Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:4].[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH2:32])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>C(#N)C>[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH:32][C:3]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:4])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2N
Reactant: O=C(Nc1cccc2cccnc12)C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1ccc2c(c1)OCCC2NC(=O)Nc1cccc2cccnc12
Yield: 14.4 %

Procedure:
A mixture of the product of Example 3A (145mg, 0.5 mmol), the product of Example 1C (103mg, 0.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 190 mg, 1.25 mmol) in acetonitrile (15 mL) was heated at reflux for 3.5 hours, cooled, and the acetonitrile removed under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The isolated organic layer was dried with magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting residue was purified by reverse-phase HPLC (acetonitrile/water) to give 27 mg of the title compound (14% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 8.83 (dd, J=4.1 and 1.7 Hz, 1H), 8.54 (dd, J=7.3 and 1.9 Hz, 1H), 8.34 (dd, J=8.5 and 1.7 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.46-7.53 (m, 2H), 7.22 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.1 and 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 4.87-4.93 (m, 1H), 4.22-4.29 (m, 1H), 4.12-4.20 (m, 1H), 2.07-2.16 (m, 1H), 1.91-2.00 (m, 1H), 1.24 (s, 9H). MS (ESI) m/e 376 (M+H)+. Calcd. For C23H25N3O2.0.35CF3CO2H: C, 68.53; H, 6.15; N, 10.12. Found C, 68.33; H, 6.00; N, 10.00.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:15])[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.1 %

Procedure:
A mixture of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoic acid (100 mg, 0.34 mmol), morpholine (29 mg, 0.34 mmol), DCC (77 mg, 0.37 mmol), and DMAP (46 mg, 0.37 mmol) in dry DCM (2.5 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rota vapor to obtain 10 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinopropan-1-one as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:35][CH:36]1[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]1.C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:35][CH:36]4[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]4)=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Reactant: CC1OC(=O)OC1CBr
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1OC(=O)OC1COC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 4-bromomethyl-5-methyl-1,3-dioxolan-2-one (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (15 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][Mg]Cl.CO.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:9])[CH2:14][CH2:13][CH2:12][O:11][CH3:10])[CH:3]=1
Reactant: COCCC[Mg]Cl
Reactant: N#Cc1cc(Br)ccn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCC(N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.3 g of 4-bromopyridine-2-carbonitrile [62150-45-2] in 10 ml of tetrahydrofuran is added to a solution of 8.79 g of 3-methoxypropylmagnesium chloride [14202-12-1] in 10 ml of tetrahydrofuran. The reaction solution is stirred at room temperature for 10 minutes and then 50 ml of methanol are added. 2.7 g of sodium borohydride are added to the solution over the course of 30 minutes, and the mixture is stirred at room temperature for 2.5 hours. It is diluted with ethyl acetate and basified with 1M sodium hydroxide solution. The phases are separated. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are evaporated. The crude title compound is obtained as an orange oil from the residue. Rt=2.47 (Gradient I).
Reaction SMILES: [CH2:1]([C:3]1[C:14](C(OCC)=O)=[C:6]2[C:7]([O:12]C)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:3]1[CH:14]=[C:6]2[C:7]([OH:12])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nn2cc(F)cc(OC)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1cc2c(O)cc(F)cn2n1
Reaction time: 1 h
Yield: 94 %

Procedure:
The compound of Example 41 (4.53 g) was dissolved in dichloromethane (50 mL). The solution was kept at 0° C. and boron tribromide (21.6 mL, 1.0 mol/L dichloromethane solution) was added. The resulting mixture was stirred for 1 hour. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The resulting solid product (4.29 g) was dissolved in ethanol (40 mL). To this solution, water (40 mL) and potassium hydroxide (4.10 g) were added and the mixture was stirred for 2 hours under reflux. This was followed by addition of water and concentrated hydrochloric acid to make the mixture acidic. The resulting mixture was extracted with three times with ethyl acetate and the organic layer was washed with saturated brine, dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting solid product (3.58 g) was dissolved in ethanol (100 mL). To this solution, concentrated sulfuric acid (2 mL) was added and the mixture was refluxed for 7.5 hours. Subsequently, ethanol was evaporated under reduced pressure and the residue was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound as a gray powder (2.88 g) (Process B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[H-].[Na+].[CH3:30][C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])[CH2:32][CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([C:31]([CH3:30])([CH3:34])[CH2:32][CH3:33])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=C1Nc2ccc(Cl)cc2C1(NCCN1CCOCC1)c1ccccc1Cl
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2C(=O)C(NCCN3CCOCC3)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A solution of 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(morpholin-4-yl)ethyl]amino]indol-2-one in 10 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.108 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 30 minutes, 0.607 g of 4-(1,1-dimethylpropyl)benzenesulfonyl chloride is added and the reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 0.45 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=3)[N:5]=[C:4]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)[nH]n1
Product: Cc1cc(Nc2cc(N3CCN(C)CC3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)[nH]n1
Reaction time: 2 h

