Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:30][CH:19]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH:18]2[CH:17]1[CH3:31].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:30][C@@H:19]4[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22][C@@H:18]4[C@H:17]3[CH3:31])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC1C(N)CC2CN(C(=O)OC(C)(C)C)CC21
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 5.05 g, 18.40 mmol), crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Intermediate 7, 7.07 g) and N,N-diisopropylethylamine (12.85 mL, 73.6 mmol) in N-methylpyrrolidinone (80 mL) was heated to 95° C. for 5 h. The mixture was diluted with ethyl acetate (600 mL), washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the desired product as a racemic mixture (3.1 g). This mixture was resolved using preparative SFC using the following conditions: Column: ChiralPak AD-H 25×3 cm, 5 μm; Column Temp: 40° C.; Flow rate: 130 mL/min; Mobile Phase: CO2/methanol=50/50; Injection Volume: 5 mL (22.2 mg/mL, 3 g solid in 75 mL methanol and 60 mL chloroform); Detector Wavelength: 263 nm. The first eluted enantiomer was the desired (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.35 g). 1H NMR (400 MHz, chloroform-d) δ ppm 10.40 (1 H, d, J=8.36 Hz), 7.88 (1 H, s), 7.58 (1 H, d, J=1.76 Hz), 6.83 (1 H, d, J=1.76 Hz), 5.64 (2 H, br. s.), 3.86-4.08 (1 H, m), 3.49-3.67 (1 H, m), 3.38-3.50 (2 H, m), 3.14-3.34 (1 H, m), 2.74-2.82 (1 H, m), 2.55-2.68 (1 H, m), 2.18-2.40 (1 H, m), 1.59-1.90 (2 H, m), 1.51 (9 H, s), 1.08-1.19 (3 H, m); MS (ES+) m/z: 478.2, 480.2 (M+H).
Reaction SMILES: Br[CH:2]([CH3:23])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC(C)CCO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH:2]([NH:31][CH3:26])[CH3:23])[S:6]1(=[O:21])=[O:22]
Reactant: CC(Br)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: CC(Br)CCO
Product: CNC(C)CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-(3-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 3-bromobutan-1-ol giving 0.27 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C1COCC1>[O:14]=[C:13]1[NH:12][C:11](=[O:15])[CH:10]=[N:9][N:8]1[C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 2-(3-aminophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.2 g, 5.88 mmol) in THF (20 mL) was added acetic anhydride (1.2 g, 11.8 mmol) and the mixture was heated at 50° C. After 2 h the mixture was cooled at room temperature, quenched with water and extracted with ethyl acetate (×3). The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the 900 mg, 62% yield, of N-(3-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 9(D) (900 mg, 62%) which is used in next step without any further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:36][CH2:37][N:38]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:39][CH2:40]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(c3cc(F)ccc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title E compound, 1-(2,5-difluorophenyl)piperazine hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,5-difluorophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=465.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.64 (m, 4H), 2.76 (t, 2H, J=64 Hz), 3.01 (m, 4H), 4.28 (t, 2H, J=6.4 Hz), 6.60 (d, 1H, J=3.2 Hz), 6.72 (m, 1H), 6.75 (m, 1H), 6.80-6.85 (m, 1H), 7.12 (m, 1H), 7.18 (m, 2H), 7.51 (br s, 2H), 7.91 (s, 1H). Anal. calculated for (C23H22F2N8O): C, 59.48; H, 4.77; F, 8.18; N, 24.12; 0, 3.44. Found C, 59.45; H, 4.70; N, 24.19.
Reaction SMILES: [H-].[Na+].N1[C:7]2=N[CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.BrCC#N.[C:16]([O:19][CH2:20]C)(=[O:18])[CH3:17].[O:22]1CCCC1>CCCCCC>[CH3:20][O:19][C:16](=[O:18])[CH2:17][O:22][CH2:7][C:6]1[CH:11]=[CH:10][CH:9]=[CH:4][CH:5]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)COCc1ccccc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of sodium hydride (60%) (3.7 g, 93.12 mmol) in tetrahydrofuran (60 mL) was added dropwise a mixture of 1H-pyrrolo[2,3-b]pyridine (391=(5 g, 42.33 mmol) and bromoacetonitrile (10 g, 84.65 mmol) dissolved in tetrahydrofuran (40 mL) at 0° C. and the reaction mixture was stirred for 30 min at same temperature, then at room temperature for 6 h (TLC, 40% ethyl acetate in hexane, Rf=0.5). After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (100 mL). The tetrahydrofuran was removed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3×100 mL). The separated organic part was washed with brine (100 mL) and dried and concentrated to get a crude mass which was purified by Combi-Flash (eluted at 20% ethyl acetate in hexane) to afford pyrrolo[2,3-b]pyridin-1-yl-acetonitrile (3) (4 g, 60%) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.06 g, 5.53 mmol), 3,5-Dibromo-1-methyl-1H-pyridin-2-one (1.23 g, 4.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400 mg, 0.691 mmol), and cesium carbonate (4.50 g, 13.8 mmol) was added 45 mL 1,4-dioxane and tris(dibenzylidineacetone)dipalladium(0) (422 mg, 0.461 mmol). This was heated in a 120° C. oil bath for 6 hours under argon. This was partitioned between ethylacetate and dilute aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 2 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one (484 mg, 1.28 mmol). MS (ESI) 380.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1
Reactant: CN1CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)cc(Cl)c3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 6,8-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])C=O)([CH3:11])([CH3:10])[CH3:9].N1CCCC[CH2:26]1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:5]2[S:1](=[CH2:26])[C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=O)N1
Reactant: C1CCNCC1
Solvent: CCO
Product: C=S1C(=O)NC(=O)C1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 424.3 %

