Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](OC2C(O)=C(C3C=CC=CC=3)S(=O)(=O)C=2C2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1C=CC=CC=1Cl>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)OC1=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1O
Solvent: Clc1ccccc1Cl
Product: O=C=Nc1ccccc1

Procedure:
2.1 g of 3-(phenylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 50 ml of o-dichlorobenzene are heated at 150° C. for 2 hours. The phenyl isocyanate formed is then distilled off under reduced pressure produced by a water pump.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: C#CC(C)O
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(O)C#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12

Procedure:
15.98 g (46.6 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 5 5.48 ml (69.9 mmol) of (±)-3-butyn-2-ol were heated for 6 h at 90-5° C. in 47 ml of toluene with 47 ml of triethylamine, 163.5 mg (233 μmol) of bis-triphenylphosphine-palladium(II)-dichloride and 8.9 mg (46.6 23 μmol) of copper(I) iodide. The reaction was filtered and the solid washed with toluene. The filtrate was evaporated in vacuo to dryness, the residue taken up in 150 ml of dichloromethane, extracted twice with 50 ml of 1 N HCl, dried with sodium sulfate, and filtered through 120 g of silica gel in a column. The title compound (11.11 g) was recovered as an off-white solid. A recrystallized sample from di-isopropyl ether had mp 129-31° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:18](=[O:19])[N:5]2[C:6]([C:15]([O-:17])=[O:16])=[C:7]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:8][S:9][C@H:4]12>[N+](C)([O-])=O>[NH2:2][C@H:3]1[C:18](=[O:19])[N:5]2[C:6]([C:15]([OH:17])=[O:16])=[C:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:8][S:9][C@H:4]12
Reactant: N[C@H]1C(=O)N2C(C(=O)[O-])=C(C3CCCC3)CS[C@H]12
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: N[C@H]1C(=O)N2C(C(=O)O)=C(C3CCCC3)CS[C@H]12
Temperature: 0 °C

Procedure:
A current of gaseous hydrogen chloride was passed through a mixture of 585 mg of the product of Step G and 12 ml of nitromethane cooled to 0° C for 15 minutes and the mixture was evaporated to dryness under reduced pressure. The residue was taken up in ether and the crystals were recovered by vacuum filtration. The residue was dissolved in 2 ml of ethanol and 1 ml of water and pyridine was added to a pH of 4. The mixture was agitated until crystallization appeared and the crystals were recovered by vacuum filtration, were rinsed with ethanol and dried to obtain 249 mg of DL cis 7-amino-3-cyclopentyl-3-cepheme-4-carboxylic acid melting at 250° C. The product occurred as colorless crystals slightly soluble in ethanol and insoluble in water and ether.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][NH:26][CH3:27])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28].[C:29]([Si:33]([CH3:39])([CH3:38])[O:34][CH2:35][CH:36]=O)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:29]([Si:33]([CH3:38])([CH3:39])[O:34][CH2:35][CH2:36][N:26]([CH3:27])[CH2:25][CH2:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([N:13]1[CH2:12][C:7]2=[C:8]3[N:4]([N:5]=[C:6]2[CH2:14]1)[C:3]([CH3:28])=[C:2]([Cl:1])[C:10]([CH3:11])=[N:9]3)=[O:16])([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CNCCOc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)CCO[Si](C)(C)C(C)(C)C)C3
Yield: 32.2 %

Procedure:
A mixture of Example 144 (100 mg; 0.25 mmol; 1 eq.), (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (87 mg; 0.50 mmol; 2 eq.) and sodium triacetoxyborohydride (58 mg; 0.28 mmol; 1.1 eq.) in DCE (10 mL) was stirred at 70° C. for 1 hour. The solution was washed with 0.1M NaOH (2×), dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 10% MeOH in EA) afforded the title compound (45 mg, 32%) as a yellow oil. HPLC (max plot) 95.0%, Rt 4.26 min. UPLC/MS: (MS+) 558.3 ([M+H]+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:12][C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[NH:18][C:17]2[CH:27]=[CH:28][CH:29]=[N:30][C:16]1=2)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([CH2:12][C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])[NH:18][C:17]3[CH:27]=[CH:28][CH:29]=[N:30][C:16]2=3)=[O:14])[CH2:3][CH2:2]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCO)CC2)c2ccccc21

