Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C([O-])(=O)C.[K+].Br[C:21]1[C:22]([C:46]([F:49])([F:48])[F:47])=[C:23]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][N:27](COCC[Si](C)(C)C)[C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(N(C)C)=O>[OH:14][CH:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:21]2[C:22]([C:46]([F:47])([F:48])[F:49])=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:3]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10]
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(C(F)(F)F)c12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(C(F)(F)F)c12
Reaction time: 0.08 h
Yield: 6.5 %

Procedure:
A mixture of 2-(5-Bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (40 mg, 0.15 mmol), bis(pinacol)diborane (47 mg, 0.18 mmol), potassium acetate (45 mg, 0.46 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (6 mg, 0.007 mmol) in dimethylacetamide (1 mL) was irradiated in a Personal Chemistry Optimizer at 120° C. for 30 min. 5-Bromo-3-(2-methoxy-phenyl)-4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (39 mg, 0.077 mmol), sodium carbonate solution (2M in water, 0.39 mL, 0.77 mmol), and additional 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (3 mg, 0.03 mmol) was added and the mixture was irradiated for an additional 30 min at 120° C. Sodium sulfate was added to the crude reaction mixture and the solids were filtered over Celite. The solids were rinsed with ethyl acetate and the combined filtrate was concentrated. The solids were resuspended in ethyl acetate, filtered through a plug of silica and the eluent was concentrated. The resulting oil was dissolved in trifluoroacetic acid (2 mL) and shaken for 5 min. The solution was concentrated and the mixture was redissolved in dimethyl sulfoxide and ethylenediamine. Purification by mass triggered reverse phase HPLC afforded 2-Hydroxy-2-{5-[3-(2-methoxy-phenyl)-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide (2.5 mg, 0.005 mmol, 7% yield). 1H NMR (500 MHz, MeOH-d4) δ 12.55 (bs, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.72 (s, 1H), 7.71 (m, 1H), 7.31 (m, 1H), 7.24 (dd, J=7 Hz, J2=2 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.95 (td, J=7.5 Hz, J2=1 Hz, 1H), 5.8 (bs, 1H), 5.56 (s, 1H), 3.65 (s, 3H), 2.90 (m, 3H), 2.84 (s, 3H). MS: m/z 471.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[S:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:13]2[S:14][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:15]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cn1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(NC(=O)OC(C)(C)C)nc2)nc1C
Yield: 27.6 %

Procedure:
A mixture of 6-tert-butoxycarbonylaminothionicotinamide (506 mg), ethyl 2-chloro-acetoacetate (492 mg) and sodium acetate (252 mg) in ethanol (20 ml) was heated for 2 hours under reflux, and to the mixture were added sodium hydrogen carbonate aqueous solution and water. The precipitated crystals were collected by filtration, and the crystals were successively washed with water, ethanol and ether to give ethyl 2-(6-tert-butoxycarbonylamino-3-pyridyl)-4-methyl-5-thiazolecarboxylate (200 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].C(OC=C)(=O)C.N1C=CC=CC=1[C@H](OC(=O)C)C.C(=O)([O-])[O-].[K+].[K+]>O(C(C)C)C(C)C.CO.O.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([OH:9])[CH3:8]
Reactant: CC(O)c1ccccn1
Agent: CC(=O)O[C@H](C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C=COC(C)=O
Solvent: CO
Solvent: O
Product: C[C@@H](O)c1ccccn1
Yield: 89 %

