Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([CH2:19]Cl)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:16][C:15]([F:18])([F:17])[C:14]([OH:31])=[O:13].[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([CH2:19][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)COCCn1nc(CCl)c2nc(Cl)nc(Nc3ccncn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)COCCn1nc(CN2CCOCC2)c2nc(Cl)nc(Nc3ccncn3)c21
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 170.4 %

Procedure:
5-Chloro-3-(chloromethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine (300 mg, 0.7 mmol), morpholine (185 mg, 2.1 mmol) and N,N-diisopropylethylamine (270 mg, 2.1 mmol) were mixed in methyl sulfoxide (2 ml) in a reaction vial. The reaction mixture was stirred 18 hours at room temperature and then purified on reverse phase HPLC and lyophilized to give 5-chloro-3-(morpholin-4-ylmethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate (350 mg).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]Cl>CO>[I:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Reactant: ClI
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 2.75 h
Yield: 66 %

Procedure:
Dideoxyuridine (2.122 g, 10.0 mmol) was dissolved in 30 mL of warm methanol and, after cooling to 25°, iodine monochloride (4.06 g, 25 mmol, 2.5 eq. Fisher) in methanol (20 mL) was added over 5 minutes. The dark purple reaction mixture was heated in a 50° bath under nitrogen for 20 minutes and then immediately cooled in an ice-water bath. After standing without stirring for 165 minutes, the resulting precipitate was collected by filtration and washed with cold methanol (2×10 mL). Vacuum-drying overnight afforded 2.232 g (66%) of iodide 21 as off-white microcrystals. This material was used without further purification in the next reaction, but other preparations were purified by chromatography or recrystallization from boiling methanol (30 mL/g) to give white needles (mp d 160°-164°). NMR indicated that the crude precipitate was homogeneous, but also that the 5'-hydroxy proton was very broad due to exchange catalyzed by trace impurities. Chromatographed or recrystallized materials afforded spectra in which this proton was, as usual, a sharp triplet.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]>C1COCC1>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N-Ethyldiisopropylamine (132 mg, 1.02 mmol) and pyrrolidine (145 mg, 2.04 mmol) were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methanesulphonyloxymethyl-phenyl)-acetate (221 mg, 0.511 mmol) obtained in Example 234.3 in THF (2 ml) and the mixture was stirred for 1 h. at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 99:1). There were obtained 153 mg (73%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a yellowish foam; MS: 408 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:47]=[CH:46][C:21]([O:22][C:23]3[CH:24]=[C:25]([C:29]4[NH:33][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[N:31][CH:30]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[N:17]=1)=O)(C)(C)C.[Cl:48]CCl>Cl>[ClH:48].[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]([C:18]2[CH:47]=[CH:46][C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[N:33]=[C:32]([CH:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)[NH:31][CH:30]=4)[CH:24]=3)=[CH:20][CH:19]=2)=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Oc3cccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)c3)cc2)c[nH]1
Reactant: ClCCl
Agent: Cl
Product: c1cc(Oc2ccc(-c3cnc(C4CCCN4)[nH]3)cc2)cc(-c2c[nH]c(C3CCCN3)n2)c1

Procedure:
First, to a solution of (S)-tert-butyl 2-(5-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate in dichloromethane, excess HCl (1M in isopropanol) was added dropwise. The precipitated solid was filtered off and dried in the vacuum oven to afford 2-(pyrrolidin-2-yl)-5-(4-(3-(2-(pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazole hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29]([C:31]5([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:31]1([C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:21]=3)[NH:26][CH:27]=2)=[O:30])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A solution of 4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (134 mg, 0.266 mmol) in DCM (10 ml) was treated with TFA (1.0 ml, 13.4 mmol) and allowed to stir for 16 hours. The reaction mixture was concentrated to dryness, and the resulting residue was partitioned between sat. NaHCO3 and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow solid. The yellow solid was filtered through a Buchner funnel and washed with 1:2 Et2O/Hex to provide 66 mg (61%) of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a pale yellow solid. M+H=404.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:15]([OH:17])=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[O-]S([O-])(=O)=O.[Ca+2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[C:35](OCC)(=O)C>CO>[CH2:28]([O:27][C:25]([NH:5][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:15]([O:17][CH3:35])=[O:16])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCOC(C)=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
Thionyl chloride (4.6 mL, 63.33 mmol, 2 eq) was added dropwise to dry MeOH (65 mL) at 0° C. and stirred for 5 min. Tyrosine (5.70 g, 31.5 mmol, 1 eq) was then added and the reaction vessel was fitted with a drying tube filled with drierite and slowly allowed to come to room temperature over 21 h. The solvent was then evaporated and crude product dried over high vacuum for 8 h. The crude product was then dissolved in a 1:1 mixture of acetone (63 mL) and a 7% solution of Na2CO3 in water (63 mL). Benzyl chloroformate (4.7 mL, 34.7 mmol, 1.2 eq) was then added dropwise and the reaction was stirred for 3 h at room temperature. Ethyl acetate was then added (300 mL), and the organic layer was washed with water (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was evaporated to give 10 as a viscous yellow oil (10.37 g). The product was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH:3]=[N:4][CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccncc2)CC1
Yield: 17.9 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyridin-4-yl boronic acid (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (5 mg, 18%), LC-MS (ESI, 3.5 min) Rt 1.10 min, m/z 317 (100%, [M+H]+); m/z (ESI) C16H18ClN4O requires 317.1164 found [M+H]+ 317.1160
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=[S:15])[CH2:3][CH2:2]1.[CH3:17][I:18]>CO>[IH:18].[CH3:17][S:15][C:14](=[NH:16])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CI
Reactant: NC(=S)Nc1ccccc1N1CCOCC1
Solvent: CO
Product: CSC(=N)Nc1ccccc1N1CCOCC1
Product: I

