Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N)c(Oc2ccccc2C(C)(C)C)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2a (580 mg, 1.9 mmol) in a 1:1 mixture of ethyl acetate and methanol (6 mL) was added palladium on charcoal (10% wt, 300 mg, 0.28 mmol). The mixture was stirred under 40 psi atmosphere of hydrogen. After 30 min, the solution was filtered over Celite® and the resulting solution was concentrated to afford the title compound 2b as a dark solution (500 mg, 96% yield). 2b was used in the next step without any further purification. [M+H]+=273.21. 1H NMR (500 MHz, CD3OD) δ ppm 1.43 (m, 9H), 3.58 (m, 3H), 6.33 (d, J=8.25 Hz, 1H), 6.93 (d, J=8.25 Hz, 1H), 7.09 (m, 2H), 7.17 (t, J=7.70 Hz, 1H), 7.41 (d, J=8.25 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=CC=C[N:4]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.NN.O>C(#N)C>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][N:4]=[C:3]1[NH2:8]
Reactant: CNc1ncccn1
Reactant: O=C(CBr)c1ccccc1
Agent: NN
Solvent: CC#N
Solvent: O
Product: Cn1c(-c2ccccc2)cnc1N
Temperature: 130 °C
Yield: 41.1 %

Procedure:
To a microwave vial containing a solution of N-methylpyrimidin-2-amine (290 mg, 2.7 mmol) in acetonitrile (5 mL) is added 2-bromo-1-phenylethanone (714 mg, 3.6 mmol). The vial is sealed and heated in a microwave reactor at 130° C. for 20 minutes and is cooled to room temperature. The mixture is treated with hydrazine hydrate (0.65 mL, 13.3 mmol) and is then heated in a microwave reactor at 100° C. for 5 minutes. The reaction is poured into water (30 mL) and filtered to afford the title compound (192 mg, 42%) as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:21].[C:22]1([PH+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br-:21].[C:35]1([P+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OCc1ccccc1OCCCCCc1ccccc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Br
Solvent: CC#N
Product: [Br-]
Product: c1ccc(CCCCCOc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 93.5 %

Procedure:
A solution of 18.7 g (69.16 mmol) of [2-(5-phenylpentyloxy)phenyl]methanol from Example 27A in 120 ml of acetonitrile is mixed with 22.55 g (65.71 mmol) of triphenylphosphonium hydrobromide and heated to reflux for three hours. The reaction solution is then concentrated to dryness. 36.6 g (61.45 mmol, 83% yield) of crystalline product are obtained and are reacted without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN1CCOCC1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[C:55]1[C:56]([C:61](O)=[O:62])=[N:57][CH:58]=[CH:59][CH:60]=1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH:18][C:61]([C:56]2[C:55]([C:50]3[N:49]=[CH:54][CH:53]=[CH:52][N:51]=3)=[CH:60][CH:59]=[CH:58][N:57]=2)=[O:62])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1N
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1NC(=O)c1ncccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methylcyclopentane-1,2-diamine (Intermediate 28; 0.225 g, 0.81 mmol) and 4-methylmorpholine (0.134 ml, 1.217 mmol) in acetonitrile (5 ml) was added TOTU (0.399 g, 1.23 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 0.163 g, 0.81 mmol). The reaction was stirred at room temperature for 1 hour and then was diluted with DCM and washed with brine. The organics were dried over magnesium sulfate, concentrated in vacuo and purified by SCX chromatography (2M ammonia in methanol). The resulting residue was purified by column chromatography (silica, 0-10% methanol/DCM) and further purified by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2CCC[C@H]2[N:11]([C:19](=[O:22])[CH2:20]Br)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[CH2:5]([CH:6]1[CH:20]2[CH:1]([N:8]([C:14](=[O:15])[CH2:13][NH:35][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[NH:11][C:19]2=[O:22])[CH2:2][CH2:7]1)[C:4]1[CH:3]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: NCCc1ccccc1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1
Solvent: CCOCC
Product: O=C1Nc2ccccc2N(C(=O)CNCCc2ccccc2)C2CCC(Cc3ccccc3)C12
Yield: 48 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-4-bromoacetyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopent[e][1,4]-diazepin-10(1H)-one and phenethylamine, the titled compound was synthesized in substantially the same manner as in Working Example 138 in a yield of 48%, m.p. 108°-109° C. (diethyl ether).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH:18]=[CH:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:24])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:23])[CH3:24])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-phenyl-5-(1-butenyl)pyridine (Example 13) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.41 (m, 3 H), 7.17 (m, 2 H), 4.33 (s, 2 H), (sept, J=6.6 Hz, 1 H), 3.24 (sept, J=6.6 Hz, 1 H), 2.28 (m, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.31 (d, J=6.6 Hz, 6 H), 1.28 (m, 2 H), 1.14 (m, 3 H), 0.71 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C22H31NO) 325, found 326 (M+H). Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30. Found: C, 81.28; H, 9.87; N, 4.07. mp 83-84° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24](O)=[O:25])=[CH:15]1.S(Cl)([Cl:29])=O.CCOCC>C(Cl)Cl>[ClH:29].[CH3:1][N:2]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:24](=[O:25])[CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)Cc1c[nH]c2ccccc12)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (0.368 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 3-indole acetic acid (prepared by the action of thionyl chloride on 3-indole acetic acid, 0.35 g) dissolved in methylene chloride (10 ml) was added and let stand for five hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour and stored in a predried bottle. The product was in the form of a black glassy solid (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:43]2=[CH:44][N:45]=[CH:46][CH:47]=[C:42]2[CH:41]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[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:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:43]3=[CH:44][N:45]=[CH:46][CH:47]=[C:42]3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 56.3 %

