Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:10][S:11]([O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: OCC1(F)CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 296C (1.4 g), methanesulfonyl chloride (1.054 mL), triethylamine (2.99 mL), and 4-(dimethylamino)pyridine (0.051 g) in CH2Cl2 (20 mL) was stirred at 0° C. for 2 hours, concentrated and chromatographed on silica gel with 30% ethyl acetate in hexanes as eluent to give the product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:30][CH:29]([OH:31])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:21]([O:39][CH3:40])=[CH:20][CH:19]=1>>[CH3:40][O:39][C:21]1[C:22]([N:24]2[CH2:30][CH:29]([OH:31])[CH2:28][NH:27][CH2:26][CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Br)nc1N1CCN(C(=O)OC(C)(C)C)CC(O)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCNCC(O)C1
Yield: 4.5 %

Procedure:
Following the procedures as described in EXAMPLE 86 and starting with 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and tert-butyl 4-(6-bromo-3-methoxy-2-pyridyl)-6-hydroxy-1,4-diazepane-1-carboxylate, 207 was obtained as an off-white solid (4.4 mg, 4.5%) over 2 steps. MS (ESI) m/z: 433.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](=[O:13])([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>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[C:8]1[C:10](=[O:13])[CH2:5][CH2:6][C:7]=1[CH3:9]
Reactant: Cc1ccc(N)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CC1=C(c2cc(C)ccc2N)C(=O)CC1

Procedure:
1.607 g (8.031 mmol) of 2-bromo-4-methylaniline, 1.180 g (8.432 mmol) of 5-methyl-1-cyclopenten-2-one boronic acid compound, 0.093 g (0.080 mmol) of tetrakis(triphenylphosphine)palladium, and 1.277 g (12.047 mmol) of sodium carbonate were loaded to 250 mL schlenk flask, and then 24 mL of degassing DME and 8 mL of H2O that had been purged with N2 were added thereto using a syringe. The mixture was reacted at 90° C. for 12 hours. The work-up was the same as in Example 3 (1.66 g, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.CC1CCCO1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:17]([OH:22])[OH:18])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC#Cc1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC1CCCO1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 2, 25 g, 117 mmol), 2-methyl-tetrahydrofuran (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3 H) 8.21 (br. s., 1 H) 8.53 (m, 2 H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acidhydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 5, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.70 (s, 2H), 7.40-7.36 (m, 2H), 7.23-7.12 (m, 2H), 7.02-6.84 (m, 7H), 5.31 (s, 2H), 4.80 (d, 1H), 3.62-3.57 (m, 1H), 3.24 (t, 1H), 3.04-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.53 (dd, 1H), 1.79-1.70 (m, 1H). MS (EI) for C28H25ClF2N5O3 found 552 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2cccc(F)c2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2cccc(F)c2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-J), the title compound was prepared as an off white solid.
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]([NH:15][C:16](=[NH:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].Cl.[CH3:22][O:23][C:24]1[CH:57]=[CH:56][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54]N[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:26][CH:25]=1>CO>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54][N:18]([C:16](=[N:15][C:13]([O:12][CH2:11][C:10]4[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:20][CH:19]=4)=[O:14])[CH3:17])[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:56][CH:57]=1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 33.3 %

Procedure:
11 ml of methylene chloride, followed by 452 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, were added to a solution of 1.1 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] in 22 ml of methanol, whilst heating the solution under reflux. The resulting mixture was then heated under reflux for a further 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent to give 466 mg of the title compound, as a powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[NH:8][CH3:9]
Reactant: CNc1c(Cl)ncnc1Cl
Reactant: N
Product: CNc1c(N)ncnc1Cl
Yield: 76.78 %

