Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.C(N(CC)CC)C.CC([Si](C)(C)[O:35][C@@H:36]([C@@H:45]([CH3:49])[C:46](=[O:48])[CH3:47])[C@@H:37]([CH3:44])[C:38](N(OC)C)=[O:39])(C)C.[NH2:52][C:53]([O:55][C@@H:56]([C@@H:91]([CH3:96])/[CH:92]=[CH:93]/[CH:94]=[CH2:95])[C@@H:57]([CH3:90])[C@H:58]([O:82][Si](C(C)(C)C)(C)C)[C@@H:59]([CH3:81])[CH2:60]/[C:61](/[CH3:80])=[CH:62]\[C@H:63]([CH3:79])[C@@H:64]([O:71][Si](C(C)(C)C)(C)C)[C@@H:65]([CH3:70])/[CH:66]=[CH:67]\[CH:68]=[O:69])=[O:54]>C(OCC)C>[CH3:49][C@@H:45]1[C@H:36]([OH:35])[C@@H:37]([CH3:44])[C:38](=[O:39])[O:48][C@H:46]1[CH2:47][C@H:68]([OH:69])/[CH:67]=[CH:66]\[C@@H:65]([C@H:64]([OH:71])[C@H:63](/[CH:62]=[C:61](\[CH2:60][C@@H:59]([C@@H:58]([OH:82])[C@@H:57]([C@@H:56]([O:55][C:53]([NH2:52])=[O:54])[C@H:91](/[CH:92]=[CH:93]\[CH:94]=[CH2:95])[CH3:96])[CH3:90])[CH3:81])/[CH3:80])[CH3:79])[CH3:70]
Reactant: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(C)=O
Reactant: C=C/C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.18 g (6.79 mmol, 10 equiv.) of (+)-β-chlorodiisopinocamphenylborane in 4 mL of diethyl ether at 0° C. is added 1.04 mL (11 equiv., distilled over calcium hydride) of triethylamine and then a solution of 2.25 g (6.79 mmol, 10 equiv.) of the compound of Example 1 in 3 mL of diethylether. After stirring for 2 hours at 0° C., the mixture is cooled to −78° C., after which time a pre-cooled (−78° C.) solution of 450 mg (0.679 mmol) of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15E)-13-[(amino-carbonyl)oxyl]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenal in 4 mL of diethylether is added via cannula. After the resultant mixture is maintained at a temperature of −78° C. for 3 hours, it is transferred to a freezer (−27° C.) for 16 hours. The reaction is then quenched with 8 mL of methanol (the pH of which is adjusted to 7 with 12 mL of buffer solution) and 4 mL of 50% hydrogen peroxide solution at 0° C. After stirring for 2 hours at 25° C., the organic layers are separated. The aqueous layer is then extracted five times with 25 mL portions of dichloromethane. The combined organic layers are then dried over magnesium sulfate, concentrated using a rotary evaporator and chromatographed (Biotage, silica gel, gradient 10-30% ethyl acetate/hexane) to yield the desired compound as a colorless, highly viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][N:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][N:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 5 h
Yield: 101.3 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (33 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and then 10% palladium carbon (17 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (31 mg) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1>P([O-])([O-])([O-])=O>[CH:2]1[N:3]=[C:4]2[N:5]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]3[OH:27])[CH:6]=[N:7][C:8]2=[C:9]([NH2:10])[N:1]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 70.1 %

Procedure:
5 kg of wet cell paste or the corresponding crude or purified extract obtained by fermenting the strain MG1655/pGM716 or the strain DH5α/pGM716 were resuspended in approximately 20 liters of 30 mM phosphate buffer at pH 7 and mixed with 980 liters of phosphate buffer in which had been dissolved at elevated temperature 10.1 kg of adenine (final concentration approximately 74.6 mM) and 18.3 kg of Ara-U (final concentration approximately 74.6 mM). The mixture was maintained at 60° C., with agitation, for 4 hours to obtain a bioconversion yield of approximately 70%. The cell paste was recovered in order to be used again in subsequent reactions by dilution at elevated temperature and diafiltration in accordance with the procedure described above. The ultrafiltrate was concentrated to a volume of approximately 1000 liters, cooled to collect the precipitate constituted by Ara-A which was subsequently crystallised from water to obtain approximately 14 kg of Ara-A with a degree of purity higher than 99.5%. According to an alternative procedure, in which the cells were not recovered and the diafiltration step was omitted, at the end of the reaction the mixture was heated to approximately 90° C. and filtered at elevated temperature to eliminate the cells, and the filtrate was cooled to precipitate Ara-A contaminated with non-reacted adenine (approximately 20 g of adenine per 100 g of Ara-A). 14 kg of Ara-A (total yield 65%) having a degree of purity higher than 99.5% were finally obtained after crystallisation from reaction of 1000 liters. Similar results were obtained starting from a mixture of the cell pastes or the corresponding crude or purified extracts obtained by fermenting the recombinant E. coli strains MG1655/p707 or MG1655/p708 and the strains DH5α/pGM707 or DH5α/pGM707 overexpressing UdP and PNP, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.N(C(OCC)=O)=NC(OCC)=O>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1ccc(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Product: COc1ccc(OCCOc2nccnc2N2CCNCC2)c(Cl)c1