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (510 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 5-50% EtOAc and hexane over a period of 120 minutes. The fractions were collected to give the title compound (135 mg, 56%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.100 g), 2-methylpropanoyl chloride (0.1 mL), TEA (0.1 mL), dry THF (5 mL) to afford 0.028 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.01 (s, 6H), 4.32 (d, J=7.6 Hz, 2H), 7.67-7.71 (m, 2H), 7.85 (d, J=11.2 Hz, 2H), 8.17 (d, J=11.6 Hz, 2H), 8.36 (m, 1H), 12.73 (s, 1H); MS (m/z): 457.37 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[NH3:10]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:9])[CH:3]=1)[NH2:10]
Reactant: N
Reactant: Fc1cc(F)cc(F)c1
Product: Nc1cc(F)cc(F)c1

Procedure:
In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[F:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(Br)c1F
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (25 g, 129.5 mmol) in dry diethyl ether (150 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 51.8 mL, 129.5 mmol). The mixture was stirred for 30 min after which a solution of 1-benzylpyrrolidin-3-one (20.4 g, 116.5 mmol) in dry diethyl ether (50 mL) was added drop wise. The mixture was stirred at −78° C. for 30 min and for 2 h at ambient temperature. Aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (isooctane/ethyl acetate/triethyl amine, 75:20:5) gave the title compound (19.5 g). MS m/z (relative intensity, 70 eV) 289 (M+, 20), 198 (69), 133 (72), 132 (51), 91 (bp).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:16][C:17]2[CH:30]=[CH:29][C:20]3[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CNC(=O)c1c(C)oc2cc(N)ccc12
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNC(=O)c1c(C)oc2cc(Nc3ccnc(Cl)n3)ccc12
Yield: 80 %

Procedure:
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 6-amino-N,2-dimethylbenzofuran-3-carboxamide (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was subjected to extraction with EtOAc. The organic layers were combined, washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give 6-(2-chloropyrimidin-4-ylamino)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][C:23]=1[NH2:24].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[NH:17][C:18]4[CH:19]=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:22][C:23]=4[N:24]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)C1CCN(c2ncccc2Cl)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(C3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the acid from step (b) above (0.48 g, 2 mmol) in DMF (20 mL) was added 3,4-diaminobenzotrifluoride (0.354 g, 2 mmol, Lancaster), followed by N,N-diisopropylethylamine (0.516 g, 4 mmol, Aldrich) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.912 g, 2.4 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane/EtOAc (3:7) to give the title compound as a purple solid. MS (ESI, pos. ion) m/z: 399 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18][N:19](C)[CH3:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:30].C(N)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:30]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Solvent: NC=O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2