Procedure:
A solution of 1-(2-morpholinophenyl)thiourea (7.2 g) in dry methanol (30 ml) was heated at reflux with methyliodide (4.2 g) for 2 hours. The solvent was removed under reduced pressure and dry ether (15 ml) was added and on scratching gave 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (m.p. 151°-152° C.).
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>COC(C)(C)C>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: O=C1CCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [NH2-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Yield: 89.2 %

Procedure:
In 30 ml of t-butyl methyl ether was suspended 897 mg of sodium amide in a nitrogen stream, and 2.13 g of 2-pyrrolidinone was slowly added thereto dropwise, followed by refluxing for 2 hours. After allowing to cool, 1.97 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by refluxing for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The thus formed crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 2.19 g (89%) of the titled compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12](Cl)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1Cl)[CH:2]([CH3:4])[CH3:3].[CH:17]1([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12]([N:23]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1[N:32]([CH:33]1[CH2:34][CH2:26][CH2:25][CH2:24][CH2:29]1)[CH:35]1[CH2:36][CH2:19][CH2:18][CH2:17][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC(C)CN1P(Cl)OCC12COP(Cl)OC2
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CN1P(N(C2CCCCC2)C2CCCCC2)OCC12COP(N(C1CCCCC1)C1CCCCC1)OC2

Procedure:
The procedure of Example 10 is repeated using 1-isobutyl-2,8-dichloro-3,7,9-trioxa-1-aza-2,8-diphosphaspiro[4.5]decane, dicyclohexylamine and triethylamine in toluene to afford the desired product.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([CH:34]([CH3:36])[CH3:35])[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([CH:34]([CH3:36])[CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[O:4])[CH3:2]
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)C(=NO)C(C)C
Solvent: ClCCl
Product: CCP(=O)(ON=C(C(=O)OC)C(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (700 mg, 1.65 mmol) and thionyl chloride (5 ml) is heated under reflux for 2 hours. The reaction mixture is concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride in methylene chloride (8 ml) is added methyl 2-hydroxyimino-3-methylbutanoate (320 mg, 2.48 mmol) in one portion. The mixture is stirred at RT for 3 hours. The reaction is then worked up in methylene chloride, washed, dried, evaporated to dryness and purified by prep. TLC to yield methyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]-3-methylbutanoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>O1CCCC1>[Br:9][C:5]1[CH:6]=[C:7]([Br:8])[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=1
Reactant: CC(=O)C(C)Br
Reactant: Nc1ncc(Br)cc1Br
Solvent: C1CCOC1
Product: Cc1nc2c(Br)cc(Br)cn2c1C
Yield: 73 %

Procedure:
A mixture of 31.8 g of 2-amino-3,5-dibromopyridine, 22 g of 3-bromo-2-butanone and 350 ml of tetrahydrofuran is heated to reflux for 9 days, and the precipitate formed is filtered off and dried in vacuo. It is then suspended in 1 l of water and adjusted to pH 8 using 6 molar aqueous sodium hydroxide solution. The precipitate formed here is filtered off and washed with water. 28 g of the title compound of melting point above 90° C. (sintering) are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[F:18][C:19]1[C:20]([C:25](Cl)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])/[CH:3]=[C:4](/[C:25](=[O:26])[C:20]1[C:19]([F:18])=[CH:24][CH:23]=[CH:22][N:21]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/N(C)C
Reactant: O=C(Cl)c1ncccc1F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1F
Temperature: 83 °C
Reaction time: 1.5 h
Yield: 16.6 %

