Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[CH2:8][C:9]([N:39]=[N+:40]=[N-:41])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccnnc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(=O)CC(c1ccccc1)c1ccnnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-phenyl-3-(pyridazin-4-yl)propanoic acid (570 mg, 2.5 mmol) in DMF (30 mL) was added Et3N (505 mg, 5.0 mmol), followed by the DPPA (722 mg, 2.6 mmol) in portions at 0° C., the resulting mixture was stirred at room temperature for 1.5 hour. The reaction was diluted with water, extracted with AcOEt (3×40 ml), the combined organic layer was washed by brine, dried over Na2SO4 and concentrated to get the 3-phenyl-3-(pyridazin-4-yl)propanoyl azide (crude 650 mg), which was used for next step directly.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH2:30][NH:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1

Procedure:
5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde (0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g) according to procedure D. Acidification with acetic acid (0.5 ml) followed by purification using a ion-exchange (SCX) Bond Elut™ cartridge, eluting with methanol-ammonia (9:1), concentration and trituration with diethylether afforded an off-white solid; δH [2H6] DMSO 8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H, m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (600 mg) was suspended in toluene (15 ml), and the suspension was heated to reflux for dissolution, after which phenyl isocyanate (292μl) was added dropwise and the mixture was heated to reflux for 30 minutes. After cooling, the precipitated solid was filtered out, washed with ether and ethyl acetate and dried to obtain 760 mg of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O1CCOCC1>C1(C)C=CC=CC=1>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)O)cc1S
Temperature: 25 °C

