Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[C:7]([O:35]C)=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2/[CH:27]=[CH:28]\[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].CN(C)C1C=CC=CC=1.O>C(Cl)Cl>[Br:5][C:6]1[C:7]([OH:35])=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2/[CH:27]=[CH:28]\[CH2:29][N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])(=[O:18])=[O:19])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(O)c1C(=O)OC
Yield: 100 %

Procedure:
Aluminium chloride (0.303 g) was added to a stirred solution of (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-methoxybenzoate (Intermediate 161, 0.528 g) and N,N-dimethylaniline (0.915 g) in DCM (20 ml). The resultant mixture was stirred for 3 hours then a mixture of ice, water and DCM were added. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-6% to give (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-hydroxybenzoate (0.514 g) as a pale purple oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH2:13])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[CH:18]3)[CH:10]([NH:13][S:40]([CH:37]2[CH2:39][CH2:38]2)(=[O:42])=[O:41])[CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: CCC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NS(=O)(=O)C1CC1)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccnc(OC)c1
Reaction time: 48 h

Procedure:
To a stirred solution of 1-[2-methoxypyridin-4-yl]-1-[(1-pyridin-2-yl-1H-indazol-5-yl)oxy]butan-2-amine (122 mg, 310 μmol) in dichloromethane (11 ml) was added triethylamine (100 μl), followed by cyclopropanesulphonic acid chloride (66 mg, 470 μmol) and DMAP (3.8 mg, 31 μmol). The stirring was continued for 48 h at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 10 mg (6.5%) as a racemic mixture of two diastereomeres.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:14]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ncc(O)cn2)cc1
Reactant: CC(C)I
Product: CC(=O)NC(C)CCc1ccc(Oc2ncc(OC(C)C)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyrimidin-2-yloxy)phenyl]-1-methylpropyl}acetamide (125 mg, 0.41 mg) was reacted with 2-iodopropane in analogy to example 36f. Yield: 9 mg (6%), M+H+: 344.14.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:62]=[CH:61][C:15]([O:16][CH2:17][C:18]3([O:42][P:43]([O:53]CC4C=CC=CC=4)([O:45]CC4C=CC=CC=4)=[O:44])[CH2:23][CH2:22][N:21]([C:24]4[CH:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:63])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].Br.O>C(#N)C.C(O)(=O)C>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:62]=[CH:61][C:15]([O:16][CH2:17][C:18]3([O:42][P:43]([OH:53])([OH:45])=[O:44])[CH2:23][CH2:22][N:21]([C:24]4[CH:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:35][CH2:36]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:63])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OP(=O)(OCc4ccccc4)OCc4ccccc4)CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OP(=O)(O)O)CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
27 g 7-[4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-(bis-benzyloxy-phosphoryloxy)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (MW: 886.85, 30.44 mmol) were suspended in 600 ml acetonitrile and treated with 53 ml of a 33% solution of anhydrous hydrobromic acid in acetic acid. The yellow suspension was diluted with 150 ml of acetic acid and was heated to 45° C. The reaction was monitored by HPLC/MS and was complete after 3 hours. The sticky suspension was added to 1.5 L of water under stirring. The off white crystals were collected, washed with 300 ml water, 150 ml ethanol and 150 ml ether. The solid was suspended in 1.3 L water and treated with 35 ml (35 mmol) of a 1M aqueous sodium hydroxide solution. The solid dissolved, and the brown-yellow solution was treated with 15 g of activated charcoal and filtered. The filtrate was extracted with 3 portions of 200 ml of a 95/5 dichloromethane/methanol mixture. The water layer was treated with 40 ml of 1 M HCl solution and the product crystallized by stirring. The solid was collected and dried. Yield: 17.3-g, 80.4%. MS: 609.7 (M+H)+, 607.8 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:22]=[C:21]([CH2:23]Br)[O:20][N:19]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:25]([O:27][C:28](=[O:42])[CH:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[CH2:33]([O:32][C:30](=[O:31])[C:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])([CH2:23][C:21]1[O:20][N:19]=[C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH:22]=1)[C:28]([O:27][CH2:25][CH3:26])=[O:42])[CH3:34]