Procedure:
Stir a mixture of (±)-1-(pyridin-2-yl)-ethanol (21.2 mmol), 4 A molecular sieves powder (3 g), vinyl acetate (6 mL) and lipase Candida Antarctica acrylic resin (0.87 g) in i-Pr2O (40 mL) at ambient temperature overnight-(J. Org. Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). Remove the solid residue by filtration. Evaporate the volatile substances and purify by chromatography eluting with hexane/EtOAc (7:3 to 1:1) to give the faster eluting (R)acetic acid 1-(pyridin-2-yl)-ethyl ester as colorless oil (50%) and the slower eluting (S)-alcohol as light yellow oil (43%). Dissolve (R)-acetic acid 1-(pyridin-2-yl)-ethyl ester (9.620 mmol) in methanol (50 mL) and add potassium carbonate (38.48 mmol) in water (10 mL). Stir the mixture at ambient temperature for 4 h. Dilute with brine, extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a colorless oil (89%).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([OH:16])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:5][O:6][C:7]1[C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C:8]=1[C:14]([NH:4][CH2:1][C:2]#[CH:3])=[O:16]
Reactant: C#CCN
Reactant: COC1=C(C(=O)O)CN(C)C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C#CCNC(=O)C1=C(OC)C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of prop-2-yn-1-amine (0.43 mL, 7.7 mmol), 4-methoxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.2 g, 7.0 mmol) and PyBOP® (4.01 g, 7.71 mmol) in DMF (25 mL) was added diisopropylethylene amine (3.67 mL, 21.0 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by ISCO chromatography (ethyl acetate/hexane 1-100%, column 40 g cartridge) to afford Intermediate 21 (1.2 g, 82%) as a white paste. HPLC/MS (Method L) RT=0.99 min, [M+]+ 209.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[P:32]([O:44][CH2:45]Cl)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[P:32]([O:44][CH2:45][N:21]1[CH:20]=[CH:19][S:18]/[C:17]/1=[N:16]\[S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:8]([C:22]#[N:23])[CH:9]=1)(=[O:14])=[O:15])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:33]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)/N=c2\sccn2COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1C#N
Yield: 84.9 %

Procedure:
4-[4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide, (Example 170, 200 mg, 0.000424 mol), di-tert-butyl chloromethyl phosphate (J. Med. Chem. 51 (2008) p 1111-1114, supplimentary data) (160 mg, 0.000619 mol) and cesium carbonate (420 mg, 0.00129 mol) were stirred in dimethylformamide (2 mL) at 60° C. for 18 hours. The mixture was cooled then partitioned between tert-butylmethyl ether (80 mL) and water (40 mL), the organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a pale yellow gum, (250 mg).
Reaction SMILES: [Br:1][CH:2]([Si:4](Cl)(Cl)Cl)[CH3:3].[CH3:8][O:9][CH2:10][CH2:11][OH:12].Cl>>[Br:1][CH:2]([Si:4]([O:12][CH2:11][CH2:10][O:9][CH3:8])([O:12][CH2:11][CH2:10][O:9][CH3:8])[O:12][CH2:11][CH2:10][O:9][CH3:8])[CH3:3]
Reactant: CC(Br)[Si](Cl)(Cl)Cl
Reactant: COCCO
Agent: Cl
Product: COCCO[Si](OCCOC)(OCCOC)C(C)Br

Procedure:
One-quarter mole of alpha-bromoethyltrichlorosilane is dissolved in 200 ml. of dry hexane and sparged rapidly with nitrogen. 0.85 moles of the beta-methoxyethanol is added slowly and the resulting mixture is stirred until the HCl evolution ceases. Distillation of the residue yields alpha-bromoethyltris(beta-methoxyethoxy)silane. This produce (0.2 moles) is heated with 0.2 moles of the diacetate ester of dodecyldiethanolamine at 135° C. for 16 hours to yield the desired quaternary ammonium salt.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:53]=[CH:52][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([C@@H:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH2:37][CH2:38][N:39]([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[CH:30]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[CH2:62][OH:63])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[Si:55]([O:54][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:62][OH:63])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([C@@H:36]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:37][CH2:38][N:39]([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[CH:30]=2)=[CH:52][CH:53]=1)([C:58]([CH3:61])([CH3:59])[CH3:60])([CH3:57])[CH3:56]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)cc2)ccc1O)C(C)C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-{4-[4-(2-{[(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]amino}ethyl)phenoxy]butyl}-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol (Preparation 62, 388 mg, 0.44 mmol) was dissolved in ethanol (5 ml) and ammonium formate (280 mg, 4.44 mmol) and 20% palladium hydroxide on carbon (58 mg) added. The stirred reaction was heated at 85° C. for 18 hours. After cooling to room temperature, further ammonium formate (140 mg, 2.22 mmol) and 20% palladium hydroxide on carbon (20 mg) were added and mixture stirred at 85° C. for 3 hours. Reaction mixture was then cooled and filtered through Arbocel™, the filtrate was collected and the solvent removed in vacuo to furnish the title compound as a glass, 311 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=O)[CH2:7][C:6]=2[CH:11]=1.[Br-].[C:13]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C(C)=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:18][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[CH:7]=1)[CH3:17]
Reactant: Cc1ccc2c(c1)CC(=O)O2
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc2cc(C)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of the product of Step 2, above (56) (10.81 mmol) and (carbethoxymethyl)triphenylphosphonium bromide (12.0 mmol) in 50 ml of xylene was heated to 155° C. for 20 hours. The reaction was cooled to ambient temperature and concentrated to dryness. The crude residue was chromatographed on silica gel with gradient elution with 5% EtOAc in hexanes to 10% EtOAc in hexanes to obtain the title compound (57).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH2:29].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH:9]1([NH:8][C:6]2[C:5]([NH2:12])=[CH:4][N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[N:7]=2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Reactant: NCCc1cccs1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc(NCCc2cccs2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of 0.2 g (0.93 mmol, 1.0 eq.) of 2-chloro-N-cyclopropyl-5-nitropyrimidin-4-amine (I-1) in 5 mL of THF was added 0.19 mL (1.4 mmol, 1.5 eq.) of triethylamine followed by 0.14 g (1.1 mmol, 1.2 eq.) of 2-thiophene ethylamine. The reaction mixture was stirred at room temperature for 30 min and 2 mL of THF was added. A solution of 1.0 g (˜5.7 mmol, ˜85% tech. grade, ˜6.0 eq.) of sodium hydrosulfite and 1.0 g (12 mmol, ˜13 eq.) of sodium hydrogen carbonate in 10 mL of water was added, and the mixture was stirred vigorously at room temperature for 1 h. The mixture was diluted with 20 mL of EtOAc and washed 10 mL of sat. brine. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo to provide 0.16 g of crude N4-cyclopropyl-N2-(2-(thiophen-2-yl)ethyl)pyrimidine-2,4,5-triamine (I-3).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1)=O.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]1[S:27][C:8]2[C:7]([N:6]=1)=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: O=C(Nc1ccc[nH]c1=O)c1ccccc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Fc1ccccc1-c1nc2cccnc2s1