Procedure:
1-Piperazinepropanol (8 g) was added to a suspension of 11-(2-chloroacetyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one (15 g) and anhydrous sodium carbonate (15 g) in absolute ethanol (250 ml).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[Cl:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[Cl:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CCCCC(=O)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(CCl)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2.1 g. of magnesium and 20 mg. of mercuric chloride in 25 ml. of ether is added 0.8 ml. of propargyl bromide. After a few minutes of vigorous stirring, to this is added a mixture of 10.75 g. of 1-chloro-2-hexanone and 7.2 ml. of propargyl bromide in 25 ml. of ether, at such a rate that the reaction mixture is maintained at 25°-28° C. After addition, the mixture is stirred at room temperature one hour, cooled in an ice-water bath and 30 ml. of saturated ammonium chloride is added dropwise. The mixture is filtered through celite and washed with ether. The ether solution is concentrated to give 11.0 g. of a yellow liquid which is vacuum distilled to give 6.9 g. of product as a colorless liquid at b.p. 60°-61° C./-4 mm.; PMRδ 3.62 (ABq, CH2Cl), 2.53 (d, J=3, C≡C--CH2), 2.06 (t, j=3, HC≡C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[C:12]([N+]([O-])=O)[CH3:13].C(O)(=[O:19])C.S(=O)(O)[O-].[Na+]>CC(C)=O.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](=[O:19])[CH3:13]
Reactant: CC(=Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 104g of 5-chloro-3-(2-nitropropen-1-yl)indole, 115g of powdered iron and 6g of ferric chloride dissolved in 1250 ml of acetone is brought to reflux. Heating ceases as soon as reflux commences and a solution of 265 ml of acetic acid in 800 ml of water is added over 30 minutes. The reaction mixture is again brought to reflux and maintained thereat for 4 hours; 25.6g of sodium bisulphite are then added, the mixture cooled to 20°C and filtered. The residue is washed with acetone. The combined filtrate and washings are concentrated after filtering and redissolved in 105 ml of hydrochloric acid and 520 ml of water, extracted with ethyl acetate, washed and dried.
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31]Cl)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[I-].[Na+].C(#N)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: C1CCNCC1
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCN1CCCCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide (200 mg, 0.44 mmol) was added sodium iodide (66 mg, 0.44 mmol), acetonitrile (2 mL), and piperidine (0.1 mL, 1.3 mmol). The reaction mixture was heated to 50° C. and stirred for 24 hrs. Water (15 mL) was added to the reaction and extracted with three 20 mL portions of ethyl acetate. The combined organics were washed with saturated NaHCO3 (20 mL), dried on sodium sulfate, and concentrated. Purification by column chromatography (5:95 methanol:chloroform) gave 1-(3-piperidin-1-yl-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a white solid (150 mg, 68%). MS: 506 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(N(CC)CC)C.[CH:64]1([C:67](Cl)=[O:68])[CH2:66][CH2:65]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:67]([CH:64]3[CH2:66][CH2:65]3)=[O:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)C4CC4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (from Example 3) in dry methylene chloride (0.4 ml) was cooled to 0° C. To this solution was added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) to give 20 mg of the title compound. (Mass, 1H and 13C data were consistent with the proposed structure).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.C(C([O:33][CH2:34][C:35]([NH2:37])=[S:36])=O)(C)(C)C>CCO.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:37]=[C:35]([CH2:34][OH:33])[S:36][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(CO)n3)c1)=N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 416.6 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.22 g) and 2-(tert.-butylcarbonyl-oxy)thioacetamide (0.11 g) in EtOH (3 mL) was heated at 80° C. for 0.5 h. The solution was diluted with AcOEt, washed with sat. NaHCO3 solution and with brine, dried and evaporated. The residue was stirred in a mixture of MeOH (8 mL) and 1.5N KOH (8 mL) at 20° C. for 20 min. H2O (30 ml) was added and the precipitated product collected by filtration to give the title compound (0.9 g) as yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1>O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)OC)cn2)CC1
Yield: 94.7 %