Procedure:
A mixture of 3-chlorosulfonyl-4-methoxybenzoic acid (4.76 g; that is prepared as described in Reference Example 44) in dry toluene (500 mL) stirred at room temperature is treated with triphenylphosphine (19.9 g) in one portion. The mixture is stirred and heated at 80° C. overnight, and then it is cooled, and treated with water (25 mL) and dioxane (25 mL), and the resulting solution is heated on a steam bath for 1 hour. The reaction mixture is allowed to cool to room temperature, and the organic layer is collected and concentrated. The resulting residue is partitioned between ethyl acetate (200 mL) and aqueous sodium hydroxide solution (500 mL; 2 N). The aqueous layer is separated, acidified by treatment with concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL). The extract is washed with water (100 mL), dried over magnesium sulfate and concentrated, to give 3-mercapto-4-methoxybenzoic acid in the form of a white solid (3.4 g), m.p. 208-210° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH2:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and ethanamine hydrochloride (17.4 mg, 0.213 mmol) were suspended in DMF (1.065 mL) and treated with DIPEA (0.186 mL, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-ethyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (26.4 mg, 0.061 mmol, 28.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3 H) 1.82-2.02 (m, 3 H) 2.18 (d, J=2.27 Hz, 1H) 2.41 (t, J=4.80 Hz, 5 H) 3.20-3.29 (m, 2 H) 3.34-3.44 (m, 3 H) 3.51-3.63 (m, 5 H) 3.95-4.03 (m, 1 H) 6.82 (d, J=9.09 Hz, 1 H) 6.99 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.93 (dd, J=9.09, 2.53 Hz, 1 H) 8.23 (t, J=5.31 Hz, 1 H) 8.57 (d, J=2.27 Hz, 1H) 10.44 (s, 1 H); [M+H] calc'd for C23H29N7O2, 422; found, 422.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25](=[O:40])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:12]=[C:13]([O:15]CC2C=CC(OC)=CC=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.P([O-])([O-])([O-])=O.C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25](=[O:40])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:12]=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(C(=O)c1cc(OCc2ccccc2)cc(OCc2ccc(OC)cc2)c1)c1ccccc1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Cc1ccccc1C(CCC(=O)O)C(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (RS)-5-[3-benzyloxy-5-(4-methoxybenzyloxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (0.54 g) in dichloromethane (10 mL), pH 7.3 phosphate buffer and tert-butanol (0.1 mL) is treated at 0° C. with 2,3-dichloro-5,6-dicyanobenzoquinone (0.34 g) and stirred at ambient temperature for 48 hours. It is then diluted with water (100 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and concentrated. The resulting oil (0.4 g) is dissolved in a solution of potassium hydroxide in methanol (20 mL; 15% w/v) and heated at reflux for 5 hours and is then allowed to cool. The mixture is concentrated, diluted with water (30 mL) and acidified to pH1 by treatment with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate (3×50 mL) and the combined organic extracts are washed with brine and dried over magnesium sulphate, and concentrated. The resulting residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and pentane (1:1 v/v). The resulting oil is triturated with a mixture of diisopropyl ether and pentane, to give (RS)-5-(3-benzyloxy-5-hydroxyphenyl)-4-(2-methylphenyl)-5-oxopentanoic acid in the form of a white solid (80 mg), m.p. 116-117° C. [Elemental analysis:- C,73.80; H,5.90%; Calculated:- C,74.24;H,5.98%].
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH:25]([CH3:27])[CH3:26])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C(C)C)C(=O)C2)nc2cc(F)cc(F)c2c1Br
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (89 mg, 0.25 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (30.0 mg, 1.25 mmol) (60% dispersion) followed by addition of 2-iodopropane (750 μL, 7.50 mmol). The reaction was heated to reflux and stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 80% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-isopropylpiperazin-2-one. Mass Spectrum (ESI) m/e=400.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1)[CH3:2].Cl.[OH:27][C@@H:28]([CH2:58]O)[CH2:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:70]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:27][C:28]([CH3:58])([CH3:70])[CH2:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:14](=[O:16])[C@@H:13]([N:11]2[CH2:12][C:8]([O:7][C:6]3[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[F:25])=[CH:9][C:10]2=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:31]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 0 °C
Yield: 54.7 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.460 g, 1.31 mmol) in N,N-dimethylformamide (10 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032, Example 80, 0.264 g, 1.70 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.22 g, 2.76 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.340 g, 2.63 mmol) was added. The mixture was stirred at room temperature for 7 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.350 g, 55%) as a yellow solid: HR-ES-MS m/z calculated for C25H33FN4O5 [M+H]+ 489.2508, observed 489.2508, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.36 (t, J=6.8 Hz, 3H), 1.47 (br. s., 1H), 1.50-1.64 (m, 1H), 1.63-1.86 (m, 1H), 3.89 (s, 2H), 4.15 (q, J=6.8 Hz, 2H), 4.21 (d, J=18.7 Hz, 1H), 4.60 (d, J=18.7 Hz, 1H), 4.68 (s, 1H), 4.83-4.93 (m, 1H), 4.89 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.96-7.07 (m, 1H), 7.07-7.26 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[F:15][C:16]([F:21])([F:20])[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:4]1[CH:3]=[C:2]([NH:19][CH2:18][CH2:17][C:16]([F:21])([F:20])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: NCCC(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Temperature: 200 °C
Yield: 60.8 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (0.158 g, 0.84 mmol), (3,3,3-trifluoropropyl)amine hydrochloride (0.125 g, 0.84 mmol) and DIEA (0.326 g, 2.52 mmol) in 1.5 mL of DMSO was heated in a microwave at 200° C. for 20 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with 0.1N HCl (×2) and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) and the product crystallized from Et2O-hexanes to give 0.144 g (61% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.6, 2.4 Hz, 1H), 4.56 (bs, NH), 3.53 (q, J=6.5 Hz, 2H), 2.51-2.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:30][C:29]([CH2:28][C:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[NH:19][CH:20]=4)=[N:31][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Product: O=C1Cc2cnc(Cc3c[nH]c4ccccc34)nc2-c2cc(Cl)ccc2N1
Yield: 46 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 46%.
Reaction SMILES: [Mg].II.[CH3:4][N:5]1[C:9]([S:10][CH2:11][CH2:12][CH2:13]Cl)=[N:8][N:7]=[N:6]1.C(Br)C.C(#N)CC.Cl.[O:23]1C[CH2:26][CH2:25][CH2:24]1>O>[CH3:4][N:5]1[C:9]([S:10][CH2:11][CH2:12][CH2:13][C:24](=[O:23])[CH2:25][CH3:26])=[N:8][N:7]=[N:6]1
Reactant: C1CCOC1
Reactant: Cn1nnnc1SCCCCl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCC#N
Solvent: CCBr
Product: CCC(=O)CCCSc1nnnn1C

Procedure:
Magnesium (0.3 g) is suspended in dried tetrahydrofuran (5 ml). To the suspension is added a small piece of iodine with stirring in nitrogen gas flow, and further added 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (0.3 g). To the mixture is added ethyl bromide (0.1 ml), and the reaction is started by heating the mixture from outside. A solution of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.8 g) in dried tetrahydrofuran (15 ml) is additionally added dropwise to the mixture. After the solution is added, the mixture is refluxed for 1 hour. To the obtained Grignard reagent is added dropwise a solution of propionitrile (0.5 g) in dried tetrahydrofuran (5 ml) with stirring under ice-cooling, and the mixture is stirred for 3 hours at room temperature. To the mixture is added 1 N-HCl (20 ml) under ice-cooling and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. After chloroform is distilled off, the residue is purified by silica gel column chromatography (Kieselgel 60) and eluted with benzene-ether (10:1) to give 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.5 g) as colorless liquid, nD25 =1.5042.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O>CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][N:9]([C:20]([NH2:19])=[O:21])[CH2:8]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 120 h