Procedure:
3-(2-Fluorobenzoylamino)-2-pyridone (2 g.), 60 ml. of xylene and 15 ml of pyridine were heated until solution was complete. To this solution was added 6.5 grams of phosphorus pentasulfide and the mixture was heated at reflux for 16 hours. The reaction mixture was decanted from a gummy residue while hot, and the solvents were concentrated to dryness. The crystalline residue was recrystallized from ethanol to give 2-(2-fluorophenyl)thiazolo[ 5,4-b]pyridine, m.p. 119°-121° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15](C)[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.CC1C(=O)NC(=O)N([C@@H]2O[C@H](COP(O)(O)=O)[C@@H](O)C2)C=1>>[C@@H:1]1([N:9]2[CH:17]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Strain CMG1115 (see Table 4 above) can be modified to a genotype additionally including tdk+ (thymidine kinase) and thyA- (thymidylate synthase negative) in order to produce deoxyuridine in accordance with the present invention. Such a modified strain derived from strain CMG1115 (containing pCG144), is streaked on LB agar plates with 100 ug/mL ampicillin and 50 mg/ml thymidine and grown at 30° C. Single colonies are picked into 25 mL of LB broth with 100 μg/ml ampicillin in a 250 mL baffle flask and incubated at 30° C. for 8 hours. This culture (0.5 mL) is then used to seed flasks with production media with the composition presented in Table 11.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=O.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[C:12]1([S:1]([C:3]2[CH:4]=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of sulfanilic acid (10 g, 0.52 mmol), benzene (4.7 g, 0.56 mmol) and trifluoroacetic anhydride (42 g) in trifluoroacetic acid (42 g) was heated to reflux for 3 days. The solvent was removed in vacuo and the residue taken up in 10% aqueous sodium hydroxide and heated to 100° C. for 15 minutes. The resulting white precipitate was filtered off, washed with water and dried to give [4-(phenylsulfonyl)phenyl]amine. 1H NMR (400 MHz, d6-DMSO) δ 7.83-7.81 (2H, m), 7.61-7.51 (5H, m), 6.62-6.58 (2H, m), 6.15 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[C:19][CH3:20])[N:13]=[CH:12][N:11]=1)=[O:9].[CH3:21][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([C:8]([OH:9])([CH3:21])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:11]=[CH:12][N:13]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1cc(C(=O)c2ccccc2F)ncn1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C)(O)c2ccccc2F)ncn1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In 3.7 ml of tetrahydrofuran was dissolved 0.4 g of 6-(2-butynyloxy)pyrimidin-4-yl 2-fluorophenyl ketone, to which 3.6 ml (1.14 mol/l diethyl ether solution) of methyl lithium was added dropwise at −78° C. After stirring at −78° C. for 3 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.34 g of 4-(2-butynyloxy)-6-(α-hydroxy-α-methyl-2-fluorobenzyl)pyrimidine (the present compound (157)).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCNCc1ccc(Cl)cc1
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
N-(4-chlorobenzyl)trimethylenediamine (8.45 g) and 1-nitro-2,2-bis(methylthio)ethylene (6.60 g) were heated under reflux in 100 ml of ethanol for 16 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with a small amount of ethanol to give 1-(4-chlorobenzyl)-2-(nitromethylene)tetrahydropyrimidine (9.8 g) represented by the following formula. Melting point: 172°-174° C. ##STR10##
Reaction SMILES: [C:1]([C:10]1[CH:15]=[C:14]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].[Na].Cl[CH2:30][C:31]([OH:33])=[O:32].Cl>O.C1(C)C=CC=CC=1.CS(C)=O>[C:1]([C:10]1[CH:15]=[C:14]([C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[O:25][CH2:30][C:31]([OH:33])=[O:32])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(OCC(=O)O)c(C(C)(C)c2ccccc2)c1