Procedure:
To 100 g of 1-ethylpiperazine warmed to 80° C. was added at 80-100° C. with stirring 50 g of methyl 6-chloropyridine-3-carboxylate. To the reaction solution was added 0.5 1 of water and the mixture was stirred. The crystal thus precipitated out was recovered by filtration, dried under reduced pressure to afford 68.8 g of the title compound as a crystal.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([C@H:9](O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](CNC)[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH2:26]([N:28](CC)[CH2:29]C)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][C:11]=1[CH2:26][NH:28][CH3:29])[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(-c2ccccc2)cc1CNC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
19.6 g of the crude product methyl (2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate are dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol) of triethylamine are added. The reaction medium is stirred at room temperature for 48 hours and then extracted with ethyl acetate. The organic phase is decanted off, washed with a sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expected product are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][CH:10]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:9][CH:10]([P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(NCc1ccccn1)P(=O)(OCC)OCC
Reaction time: 12 h

Procedure:
A mixture of 2-pyridinecarboxaldehyde (1.23 g, 11.5 mmol), tetraethyl aminomethylenediphosphonate (3.0 g, 9.9 mmol) and a catalytic amount of p-toluenesulfonic acid dissolved in 10 ml toluene was heated to reflux for 7 h. Toluene was evaporated and the residue dissolved in ethanol was submitted for 12 h to catalytic hydrogenation with 10% palladium on charcoal. Ethanol was evaporated and the title compound was obtained as an oil (1.30 g, 33%) by column chromatography (silica gel, CH2Cl2/MeOH 9/1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[CH2:16]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])[CH3:17]>O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCCOc1cc(C=O)ccc1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(O)c(OCCCOC)c1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
4-hydroxy-3-(3-methoxypropoxy)benzaldehyde (15 g, 71.3 mmol) was dissolved in tetrahydrofuran (142 mL) and (ethoxycarbonylmethylene)triphenylphosphorane (24.8 g, 71.3 mmol) was added at room temperature portionwise. The mixture was then stirred overnight. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2) to yield 16 g (80%) of the desired product as a yellow oil of a mixture of E and Z isomers.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(O)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(O)c2F)CC1

Procedure:
Preparation according to Example 2: 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenol (1.1 g, 4.97 mmol), methanol (20 ml), palladium on carbon (0.26 g) and hydrochloric acid (0.2 ml, conc). Yield: 1.1 g. MS m/z (relative intensity, 70 eV) 223 (M+, 32), 222 (17), 209 (13), 208 (bp) 84 (20).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:8][C:7]2([C:12]2[S:13][C:14]([S:17](=[O:24])(=[O:23])/[N:18]=[CH:19]\[N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:9]([C:7]1([C:12]2[S:13][C:14]([S:17](=[O:23])(=[O:24])/[N:18]=[CH:19]\[N:20]([CH3:21])[CH3:22])=[CH:15][CH:16]=2)[CH2:8][CH:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:11]
Reactant: CN(C)/C=N\S(=O)(=O)c1ccc(C2(C(=O)O)CC2C2CCCC2)s1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)/C=N\S(=O)(=O)c1ccc(C2(C(=O)Nc3nccs3)CC2C2CCCC2)s1
Yield: 50.5 %

