Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[C:9]([O-:12])(=[O:11])[CH3:10].[NH4+:13].C([O-])(=O)CC([O-])=O>>[NH2:13][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:10][C:9]([OH:12])=[O:11]
Reactant: [NH4+]
Reactant: Cc1ccsc1C=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])CC(=O)[O-]
Product: Cc1ccsc1C(N)CC(=O)O

Procedure:
12.6 g of 3-methyl-thiophene-2-carbaldehyde was dissolved in 150 mL of 95% alcohol, and 15.4 g of ammonium acetate was added at 45° C., then 20.8 g of malonate was added. The solution was refluxed for 16 hours, then cooled, and filtered to give a solid of 3-amino-3-(3-methyl-thiophene-2-yl)propionic acid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][N:18]([CH3:1])[C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Potassium carbonate (2.43 g, 17.6 mmol) and methyl iodide (1.3 ml, 20.9 mmol) were added to a solution of the 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (3.73 g, 16.0 mmol) in dimethylformamide (35 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with water (twice) and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,60 g) and then fractionated with 2% ethyl acetate-toluene to yield the title compound (2.61 g, 66.0% yield) as bright golden yellow crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[NH3:18]>CO>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: N
Reactant: CSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CO
Product: CSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.), methanol (100 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (4.3 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethanol to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (1.5 g.) m.p. 201°-202°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]2[CH2:15][CH2:16][CH:6]1[C:7]1[CH:8]=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=1[CH2:13]2.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][CH:14]4[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]([CH2:16][CH2:15]4)[C:7]=3[CH:8]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C2CCC1c1cc(N)ccc1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2CCOC)ncc1Cl
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamine (101 mg, 0.435 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.140 g, 0.443 mmol), and 10-Camphorsulfonic acid (0.141 g, 0.607 mmol) were combined in Isopropyl alcohol (4 mL) and heated with microwave irradiation to 120° C. for a total of 1.5 h. The mixture was treated with Macroporous carbonate resin (3.16 mmol/g loading; 0.45 g, 1.4 mmol) and stirred for 30 min, concentrated in vacuo and chromatographed (ISCO 2×12 g SiO2, 0-10% MeOH:DCM). The amide product elutes with 10% MeOH, while the ester elutes before in ˜8% MeOH. 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.2.1.0(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was isolated as a yellow solid (95 mg, 43%). m.p.=233-236° C.; LCMS (m/e) 511 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.22 (s, 1H), 8.53 (m, 1H), 8.17 (s, 1H), 7.51 (m, 2H), 7.42 (m, 1H), 7.15 (m, 1H), 6.77 (s, 1H), 3.59 (m, 1H), 3.41 (m, 3H), 3.28 (m, 1H), 3.23 (s, 3H), 2.95 (m, 1H), 2.75 (m, 3H), 2.55 (m, 1H), 2.25 (m, 1H), 2.04 (m, 2H), 1.45 (m, 2H). 2-{5-Chloro-2-[12-(2-methoxy-ethyl)-12-aza-tricyclo[7.210(2,7)]dodeca-2(7),3,5-trien-4-ylamino]-pyrimidin-4-ylamino}-3-fluoro-benzoic acid isopropyl ester was isolated as a yellow foam (15 mg, 6%). LCMS (m/e) 540 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 8.08 (s, 1H), 7.81 (d, 1H, J=7.8 Hz), 7.38 (dd, 1H, J=9.5, 10.1 Hz), 7.0-7.2 (m, 3H) 6.84 (m, 2H), 5.24 (sept, 1H, J=6.3 Hz), 3.75 (m, 1H), 3.53 (m, 3H), 3.34 (s, 4H), 3.09 (m, 1H), 2.2-2.3 (m, 3H), 1.72 (m, 1H), 1.33 (d, 6H, J=6.3 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].O>CN(C=O)C>[CH3:25][C:24]([OH:26])([CH3:27])[CH2:23][NH:22][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3-nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution of 1-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes. A solid was isolated by filtration, washed with water, and dried to yield 60.9 g of 2-methyl-1-[(3-nitroquinolin-4-yl)amino]propan-2-ol, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:18]=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=C([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:18]3[CH:27]=[C:26]([O:25][CH3:24])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g (10.80 mmol) of 2-(4-bromophenyl)-5,7-dimethyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 13A in DMF is treated with 2.97 g (16.21 mmol) of 3,4,5-trimethoxyaniline and 2.24 g (16.21 mmol) of potassium carbonate. The reaction mixture is stirred overnight at 90° C. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice more with toluene and the toluene is stripped off again. The crude product is extracted by stirring with a little methanol and filtered off with suction.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[N:9][OH:10])[S:2]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][N:9]=[C:3]1[CH:4]2[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]2)[S:2]1
Reactant: C1=COCCC1
Reactant: ON=C1SC2C=CC1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C1=CC2CCC1SC2=NOC1CCCCO1
Yield: 93.4 %

