Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(N1CCC(C(=O)NC2CCCCC2)CC1)=O)(C)(C)C>>[CH:18]1([NH:24][C:14]([C:11]2([F:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Reactant: NC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Product: O=C(NC1CCCCC1)C1(F)CCNCC1

Procedure:
The title compound is prepared according to the reaction sequence 3.01a-2.01b described above using 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid instead of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid and cyclohexylamine as in 3.01a: LC-MS A: tR=0.49 min; [M+H]+=229.25.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N,N-dimethylethylenediamine (0.5 g) in dichloromethane (10 ml) at 0° C. was added triethylamine (0.87 ml) and methane sulphonyl chloride. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution, the combined organics were dried (MgSO4) and the solvents removed in vacuo to yield a crude product. This was purified by flash chromatography to yield N-(2-dimethylamino-ethyl)-methanesulfonamide (0.46 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[C:12]([O:16][C:17](=O)[O-:18])([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.5 mg of 5-bromo-1-oxo-isoindoline was dissolved in 20 ml of tetrahydrofuran, cooled down to 0° C. Then, 85 mg of N,N-dimethylaminopyridine and 3.0 ml of tert-butylcarbonate were added, and the mixture was stirred at room temperature for 30 min. Methanol was added to the reaction solution, and the solvents were distilled outunder reduced pressure. Water was added to the residues, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 300 mg of the above compound as a white solid.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C([Cl:11])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:45]=[CH:46][CH:47]=1)[O:18][C:19]1[N:20]=[C:21]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[C:22]([C:28]([NH2:30])=[O:29])=[N:23][C:24]=1[CH:25]([CH3:27])[CH3:26].C(=O)([O-])O.[Na+]>CN1CCCC1=O.CN(C)C=O.C(#N)C>[Cl:11][CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:14][C:15]1[CH:16]=[C:17]([CH:45]=[CH:46][CH:47]=1)[O:18][C:19]1[N:20]=[C:21]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[CH:36][CH:37]=2)[C:22]([C:28]([NH2:30])=[O:29])=[N:23][C:24]=1[CH:25]([CH3:26])[CH3:27])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Reactant: O=C(O)/C=C/CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-bromocrotonic acid (632 mg) and acetonitrile (11 mL) were added oxalyl dichloride (308 μL) and N,N-dimethylformamide (2 droplets) under ice-cooling, followed by stirring at room temperature for 2 hours. To a mixture of 5-(3-aminophenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (1.1 g) and N-methylpyrrolidone (22 mL) was added a solution of the acid chloride prepared above under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-{[(2E)-4-chlorobuta-2-enoyl]amino}phenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (125 mg) as a solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]([F:20])([F:19])[F:18])[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH3:26].O>CN(C)C=O>[CH3:26][N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3C(F)(F)F)c(=O)c12
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 22; 710 mg, 2.1 mmol) and iodomethane (0.33 mL, 5.3 mmol) in N,N-dimethylformamide (5 mL) in a sealed tube was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 90 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, dissolved in ethyl acetate and heated at reflux with activated charcoal for 10 min. The mixture was filtered through Celite® and evaporated to give (4S,7R)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (602 mg, 81%) as a light yellow solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][C:3]=1[CH3:18].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: ClCCCBr
Reactant: Cc1cc(-c2cn3cccc(C)c3n2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn3cccc(C)c3n2)ccc1OCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step B (6.0 g) in N, N-dimethylformamide (200 mL) was added to a suspension of 60% sodium hydride (2.0 g) in N, N-dimethylformamide (200 mL). The mixture was stirred at ambient temperature for 1 hour and then treated with 1-bromo-3-chloropropane (30 mL). The mixture was stirred at ambient temperature for 18 hours and partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate, filtered and evaporated to give the title compound (6.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([CH3:22])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][O:49][C:50]1[C:55]([NH2:56])=[C:54]([O:57][CH3:58])[N:53]=[C:52]([NH:59][CH2:60][CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[N:51]=1>CN(C=O)C>[CH3:58][O:57][C:54]1[C:55]([NH:56][C:19]([C:17]2[O:18][C:14]([CH2:13][C:9]3[C:10]([CH3:12])=[C:11]4[C:6](=[CH:7][C:8]=3[CH3:22])[O:5][CH2:4][CH2:3][C:2]4([CH3:1])[CH3:23])=[CH:15][CH:16]=2)=[O:21])=[C:50]([O:49][CH3:48])[N:51]=[C:52]([NH:59][CH2:60][CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[N:53]=1
