Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:32]([Cl:31])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Clc1cccc(Cl)c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2c(Cl)cccc2Cl)c1=O
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,6-dichlorobenzyl bromide (440 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (150 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (br. s., 1 H), 9.98 (br. s., 1 H), 7.43 (dd, 2 H), 7.30 (dd, 1 H), 5.26 (s, 2 H), 4.60 (t, J=12.00 Hz, 1 H), 2.14-2.31 (m, 2 H), 1.77 (d, J=12.88 Hz, 2H), 1.47-1.66 (m, 3 H), 1.27 (q, 2 H), 1.10 (q, 1 H)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15]>>[O:16]=[C:14]([CH3:15])[CH2:13][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: CC(=O)CCl
Product: CC(=O)CSc1ccc(CC(=O)O)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 4-mercaptophenylacetic acid and chloroacetone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]([C:8]#[N:9])=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCOCC1

Procedure:
A mixture of tetrahydropyran-4-one (12 g), ethyl cyanoacetate (13.6 g), ammonium acetate (1.2 g), glacial acetic acid (2.4 ml) and toluene (15 ml) is stirred at reflux for 16 hours. The mixture is diluted with toluene and the organic layer is separated, washed with water, then brine, and dried over magnesium sulfate. It is concentrated at reduced pressure to an oil which solidifies. It is further purified by flash chromatography through silica gel with methylene chloride as eluent. The desired fractions are combined and concentrated to dryness at reduced pressure to afford 4-(alpha-ethoxycarbonyl-cyanomethylene)-tetrahydropyran.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(F)cc3F)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(F)cc2F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 65-4 (730 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (480 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([Br:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([Br:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]=1[CH2:25][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Br)n(-c2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(-c2ccccc2)c(Br)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 5-bromo-2-bromomethyl-1-(4-fluoro-phenyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 625 (M+Na+).
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[C:5](=[C:8]1[CH2:12][CH2:11][C:10]2([CH:17]([CH3:18])[CH2:16][C:15]([O:19]C(C)C)=[CH:14][C:13]2=O)[CH2:9]1)([CH3:7])[CH3:6].Cl>CCOCC>[C:5](=[C:8]1[CH2:12][CH2:11][C:10]2([CH:17]([CH3:18])[CH2:16][C:15](=[O:19])[CH:14]=[C:13]2[CH2:2][CH3:3])[CH2:9]1)([CH3:7])[CH3:6]
Reactant: CCBr
Reactant: CC(C)=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCC1=CC(=O)CC(C)C12CCC(=C(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A Grignard solution was prepared from magnesium (1.17 g, 0.048 g-atom) and ethyl bromide (5.2 g, 0.048 mol) in anhydrous ether (50 mL) under nitrogen. 2-Isopropylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one (4 g, 0.015 mol), prepared according to Example 2, in anhydrous ether (20 mL) was added dropwise at room temperature and the mixture then heated at reflux for 4 hours. The solution was cautiously added to 2 N hydrochloric acid (200 mL) and stirred for 1 hour at room temperature. The mixture was extracted with ether and the ether extracts washed with saturated sodium bicarbonate, brine, and dried (Na2SO4). Kugelrohr distillation afforded
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([O:8][CH2:9][C@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Yield: 89.1 %

Procedure:
A procedure similar to that described in Preparation 9 was repeated, except that 16.4 g of benzyl N-[2-t-butyldimethylsilyloxy-1(R)-methylethyl]carbamate (prepared as described in Preparation 24), 3.5 g of 10% w/w palladium-on-carbon and 100 ml of ethanol were used, to give 8.55 g of the title compound having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-10.1° (methanol, c=1.155).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1)=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.C(O)(=O)C>>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[CH:28][CH:29]=1)=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CC(=O)O
Product: CCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of CbzPheNle-pNA (prepared in 2 (1); 51 mg) in 30%HBr-acetic acid was stirred for 30 minutes. The solvent was distilled off under reduced pressure. The reaction mixture was dissolved into anhydrous DMF (2 ml). N(Et)3 (0.013 ml) was added dropwise thereto to obtain PheNle-pNA.Et4NHBr.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C[N:19](C)[C:20]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)=[CH2:21].[OH-].[NH4+]>C(O)C>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:19]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:21]=1
Reactant: C=C(c1ccco1)N(C)C
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccco2)nc1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of 147 g of diethyl ethoxymethyleneoxalacetate in 600 mL of absolute ethanol is stirred at 5° C. while a solution of 68.8 g of 1-dimethylamino-1-(2-furyl)ethylene in 400 mL of absolute ethanol is added dropwise over 1 hour. After stirring for an additional 2 hours, the reaction mixture is treated with 250 mL of concentrated aqueous ammonium hydroxide. The resulting mixture is stirred at ambient temperature overnight and then concentrated in vacuo. Chromatography of the residue on silica gel using chloroform as eluant affords the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@H:4]([C@H:7]([O:9][C:10]2[C:11]3[N:12]([N:35]=[CH:36][CH:37]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:15]=2)[CH3:8])[CH2:3]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>>[N:22]1([C:19]2[CH:18]=[CH:17][C:16]([C:14]3[N:15]=[C:10]([O:9][C@@H:7]([C@H:4]4[CH2:5][NH:6][C:2](=[O:1])[CH2:3]4)[CH3:8])[C:11]4[N:12]([N:35]=[CH:36][CH:37]=4)[CH:13]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1.[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl 4-(4-(4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate 5.43 (51 mg, 0.1 mmol) was dissolved in TFA (4 mL, 52.23 mmol) and mixture was stirred at room temperature. After 4 hours, reaction mixture was concentrated and azeotroped with toluene to yield (R)-4-((R)-1-((6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.44 as a trifluroacetic acid salt (41 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Br)[CH:9]=1)(=[O:3])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:35]2[CH2:34][CH2:33][C:32]([C:29]3[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=3)([OH:38])[CH2:37][CH2:36]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1cc(NC(=O)CBr)nc(-c2ccccc2)n1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(O)(c3ccc(Br)cc3)CC2)nc(-c2ccccc2)n1
Reaction time: 5 h