Procedure:
In a 500 ml three neck flask equipped with mechanical stirrer, nitrogen inlet and Dean-Stark trap/condenser was added 40.0 grams (0.121 moles) 2,4-dicumylphenol, 150 ml dimethylsulfoxide (DMSO), 0.121 moles of sodium hydroxide (9.68 grams of 50% aqueous NaOH), and 100 ml toluene. The mixture is stirred and heated to azeotropically remove water. After water removal is complete the temperature is lowered to about 90° C. and 14.10 grams (0.121 moles) of the sodium salt of chloroacetic acid is added. The reaction is stirred at 90° C. for 16 hours. The product is isolated by cooling and pouring the reaction mixture into 500 ml of a 2% aqueous hydrochloric acid. After filtration, washing with water and drying a white powder was obtained which exhibited a melting point of 114° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:12]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[OH-].[Na+]>O.C(O)C>[CH2:1]([C:3]1[C:4]([CH:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CSC(CC)c1cc2c(cc1CC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(cc1C(CC)SCC(=O)O)OCO2
Yield: 77 %

Procedure:
4.0 g of ethyl [{1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propyl}thio]acetate and 2.6 g of sodium hydroxide were dissolved in a mixture of 20 ml of water and 20 ml of ethanol. The solution was heated under reflux for 2 h. Ethanol was distilled off and the residue was washed with ether. The aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified according to silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.8 g of the intended compound in the form of white crystals.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24]2[CH:28]=[CH:27][NH:26][C:25]=2C(OCC)=O)[CH2:18][CH2:17]1)=O)(C)(C)C.[Na].Cl>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][N:23]2[C:24]3[CH:28]=[CH:27][NH:26][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])[CH2:20][CH2:21]1
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(CC2CCNCC2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.058 g, 0.44 mmol) was added to a stirred solution of 4-[(2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)-methyl]piperidine-1-carboxylic acid tert-butyl ester (0.156 g, 0.44 mmol) in CH2Cl2(2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue was taken up in ethanol (1 mL) containing sodium (0.015 g, 0.66 mmol). The resulting mixture was heated in a microwave reactor at 120° C. for 10 minutes. 6M HCl (0.5 mL) was added and the reaction mixture was heated again in the microwave at 100° C. for 3 minutes. The pH was adjusted to neutral pH with 2M HCl and the solution was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (0.038 g, 14%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=O)=[CH:5]2.[N+]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)N[C:23]([C:28]([O:30]CC)=O)=[CH:22]2)([O-])=O>>[C:4]([C:27]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH2:11][OH:13])=[CH:5]3)=[O:30])=[CH:25][CH:26]=1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]c(CO)cc3c2)cc1

Procedure:
Ethyl 5-aminoindole-2-carboxylate. Analogous to the procedure used to prepare Example 3, step (a), ethyl 5-nitroindole-2-carboxylate (2.3 g, 9.9 mmol, Acros) provided the title product. MS (ESI, pos. ion) m/z: 205 (M+1).