Procedure:
To a solution of 12.5 g (107 mmol) of 2,4-thiazolidinedione and 25.0 g (107 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 300 ml of ethanol, 1.05 ml (10.7 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 15.23 g of the desired compound (42.8% yield, pale yellow crystals).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([OH:18])(=[O:17])[CH2:13]C(O)=O.C([O-])(=O)C.[NH4+:23]>C(O)C>[NH2:23][CH:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH2:13][C:12]([OH:18])=[O:17]
Reactant: [NH4+]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: N#Cc1ccc(C(N)CC(=O)O)cc1F
Yield: 51.6 %

Procedure:
500 mg (3.35 mmol) 2-fluoro-4-formylbenzonitrile were suspended in 2 ml ethanol. 349 mg (3.35 mmol) propanedioic acid and 0.54 g (7.04 mmol) ammonium acetate were added. The mixture was refluxed for 6 hours and after cooling filtrated. The residue was washed with ethanol and dried in vacuum to give 360 mg (52%) 3-amino-3-(4-cyano-3-fluorophenyl) propionic acid.
Reaction SMILES: Br[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Mg]Cl)(C)C.[CH:15](N1CCCCC1)=[O:16]>O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:15]=[O:16]
Reactant: O=CN1CCCCC1
Reactant: BrCOc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccccc1C=O

Procedure:
Alternatively, treatment of the methoxybenzene (6a) with bromine in acetic acid in the presence of iron(0) provides the 2-bromomethoxybenzene (6c). Reaction of (6c) with isopropylmagnesium chloride and 1-formylpiperidine in a solvent such as tetrahydrofuran affords the 2-methoxybenzaldehyde (2d). Removal of the methyl group is accomplished by reaction of the 2-methoxybenzaldehyde (2d) with boron tribromide in a solvent such as dichloromethane to give the 2-hydroxybenzaldehyde (2c).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:13]1([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[NH:9][C:10](=[O:12])[CH3:11])[CH2:15][CH2:14]1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(F)cc1C1CC1
Reaction time: 6 h