Procedure:
N-(6-{[2-(Acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-bromoacetamide (23) (30 μL of a 0.167M solution) was dispensed to a well of a 96 well microtitre plate, followed by [4-(4-bromophenyl)-4-hydroxypiperidine] (30w1 of a 0.167M solution) and N,N-diisopropylethylamine (30 μl of a 0.167M solution). The plate was placed in an oven at 63° C. for 5 hrs. The solvent was removed in vacuo yielding the title compound. LCMS (Method A) RT=2.43 min, m/z (ES+) 569 (MH)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:13]=[O:14].[N-]=C=O.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[C:30]3[CH:36]=[CH:35][NH:34][C:31]3=[N:32][CH:33]=2)[CH:23]=1>>[CH2:15]([NH:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([C:36]2[C:30]3[C:31](=[N:32][CH:33]=[C:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:29]=3)[NH:34][CH:35]=2)=[O:7])[C:3]=1[Cl:11])=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: CCCCN=C=O
Reactant: Nc1cccc(C(=O)O)c1Cl
Agent: [N-]=C=O
Product: CCCCNC(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1Cl

Procedure:
Additional compounds were prepared following the protocol of Scheme 57, replacing 3-amino-2-chlorobenzoic acid 586 with an appropriate carboxylic acid and optionally replacing 1-isocyanatobutane with an appropriate isocyanate in Step 1 and optionally replacing 5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine 89 with an appropriate substituted 7-azaindole (see Example 17) in Step 2. The following compounds were made following this procedure:
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[C:8]([CH3:29])=[C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=2)=[O:17])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2>N1C=CC=CC=1>[CH3:28][O:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[C:16]([C:9]1[N:10]2[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]2)=[C:7]([NH:6][S:1]([CH3:4])(=[O:3])=[O:2])[C:8]=1[CH3:29])=[O:17]
Reactant: COc1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(C)c(NS(C)(=O)=O)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
0.292 ml (3.78 mmol) of mesyl chloride is added to a solution of 350 mg (1.08 mmol) of the compound of Example 29 in 3 ml of pyridine, and the medium is stirred at room temperature for 4 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in 1 N hydrochloric acid and extracted with dichloromethane. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is crystallized from ethanol. 327 mg of yellow crystals are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nc(N)nc(-c2ccc(F)cc2)c1C#N
Temperature: 25 °C
Yield: 54 %