Procedure:
Compound D (2.373 g, 5.92 mmol) was treated with N-methylpiperazine (10 ml) and the mixture stirred at 110° for 2 hours. The excess N-methylpiperazine was removed in vacuo then the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate, and concentrated. The residue was crystallised from methanol to give colourless crystals of desired product V-1 (1.82 g, 66%), 1H-NMR DMSO-d6, δ 0.81 (4H, d), 1.79 (1H, m), 2.01 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 (1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.22 (1H, s), 10.39 (1H, s), 11.69 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Li])CCC.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:5][CH:2]([CH3:1])[C:3]#[C:4][C:19]1([OH:22])[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C#CC(C)O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(C#CC(C)O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3-butyn-2-ol (42 g, 0.6 mol) in dry THF (800 ml) under nitrogen was cooled with a dry-ice/acetone bath. n-Butyl lithium (390 ml of 2.5M and 230 ml of 1.5M) in hexane was added rapidly, dropwise. The suspension became gelatinous and another 800 mls of dry THF was added. The reaction was stirred at approximately -78° C. for 1 hour and then at 0° C. for 20 minutes. The reaction was cooled to -78° C. and 1-ethoxycarbonyl-4-piperidinone (104 g, 0.607 mol) in 300 ml of dry THF was added rapidly dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was cooled in an ice-bath, diluted with THF (1.51 ), decomposed with saturated NH4Cl, and the THF layer was washed three times with 200 ml of saturated ammonium chloride. The aqueous layers were back-washed with THF (200 ml×3). The organic layers were combined and dried over MgSO4 and evaporated to give an oil. A one-fifth portion of the oil was purified by flash chromatography on silica gel and elution with 30% ethyl acetate/ether afforded the desired product diol (19.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([CH3:40])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([CH3:40])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCOCC1
Solvent: C1CCOC1
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.91 g (5.08 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 2.00 g (7.63 mmol) of (4-methyltetrahydro-2H-pyran-4-yl)methyl trifluoromethanesulphonate and 6.61 ml (6.61 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 212 mg (8% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: Cc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1C(F)(F)F
Yield: 157.1 %

Procedure:
To a refluxing mixture of 5.0 g 4-Methyl-2-(trifluoromethyl)benzonitrile in 50 ml tetrachloromethane were added a mixture of 5.77 g N-bromosuccinimide and 1.77 g 2,2′-azobis(2-methylpropionitrile). The reaction mixture was heated under reflux for three hours. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to obtain 11.2 g crude 4-Bromomethyl-2-trifluoromethyl-benzonitrile (impurified with the dibromo product) as a white solid. This material was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:37][O:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at RT for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=569.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18](Cl)=[O:19])[S:17][C:10]=12.CCN(CC)CC>C(Cl)Cl.O>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:19])[S:17][C:10]=12
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
1-Methylpiperazine (0.574 mL, 5.17 mmol) was added to a suspension of 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride (435, 1 g, 4.31 mmol) and Et3N (1.80 mL, 12.93 mmol) in DCM (50 mL). The reaction mixture was stirred for 1 h at room temperature, diluted with water and a saturated aqueous solution of ammonium chloride and extracted with DCM. The organic layer was successively washed with a saturated aqueous solution of ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20CV), to afford the title compound 436 (1.16 g, 3.93 mmol, 91% yield) as a yellow solid. MS (m/z): 296.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.Cl.[NH2:18]O>CO>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:14][N:18]=1)=[O:16]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)on1
Yield: 78.6 %

