Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C@H:11]1[NH:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])(=[O:27])[CH3:26]>O1CCOCC1.O.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.CCOC(C)=O>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:6]2[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:16]3[C@H:11]([CH3:10])[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15]3)[CH:7]=2)=[CH:30][C:29]=1[F:37])(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)O)CC[C@H]3C)nc(N)n2)cc1F
Temperature: 117 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (1.69 g, 10.31 mmol), (3S,6R)-6-methyl-3-piperidinecarboxylic acid (2.037 g, 10.31 mmol) and NaHCO3 (3.90 g, 46.4 mmol) in 1,4-dioxane (100 mL) and water (50 mL) was stirred overnight at 117° C. into a sealed tube. The reaction was allowed to cool to room temperature. LCMS showed that most of the starting material 4,6-dichloro-2-pyrimidinamine had been consumed. Then (4-acetyl-3-fluorophenyl)boronic acid (2.81 g, 15.5 mmol) and Pd(Ph3P)4 (0.238 g, 0.206 mmol) were added, and the reaction mixture was stirred for 24 hours at 117° C. The mixture was poured into water (300 mL) and EtOAc (200 mL). At this moment the pH of the solution was 9. The compound stayed in the water layer. The water layer was separated from the organic layer. There was some black colored and yellow colored suspension in the warer layer, which was filtered out. (They were not product). To the aqueous layer, 6N HCl was added dropwise until the pH=4. A precipitate was formed. The precipitate was filtered, washed with water, and dried to afford the title compound (1.87 g) as a light yellow solid. LC-MS (ES) m/z=373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[CH2:21]([S:23][CH:24]([CH3:39])[CH2:25][CH:26]1[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[CH2:29][C:28](=[O:38])[CH2:27]1)[CH3:22].CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:29]2[C:28](=[O:38])[CH2:27][CH:26]([CH2:25][CH:24]([S:23][CH2:21][CH3:22])[CH3:39])[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2=[O:37])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1CC(C)SCC
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)CC1CC(C)SCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (1 g) in dry dichloromethane (5 ml) was added at 0°-10° C. to a stirred solution of triethylamine (0.62 ml) and 5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (1.3 g) in dry dichloromethane (20 ml) and the mixture stirred at ambient temperature for 2 hours. Triethylamine (1.9 g) and acetone cyanohydrin (0.1 ml) were added successively to the solution and the mixture stirred at ambient temperature for a further 18 hours. The mixture was washed successively with 2N hydrochloric acid (10 ml) and water (2×10 ml) dried over magnesium sulphate and evaporated under reduced pressure to give 2-(4-chloro-2-nitrobenzoyl)-5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (0.6 g), mp 102°-104° C., as an orange crystalline solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][NH:28][C:23]2[N:24]=[C:25]([F:27])[CH:26]=[C:21]([F:20])[N:22]=2)=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Yield: 34 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.100 g, 34% yield); 1H-NMR (300 MHz, CDCl3, δ) 8.08 (d, J=6.9 Hz, 1H), 7.64-7.85 (m, 3H) 7.37-7.33 (m, 2H), 7.25-7.20 (m, 1H), 6.85-6.80 (m, 1H), 6.07 (t, J=9.3 Hz, 1H), 5.86-5.85 (m, 1H), 5.99 (d, J=5.4 Hz, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH:19]=[CH:20]C=2O)=[O:15])=[C:9]([F:31])[CH:8]=1.Cl>O1CCCC1.N1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:15])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH:19]=[CH:20][C:5]=3[O:4][C:2]2=[O:3])=[C:9]([F:31])[CH:8]=1
Reactant: O=C(Nc1ccc(Cl)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 1 (1.5 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 2.5 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](OCC)=O)[CH:19]=[C:18](C)[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C[Mg]Cl.[C:31](=O)([O-])[O-].[Na+].[Na+].[O:37]1[CH2:41][CH2:40]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([C:41]([OH:37])([CH3:40])[CH3:31])[CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: O=C([O-])[O-]
Agent: C[Mg]Cl
Agent: [Na+]
Product: COc1cc(Nc2nc(C)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidine-4-carboxylate (184 mg, 0.5 mmol) in tetrahydrofurane (10 mL) was added at 0° C. over 2 min a 3 M solution of methylmagnesiumchloride in tetrahydrofurane (0.55 mL, 1.65 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by 1 h at 20° C. The mixture was poured on saturated sodium carbonate solution (20 mL) and the product was extracted with ethyl acetate (40 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was crystallized from dichloromethane/heptane to give the title compound to give the title compound (105 mg, 59%) as an off-white solid. MS ISP (m/e): 354.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.76 (d, 1H), 7.63 (s, 1H), 7.18 (d, 1H), 7.02 (dd, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 4.04 (s, 1H), 3.88 (s, 3H), 2.47 (s, 3H), 2.30 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+:15]([O-:18])(O)=[O:16].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[C:22]([N+]([O-])=O)[CH:21]=1.[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:29]=[C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([OH:19])=[C:21]([N+:15]([O-:18])=[O:16])[CH:22]=3)[N:28]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(O)c([N+](=O)[O-])c3)n2)s1
Yield: 17.8 %