Procedure:
To a stirred suspension of 0.50 g (2,49 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml toluene under argon at room temperature were added 384 mg (2.74 mmol)p-fluorobenzeneboronic acid, 288 mg (0.25 mmol) tetrakis(triphenyl-phosphine)palladium(O) and 638 mg (4.98 mmol) anhydrous potassium carbonate. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed trituration in ether/hexane afforded 350 mg (54%) 2-amino-4-(4-fluoro-phenyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. EI-MS m/e (%): 260 (M+, 37), 259 ([M—H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
To a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1 g, 4.29 mmol) in dichloromethane (50 ml) was added phenyl boronic acid (1.05 g, 8.6 mmol), pyridine (680 mg, 8.6 mmol) and copper(II) acetate (1.18 g, 6.5 mmol). The reaction mixture was stirred for 16 h at room temperature. Then, the reaction mixture was filtered through celite, concentrated and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 435 mg (33%) of 5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.38 ppm (dd, 2H, Haro); 7.35-7.26 ppm (m, 5H, Haro); 7.19 ppm (s, 1H, Haro); 7.15 ppm (dd, 2H, Haro); 7.02 ppm (ddt, 1H, Haro); 3.82 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:11]=[C:10]2[NH:35]C(=O)C(F)(F)F)=[O:6].C(O)(C)C.O1CCCC1>C(N(CC)CC)C>[NH2:35][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([C:4]3[CH:42]=[C:43]([F:45])[CH:44]=[C:2]([F:1])[CH:3]=3)=[O:6])[CH:8]=2)[N:12]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc2c(c1)c(NC(=O)C(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Yield: 98.9 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (6.12 g, 10 mmol) was heated at 100° C. in a mixture isopropanol/tetrahydrofuran 8:2 (100 mL) and triethylamine (12.2 mL) for 48 hours. The volatiles were partially evaporated and the resulting mixture cooled and filtered. The solid was washed with diethyl ether. After drying under vacuum at 70° C. the title compound was obtained as a white solid (5.1 g, 99% yield).
Reaction SMILES: [C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[N+]([CH:18]([CH3:20])[CH3:19])([O-])=O.C[O-].[Na+]>CO>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]1([CH3:20])[CH3:19])#[N:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)/C(C#N)=C/c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A mixture of 511 mg (2.73 mmoles) of cyanoester 2 (produced in accordance with Example II), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 2.64 mmoles of sodium methoxide (prepared from 61 mg of sodium and methyl alcohol) in 4.0 mL of absolute methanol was stirred at room temperature for 10 minutes and subsequently heated at reflux, protected from atmospheric moisture, for 71/2 hours. The product was isolated as described in the procedure of Example VIII, affording 483 mg (77% yield) of cyclopropanoid cyanoester 11, stereochemically homogeneous as shown by NMR analysis: δ3.83 (singlet, CO2CH3) and δ3.30 (singlet, cyclopropyl H).
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:4]([O:6]CC)=O)#[N:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCC>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[NH:10][CH:9]=[C:3]([C:1]#[N:2])[C:4]2=[O:6]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(OC)c(OC)c1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC

Procedure:
A mixture of 40 g of ethyl 2-cyano-3-(3,4-dimethoxyphenylamino)acrylate and 1.2 L of Dowtherm® A was refluxed for 10 h, cooled, and diluted with hexane. The resulting solid was filtered, washed with hexane followed by dichloromethane, and dried; mp 330-350° C. (dec).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=[O:8])=CC=1.[CH2:12]([C:14]1S[C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[N+:18]=1[CH2:19][CH3:20])C.[CH2:25]([OH:27])C>>[CH2:14]([N:18]([CH2:19][CH3:20])[C:17]1[CH:21]=[C:22]([OH:8])[C:23](=[CH:24][CH:16]=1)[CH:25]=[O:27])[CH3:12]
Reactant: CCO
Reactant: CCc1sc2ccccc2[n+]1CC
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCN(CC)c1ccc(C=O)c(O)c1

Procedure:
In 25 ml of ethanol, 1.82 g of the compound obtained in (1) and 1.06 g of 4-diethylaminosalicylaldehyde were dissolved, followed by heating to 100° C. To the resulting solution, 0.7 ml of piperidine was added and the mixture was heated under reflux for 2 hours. Then, the solution was ice-cooled. The colorless crystals so precipitated were collected by filtration, washed with ethanol and dried under vacuum for 2 days, whereby 0.83 g of the decolorizable compound I-1 was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CC(C)(C)C(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2,2-dimethyl-propionamide is prepared as described in Example 50 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and pivaloyl chloride (Fluka, Buchs, Switzerland). Analytical HPLC: tR=7.25 min (Grad 2); ES-MS: m/eo=484.0.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[N:12]=[N:13][C:14]([Cl:18])=[CH:15][C:16]=1Cl)=[O:10])[CH3:7]>C(OCC)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[N:12]=[N:13][C:14]([Cl:18])=[CH:15][C:16]=1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCNCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(Cl)cc1N(CC)CC
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Diethylamine (86 mg, 1.3 equivalents, 1.2 mmol) is added to a solution of 4,6-dichloro-pyridazine-3-carboxylic acid ethyl ester (0.2 g, 0.91 mmol) in ethyl acetate (10 mL) at room temperature. After overnight stirring, the reaction is quenched with water (6 mL). The organic layer is separated and the aqueous layer extracted (2×15 mL) with ethyl acetate. The combined organic layers are dried and solvent removed to give 230 mg of 6-chloro-4-diethylamino-pyridazine-3-carboxylic acid ethyl ester as a yellowish oil.