Procedure:
A solution of 10 g (0.06 m) of 2-thiabicyclo[2.2.2]oct-5-en-3-one oxime, 9 g (0.1 m) of 98% dihydropyran, and a catalytic amount of p-toluenesulfonic acid in 30 ml of methylene chloride was heated under reflux overnight. Sodium bicarbonate was added to neutrality. The residue after removal of solvent was purified by dry column chromatography (silica gel-ethyl acetate:hexane::1:1) to give 14.4 g of yellow solid. Recrystallization from ether-hexane yielded 10.1 g of the title compound as a white solid, m. 84°-5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=O)=[CH:15][C:14]=3[CH:25]=2)=[CH:6][C:5]=1[F:26])[CH3:2].S(Cl)(Cl)=O.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([NH:19][C:13]4[CH:14]=[CH:25][C:10]([CH2:34][N:32]([CH3:31])[CH:33]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:12]=4)=[O:24])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][C:5]=1[F:26])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1F
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In DMF (5.5 ml) was dissolved 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (398 mg). To the solution was added thionyl chloride (0.20 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0 ml). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (394 mg) was added THF (10.0 ml), and then was added triethylamine (1.17 ml). To the obtained mixture was added dropwise at 0° C. the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 4 hours. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide solution, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (453 mg, 73%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](O)=[O:19])=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:49]([O:51][C:52](=[O:60])[C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[CH3:50]>CC(C)=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:19])[NH:59][C:56]3[CH:57]=[CH:58][C:53]([C:52]([O:51][CH2:49][CH3:50])=[O:60])=[CH:54][CH:55]=3)=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.21 mmol) in acetone (30 mL) and tetrahydrofuran (10 mL) was treated with triethylamine (21 mg, 0.21 mmol) and stirred at room temperature 1 hour. A solution of cyanuric chloride (46 mg, 0.25 mmol) in tetrahydrofurane (2 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 2 hours, then 4-amino-benzoic acid ethyl ester (51 mg, 0.31 mmol) and a further aliquot of triethylamine (42 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester as a light yellow solid, 100 mg (77%), δH (300 MHz; CDCl3) 8.01-8.08 (4H, m), 7.94 (1H, d), 7.73-7.77 (3H, m), 7.48 (1H, dd), 6.82 (1H, d), 4.38 (2H, q), 3.89 (2H, m), 3.64 (2H, m), 3.47 (3H, s), 1.48 (9H, s), 1.40 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:15])[NH:7][C:6]=2[CH:16]=1.[OH-].[K+].S([O-])(O[CH3:23])(=O)=O>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([S:15][CH3:23])=[N:7][C:6]=2[CH:16]=1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2cscc21
Reactant: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CSC1=Nc2cc(Cl)ccc2Nc2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.8 g. of 7-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepine-10-thione in 10 ml of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 g. of methyl sulfate. After addition is complete, the reaction mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml., diluted with water and extracted with chloroform. The chloroform solution is concentrated under reduced pressure to give a solid, which is recrystallized from methanol-water to give yellow crystals, m.p. 111°-113°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH2Cl2 (20 mL) was added Dess-Martin Periodinane (5.1 g, 12.1 mmol) at 0° C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-methylbenzaldehyde as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[C:1]([C:5]1[C:6]([O:13][CH2:21][CH2:22][CH3:23])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(C=O)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
To a solution of 3-tert-butyl-2-hydroxy-benzaldehyde (2.04 g, 11.5 mmol) and K2CO3 (7.91 g, 57.3 mmol) in anhydrous DMF (23 ml) was added 1-iodopropane (2.34 ml, 24.0 mmol). The reaction mixture was left to stir for 48 h at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over MgSO4, filtered and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography (silica gel, gradient elution of hexanes to 20% EtOAc/hxanes) gave 3-tert-butyl-2-propoxy-benzaldehyde (2.55 g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.19 (t J=8.0, 1H), 3.89 (t, J=8.0 Hz, 2H), 1.91-1.82 (m, 2H), 1.37 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:28])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:34]([C@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:44])([OH:36])=[O:35]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 125.2 %