Reactant: C=CCOC(=O)NC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(CBr)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A dimethyl formamide (260 mL) solution of 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.29 g, 56 mmol) and 2-allyloxycarbonylamino-malonic acid diethyl ester (8.25 g, 32 mmol) was cooled to 0° C. and cesium carbonate (25.41 g, 78 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2 L) and washed with water (5×200 mL) and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate:hexane (3:7) to afford the title compound as a clear colorless oil (10.95 g; 83%). MS (Cl) m/z 260.1 (M−99). G. 2-Allyloxycarbonylamino-malonic acid diethyl ester
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of phenylmethyl 2-(3-hydroxypropyl)-1-piperidinecarboxylate (2.14 g, 7.72 mmol) in anhydrous dichloromethane (34 ml) was added carbon tetrabromide (5.12 g, 15.43 mmol)). The resulting solution was cooled in ice/water. A solution of triphenylphosphine (4.05 g, 15.43 mmol) in 10 ml dry DCM was added dropwise over 30 mins., producing a deep amber/brown solution. After complete addition the reaction was allowed to warm slowly to ambient temperature and stirring continued overnight. The reaction mixture was filtered to remove the precipitate, washed with ether and the filtrate evaporated to approx 10 ml. This was then loaded onto a 100 g silica cartridge and purified by chromatography using a gradient of Flashmaster 0-25% ethylacetate in cylcohexane over 40 mins. on a Flashmaster collecting all the eluent. The product peak was identified by TLC and the fractions combined and evaporated in vacuo to give the title compound as a clear oil (2.13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].O.[C:26]([OH:30])(=[O:29])[CH:27]=O>C(Cl)Cl.CN(C=O)C>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([NH:1][CH:27]([C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:26]([OH:30])=[O:29])[CH:3]=1)(=[O:6])[NH2:7]
Reactant: NC(=O)c1ccc(Cl)c(N)c1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(Nc2cc(C(N)=O)ccc2Cl)C(=O)O)cc1OC
Temperature: 65 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
A mixture of 3-amino-4-chlorobenzamide (170 mg, 1.0 mmol), 3,4-dimethoxyphenylboronic acid (182 mg, 1.0 mmol) and glyoxylic acid monohydrate (92 mg, 1.0 mmol) in methylene chloride (4.0 mL) and DMF (0.3 mL) was heated at 65° C. for 3.0 h and then stirred at rt for 18 h. The precipitate formed was collected by filtration and washed with methylene chloride to give 3A (200 mg, 57% yield) after drying. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.80 (s, 3H) 3.81 (s, 3H) 5.17 (s, 1 H) 6.92 (d, J=8.35 Hz, 1H) 7.04 (s, 1H) 7.04-7.11 (m, 3H) 7.33 (d, J=7.91 Hz, 1 H); LC-MS 365 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[OH:25][CH2:26][CH2:27][NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:25][CH2:26][CH2:27][NH:28][C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]2[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:7])[CH:14]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCO)cc1
Yield: 92.1 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), 2-hydroxyethylamine (5.7 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (48 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(4′-{[(2-hydroxyethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (31.2 mg, 92%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.49,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.67,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.97,(1H, m), 4.73,(1H, t), 3.52,(2H, q), 3.35,(2H, m), 2.19,(3H, s). LCMS: retention time 2.72 min, MH+365.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][C:7](I)=[CH:8][CH:9]=2)(=O)C.[CH:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>[Cu]=O>[C:15]1([C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[C:29](=[CH:28][C:27]([C:6]5[C:5]6[NH:4][C:16]7[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=7)[C:10]=6[CH:9]=[CH:8][CH:7]=5)=[CH:26][CH:25]=4)[NH:30][C:31]=3[CH:19]=2)[C:16]2[NH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)n1c2cc(I)ccc2c2ccc(I)cc21
Agent: O=[Cu]
Product: c1ccc2c(c1)[nH]c1c(-c3ccc4c(c3)[nH]c3cc(-c5cccc6c5[nH]c5ccccc56)ccc34)cccc12
Temperature: 170 °C
Yield: 139 %

Procedure:
A mixture of 4.0 g of 9-acetyl-2,7-diiodocarbazole and 2.2 g of carbazole were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 1.6 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid (6 g) was then taken up for further deprotection using 1.2 g KOH with THF (6 ml), methanol (12 ml) and water (12 ml) at reflux temperature. The reaction mixture was then extracted using ethyl acetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene:hexane (1:2) as eluent, yielded 3.0 g of 2,7-dicarbazolylcarbazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.CSC.C(OCC)C.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc(CCCN2CCOCC2)cc1
Reaction time: 24 h
Yield: 78 %

