Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:52])[C:32](=[N:39][O:40][C:41](=[O:51])[C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:53])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:52])[C:32](=[N:39][O:40][C:41](=[O:51])[C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Yield: 19.4 %

Procedure:
A solution of diphenylmethyl 3-acetoxymethyl-7β-[2-(4-nitrobenzoyloxyimino)-2-phenylacetamido]ceph-3-em-4-carboxylate (syn-isomer) (1.0 g) in trifluoroacetic acid (10 ml.) was allowed to stand at room temperature for ten minutes. After evaporation of trifluoroacetic acid under reduced pressure, the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. A solid precipitated during the bicarbonate extraction and was collected, washed with water and ethyl acetate, and partitioned between ethyl acetate and 2N-hydrochloric acid. The phases were separated and the upper layer was washed with water, dried, concentrated to ca. 10 ml. and added dropwise with stirring to petroleum (b.p. 40-60°; 200 ml.). The precipitated solid was filtered and dried to give 3-acetoxymethyl-7β-[2-(4-nitrobenzoyloxyimino)-2-phenyl-acetamido]ceph-3-em-4-carboxylic acid (syn-isomer) (0.150 g; 20%), [α]D + 17° (c 0.8, DMSO) λmax. (EtOH) 266.5 nm (ε 33,000), νmax. (Nujol) 3270 (NH), 1780 (β-lactam) 1520 and 1338 (NO2), 1675 and 1520 cm.-1 (CONH), τ (DMSO-d6) values include 1.58 and 1.69 (two doublets J 8 Hz; p-substituted phenyl), 2.1 to 2.5 (multiplet; aromatic protons), 7.79 (singlet; OCOCH3).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>[Pd].CCOC(C)=O>[O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CN1CCCC(CCc2ccc3cccnc3n2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCCC(CCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 24 h

Procedure:
A mixture of 1-6 (102 mg, 0.3 mmol), 10% Pd/C (50 mg), and EtOAc (25 mL) was stirred under a hydrogen atmosphere (1 atm) for 24 h. The catalyst was then removed by filtration through celite and the filtrate concentrated. Flash chromatography (silica, 20% CH3OH/EtOAc) gave 1-7 as a yellow gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[O:24]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([C:34]2[CH:35]=[CH:36][C:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 7-bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-phenoxyphenylboronic acid: MS (m/z) 487.1 (M+1).
Reaction SMILES: C([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][C:38]2[C:43]3[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=3[C:41]([O:49]C(OC(C)(C)C)=O)=[CH:40][CH:39]=2)C(=O)OC(C)(C)C)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])=[N:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:74][C:73]([F:76])([F:75])[C:71]([OH:77])=[O:72].[N:7]1[NH:8][N:4]=[N:5][C:6]=1[C:9]1[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=1)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:26][CH2:27][NH:28][CH2:36][CH2:37][C:38]1[C:43]2[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=2[C:41]([OH:49])=[CH:40][CH:39]=1)=[O:18]
Reactant: C=CCn1nnc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COc2c(CCNCCN(C(=O)CCOCCc3cccc(-c4nn[nH]n4)c3)C3CCCCC3)ccc(O)c2N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(3-(3-(2-allyl-2H-tetrazol-5-yl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Example 15, Step v)] (170 mg), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (97 mg) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) were dissolved in DCM (2 mL) and sealed into a microwave tube. The reaction was heated to 100° C., over a period of 30 min in the microwave reactor. After cooling to rt, TFA (1 mL) was added and the mixture stirred for 30 min. The mixture was concentrate in vacuo do give a crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (41.8 mg) as a solid. MS [M+H]+=578.3 (calc=578.3091) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.80 (dt, J=1.6 and 7.4 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.44 (dt, J=1.5 and 7.9 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.46 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 3.74 (t, J=6.5 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H), 3.71-3.63 (m, 1H), 3.48 (t, J=5.8 Hz, 2H), 3.14 (t, J=7.1 Hz, 2H), 3.04 (t, J=5.7 Hz, 2H), 2.94 (t, J=6.3 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 1.79-1.71 (m, 2H), 1.68-1.57 (m, 3H), 1.44-1.23 (m, 4H), 1.16-1.03 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[C:7]([NH2:12])[C:6]4[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccc(C(C)(C)C)cc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p.>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Product: COC(=O)COc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 259 and using 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (310 mg) and methyl bromoacetate. Colorless crystals (300 mg). 1H-NMR (CDCl3) δ: 3.23 (3H, s), 3.78 (3H, s), 4.59 (2H, s), 5.34 (2H, s), 6.82 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.24-7.31 (2H, m), 7.37 (1H, d, J=1.8 Hz), 7.40-7.49 (3H, m), 7.65 (1H, dd, J=1.8, 8.7 Hz), 8.39 (1H, d, J=8.7 Hz). HPLC analysis: purity 100% (retention time: 4.80 min). MS (ESI+): 536 (M+H), 538.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Li]>O1CCCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:15]2[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:28])[CH3:2])=[CH:9][CH:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2ccc(F)cc2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
To a 2-(4-Acetyl-phenyl)-N-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-acetamide (0.270 grams, 0.741 mmole) in tetrahydrofuran (15 ml) at −78° C. 1.0 M methyl lithium in tetrahydrofuran (1.63 ml, 1.63 mmole) was added via syringe and stirred at −78° C. for 75 minutes. Another 0.8 ml methyl lithium was added and the mixture was warmed to 0° C. for 10 minutes and cooled to −78° C. The mixture was quenched with water, allowed to warm to room temperature and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to a white solid which was purified by chromatography on silica eluting with 2% methanol/methylene chloride to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.032 g). M.P. 135-137° C.; Anal. calcd. for C22H21N2O3F: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.46; H, 5.92; N, 7.73.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C([BH3-])#N.[Na+]>>[CH:12]1([NH:6][C:5]2[CH:7]=[CH:8][CH:2]=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1ccc(NC2CC2)cc1