Procedure:
The title compound was prepared starting from 2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61 mmol; prepared in Example 52, Step 2) according to the procedure described in Example 52, Step 3, but utilizing diethyl azodicarboxylate (DEAD) instead of TMAD. Yield 50 mg (21%) HRMS m/z calcd for C17H21CIN4O3(M)+364.1302, found 364.1307.
Reaction SMILES: Br[CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CC(C)=O.O>[N:22]([CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1C=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of rac-3-bromo-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (13.2 g, 36.0 mmole) in 180 ml acetone and 24 mL water was treated with a solution of sodium azide (3.51 g, 54.0 mmole) dissolved in 24 mL of water and stirred at ambient temperature. After 30 minutes, 500 mL of water was added. The precipitated product was collected and dried, yielding 10.6 g (89%) of the title compound as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH2:28][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:28][C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:26][C:27]=3[CH:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Cc1cc(CNCCCN3CCN(CCCNCc4ccc5c(c4)Cc4ccccc4-5)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-fluorenecarboxaldehyde (1.018 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2 25×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][N:16](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15][CH2:14][C:5]=1[NH:6]2.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1[N:53]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=[CH:54]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:4][C:3]1[C:7]([N:53]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:55]=[CH:54]2)=[CH:8][CH:9]=[CH:10][C:2]=1[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][NH:16][CH2:15][CH2:14][C:5]=1[NH:6]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2ccccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 15.75 h
Yield: 114.9 %

Procedure:
Alternatively, a mixture of 9-bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (78.3 mg, 0.146 mmol), 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (52.9 mg, 0.146 mmol), and 2 M aqueous sodium carbonate (0.219 mL, 0.438 mmol) in toluene (1.2 mL) and ethanol (0.3 mL) was degassed by bubbling with argon for ca. 5-10 min (1 minute with sonication). The mixture was treated with tetrakis(triphenylphosphine)palladium (8.4 mg, 0.007 mmol) and heated at 90° C. under argon. After 15.75 h, the mixture was cooled to room temperature and concentrated under vacuum. The residue was stirred in methanol, treated with a small amount of TFA and water and the resulting mixture was sonicated until the gummy insoluble material was replaced by a flocculent precipitate. The mixture was filtered and subjected to purification by preparative HPLC. Fractions containing the desired product by LCMS were combined, treated with saturated aqueous sodium bicarbonate and concentrated under vacuum to provide an aqueous suspension. The precipitate was collected by filtration, washed with water and dried under vacuum to provide the desired product as a white solid (37.7 mg, 56% yield). LCMS (M+H+) m/z 450.2. 1H NMR (400 MHz, DMSO-d6) δ 10.83-10.93 (1 H, m), 8.19-8.41 (2 H, m), 8.03 (1 H, br. s.), 7.86-7.97 (1 H, m), 7.79 (1 H, t, J=7.3 Hz), 7.58-7.70 (2 H, m), 7.41-7.57 (2 H, m), 7.23-7.41 (2 H, m), 6.74-6.88 (1 H, m), 3.02-3.28 (2 H, m), 2.90 (2 H, br. s.), 2.71 (2 H, br. s.), 1.76 (3 H, s).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23]>CC(N(C)C)=O.CCOC(C)=O>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([S:7][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(S)c1
Reactant: N#Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cncc(Sc2cccc(CO)c2)c1
Temperature: 110 °C
Yield: 99.1 %