Procedure:
Combine 4,6-dichloro-N-methylpyrimidin-5-amine (0.6 g; 0.0034 mol), and liquid ammonia (6 mL) and stir at 80° C. for 4 h. Extract with EA and evaporate to give the title compound (0.41 g; 76.78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]3[CH:13]=[C:14]([N:18](C(=O)CC(C)(C)C)[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].F[C:30](F)(F)[C:31]([OH:33])=[O:32]>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]3[CH:13]=[C:14]([N:18]([CH2:30][C:31]([OH:33])=[O:32])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2]
Reactant: CC(=O)N(C(=O)CC(C)(C)C)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(CC(=O)O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-tert-butylacetylacetamide 4 (9.0 g, 0.023 mol) in dichloromethane (200 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred at room temperature for four hours. The solution was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using chloroform/methanol (9/1). 5.5 g of Hapten-A was obtained as a foamy solid. NMR13C: 172.7, 172.2, 153.1, 151.6, 147.6, 147.2, 143.7, 131.56, 131.2, 131.0, 129.8, 112.9, 110.4, 84.1, 51.6, 29.5 and 22.6
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CCN(CC)CC.CN(C=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Yield: 95 %

Procedure:
1-Phenylpiperazine 2 (2.21 g, 7.81 mmol) was reacted with N-(4-bromobutyl)phthalimide (1.26 g, 7.81 mmol) in the presence of K2CO3 (8.0 g) in Et3N (1.0 mL) and DMF (20 mL) to give a yellow solid 3a, 2.70 (95%) (Procedure A). 1H NMR (CDCl3) 1.55-1.82 (m, 4H, CH2CH2), 2.40-2.45 (t, J=7.5 Hz, 2H, NCH2), 2.57-2.61 (t, J=4.8 HZ, 4H, N(CH2)2), 3.17-3.20 (t, J=4.8 Hz, 4H, N(CH2)2), 3.71-3.75 (t, J=6.7 Hz, 2H, NCH2), 6.82-6.94 (3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.83-7.86 (m, 2H, Ar—H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Cl)C=C>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH2:15][CH:14]=[CH2:13])[CH:10]=[O:11]
Reactant: CC1(C)C2CCC(CC=O)C1C2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCCl
Solvent: CN(C)C=O
Product: C=CCC(C=O)C1CCC2CC1C2(C)C
Yield: 17.2 %

Procedure:
In a procedure similar to Example 6, 100 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde at a purity of 98.3% (0.59 mole) in 50 ml of DMF, 82 g of potassium t-butoxide (0.69 mole) in 300 ml of DMF, and 55 g of allyl chloride in 50 ml of DMF (0.78 mole) were reacted in the usual way to afford 110.5 g of crude product composed of 36% starting material, 31% O-alkylate and 21% C-alkylate. The product was heated at 165°-185° C. for 6 hours. The crude aldehyde, 105.6 g, was distilled to afford 21.4 g of purified product (17% yield). A major impurity in the crude was the dialkylation product. BP product 114° C./1.2 mmHg; 1H-NMR (300 MHz), δ 1.05 (3H, s), 1.21 (3H, s), 1.3-2.6 (12H, m), 5.01 (2H, m), 5.7 (1H, m), 9.47 (1H, m); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2970, 2700, 1730, 1640, 1450, 1370, 910 cm-1 ; MS (m/e), 205 (M+ -1), 191, 175, 163, 122, 107, 93, 41 (Base);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol)(Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.18 g, 75.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34]1>>[CH2:38]([N:35]1[CH2:36][CH2:37][CH:33]([NH:32][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:34]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NC1CCN(Cc2ccccc2)C1
Product: O=C(NC1CCN(Cc2ccccc2)C1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-amino-1-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][CH:13]3[O:12][N:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:14]3)[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)C2)c1
Yield: 65.3 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (19.3 mg, 0.077 mmol), 1-[bis(4-fluorophenyl)methyl]piperazine (20.4 mg, 0.070 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (45.0 mg, 0.212 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.8 mg (64.7%) of the target compound was obtained.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1>C(O)C>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([N:18]2[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1-c1cccc(C(F)(F)F)c1
Yield: 68.9 %