Procedure:
According to method 16h was used (±)-(Z)-2-cyclopentyl-1-[5-(dimethylaminomethylene-sulfamoyl)-thiophen-2-yl]-cyclopropanecarboxylic acid (65 mg, max. 0.344 mmol), 2-amino-thiazole (19 mg, 0.188 mmol), TBTU (60 mg, 0.188 mmol) and triethylamine (57 μL, 0.402 mmol) to give 43 mg of purified product. MS (m/e): 453.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:10](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 mL) and 1,1′-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92% yield). 1H-NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.00 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H). MS (ES+) m/z 213.1 (M+1).
Reaction SMILES: [C:1]1([O:7][CH:8]([CH2:10][O:11][CH:12]([CH2:14][OH:15])C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCCC>S(=O)(=O)(O)O.O>[C:16]([O:15][CH2:14][CH2:12][O:11][CH2:10][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(CO)OCC(C)Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCCC
Product: O=C(OCCOCCOc1ccccc1)c1ccccc1
Temperature: 115 °C

Procedure:
In a 2-L one-neck flask equipped with a magnetic stirrer, a heating mantle, and a Dean-Stark trap connected to a nitrogen purged condenser were placed 517.5 g dipropylene glycol phenyl ether technical grade containing a total hydroxyl content of 3.0 moles, 363.3 g (2.97 mole) benzoic acid, 300 ml heptane, and 20 drops concentrated sulfuric acid. The flask was heated to 115° C. to establish a constant heptane reflux through the trap where the water of esterification was collected. The reaction was allowed to continue for a total of 48 hours, at which point the theoretical amount of water was collected. The reaction mixture was cooled to 25° C. and then filtered through a small bed of activated basic alumina to neutralize the catalyst. The filtrate was placed in a boiling flask and the heptane removed at low pressure in a Büchi rotary evaporator. The residue was flash distilled under vacuum to isolate the diethylene glycol phenyl ether benzoate boiling at 165° C. @ 0.1 mmHg. The boiling point at reduced pressure was corrected to the normal boiling by means of a computer program that fits vapor pressure data to an Antoine equation of the form log P=A−B/(T+C). The normal boiling point was calculated at approximately 440° C. A sample of the product was then tested as specified by EPA Method 24 and found to contain only 0.7 percent volatiles.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18](O)[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=2)=[N:6]1.P(Cl)(Cl)([Cl:31])=O.CCN(C1C=CC=CC=1)CC>>[Cl:31][C:18]1[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl

Procedure:
6.54 g (17.2 mmol) of methyl 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxypyrimidine-5-carboxylate (example 105A) were taken up in 26.5 ml (284 mmol) of phosphoryl chloride. Then 5.95 g (34.5 mmol) of diethylaniline were added and the mixture was reacted at 90° C. for 60 min. After cooling, the precipitate formed was filtered off and washed with water. Then it was dried under high vacuum. Thus, 6.11 g (78% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.[Br:18][C:19](Br)=[N:20][OH:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:21][N:20]=[C:19]([Br:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CC(Br)=NO1

Procedure:
To a solution of N-tert-butoxycarbonyl allyl amine, 20 gm, in 700 ml of ethyl acetate and containing 65 gm of NaHCO3 and 50 ml of water, was added portion-wise 80 gm of dibromoformaldoxime at room temperature with vigorous stirring. After completion of the reaction, the organic portion was washed with water (2×100 ml), 100 ml each of 5% NaHCO3, brine and dried over anh. MgSO4 and concentrated to give an oil. Purification by chromatography on silica gel gave the desired product as an oil which solidified on standing. IR(KBr): 3322, 2988, 1680, 1529 cm-1. 1H NMR (80 MHz, CDCl3): delta 1.45 (s, 9H, t-butyl), 2.8-3.5 (m, 4H, CH2CHO, CH2N), 4.6-5.1 (broad s, superimposed on a multiplet, 2H, NH, CHO).