Procedure:
Add K2CO3 (6.91 g, 50.0 mmol) to a solution of (3-mercaptophenyl)methanol (2.94 g, 21.0 mmol) and 5-bromonicotinonitrile (3.66 g, 20.0 mmol) in DMA (100 mL). Heat the mixture at 110° C. for 2 h. Cool to room temperature. Dilute with EtOAc. Filter. Wash the residue with EtOAc. Concentrate. Dissolve the residue in EtOAc and filter. Concentrate to afford the title compound (4.80 g, quant.): 1H NMR (CDCl3) δ 2.20 (t, J=5.5 Hz, 1H), 4.74 (d, J=5.5 Hz, 2H), 7.38-7.44 (m, 3H), 7.52-7.53 (m, 1H), 7.62 (dd, J=2.0, 2.3 Hz, 1H), 8.62 (dd, J=2.0, 2.3 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:24][P:25]([O:37]COC(=O)C(C)(C)C)([CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH2:7][N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11].CC1C=CC(S(O)(=O)=[O:54])=CC=1>CO.C(O)(=O)C.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:24][P:25]([OH:37])([CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[C:7]([N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[O:54]
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H]1CCCN1CC(CCCCN)CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1CCCN1C(=O)C(CCCCN)CP(=O)(O)CCCCc1ccccc1
Yield: 75 %

Procedure:
A solution of 0.800 g (1.16 mmol) of (±)-1-[6-amino-2-[[[(2,2-dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]methyl]hexyl]-L-proline, (2,2-dimethyl-1-oxopropoxy)methyl ester, 4-methylbenzenesulfonic acid (1:1) salt (prepared as described in Example 12) in a mixture of 15 ml of methanol and 1 ml of acetic acid was cooled in an ice-water bath under argon and treated with 250 mg of 10% Pd-C. The reaction mixture was subjected to a slow flow of H2 at 1 atm for 31/2 hours, then filtered and concentrated in vacuo to 0.710 g of residue which was purified by reverse phase gradient elution chromatography on a 25×250 mm HP-20 column (500 ml H2O to 500 ml CH3CN, linear gradient at ca. 4 ml/min flow). The product containing fractions were pooled and lyophilized to yield 0.476 g (75%) of the title product isolated as a 0.9 H2O solvate.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[CH:5]=[C:6]([S:10]([NH2:1])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: N
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Product: N#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of ammonia in dioxane (0.5 M in dioxane; 50 mL; 25 mmol) was added a solution of 3-cyanobenzene-1-sulfonyl chloride (ABCR; 605 mg; 3 mmol) in dioxane (10 mL) and the mixture was allowed to stir at RT for 30 min. The solvent was removed in vacuo to give the title compound as a white solid (450 mg; 82%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.25 (1H, t, J=1.7 Hz), 8.18-8.12 (2H, m), 7.85 (1H, t, J=7.9 Hz), 7.63 (2H, br s). LC/MS (Method C): 181 (M+H)+. HPLC (Method E) Rt 2.42 min (Purity: 99.3%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1>C(O)C.O>[OH:1][C@H:2]([CH2:3][NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:21][CH:22]=1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is heated under reflux for 14 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and heated under reflux for 13 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: N#Cc1c(N)cccc1CCC1CCCCC1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile (Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H), 1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m, 2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q, J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63 (brs, 2H). MS 413 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:20]2[CH2:19][CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-bromo-5-nitropyridine (4.23 g, 0.02 mol) and the alkyne prepared in Step (a) (4.0 g, 0,019 mol) in 7.9 mL of triethylamine and 100 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.27 g (0.0004 mol) of bis(triphenylphosphine)palladium chloride and 0.07 g (0.0004 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 100 mL of dichloromethane and 100 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 50 mL of dichloromethane and the combined organic layers are washed with 50 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 133°-134° C.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)cc(-c2cc(CN(C)S(=O)(=O)c3ccc(F)c(Cl)c3)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of tert-butyl 2-(2-bromo-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (10) (140 g, 0.27 mol, 1 eq), 3-fluoro-5-methoxyphenylboronic acid (45.7 g, 0.27 mol, 1 eq, Combi-Blocks Inc., San Diego, Calif., USA) and potassium carbonate (111 g, 0.81 mol, 3 eq) in dioxane/water (3:1, 800 mL) was added tetrakis(triphenylphoshine)palladium (3.08 g, 2.7 mmol, 0.01 eq). The mixture was heated at 60° C. for 3 h under N2. Solvent was evaporated, and the solid was dissolved in DCM and filtered. The DCM was evaporated and the crude product was recrystallized from ethanol to yield tert-butyl 2-(3-fluoro-5-methoxyphenyl)-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxyacetate (11) (70 g, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromobenzoyl chloride (5.6 g) in 50 mL of tetrahydrofuran was cooled to 0° C. and treated with aqueous methylamine (5 mL of 40%). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. At the end of this period, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with 10% HCl followed by sodium carbonate. Upon drying over magnesium sulfate and evaporation, a white solid was obtained (4.64 g); MS: 214; NMR: 3.0 (d, J=5, 3), 6.2 (br, 1), 7.5-7.6 (m, 2), 7.6-7.7 (m, 2).