Procedure:
A mixture of 90.5 g (0.25 mol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one, 100 g (0.96 mol) of formamidine acetate and 1.0 L of formamide was heated on a steam bath for 16 hr. The mixture was cooled to 0° and the resulting precipitate collected by filtration. The precipitate was washed with water and dried to constant weight to give off-white crystals, mp 120°-121° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH3:9][SH:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:9][S:10][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: C=Cc1cnccn1
Reactant: CS
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CSCCc1cnccn1

Procedure:
2-Pyrazinyl-ethyl methyl sulfide was prepared by reacting vinylpyrazine [c.f. J.Org.Chem. 27, 1363 (1962] with methylmercaptan by the action of ultra violet light and in the presence of benzoyl peroxide by the method described in Acta Chem. Scand. 8, 295 (1954). The product was identified by mass spectrometry. It has a b.p. of 57°-69° C. at 0.05 mm. Hg.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[CH2:53][C:54]1[O:55][C:56](=[O:60])[O:57][C:58]=1[CH3:59].CN1CCOCC1>C(Cl)Cl.CC(O)=O>[CH3:59][C:58]1[O:57][C:56](=[O:60])[O:55][C:54]=1[CH2:53][O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[NH:21][N:22]=[N:23][CH:24]=1)=[O:19])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: Cc1oc(=O)oc1CO
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (100 mg, 245 μmol, 1.0 eq.), EDCI (52 μL, 294 μmol, 1.2 eq.) and HOBt (39.7 mg, 294 μmol, 1.2 eq.) were dissolved in DCM (5 mL). After stirring for 10 minutes, 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (127 mg, 979 μmol, 4.0 eq.) was added. The mixture was stirred for 1 hour and 4-methylmorpholine (40.4 μL, 1.5 eq.) was added. After 1 hour, the crude material was dissolved in AcOH and purified by preparative HPLC to yield the title compound (20 mg). MS m/z [M+H]+ calc'd for C27H28N4O7, 521.20. found 521.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:18])[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.[CH2:19](N(CC)CC)C.IC.O>CS(C)=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([S:18][CH3:19])[C:5]=3[N:10]=2)=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: Nc1nc(S)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-thiol (1.2 g, 4.31 mmol) and triethylamine (1.50 ml, 10.8 mmol) in DMSO (25 ml) was added iodomethane (0.54 ml, 8.62 mmol). The reaction mixture was stirred for 12 h under N2 at 25° C. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 80:1), yielding the title compound as a light yellow solid (0.76 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:32])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:25]3[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([F:22])[CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
The 7-benzyloxy-4-chloro-6-cyanoquinoline (8.82 g, 30.0 mmol) described in WO98/13350 was suspended in 1-methylpyrrolidone (30 ml), and then 3-fluoro-4-nitrophenol (5.18 g, 33.0 mmol) and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) were added and the mixture was heated and stirred at 110° C. for 4 hours. After returning the reaction system to room temperature, water was added and a solid precipitated. The obtained solid was filtered out, washed with water, methanol and ethyl acetate and dried at 60° C. to obtain the title compound (4.98 g, 12.0 mmol, 40%) as colorless crystals.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:3][C:2](=[S:1])[C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)NC(C(N)=S)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Hydrogen sulphide was bubbled through a solution of diethyl 2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (1 g, 2.6 mmoles) in triethylamine (0.36 ml, 2.6 mmoles) and pyridine (20 ml) at room temperature for 2 hours. The solution was degassed with nitrogen and poured into water (300 ml). After stirring for 2 hours, the precipitate was filtered off, dissolved in methylene chloride and dried (Na2SO4). The solvent was removed in vacuo and the residue triturated with CCl4 and filtered to give the title compound (0.5 g). M+ 419; (CDCl3) δ 9.3 (s,NH2), 5.2 (s,H).