hydrochloric acid was added, the organic phase separated, and the aqueous phase basified to pH 10 with aqueous potassium carbonate solution. The mixture was extracted with chloroform (2×100 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant solid was recrystallized twice from acetonitrile and then once from a mixture of isopropanol and ether to yield 6,7-dimethoxy-4-[4-(3-n-butylureidomethyl) piperidino]quinazoline (3.3 g.), m.p. 141°-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH3:14]OS(=O)(=O)OC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][CH3:14])=[C:3]([CH:9]=1)[CH2:4][OH:5]
Reactant: CCOC(=O)c1cc(C)ccc1N
Reactant: COS(=O)(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1ccc(C)cc1CO

Procedure:
Ethyl 2-amino-5-methylbenzoate was treated with dimethylsulfuric acid to give a N-methylated product. The N-methylated product was reduced using lithium aluminum hydride to give 5-methyl-2-methylaminobenzyl alcohol. The obtained alcohol was reacted with thionyl chloride in benzene to give the desired compound, yield 22% (based on the amount of the starting benzoate).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O:20][C:21]1[CH:22]=[C:23]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:24][CH2:25][CH2:26][CH:27]=[N:28][NH:29][C:30]([NH2:32])=[S:31])(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([N:29]([C:30](=[NH:32])[SH:31])[N:28]=[CH:27][CH2:26][CH2:25][O:24][C:23]1[CH:33]=[C:34]([CH3:36])[CH:35]=[C:21]([O:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])(=[O:19])=[O:18])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NNC(N)=S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NN(Cc2ccccc2)C(=N)S)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A solution of benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL) was added dropwise over 20 minutes to a mixture of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-propionaldehyde thiosemicarbazone (55.3 mg, 0.13 mmol, as prepared in the preceding step) and sodium bicarbonate (28.8 mg, 0.34 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL). The reaction was stirred for 5 hours at ambient temperature, then additional benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The reaction was stirred overnight at ambient temperature then concentrated to remove solvents. The residue was triturated with dichloromethane and filtered through Celite. After concentration, crude product was purified by flash column chromatography through silica gel (1:1 diethyl ether/hexane) to give the title compound as an oil (42 mg, 1:4 mixture of isomers, 62%). 1H-NMR (300 MHz, CDCl3) δ 7.80-7.85 (m, 2H), 7.57-7.63 (m, 1H), 7.23-7.40 (m, 5H), 6.98-7.12 (m, 2H), 6.59 (br s, 1H), 6.52 (br s, 1H), 6.46 (t, 1H, J=2 Hz), 4.29 and 4.28 (s, 1H), 4.10 (t, 2H, J=6.5 Hz), 4.01 (s, 3H), 2.94 and 2.73 (q, 2H, J=6 Hz), 1.55 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H27N3O5S2 : 514.1 (M+H). Found: 513.6.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
To a solution (100 mL) of tert-butyl 3-(4-hydroxyphenyl)propanoate (5.5 g, 24.7 mmol) in N,N-dimethylformamide was added 60% sodium hydride (1.09 g, 27.2 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 15 min. Then, 3-bromobenzylbromide (6.55 g, 25.91 mmol) was added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.5 g, yield 78%) as a colorless powder.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.O.N>C(O)(=O)C>[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(F)cccc2[nH]1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2c(F)cccc2N1
Temperature: 14 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
3.63 g of sodium cyanoborohydride are gradually added to a solution of 2.87 g of 4-fluoro-2-methylindole in 98 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is left to warm up to ambient temperature. After 2 hours, the reaction mixture is poured into a mixture of water and ice, and is then treated with a 28% aqueous ammonia solution until the pH is 9. The mixture is then extracted twice with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 300 g silica column, elution being carried out with a 100/0 to 90/10 v/v heptane/ethyl acetate gradient. 2.19 g of 4-fluoro-2-methyl-2,3-dihydro-1H-indole are thus obtained in the form of a colorless oil, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([O:18]CC)=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[OH-].[Na+].CCO.O>>[C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([OH:18])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c(N2CCOC(CF)C2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Yield: 100.3 %

Procedure:
A mixture of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 0.00054 mol), Sodium hydroxide (0.12 g, 0.0030 mol) in EtOH (10.0 mL, 0.171 mol) and water (3.0 mL, 0.17 mol) was stirred at it until completion by LCMS. The mixture was concentrated and the residue was acidified by 1NHCl. The precipitate was collected and dried in air and vacuum to afford 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylic acid (225 mg, 99%). LCMS: (FA) ES+ 415, ES− 413.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)#[CH:15].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Cl)ncc1I
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 49.2 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (15.53 mg, 0.022 mmol) was added to a solution of N-(2-chloro-5-iodopyridin-4-yl)methanesulfonamide (14) (184.0 mg, 0.553 mmol), tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (160.0 mg, 0.830 mmol), triethylamine (347 μL, 2.49 mmol) and copper iodide (6.32 mg, 0.033 mmol) in anhydrous DMF (2.0 mL). The reaction mixture was heated at 60° C. for 1 h under microwave irradiation, then partitioned between water (60 mL) and EtOAc (60 mL). The aqueous layer was extracted with more EtOAc (2×60 mL), the combined extracts were washed with brine (2×40 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was absorbed on silica gel (2.0 g) and the free-running powder was placed on a 20 g isolute silica column. Elution with dichloromethane and 1% ethanol in dichloromethane afforded the title compound (108 mg, 49%). 1H-NMR (500 MHz, DMSO-d6) 1.61 (s, 9H), 3.48 (s, 3H), 7.12 (d, J=0.6 Hz, 1H), 7.91 (br t, J=0.5 Hz, 1H), 8.07 (d, J=0.5 Hz, 1H), 8.61 (d, J=0.5 Hz, 1H), 8.78 (d, J=0.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:32]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 3 ml of methylene chloride, cooled to 0° C., under argon, is added 346 μl of triethylamine followed by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 2 N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 295 mg of the desired product as a white solid, m.p. 170-180° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([OH:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>CN(C=O)C>[CH2:19]([O:25][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:7][CH2:6][CH:5]=[CH:4][CH:3]=[CH:2][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC=CC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4,4′-Difluorobenzophenone (34) (4.8 grams, 22 mmol) was dissolved in anhydrous DMF (1 liter), NaH (95%; 5.6 grams, 220 mmol) was added and the solution was cooled to 0° C. 2,4-Hexadienol (5.8 mL, 51 mmol) was slowly added to the solution and the reaction mixture was allowed to warm to room temperature with stirring under argon overnight. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane, and washed with water. The organic phase was dried (MgSO4) and concentrated and purified by column chromatography (silica gel; hexane/CH2Cl2, ⅓) to afford 2.07 grams (25%) of compound 35 as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J=6.6 Hz, 6 H), 4.68 (d, J=6.0 Hz, 4 H), 5.69-5.84 (m, 4 H), 6.05-6.19 (m, 2 H), 6.31-6.45 (m, 2 H), 7.08 (d, J=9.0 Hz, 4 H), 7.68 (d, J=10.2 Hz, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[N:21]=1)=[CH:16][CH:15]=3
Reactant: COCC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Product: COCC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and methoxyacetyl chloride.