Reactant: Cc1cc2c(c(C)c1Cc1ccc(C(=O)O)o1)C(C)(C)CCO2
Reactant: COc1nc(NCCCN2CCOCC2)nc(OC)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc(NCCCN2CCOCC2)nc(OC)c1NC(=O)c1ccc(Cc2c(C)cc3c(c2C)C(C)(C)CCO3)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
In a 50-mL round-bottom flask, 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoic acid (114.53 mg, 0.364 mmol) and HATU (152.36 mg, 0.400 mmol) were dissolved in DMF (2 mL). To this solution 4,6-dimethoxy-N2-(3-morpholin-4-ylpropyl)pyrimidine-2,5-diamine (209) (108.32 364 mmol) and triethylamine,(91.98 mg, 0.911 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solution was filtered through a PTFE (polytetrafluoroethylene) membrane micro filter. The crude mixture was purified by HPLC C18 column, eluted with aceonitrile/water/0.1% ACOH (30% ACN-70% CAN over 30 min) to yield N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furamide (I1) (15.9 mg, 7% yield). 1H NMR (CDCl3) δ 1.31(s, 6H), 1.80(m, 4H, J=6.80, 6.42, 6.04 Hz), 2.15(s, 3H), 2.23(s, 3H), 2.49(m, 6H), 2.63(t, 2H, J=6.80 Hz), 3.49(q, 2H, J=6.04, 5.67 Hz), 3.75(t, 4H, J=4.53 Hz), 3.87(s, 6H), 3.98(s, 2H), 5.74(s, 1H), 5.80(d, 1H, J=3.02 Hz), 6.56(s, 1H), 7.01 (d, 1H, J=3.02 Hz), 7.05(s, 1H). (M+1) 594.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[CH2:4][NH:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[S:7].[I:25]C.[C:27](O)(=O)C.O(C(C)C)C(C)C>C(OCC)(=O)C>[IH:25].[CH3:24][O:23][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]([S:7][CH3:27])=[N:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)O
Reactant: COc1ccc(N2CCN(NC(=S)NCC(OC)OC)CC2)cc1
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccc(N2CCN(N=C(NCC(OC)OC)SC)CC2)cc1
Product: I
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
A mixture of 5.3 parts of N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]thiourea, 6 parts of iodomethane, 5 parts of acetic acid and 90 parts of ethyl acetate is stirred for 2 days at room temperature. Upon the addition of 2,2'-oxybispropane, the product is crystallized. It is filtered off and dried, yielding 6 parts (80%) of methyl N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydroiodide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:35])[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(CC2(O)CCNCC2)C1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A mixture of 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-piperidinol (0.035 g, 0.000074 mol) and formaldehyde (0.006 mL, 37% in water, 0.000082 mol) in dichloroethane (4 mL) was stirred at room temperature under an atmosphere of nitrogen for one hr. Sodium triacetoxyborohydride (0.022 g, 0.000104 mol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for eighteen hours. Molecular sieves (0.05 g, 3A, 4-8 mesh) and additional formaldehyde (0.006 mL, 37% in water, 0.000082 mol) was added and the reaction mixture was stirred at room temperature for eighteen hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersil HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to yield 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-1-methyl-4-piperidinol (0.020 g, 0.000041 mol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: NC(=O)C1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide. MS (ESI): mass calcd. for C22H21FN4O3S, 440.13; m/z found, 441.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 7.98 (d, J=7.7, 1H), 7.75 (m, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 7.28-7.22 (m, 2H), 6.93 (s, 2H), 2.27-2.16 (m, 2H), 2.04-1.91 (m, 2H), 1.57 (s, 2H), 1.49-1.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17](N)[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.C=O.[C:24]([BH3-])#[N:25].[Na+].[C:28](O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([N:25]([CH3:24])[CH3:28])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: [BH3-]C#N
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)N1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1

Procedure:
To a solution of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (1.64 g) in acetonitrile (50 ml) were added 37% formaldehyde solution (4 ml) and sodium cyanoborohydride (1 g) and the mixture was stirred for 25 minutes at room temperature and further for 1 hour neutralizing with acetic acid and concentrated. To a residue was added saturated sodium carbonate solution and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel (42 g) and eluted with a mixture of chloroform-methanol (20:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was washed with ether and then acetic acid to give 5-chloro-3-[(4-dimethylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.32 g), which was dissolved with heating in a mixture of chloroform (10 ml) and ethanol (5 ml). After cooling, to the mixture was added ethanol solution containing hydrogen chloride (about 23 %). The residue obtained by concentration under reduced pressure was recrystallized from a mixture of ethanol (10 ml) and water (0.5 ml) to give colorless crystals of 5-chloro-3-[(4-dimethylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazlinone hydrochloride (0.31 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:22][CH2:23][O:24][CH3:25])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]=[O:9].[OH-:26].[Na+]>CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:25][O:24][CH2:23][O:22][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:8]([OH:26])=[O:9]