Procedure:
A mixture comprising N-(2-bromo-4-fluorophenyl)acetamide (1 g, 4.31 mmol), cyclopropylboronic acid (0.481 g, 5.60 mmol), tricyclohexylphosphine (0.121 g, 0.431 mmol), potassium phosphate (tribasic) (3.20 g, 15.08 mmol), toluene (10 ml) and water (10 ml) was equally divided between two 10-20 ml microwave tubes. Each reaction tube was sealed, evacuated and filled with nitrogen (3×) and placed in the microwave at 100° C. for 6 hrs. The contents of the vials were combined, diluted with EtOAc and the layers separated. The organic extracts were washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown solid. The product was used crude in the next step.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.NN.Cl>CCO>[NH2:10][C:9]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Product: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Temperature: 105 °C
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene) malononitrile (958 mg, 7.04 mmol) in EtOH (12 mL) was added (4-methoxyphenyl)hydrazine (1.12 g, 8.09 mmol). (Prior to using the hydrazine its HCl salt was washed with NaHCO3/CH2Cl2. The organic phase was concentrated and used directly.) The solution was heated to 105° C. in the microwave for 20 minutes. CH2Cl2 was added and the organic phase was washed with 1 M HCl and the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.30 g, 81%) which was used as such in the next step. The procedure was adapted from J. Med. Chem. 2004, 47, 5894-5911.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[CH2:27][S:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[CH2:27][S:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH:6]=1
Reactant: COC(=O)Cc1ccc(C#C[Si](C)(C)C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(CC(=O)OC)cc1Oc1ccc([N+](=O)[O-])cc1CSCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trimethylsilanylethynyl-phenyl}-acetic acid methyl ester (0.410 g, 0.8 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (1M in THF; 1.2 mL, 1.2 mmol), and the reaction was stirred for 30 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up with EtOAc and H2O, and the residue was purified by silica gel chromatography to give {4-Ethynyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:5][CH2:4][C:3]1=[O:20].[C:21](=[O:24])(O)[O-].[Na+].C(Cl)(Cl)=O.[NH3:30]>C1C=CC=CC=1.CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:21](=[O:24])[NH2:30])[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C([O-])O
Reactant: N
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 2 h
Yield: 87.5 %

Procedure:
2.1 g. (7.32 mmoles) of (+)-1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2one are dissolved in 20 ml. of benzene. 1.26 g. of solid sodium bicarbonate are added to the solution, and then 22 ml. of a 10% solution of phosgene in benzene are added dropwise at 10° to 15° C. The mixture is stirred for 2 hours, then 10 ml. of a 10% solution of ammonia in methanol are added, and the mixture is stirred at room temperature overnight. The separated inorganic salts are filtered off, and the filter cake is washed with benzene. The filtrate is evaporated to dryness under reduced pressure, and the residue is recrystallized from ethanol. 2.12 g. (87.5 %) of (-)-1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 214°-217° C., [α]D25 = -616.5° (c = 1, chloroform).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].CN(C)[CH:14]=[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16](OCC)=[O:17].Cl.CCN(C(C)C)C(C)C>CC(O)C>[OH:17][C:16]1[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccnc(OC)c1
Reactant: NNc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Temperature: 25 °C

Procedure:
Combined 6-hydrazinylnicotinic acid (167 mg, 1.090 mmol), ethyl 3-(dimethylamino)-2-(2-methoxypyridin-4-yl)acrylate (300 mg, 1.199 mmol), 2-propanol (3632 μl), and hydrochloric acid (1.85% aqueous, 2.15 mL, 1.090 mmol). The reaction was stirred at room temperature. After 1 hour Hunig's base (949 μl, 5.45 mmol) was added to the suspension which became a yellow solution. The reaction was washed with EtOAc (2×15 mL) and the aqueous phase was concentrated in vacuo, yielding a yellow solid. The solid was triturated with 1N HCl (50 mL), collected by filtration, and washed with water. The solid was then slurried in methanol (2×60 mL) and diethyl ether (2×60 mL), the dried under vacuum to give the title compound. MS m/z [M+H]+ 313.0.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:19]([CH:16]([CH2:17][CH3:18])[CH2:15][N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:21])[CH3:20]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 19.9 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.092 mmol), β-alanine (492 mg, 5.5 mmol) and NaOMe solution (8.3 mL, 4.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 8 mg of the title compound as a yellow solid. MS: (+) m/z 438.33 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][N:74]=1)[CH2:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH2:77][CH2:78][CH:73]1[CH2:72][N:64]([CH3:63])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(Cc1ccccn1)CC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN(C)Cc3ccccn3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-methyl-N-(piperidin-2-ylmethyl)-pyridin-2-ylmethyl-amine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])C)=[C:4]([C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH:3]=1.O.NN.[CH2:42](O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:42])[CH3:29])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:4]=2[CH:3]=1
Reactant: CCO
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccc1Cl)c1cc(F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(o-chlorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.