Procedure:
230 mg (0.38 mmol) (R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl]pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 0.2 g (R)-1-[[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl]-pyrrolidine-2-carboxylic acid as colorless glass (that still contained small amounts of ethanol)
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].C(=O)=O>O>[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[NH2:17][C:16]([NH2:18])=[NH2+:15].[NH2:17][C:16]([NH2:18])=[NH2+:15]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Tartaric acid (2.00 g, 13.33 mmol) was dissolved in 5 ml of distilled water. Guanidine carbonate (2.40 g, 13.33 mmol) was added at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 24 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].NC1C(C)=CC=CC=1N[C:21]1[N:26]=[CH:25][N:24]=[C:23]([N:27]([CH3:51])[C:28]([N:30]([C:39]2[C:44]([Cl:45])=[C:43]([O:46][CH3:47])[CH:42]=[C:41]([O:48][CH3:49])[C:40]=2[Cl:50])COCC[Si](C)(C)C)=[O:29])[CH:22]=1.C(N(C(C)C)CC)(C)C.[C:61](O)(=[O:64])[CH:62]=[CH2:63].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:50][C:40]1[C:41]([O:48][CH3:49])=[CH:42][C:43]([O:46][CH3:47])=[C:44]([Cl:45])[C:39]=1[NH:30][C:28](=[O:29])[N:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=2[NH:9][C:61](=[O:64])[CH:62]=[CH2:63])[CH:22]=1)[CH3:51]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3cccc(C)c3N)ncn2)c1Cl
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Reactant: C=CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1c(F)cccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2G (Example 123), substituting 3-fluoro-2-nitroaniline in step (d), omitting step (e), and modifying step (g) to the following procedure: To a solution of 1-(6-((2-amino-3-methylphenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)urea (31 mg, 0.051 mmol), diisopropyl ethylamine (13.1 g, 0.103 mmol), and acrylic acid (39.9 g, 0.055 mmol) in DCM (1 ml, 15.54 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (48.1 g, 0.076 mmol, 50% solution EtOAc) at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column to obtain the SEM protected title compound (24 mg, yield: 71% in three steps). Following the final step (g), the title compound was isolated (12 mg, yield: 62%). 1H-NMR (400 MHz, CDCl3) δ 3.40 (s, 3H) 3.93 (m, 6H) 5.91 (d, 1H) 6.20 (s, 1H) 6.30-6.45 (m, 1H) 6.50-6.58 (m, 2H) 7.01 (t, 1H) 7.28-7.35 (m, 1H) 7.42-7.63 (m, 2H) 8.41 (s, 1H) 12.43 (br. s., 1H); ESI-MS: 535 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/OC)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.C(/C(=C(/OC)\C)/[C:26]#[N:27])(=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/[NH:27][CH3:26])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Product: CN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
The procedure of Example 15 is repeated substituting an equimolecular amount of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile for the 2-benzoyl-3-methoxycrotononitrile employed in that example. There is thus obtained the title compound after purification by column chromatography.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Br:8])(=[O:4])=[O:3].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[BrH:8].[C:14]([S:15][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[NH:13])[NH2:16]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: CS(=O)(=O)c1ccccc1CSC(=N)N
Temperature: 25 °C

Procedure:
A solution of 36.5 g of 2-(methylsulfonyl)benzyl bromide and 11.4 g of thiourea in 500 ml absolute ethanol was stirred at reflux temperature for 11/2 hours and then allowed to cool to room temperature. Upon standing, the solution yielded white feather-like crystals which were collected by filtration, washed with cold 1-chlorobutane, and dried in vacuo. The yield of 2-(methylsulfonyl)phenylmethyl carbamimidothioate hydrobromide, m.p. 203°-206° C., was 36.3 g.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CS(C)=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[C:15](=[CH:18][O:19][C:25](=[O:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Solvent: CS(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O

Procedure:
7-(2-Phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (4 g.), dimethylsulfoxide (20 ml) and acetic anhydride (20 ml.) were treated in a similar manner to that of Example 4 (2) to give 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylic acid (2 g.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:24]([Cu])#[N:25]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Yield: 24.9 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.91 g, prepared according to Arend et al. WO 2004108681) and CuCN (436 mg) in DMF (5 mL) was refluxed for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (195 mg). LC MS ESI: 337 (M+1)+.