Procedure:
3-Dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1 mmol, 0.21 g) in 2-methoxyethanol (5 mL) was treated with N-(4-hydroxy-2-nitro-phenyl)-guanidine nitrate (2 mmol, 0.52 g) in the presence of NaOH (40 mg). The reaction mixture was refluxed under N2 for 24 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc) and recrystallisation from EtOAc/PE to afford the title compound as a yellow powder (61 mg). 1H-NMR (300 MHz, CDCl3) δ 2.71 (s, 3H, CH3), 2.73 (s, 3H, CH3), 7.01 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.18 (m, 1H, Ph-H), 7.64 (m, 1H, Ph-H), 8.42 (d, 1H, J 5.2 Hz, pyrimidinyl-H), 8.75 (d, 1H, J=2.7 Hz, Ph-H), 10.45 (br. s, 1H, OH).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.ClC1C(Cl)=CC=CC=1NN>CO>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1cccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: N#Cc1cnn(-c2cccc(Cl)c2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(2,3-Dichlorophenyl)hydrazine hydrochloride (CAS no. 21938-47-6) (6.06 g, 28.4 mmol) was partitioned between EtOAc and 2M NaOH. Separated. The organic solution was dried (MgSO4), filtered and reduced to give the free base. 2-(Ethoxymethylene)malononitrile (3.47 g, 28.39 mmol) was added portionwise to a stirred solution of (2,3-dichlorophenyl)hydrazine in MeOH (50 mL), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 1 hour. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then was evaporated to afford the product (7.19 g, 100%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 6.75 (2H, s), 7.48-7.53 (2H, m), 7.77 (1H, s), 7.79-7.84 (1H, m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH2:14])=[N:8][C:9]=2[NH2:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:13][C:9]1[N:8]=[C:7]([NH:14][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[N:6]=[C:5]2[C:10]=1[N:11]=[CH:12][N:4]2[CH2:3][CH2:2][Cl:1]
Reactant: O=Cc1cccnc1
Reactant: Nc1nc(N)c2ncn(CCCl)c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(NCc2cccnc2)nc2c1ncn2CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
100 mg (0.47 mmol) of 9-(2-chloroethyl)-2,6-diamino-purine (example 12, step A) were dissolved in 10 ml MeOH and 3 g molecular sieves (4 Å), 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde and 0.135 ml (2.35 mmol) acetic acid were added. The mixture was stirred for 2 hours at room temperature. 23.6 mg (0.38 mmol) sodium cyano-borohydride were added and stiffing was continued for 4 hours. Additional 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde were added and 72 mg sodium cyano-borohydride were added in three portions over three days at room temperature. The solvent was evaporated and the residue was taken up in 50 ml ethyl acetate. The organic layer was washed with sat. aqueous sodium carbonate and brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give 0.254 g of the crude product as yellow oil. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 99.5/0.5→80:20) to give 88 mg of the desired product as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Procedure NN: 4′-Nitro-biphenyl-4-carboxylic acid 200 mg (0.82 mmol), 152 mg of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.99 mmol), 515 mg of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (0.99 mmol) and 100 mg of triethylamine (0.99 mmol) are put into 5 ml of dichloromethane and stirred at room temperature for overnight. The reaction mixture is diluted with dichloromethane, washed by brine, dried over Na2SO4 and evaporated. The crude product is applied to silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1), followed by SCX column to give the product. 163 mg (52%) Observed mass; 380 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([F:25])=[CH:18][C:17]=1F.CC(OC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:17]2[CH:18]=[C:19]([F:25])[C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[F:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 2-chloropyridin-4-ol (100 g, 772 mmol) in anhydrous DMF (2 L) was added K2CO3 (128 g, 926 mmol) in one portion at RT. The mixture was stirred for 10 min at RT, and was then treated with 1,2,4-trifluoro-5-nitrobenzene (88 mL, 772 mmol) slowly over 10 min. The internal temp of the reaction mixture was maintained below 24° C. during the addition. The reaction was stirred at RT for 1 h and then it was stopped by adding ice/water (10 L). The mixture was stirred for 2 h and then filtered to remove the solids. The solids were washed with water (5 L), hexanes (3 L) and then dried under vacuum at 50° C. to give 194.7 g of crude material. The solids were treated with MTBE (200 mL), stirred for 2 h, collected by filtration, washed with MTBE (50 mL) and dried under vacuum at 40° C. for 3 h to afford 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (164.6 g, 74.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)(C)C.[H-].[C:13]([CH:17]1[CH2:20][C:19](=[O:21])[CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([C@@H:17]1[CH2:20][C@H:19]([OH:21])[CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cool lithium aluminum hydride (16 mL, 16 mmol, 1.0 M solution in tetrahydrofuran) under a nitrogen atmosphere to 0° C. Add tert-butanol (4.6 mL, 48.1 mmol) dropwise, warm to room temperature, and stir the resulting solution for 1 hour. Cool the hydride solution to −78° C. and add a solution of 3-tert-butylcyclobutanone (1 g, 7.9 mmol) in dry tetrahydrofuran (3 mL) dropwise. Stir for 1 hour at −78° C. and then warm to room temperature over 1 hour. Slowly quench the mixture with 0.1 N hydrochloric acid. Dilute the resulting mixture with ethyl acetate and a saturated aqueous solution of sodium potassium tartrate (Rochelle salt) and stir the biphasic mixture overnight. Filter the mixture to remove precipitates and separate the aqueous layer. Saturate the aqueous phase with sodium chloride and extract with ethyl acetate. Add the organic extract to the ethyl acetate solution of the reaction mixture and wash the resultant mixture with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, and concentrate to give the title compound as a 9:1 mixture of cis/trans diastereomers.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:16]([NH:19][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: C#CCN
Reactant: O=C(Nc1nnn[nH]1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCNc1ccc(C(=O)Nc2nnn[nH]2)cc1