Procedure:
A mixture of 30.6 g (0.141 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine and 42 g (0.321 mole) of nitrourea (80%) in 500 ml of acetone was stirred for 5 days (5 days not required, but convenient) at room temperature. The mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between 150 ml of water and 100 ml of ethyl acetate and the layers separated. The aqueous layer was washed with 100 ml of ethyl acetate. The ethyl acetate layers were washed with 75 ml of 5% aqueous sodium hydroxide solution followed by 75 ml of water, dried over sodium sulfate and concentrated in vacuo. The residual oil was crystallized from ethyl alcohol-ethyl acetate to give 22 g (60%) substantially the title compound. Recrystallization twice from ethyl alcohol gave 9.9 g of white crystalline solid, m.p. 151°-152.5° C.
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>C(=O)([O-])[O-].[K+].[K+].C(#N)C>[OH:9][C@@H:6]1[CH2:7][N:8]([CH2:12][CH2:11][C:10]#[N:13])[C@@H:4]([CH2:3][OH:2])[CH2:5]1
Reactant: C=CC#N
Reactant: OC[C@H]1C[C@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1C[C@@H](O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(3S,5R)-5-Hydroxymethylpyrrolidin-3-ol hydrochloride (0.4 g) described in Biochemistry, Vol. 5, pp. 1154–1155 (1966) was dissolved in aqueous potassium carbonate solution (2 mL) and acetonitrile (2 mL). Acrylonitrile (0.5 mL) was added and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction mixture was concentrated and the obtained residue was suspended in chloroform-methanol and dried by adding magnesium sulfate. Magnesium sulfate was filtered off and the solvent was concentrated to give 3-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (0.47 g).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][C@@:8]2([CH3:35])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28](F)=[C:27]([Cl:33])[CH:26]=3)[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH2:81])[CH2:80][CH2:79]2)=[N:76][CH:77]=1>CN(C=O)C.CCOC(C)=O>[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH:81][C:22]([C:19]3([NH:18][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:37][CH:36]=6)([CH3:35])[C:9](=[O:34])[N:10]([C:25]6[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:33])[CH:26]=6)[C:11]5=[N:15][CH:14]=4)=[O:17])[CH2:20][CH2:21]3)=[O:24])[CH2:79][CH2:80]2)=[N:76][CH:77]=1
Reactant: NC1(c2ccc(I)cn2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccc(I)cn5)CC4)CC3)n21
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropane-carboxylic acid (1.21 g, 2.32 mmol), HATU (970 mg, 2.55 mmol) and diisopropyl-ethylamine (808 μL, 4.64 mmol) in DMF (4 mL) was added 1-(5-iodo-pyridin-2-yl)-cyclopropylamine (724 mg, 2.78 mmol). The mixture was stirred for 1.5 h and then diluted with EtOAc (30 mL). The layers were separated and the organic layer was washed with water (3×30 mL) and brine (1×25 mL), dried with MgSO4, filtered, and concentrated to afford a crude solid. The crude material was purified by flash chromatography on silica gel, eluting with 50% hexanes in ethyl acetate (and increasing polarity to 75% ethyl acetate) to afford 1.60 g of the title compound:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Yield: 44.3 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.0294 g, 0.113 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.016 g, 0.124 mmol) gives the title compound (0.0187 g 44.2%): TOF MS ES+ 374.2 (M+H)+, HRMS calcd for C20H25N3O3F 374.1880 (M+H)+, found 374.1863, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=5.2 min, 95.2% purity.
Reaction SMILES: CS[C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH2:13]([N:20]1[CH:24]=[C:23]([C:3]2[N:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:7]3[CH:6]=[CH:5][N:4]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CSc1nccc2nc(N)nn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: Nc1nc2ccnc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 130 °C

Procedure:
A microwave vial containing 5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.05 g, 0.276 mmol), 1-benzyl-1H-pyrazole-4-boronic acid (123 mg, 0.607 mmol), copper(I) thiophene carboxylate (116 mg, 0.607 mmol) and tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) in THF (1.2 mL) was heated under microwave irradiation (130° C., 15 min). The reaction mixture was filtered through celite and the cake washed with dichloromethane. The filtrate was washed with water followed by brine, dried over magnesium sulfate and concentrated under vacuum. Trituration with diethyl ether provided a yellow solid that did not require further purification. Yield: 0.05 g, 63%; LCMS method: 2, RT: 3.18 min, MI: 292 [M+1].