Reactant: [OH-]
Reactant: COCOc1cc(C=O)cc(OCOC)c1C/C=C/c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzaldehyde (220f) (42 g, 0.12 mol) in MeOH/H2O (500 mL) was added AgNO3 (21 g, 0.12 mol), followed by NaOH (15 g, 0.36 mol) in one portion at room temperature. The mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum to remove MeOH. The residue was extracted with Et2O (2×100 mL) to remove impurities. The aqueous layer was acidified with conc. HCl to pH 4. The resulting white solid was filtered and dried under vacuum to give the title compound (31 g, 62% yield) as white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[C@H:28]([CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].[I:51][CH2:52][C:53]([NH2:55])=[O:54]>CC(C)=O>[I-:51].[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[C@H:28]([CH2:44][N+:45]3([CH2:52][C:53](=[O:54])[NH2:55])[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CN4CCCC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[N+]4(CC(N)=O)CCCC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Product: [I-]
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(pyrrolidin-1 -yl)methylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.77 g) in acetone (8 ml) was added iodoacetamide (0.93 g) at ambient temperature. The mixture was stirred overnight at the same temperature. The reaction mixture was evaporated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(1-carbamoylmethylpyrrolidinio)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (0.71 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-:23].[K+].[K+]>CN(C)C=O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:23][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: ClCCN1CCCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccccc2OCCN2CCCC2)cc1
Temperature: 50 °C

Procedure:
1.76 mol of 4-hydroxybiphenyl, 2.29 mol of 1-(2-chloroethyl)pyrrolidine and 5.3 mol of potassium carbonate are placed in 2.5 liters of dimethylformamide. The whole is heated at 50° C. ovemright. After cooling, the solid is filtered off and the solvent is removed by evaporation. The residue is taken up in ethyl acetate. After washing of the organic phase drying and evaporation, a residue is obtained which is purified by chromatography over silica using an ethyl acetate/ethanol mixture (80/20) as eluant. The expected product is obtained after crystallisation of the residual oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[CH:12](=O)[CH:13]([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1/[N:5]=[CH:12]/[CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCc1cccc(CC)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1/N=C/C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzene (150 mL) was added to 2,6-diethylaniline (18.59 g, 124.6 mmol) and 3 angstrom molecular sieves (ca. 50 mL). Then isobutyraldehyde (9.43 g, 131 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.011 mmol) were added. The flask was sealed and heated to 50° C. After stirring overnight the very pale yellow solution was filtered and the volatiles were removed under reduced pressure to afford the product as a clear, pale yellow oil. Yield: 22.5 g, 84.6%. 1H NMR (C6D6): δ 7.21 (1H, d), 7.02 (2H, m), 2.47 (4H, q), 2.39 (1H, m), 1.11 (6H, t), 1.01 (6H, d).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][CH2:10][CH2:11][NH2:12].Cl[C:14]1[C:23]([C:24]([C:26](=[CH:32]N(C)C)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][C:18]([Cl:37])=[C:19]([F:36])[CH:20]=2)[N:15]=1>ClC(Cl)Cl>[Cl:37][C:18]1[C:19]([F:36])=[CH:20][C:21]2[C:16]([CH:17]=1)=[N:15][C:14]1[N:12]([CH2:11][CH2:10][F:9])[CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:25])[C:23]=1[CH:22]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2.7 cm3 of triethylamine are added to a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm3 of trichloromethane. 3.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-di methylaminoacrylate are added to the solution obtained at about 20° C. After stirring at this temperature for 16 hours, the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 20 cm3 of ethanol and 3 cm3 of triethylamine and heat at about 75° C., with stirring for 2 hours. After cooling to about 20° C. the insoluble matter is drained and washed with twice 10 cm3 of ethanol and twice 10 cm3 of diisopropyl ether. 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(2-fluoro-ethyl)-4-oxo-1,4-di hydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 268° C., which can be used for the subsequent steps without further purification.