Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:3][CH:2]=1.Cl[CH2:25][S:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[O:23])=[CH:28][CH:29]=1
Reactant: ClCSc1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1c2ccccc2n(CSc2ccncc2)c(=O)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of 491 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione and 287 mg (1.8 mmol) of 4-chloromethylthiopyridine in 15 ml of dimethylformamide, 0.27 ml (1.8 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent:ethyl acetate/hexane=2:1 to 4:1 to ethyl acetate) to give 0.315 g of the desired product (46.7% yield, colorless oil).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15]1)=[O:11]
Reactant: CCSc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10.4 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 20.3 g of 3-hydroxy-5-ethylthio-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for 1 hour, cooled to -10° C and filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-methylcarbamoyl)-5-ethylthio-1,2,4-thiadiazole-3-one melting at 131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N+:19]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCOC(C)=O.CC(O)=O.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc(Cl)c2)c2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Sc2ccnc(Cl)c2)c2ccccc12

Procedure:
A solution of 2-chloro-4-(4-nitronaphthalen-1-ylthio)pyridine (1.68 g, 5.30 mmol) in a mixture of MeOH (30 mL), EtOAc (100 mL) and AcOH (10 mL) was subjected to hydrogenation by two passages through a Thales H-cube (1.0 mL min−1, 50° C., 70 mm, 10% Pt—C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford 4-(2-chloropyridin-4-ylthio) naphthalen-1-amine as a brown oil (1.40 g, 90% purity (LCMS), 83%); Rt 4.50 min (Method 1 basic); m/z 287 (M+H)+ (ES+). The material so obtained was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>O>[F:33][C:34]1[CH:35]=[C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CCC1CCN(Cc2cccc(F)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 52.5 °C
Yield: 94.6 %

Procedure:
A mixture of 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (4 g, 12.8 mmol), acetonitrile (26 mL), water (1.4 mL), potassium carbonate (2.3 g, 16.6 mmol) and 3-fluorobenzyl chloride (1.55 mL, 12.8 mmol) was stirred at about 50 to 55° C. After cooling, water (84 mL) was added dropwise thereto. The mixture was stirred at room temperature for about 1 hour. Precipitated crystals were separated, washed with water (80 mL) and dried to obtain 5.09 g (yield 95%) of the desired compound as crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][C:21]=2[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:35]([O:34][C:21]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:20]=1[CH:17]1[CH2:18][CH2:19][NH2+:15][CH2:16]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: c1ccc(COc2ccc(C3CC[NH2+]C3)c(OCc3ccccc3)c2)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
In a 50 ml round-bottomed flask, 1 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Example 4) are dissolved in 16 ml of dichloromethane and then 4 ml of trifluoroacetic acid are added. The reaction mixture is stirred for 1 hour. The solvents are evaporated off and the residue is then taken up in isopropyl ether. 1.26 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate are obtained. Yield=76%.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26](C)[C:27](N)=O)=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C(N)=O)c1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 140 °C
Yield: 30.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.200 g, 0.67 mmol), 1-(4-aminophenyl)-1-methylurea (0.220 g, 1.33 mmol) and cone. HCl (2 drops) in NMP (5 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (40 mL) and then saturated sodium bicarbonate was added until pH˜8. The resulting solid was isolated by filtration then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.071 g, 30%) as a colorless oil. MW=349.86. 1H NMR (CDCl3, 500 MHz) δ 7.83-7.80 (m, 1H), 7.68-7.63 (m, 1H), 7.28-7.26 (m, 2H), 7.10-7.06 (m, 2H), 6.85 (s, 1H), 6.67-6.62 (m, 2H), 5.55 (s, 1H), 3.76 (br s, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (s, 3H), 2.81 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); ESI MS m/z 350 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[CH3:14][N:15](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Yield: 84 %

Procedure:
Into a microwave vial was added 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.75 g, 7.00 mmol), Pd(PPh3)4 (1.132 g, 0.9798 mmol), and zinc cyanide (0.8222 g, 7.002 mmol). The vial was sealed, and then DMF (28 mL) was added. The vial was evacuated and purged with N2 gas (3 times). The reaction mixture was irradiated on the microwave for 3-5 minutes at 150° C. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (60 mL). The organic layer was washed with water (30 mL), brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The crude material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→55:45) as eluent to yield the desired product as a light yellow solid 1.15 g (84% yield). 1H NMR (CDCl3, 400 MHz): δ=4.01 (s, 3H), 7.14 (t, J=1.52 Hz, 1H), 7.19 (dd, J=8.21, 1.39 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].C([N:15]([CH2:18]C)CC)C.C1C[O:23]CC1>>[O:23]1[CH:18]=[N:15][NH:8][C:1]1=[O:2].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Product: O=c1[nH]nco1
Product: c1c[nH]cn1