Procedure:
A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) at room temperature was treated with 5M BH3/dimethylsulfide in diethyl ether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3N aqueous HCl (10 mL), heated to reflux for 1 hour, and partitioned between ethyl acetate and 1N NaOH. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% 2N NH3 in methanol/dichloromethane to provide the desired product (565 mg, 78%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cn2c(N)cc(=O)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidin-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidin-2,4-dione acetic acid salt, [M-3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (17.0 g, 69.0mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][CH2:21][O:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)([O-:25])(=[O:24])=[O:22]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C)ccc1C=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 30 %

Procedure:
A solution of 2-hydroxy-4-methylbenzaldehyde (3 g, 21.6 mmol), potassium carbonate (14.9 g, 107.8 mmol) and the title A compound, toluene-4-sulfonic acid 3-methoxy-propyl ester (8.07 g, 32.4 mmol) in DMF (50 mL) is stirred at 50° C. for 3 h. The solvent is concentrated under reduced pressure, H2O is added, and the aqueous layer extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound together with 30% of remaining tosylate: Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.25, 5.39 min. The mixture is further used as is in the next step.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:54]1[N:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][CH:55]=1)CCC>CN(C=O)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>[C:42]([O:41][C:40]([NH:39][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH2:10][C@@H:11]([NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:54]2[CH:55]=[CH:56][CH:57]=[C:58]([O:60][CH3:61])[N:59]=2)=[CH:17][CH:18]=1)=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1

Procedure:
A solution containing the product from Example 92D (0.20 g, 0.28 mmol) in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and the product from Example 113A (0.336 g, 0.84 mmol), heated at 100° C. for 16 hours, cooled, filtered through celite®, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:11][N:12]([CH3:13])[S:6]([C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)(=[O:8])=[O:7]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-imidazole-4-sulfonyl chloride (0.5 g, 3.0 mmol; Matrix Scientific, Columbia, S.C.) in dichloromethane (10 mL) was added dimethylamine hydrochloride (0.245 g, 3.0 mmol) and triethylamine (1.3 mL, 9.0 mmol) at room temperature. The mixture was stirred for 16 hours at room temperature. TLC (petroleum ether/ethyl acetate=0:1) indicated the reaction was complete. The reaction mixture was washed with aq. ammonium chloride (30 mL) and extracted with dichloromethane: methanol=4:1 (3×50 mL). The combined organic phases were concentrated and precipitated from methanol to afford (I-35a) (0.36 g, 68.2%) as a white solid; 1H NMR (400 MHz, CD3OD): δ 7.74 (1H), 7.61 (1H), 2.68 (6H).
Reaction SMILES: C(ON=O)C(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22](N)[S:23][C:17]=2[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Br-:25]>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([Br:25])[S:23][C:17]=2[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: [Br-]
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Suspended CuBr2 (905 mg, 4.05 mmol) in 5 mL of DMF and added i-butylnitrite (0.57 mL), 4.86 mmol). To this was added 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (860 mg, 3.36 mmol) and the mixture was stirred for 2 h at 60° C. LC-MS analysis indicated the desired bromide. Concentrated the mixture to a brown-red residue. Dissolved the residue in CH2Cl2 and purified via SiO2 chromatography (EtOAc/hexanes 0-20%) to give 650 mg of 2-bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:22][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])[C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([OH:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCc1ccccc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCc1ccccc1

Procedure:
By substituting 4-benzylamino-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 218°-219°C after recrystallization from aqueous methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[Br:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: BrCCCc1ccncc1
Reaction time: 2 h
Yield: 111.1 %

Procedure:
3.0 g of 4-pyridinepropanol was dissolved in 90 ml of chloroform, 9.4 g of carbon tetrabromide and 7.5 g of triphenylphosphine was added under ice cooling, and the mixture was stirred for 2 hours. Ether was added to the reaction solution, and the mixture was extracted with 1N hydrochloric acid, and then the aqueous layer was washed with ether. The aqueous layer was adjusted to be basic with 6N sodium hydroxide, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 4.86 g of 4-(3-bromopropyl)pyridine.