Procedure:
A mixture of 20 g (0.097 mol) of 4-fluoro-N-1H-tetrazol-5-ylbenzamide, 12.8 ml (0.193 mol) of propargylamine, 5.6 g of anhydrous potassium fluoride, and 13 g of potassium carbonate, in 320 ml of dimethylsulfoxide is heated at 50°-70° C. for six to twenty hours. The reaction is poured into water and the precipitate is collected, washed with water, and dried in vacuo to give the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[C:4]([O:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:28][CH3:38])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:7]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)/C=C\C(=O)OCCCCCCCC/C=C\CCCCCCCC

Procedure:
A mixture of maleic anhydride (88.25 g), oleyl alcohol (483.28 g), p-toluenesulfonic acid monohydrate (8.56 g), and toluene (650 mL) was refluxed under nitrogen. Water was separated from the distillate in a Barrett distilling receiver. When the theoretical amount of water (17 g) was collected, the heating was stopped and the toluene removed in vacuo on a rotary evaporator. The product was a brown oil (532 g) and was used in Example 4 without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>>[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1
Reactant: CSc1ccc(CCl)cc1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOCCc3ccccc3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 578 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:6]1[CH2:7][CH2:8]2)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[C:38]([O:37][C:35]([N:34]1[CH:9]2[CH2:8][CH2:7][CH:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH:10]2[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C1C(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C2CCC1N2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1

Procedure:
A solution of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo [2.2.1] heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.15 g, 2.58 mmol) and lithium hydroxide (0.062 g, 2.57 mmol) in THF:methanol:water (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was then concentrated in vacuo to give 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1] heptane-2,7-dicarboxylic acid 7-tert-butyl ester as a crude solid (0.150 g, 100%). MS: 568 (M+H)+.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH2:37])=[CH:28]1.[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH:37][C:41]2[C:42]([F:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:28]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCc1csc2ccccc12
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1csc2ccccc12

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ −168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH3:22])=[O:20].CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=1
Reactant: COC(=O)CCl
Reactant: N#Cc1cc(Br)c[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)Cn1cc(Br)cc(C#N)c1=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 74.8 %

Procedure:
To 5-bromo-3-cyano-2(1H)-pyridinone (1.4 g, 7.0 mmol) and potassium carbonate (1.9 g, 1.3 mL, 14.1 mmol), THF (26.4 mL) and methyl chloroacetate (1.53 g, 1.2 mL, 14.1 mmol) were added. The reaction was stirred at 80° C. The starting material didn't dissolve well in THF. After 3.5 hours, mainly staring material was observed. DMF (18 mL) was added and the starting material went into solution. The reaction was heated at 80° C. for 45 minutes. The desired mass was observed by LCMS. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude product was separated by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(5-bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate as a yellow solid (1.42 g, 74%). ESI-MS m/z calc. 271.07. found 271.3 (M+1)+. Retention time 0.59 minutes.