Procedure:
As depicted in Scheme 41, the 1,3,4-oxadiazol-2(3H)-one-imidazole was synthesized by treatment of the hydrazide with carbonyldiimidazole and triethyl amine in THF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.ClC1C=C(C2C(CO[C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=CN=3)=C(C)ON=2)C=CC=1.[NH2:49]C1CCOCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:49])=[O:21])=[C:17]([CH:46]4[CH2:47][CH2:39][O:44][CH2:43][CH2:42]4)[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(N)=O)c(C2CCOCC2)n1
Yield: 85 %

Procedure:
As described for example 98b, 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.21 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (73 mg, 85%) which was obtained as a white solid. MS: m/e=413.1 [M+H]+.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)OCC[O:18]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCC.CCOCC>C1COCC1>[O:2]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)OCCCCC1(c2ccccc2)OCCO1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)OCCCCC(=O)c1ccccc1

Procedure:
This compound was synthesised as described under 1.e) with 1.45 ml of a 1N solution of HCl, 2.90 g (8.1 mmol) of 4-(2-phenyl-1,3-dioxolan-2-yl)butyl phenoxyacetate obtained under a) in 13 ml of THF for 17 h. Column chromatography (SiO2, heptane/ether 8:2) afforded 1.98 g (78%) of a slightly yellow oil.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=3[O:66][CH3:67])=[N:49][C:50]([O:54][CH3:55])=[N:51]2)=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C.[CH2:77]([SH:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:77]([S:84][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=3[O:66][CH3:67])=[N:49][C:50]([O:54][CH3:55])=[N:51]2)=[CH:46][CH:45]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: SCc1ccccc1
Reactant: COc1nc(-c2ccc(C(F)(F)F)cc2OC)c2ccc(Br)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1nc(-c2ccc(C(F)(F)F)cc2OC)c2ccc(SCc3ccccc3)cc2n1
Reaction time: 1 h

Procedure:
A solution of Pd2(dba)3 (9.20 mg, 10.04 μmol), Xantphos (0.012 g, 0.020 mmol), 7-bromo-2-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (0.166 g, 0.402 mmol), and n,n-diisopropylethylamine (0.211 ml, 1.205 mmol) in 2 mL dioxane was heated to 60° C. and was treated with benzyl mercaptan (0.048 ml, 0.402 mmol). After stirring for one hour, LC/MS showed mostly product, so the reaction mixture was concentrated. This material was carried on to step 5 without purification. (M+H)+=457.2.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.O[CH:24]1[S:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:25]1=[O:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:5][C:6]([C:9]1[CH:13]=[CH:12][N:11]([CH:24]2[S:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)[C:25]2=[O:39])[N:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: O=C1C(O)SCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccn(C2SCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of thionyl chloride (5.3 mL, 73 mmol) in 120 mL of methylene chloride at ˜10° C. was slowly added 3-(1,1-dimethylethyl)-1H-pyrazole (11.32 g, 91 mmol). The resulting solution was stirred for ˜20 minutes and was then cooled further to ˜0° C. To this solution was added N,N-diisopropylethylamine (26.5 mL, 152 mmol) dropwise at ˜0° C. and then 5-hydroxy-3-[3-(trifluoromethyl)phenyl]4thiazolidinone (16 g, 61 mmol) portionwise at temperatures between 0° C. and 10° C. After the addition, the reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 days. To the reaction mixture was then added 120 mL of concentrated sodium bicarbonate aqueous solution. The methylene chloride layer was separated and the aqueous layer was extracted twice with methylene chloride (˜120 mL each). The methylene chloride layers were combined, dried over MgSO4 and then concentrated. The residue was loaded on silica gel in a flash chromatography column and eluted with hexanes followed by methylene chloride to give 15.74 g of a crude product. The crude product was further purified by trituration in hexanes followed by filtration to give the title compound, a compound of this invention, as a tan solid (11.8 g) melting at 66–69° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[N+](=O)[O-]
Yield: 37.5 %

Procedure:
Trifluoromethanesulfonic acid 3-methyl-2-nitrophenyl ester (26.7 g, 93.6 mmol), 1-tert-butoxycarbonyl piperazine (17 g, 91.3 mmol) and triethylamine (14 mL, 100 mmol) in 250 mL of acetonitrile was heated under reflux for 25 h. The mixture was concentrated in vacuo, diluted with water and extracted with ether. The ether was washed with aqueous ammonium hydroxide and brine, dried, and evaporated. Purification by silica gel chromatography (10% ethyl acetate-hexane) afforded 11 g of 4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester as a golden solid, m.p. 101-102° C.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([NH2:5])=[O:4].C(=O)=O.[NH2:13][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15]>CO>[NH2:18][C:17]1[N:16]=[C:14]([NH2:13])[N:15]=[C:1]([CH2:2][C:3](=[O:4])[NH2:5])[N:19]=1
Reactant: N=C(N)NC(=N)N
Reactant: CCOC(=O)CC(N)=O
Agent: O=C=O
Solvent: CO
Product: NC(=O)Cc1nc(N)nc(N)n1
Temperature: 15 °C
Reaction time: 0.58 h