Procedure:
To a light yellow solution of (E)-ethyl 3-(dimethylamino)acrylate (5.15 g, 36.0 mmol) in toluene (50 mL) was added triethylamine (3.64 g, 5.02 mL, 36.0 mmol) at room temperature. To this, a dark brown suspension of 3-fluoropicolinoyl chloride (30) (4.79 g, 30 mmol) in toluene (50 mL, heated to dissolve, but not dissolved completely) was added in one portion using a funnel. Then, the resulting dark brown solution was heated to 83° C. and stirred for 1.5 h at this temperature. During this period, it turned to a dark brown solution and TLC analysis indicated the presence of a new spot. Then, the heating was stopped and the dark brown mixture was diluted with ethyl acetate (200 mL) and the brown solution was washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude brown mixture which was purified using ISCO (120 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 20% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain the (Z)-ethyl 3-(dimethylamino)-2-(3-fluoropicolinoyl)acrylate (31) (1.33 g, 15% yield) as a dark brown paste.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:15](O)[CH3:16]>O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CNc1cccc([N+](=O)[O-])c1
Reactant: CCO
Solvent: O
Product: CCOC(=O)CNc1cccc([N+](=O)[O-])c1

Procedure:
2 g of 3-nitrophenylglycine are heated for 20 hours with stirring at a temperature in the region of 100° C. in 100 cm3 of absolute ethanol containing 20 cm3 of 6.5N hydrochloric ethanol. The suspension is filtered at a temperature in the region of 50° C.; the filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in water and then extracted with about 100 cm3 of ethyl acetate. The aqueous phase is made alkaline by addition of sodium carbonate until a pH in the region of 10 is obtained. The medium is extracted with ethyl acetate; the combined extracts are washed with aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure (5 kPa) at 40° C. 1 g of ethyl 3-nitrophenylglycinate is obtained in the form of a yellow oil. (Rf=0.38 in a 95/5 by volume mixture of dichloromethane/methanol, on a Merck 60F254R silica plate)
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:12][C:13]1[C:14]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])=[N:15][C:16]([Cl:20])=[N:17][C:18]=1[CH3:19]>CN(C)C=O>[ClH:20].[CH3:12][C:13]1[C:14]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])=[N:15][C:16]([NH:4][CH2:1][CH2:2][CH3:3])=[N:17][C:18]=1[CH3:19]
Reactant: CCCN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 87.8 %

Procedure:
After propylamine(0.43 ml, 5.22 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine (0.5 g, 1.74 mmol) in dimethylformamide, 530 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.O1CCOCC1.[OH-].[Na+].O>C(O)C>[CH2:15]([S:14][CH2:13][CH:5]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:4]([OH:22])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(CSCc1ccccc1)CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C(CSCc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
A mixture of 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethyl ester (0.230 g), dioxane (10 mL), sodium hydroxide (1N, 3 mL), water (2 mL) and ethanol (4 mL) was stirred for 20 hours at room temperature. The solvents were evaporated and the residue dissolved in water (50 mL). The aqueous solution was washed twice with ether and then acidified to pH2. The product was extracted from the aqueous solution with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give acid 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid (0.210 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:7](=[O:9])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:11][CH3:12])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: COc1ccc(F)cc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-fluoro-2-methoxybenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.96, 7.10-6.98, 6.86-6.84, 4.03-3.37, 1.51, 0.80-0.72, 0.49-0.44, 0.15-0.10. MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=O)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH2:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH:36][C:24]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:11]=1[CH:21]([CH3:23])[CH3:22])=[O:26]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 42, 244 mg, 0.685 mmol) in CH2Cl2 (12 ml) was added EDC (262 mg, 1.37 mmol) and DMAP (125 mg, 1.03 mmol), followed by 3,4-difluorobenzyl amine (197 mg, 1.03 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[C:19]([NH:26][CH3:27])=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=2)=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29].CCN(CC)CC>O1CCOCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=3)[N:26]([CH3:27])[C:4]2=[O:3])=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29]
Reactant: CNc1nc(SC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c([N+](=O)[O-])c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of diphosgene (3.5 g, 17.7 mmol) in dioxane (350 mL) at 0° C. was slowly added a solution comprised of 5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (5.2 g, 16.1 mmol) and Et3N (4.5 mL, 32.1 mmol) in dioxane (250 mL). The resultant reaction mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The combined organics were dried (Na2SO4) and concentrated to give crude product, which was washed with cold MeOH (5 mL) to give 3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (5.0 g, 89% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1 H), 8.20 (m, 1 H), 7.82 (m, 1 H), 7.64 (dd, J=6.9, 8.4 Hz, 1 H), 4.82 (s, 2 H), 3.29 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 350.3 (M+H+).