Procedure:
4-Iodoaniline (F-0) is reductively alkylated with [(1-ethoxycyclopropyl)oxy]trimethylsilane and sodium cyanoborohydride to give the N-cyclopropyl aniline (F-1). Treatment with diethyl ethoxymethylenemalonate in pyridine affords the enamine (F-2) which is cyclized with polyphosphoric acid to the quinoline (F-3). Treatment with p-chlorobenzylamine at elevated temperature converts the ester to the amide (F-4). Palladium catalyzed coupling of the iodide with propargyl alcohol affords F-5. Reaction with platinum and hydrogen gas affords the saturated propyl alcohol (F-6).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)C)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([CH:48]=[C:49]([C:2]2[C:10]3[C:9]([NH:11][CH2:12][C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:50]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)C(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc(CNc3ncnc4c3c(-c3cc(O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 46 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 3-hydroxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (92 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 44 mg (46% yield, 89% purity) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[C:14]([C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15].CCN(CC)CC>C1COCC1>[C:14]([C:16]1[CH:17]=[C:18]([NH:22][C:7]([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: Cc1ccoc1C(=O)O
Reactant: C#Cc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C#Cc1cccc(NC(=O)c2occc2C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A dry 25 mL flask was charged with 3-methylfuran-2-carboxylic acid (0.500 g, 3.46 mmol) and thionyl chloride (10 mL). The reaction was heated to 50° C. and allowed to react for 2 h. The reaction was then cooled to room temperature and concentrated affording the crude acid chloride. The acid chloride was then dissolved in THF (5 mL) and 3-ethynyl-phenylamine (0.41 g, 3.47 mmol) was added followed by NEt3 (0.95 mL, 7 mmol). The mixture was allowed to stir at 55° C. for 3 hours and the cooled to room temperature. The reaction was then partitioned between EtOAc and water. The organic layer was then washed once with 1M HCl (5 mL) and then once with saturated aqueous NaHCO3 (5 mL). The organic extracts were then concentrated to give the title compound as a light brown solid (631 mg, 2.80 mmol, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:19])[C:5]([OH:18])=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][C:29](=[O:33])[CH:30](Cl)Cl)[CH3:27].Cl>COCCOC>[CH2:26]([O:28][C:29]([CH:30]1[O:18][C:5]2[CH:6]=[C:7]([S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)(=[O:10])=[O:9])[C:2]([CH3:1])=[CH:3][C:4]=2[O:19]1)=[O:33])[CH3:27]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)c2cc(O)c(O)cc2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3ccc(C)cc3)cc2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 12.0 g (43.1 mmol) of 4-methyl-5-(4-methylphenylsulphonyl)-1,2-benzenediol and 30 g (216 mmol) of freshly calcined potassium carbonate in 200 ml of dry 1,2-dimethoxyethane is stirred for 5 minutes, under nitrogen, using a high-speed stirrer. In the course of this the temperature rises to 75°. Then, while stirring moderately (propeller stirrer), there is added dropwise thereto, in the course of one hour, a solution of 6.77 g (43.1 mmol) of dichloroacetic acid ethyl ester in 50 ml of dry 1,2-dimethoxyethane and the mixture is then boiled under reflux for 15 hours. It is subsequently poured onto an ice/water mixture and adjusted to pH 1-2 with concentrated hydrochloric acid. Some of the 1,2-dimethoxyethane is evaporated off in a rotary evaporator and the solution remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The resulting black oil is dissolved in ethanol, 0.5 g of p-toluenesulphonic acid is added, and the whole is boiled under reflux in a vessel provided with a Soxhlet attachment that is filled with molecular sieve. The ethanolic solution is then concentrated completely by evaporation and chromatographed over silica gel (solvent ethyl acetate/hexane in a ratio of 1:1). The uniform fractions containing the desired substance are combined and concentrated by evaporation. In this manner 5-methyl-6-(4-methylphenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester is obtained in the form of a yellow oil, which can be hydrolysed directly.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.BrCCOCCO[CH2:23][CH2:24][Br:25]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:23][CH2:24][Br:25])([CH2:10][CH2:11][CH2:12][CH2:4][CH2:3][CH2:2][Br:1])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCOCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: BrCCCCCCC1(CCCCCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
2,7-Dibromofluorene (1.23 g, 5 mmol) was added to a mixture of aqueous potassium hydroxide (100 mL, 50 w %), tetrabutylammonium bromide (0.330 g, 1 mmol), and 1,2-bis(2-bromoethoxy)ethane (13.9 g, 50 mmol) at 75° C. After 15 min, the mixture was cooled to room temperature. After extraction with CH2Cl2, the combined organic layers were washed successively with water, aqueous HCl (1 M), water, and brine and then dried over Na2SO4. After removal of the solvent and the excess 1,2-bis(2-bromoethoxy)ethane; the residue was purified by silica gel column chromatography using hexane and dichloromethane (1:2) as the eluent, and recrystallized from ethanol and CH2Cl2 (5:1) to afford M2 as white needle crystals (1.50 g, 48.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2>C1COCC1.C(N(CC)CC)C>[CH:32]12[CH2:37][CH:36]1[CH2:35][N:34]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:33]2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: C1NCC2CC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 39 %