Procedure:
Ethyl malonamate (34.7 g, 0.26 mole) and methanol (100 ml) were placed in a flash equipped with a dropping funnel, a stirrer, and a soda lime trap (to exclude CO2). The flask was cooled to about 15° C. in an ice-water bath. Freshly prepared biguanide (26.3 g, 0.26 mole, in 250 ml methanol) was added, with stirring, over 35 min at 15°-20° C. A white precipitate began to form within 8-9 min. The mixture was allowed to stir overnight at room temperature. It was then cooled to 15° C., and the white precipitate was filtered, washed with cold water to remove sodium sulfate, and finally washed with cold methanol. A crude yield of 32.7 g (76%) was obtained. A pure sample recrystallized from water had a mp of 295°-96° C. (dec.) when placed in a preheated bath at 295° C. Anal. calcd. for C5H8N6O: C, 36.59; H, 4.91; N, 48.76. Found: C, 36.73; H, 5.08; N, 48.51.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.Br[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].F[B-](F)(F)F>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:24][C:22]1[CH:23]=[CH:18][C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:20]([C:9]#[C:8][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:21]=1
Reactant: COC(=O)Cc1ccc(C)cc1Br
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1cc(C)ccc1CC(=O)OC)(CC)CC
Temperature: 70 °C

Procedure:
A solution of triethylsilyl acetylene (0.27 mL, 1.5 mmol) in degassed DMF (4 mL) and Et3N (2.0 mL, 15 mmol) was added to a mixture of methyl 2-(2-bromo-4-methylphenyl)acetate (A84) (0.30 g, 1.2 mmol), PdCl2(PPh3)2 (0.043 g, 0.062 mmol), CuI (0.012 g, 0.062 mmol) and t-Bu3PH.BF4 (0.018 g, 0.062 mmol) in degassed DMF (10 mL). The resulting mixture was heated at 70° C. for 17 hours then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (150 mL). The filtrate was concentrated under reduced pressure and adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-15% EtOAc in petroleum spirits) to yield the title compound A85 as a yellow oil (0.326 g, 72% purity contaminated with starting material); 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.12-7.08 (m, 1H), 3.82 (s, 2H), 3.68 (s, 3H), 2.31 (s, 3H), 1.05 (t, J=7.9 Hz, 9H), 0.72-0.64 (m, 6H).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH2:14]([O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][C@@H:30]([OH:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=1[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:49][CH2:48][C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[NH:45][C:44]2=[O:54])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:54]=[C:44]1[N:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:2]([O:35][C@@H:30]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][C:25]3[CH:24]=[C:23]([CH3:36])[C:22]([O:21][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:27]([CH3:28])[CH:26]=3)=[O:3])[CH2:42][CH2:41]2)[CH2:49][CH2:48][C:47]2[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=2[NH:45]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere 1.93 g (9.58 mmol) 4-nitrophenyl chloroformate was added to a solution of 1.17 g (9.58 mmol) 4-dimethylaminopyridine in 50 mL pyridine, the mixture was stirred for 1.5 h at RT, combined with 3.0 g (9.58 mmol) methyl (R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate and the mixture was stirred for 20 min at RT. Then 2.35 g (9.58 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added and the mixture was stirred for 20 h at RT. The reaction mixture was concentrated by evaporation i. vac., the residue was taken up in EtOAc, the organic phase was washed with 10% KHSO4 and saturated NaHCO3 solution and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, gradient Cyc/EtOAc 1:1 to 1:2).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C@H:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:3]1.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]([C@@H:4]2[CH2:3][C:2]([F:1])([F:21])[CH2:8][CH2:7][NH:6][C:5]2=[O:9])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)(=[O:12])=[O:13])=[CH:27][CH:26]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(OC(F)F)cc1)S(=O)(=O)c1ccc(Cl)cn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
5-Chloro-pyridine-2-sulfonic acid ((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amide (0.21 g, 0.61 mmol), 4-(difluoromethoxy)benzyl bromide (0.23 g, 0.91 mmol), K2CO3 (0.85 g, 6.08 mmol), KI (0.02 g, 0.12 mmol) were added to dry DMF (10 ml) and the resultant reaction mixture was stirred for 1.5 h at 65° C. and for additional 3 h at room temperature under an argon atmosphere. The solvent was removed under reduced pressure and the residue was purified over silica gel (first: ethyl acetate/n-heptane 1:2 v/v; second: dichloromethane/MeOH, 100:0-95:5): brownish oil, 0.23 g;
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2CC(F)(F)F)CC1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a light brown foam (83%).