Procedure:
To a stirred solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (3.86 g, 0.01754 mole) in methanol (78 mL) was added hydroxylamine hydrochloride (3.657 g, 0.0526 mole) at ambient temperature. The resulting mixture was then heated to reflux overnight. Volatiles were then removed by evaporation and the resulting residue was diluted with water and the product extracted with chloroform. The chloroform layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 2.8 g (79%) of 5-phenyl-isoxazole-3-carboxylic acid methyl ester. LCMS: 204.06 (M+1)+, 97.58%. To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid methyl ester (2.8 g, 0.01379 mol) in a mixture of THF (10 mL), methanol (10 mL) and H2O (10 mL) was added LiOH.H2O (0.87 g, 0.02073 mol) and the resulting mixture was stirred at ambient temperature for 2.5 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.2 g (85%) of 5-phenyl-isoxazole-3-carboxylic acid. LCMS: 190.04 (M+1)+, 96.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH:8]([P:17](=[O:24])([O:21]CC)[O:18]CC)[P:9](=[O:16])([O:13]CC)[O:10]CC)=[CH:5][CH:4]=1>C[Si](C)(C)Br>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([P:17](=[O:18])([OH:24])[OH:21])[P:9](=[O:10])([OH:13])[OH:16])=[CH:25][CH:26]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccc(OC)cc1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: COc1ccc(OC(P(=O)(O)O)P(=O)(O)O)cc1
Reaction time: 3 h

Procedure:
Tetraethyl (4-methoxyphenoxymethylene)-bisphosphonate (4 g) was dissolved in trimethyl bromosilane (16.4 ml). After 3 hours at room temperature, the mixture was evaporated in vacuo. The remaining oil was heated with absolute ethanol (30 ml) on the steam bath for 2 hours. Evaporaton in vacuo and crystallization from ether gave the title compound as colourless crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:6][C:5]([CH3:18])=[CH:4][C:3]=1[CH2:19]O.[BrH:21].S(=O)(=O)(O)O>>[Br:21][CH2:19][C:3]1[CH:4]=[C:5]([CH3:18])[CH:6]=[C:7]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)[C:2]=1[OH:1]
Reactant: Br
Reactant: Cc1cc(CO)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(CBr)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
4 (0.802 g, 2.94 mmol) was placed into a round bottom flask. Hydrobromic acid (18 mL of a 48 wt % aqueous solution) was added. Concentrated sulfuric acid (3 mL) was added dropwise to the stirring mixture. The reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was allowed to cool and contents filtered. The resulting solids were dried for 30 minutes and the solid was slurried in diethyl ether. Most of the solids dissolved to give a yellow solution. The solution was dried over MgSO4 and filtered. The volatiles were removed under vacuum to give a yellow sticky solid (1.01 g, 100% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C=O)C>[CH3:29][C:8]1[CH:9]=[C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:11]=[C:12]([CH3:13])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 278 mg (57%). MP 180-181° C. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J=6.4 Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES) m/z: 452.21 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].CN(C)C1C=CC=CC=1.C[Si](Cl)(C)C.C(Cl)(Cl)=O>C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
To a suspension of 6β-phenylacetamidopenicillanic acid potassium salt (1 mmol.) and N,N-dimethylaniline (3 mmol.) in 6 ml. of dry methylene chloride under nitrogen at 0° there is added 1 mmol. of trimethylsilyl chloride. The mixture is stirred for 30 minutes. Then a solution of 1.26 ml. of 12.5% phosgene in benzene is added to the above trimethylsilyl ester mixture. This reaction mixture is stirred at 0° for 2 hours and then the solvents are removed in vacuo. Fresh dichloromethane (6 ml.) is added followed by 2 mmol. of N,N-dimethylaniline and then 2 mmol. of o-aminothiophenol. The mixture is stirred at 0° for 2 hours and then diluted with aqueous sodium bicarbonate solution and dichloromethane to adjust the pH to 7.5-8.0. The aqueous layer is extracted twice with dichloromethane, cooled in an ice-water bath, and then acidified to pH4. The resulting precipitate is collected, washed with acetone:water (1:1) and then acetone, and finally dried to give the desired product, 6β-aminopenicillanic acid.