Procedure:
A solution of 21.4 grams of mucobromic acid and 13.3 grams of 3-trifluoromethylphenyl hydrazine in 60 milliliters of ethanol was stirred for about 10 minutes. The ethanol was removed by evaporation under reduced pressure, and then 40 milliliters each of glacial acetic acid and acetic anhydride were added to the reaction vessel. The acidic reaction mixture was heated at reflux for 4 hours. The reaction solvent was removed by evaporation under reduced pressure whereupon a solid precipitate formed. The solid was purified by recrystallization from ethanol. A yield of 20.7 grams of 1-(3-trifluoromethylphenyl)-4,5-dibromo-1,6-dihydro-6-oxopyridazine was obtained.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([NH2:2])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 ml of a 28% aqueous solution of ammonium hydroxide were added dropwise at 0° to +5° C. under an inert gas atmosphere to a solution of 2.5 g of 5-chloropentane sulfonyl chloride (preparation described in: Bull. Soc. Chim. Belg. (1965) Vol. 74, p. 21) in 30 ml of tetrahydrofuran. The temperature was allowed to rise from 3° C. to 16° C., and the mixture was stirred at ambient temperature for 2 hours. The tetrahydrofuran was evaporated under reduced pressure and the residue was taken up in water, extracted with methylene chloride, washed with water, then with an aqueous solution of sodium chloride,. dried and evaporated under reduced pressure to obtain 2.01 g of the expected product melting at 62° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:13](O)=[N:12][CH:11]=[N:10][C:9]=2[S:8][CH:7]=1.P(Cl)(Cl)([Cl:18])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:13]([Cl:18])=[N:12][CH:11]=[N:10][C:9]=2[S:8][CH:7]=1
Reactant: Oc1ncnc2scc(-c3ccco3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2scc(-c3ccco3)c12

Procedure:
5-(2-furyl)-4-hydroxythieno[2,3-d]pyrimidine (180 mg, 0.80 mmol) in phosphorus oxychloride (2.0 ml) was heated to reflux for 2 hours. 5-(2-furyl)-4-chlorothieno[2,3-d]pyrimidine obtained by distilling off the solvent under reduced pressure, without further purification, together with 2-aminoindan (130 mg, 0.98 mmol) and triethylamine (0.90 ml, 6.4 mmol) in dry ethanol (5 ml) was heated to reflux under an argon atmosphere for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (130 mg, 0.39 mmol) having the following physical properties:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](COC)=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1>>[O:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17](=[O:21])[O:18]5)=[CH:13][CH:12]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]1=[O:21]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COCc1cc(=O)oc2cc(N)ccc12
Product: O=c1ccc2ccc(Nc3ncc(F)c(Nc4ccc5ccc(=O)oc5c4)n3)cc2o1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin were reacted to yield N2,N4-bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.38 (s, 1H), 8.42 (d, 1H, J=3 Hz), 8.28 (m, 1H), 8.05-7.93 (m, 2H), 7.77-7.50 (m, 4H), 6.31 (s, 1H), 6.29 (s, 1H), 4.66 (s, 2H), 4.65 (s, 2H), 3.43 (s, 3H), 3.41 (s, 3H); LCMS: MS (m/e): 505 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl[CH2:21][CH:22]1[CH2:24][O:23]1>CN(C=O)C.O>[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:21][CH:22]4[CH2:24][O:23]4)[CH:14]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: ClCC1CO1
Reactant: Cn1cnc2ccc(-c3cccc(O)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc2ccc(-c3cccc(OCC4CO4)c3)cc21
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of NaH (161 mg, 6.69 mmol) in DMF (5 mL) was added 3-(1-methyl-1H-benzo[d]imidazol-6-yl)phenol (500 mg, 2.23 mmol) at 27° C. After 0.5 h, 2-(chloromethyl)oxirane (246 mg, 2.68 mmol) was added and the reaction mixture was stirred 16 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next step without further purification. (500 mg, yield 80%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:38])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(CCc3ccccc3)cc2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
5.15 g (10.31 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2-phenylethyl)-phenyl]methyl}dihydrofuran-2-(3H)-one in 166 ml of dimethoxyethane and 85 ml of water are hydrolysed, under protective gas, with 41 ml of a 1 M lithium hydroxide solution. After 3 h, the dimethoxyethane is evaporated off on an RE, and the residue is treated with an ice-cold mixture of 506 ml of sat. NH4Cl solution, 42 ml of 10% citric acid solution and 207 ml of methylene chloride. Methanol is added to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride/methanol, 10:1. The organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (II)=17.8 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Reactant: c1c[nH]cn1
Product: Fc1ccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-(2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.