Procedure:
In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-formamide (100 mg, 0.22 mmol). Several drops of triethylamine were added, then 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1). 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid was obtained (40 mg, 39% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10].[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 38 °C
Reaction time: 20 h

Procedure:
A 267.2 mg (1 m mol) of N-benzyloxycarbonyl-L-aspartic acid and 537.6 mg (3 m mol) of L-phenylalanine methyl ester were dissolved in 5 ml of McIlvain's buffer solution (pH: 7.0). The resulting solution was admixed with 100 mg of Thermoase and 100 mg of potato inhibitor and shaken at 38° C. for 20 hours. The precipitate was collected and washed with water and dried to obtain 580 mg of a crude crystalline addition compound of N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester and L-phenylalanine methyl ester (1:1) (melting point: 123° to 125° C.; Yield: 95.5% based on N-benzyloxycarbonyl-L-aspartic acid).
Reaction SMILES: Cl.[O:2]=[C:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:9][CH2:8]1.[BH4-].[Na+]>CO.ClCCl>[OH:2][CH:3]([C:23]1([CH2:36][CH2:37][CH3:38])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:22])[CH2:11][CH2:12]1
Reactant: CCCC1(C(=O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCC1(C(O)CCCN2CCC(N3Cc4ccccc4C3=O)CC2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 311 Part D free amine (300 mg, 0.61 mmol) in 12 ml of methanol was cooled to 0° C. under an argon atmosphere and 2 equiv. of sodium borohydride (48.5 mg, 1.28 mmol) was added. The reaction mixture was stirred at 0° C. for 45 min. The reaction was quenched with 1 N hydrochloric acid and extracted with ethyl acetate (3×20 ml). The extract was washed with brine and dried over sodium sulfate. Evaporation yielded an oily residue which was dissolved in dichloromethane, dried over sodium sulfate and evaporated to yield 550 mg of a colorless solid. The crude product was purified on a Merck EM silica column eluting with 5% methanol/dichloromethane yielding 290 mg (96%) of title compound as colorless solid.