Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:8]=2[Cl:7])=[CH:17][CH:16]=1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 80.8 %

Procedure:
13 g (0.14 mole) of dimethylcarbamic acid chloride were added dropwise to 29 g (0.1 mole) of 4-(2-chloro-4-trifluoromethyl-phenoxy)-aniline, dissolved in 50 ml of pyridine, at 0° C. The mixture was warmed to 70°-75° C for half an hour, the bulk of the pyridine was stripped off in vacuo and the residue was poured into water and acidified with dilute hydrochloric acid. The precipitate was filtered off, dried and recrystallized from toluene. 29 g (89% of theory) of N,N-dimethyl-N'-[4-(2-chloro-4-trifluoromethylphenoxy)-phenyl]-urea were obtained as pink crystals of melting point 140° C.
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Br:17]Br.OO>O>[N+:4]([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([Br:17])[O:12][C:13]2=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: BrBr
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: OO
Solvent: O
Solvent: ClCCl
Product: O=C1OC(Br)c2ccc([N+](=O)[O-])cc21

Procedure:
To 125 ml of a dichloromethane solution of 6-nitrophtalide (8.0 g, 0.047 mol), bromine (8.25 g, 0.052 mol, 1.15 eq) and hydrogen peroxide (5.07 g of a 35% solution in water, equivalent to 1.77 of hydrogen peroxide, 0.052 mol, 1.15 eq) were added. The mixture was gently refluxed for 11 hours, then cooled down and concentrated by solvent evaporation. The aqueous layer was separated, and the organic phase washed with water before drying up (Na2SO4).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCc1cc(N)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.131 g, 0.267 mmol) and 5-ethyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.091 g, 0.27 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.134 mL, 0.535 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.23-9.40 (m, 1H), 8.44 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.75 (dd, J=8.4, 1.6 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.29-7.45 (m, 2H), 7.21-7.29 (m, 1H), 7.07-7.21 (m, 2H), 6.91 (t, J=6.8 Hz, 1H), 6.78 (s, 1H), 6.54 (d, J=5.1 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.06-3.20 (m, 2H), 2.86-3.01 (m, 5H), 2.57-2.72 (m, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (dd, J=11.6, 0.6 Hz, 2H), 1.60-1.71 (m, 2H), 1.40-1.55 (m, 1H), 1.20-1.39 (m, 2H), 1.06 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 796.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=O)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(#N)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=[S:19])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ncc(Br)cc2C1=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ncc(Br)cc2C1=S
Yield: 59.6 %

Procedure:
To a solution of 5.9 g (0.016 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one in 25 ml of acetonitrile was added 2.07 g (0.005 mole) of phosphorus pentasulfide. The mixture was heated to reflux for 3 hr. The reaction mixture was diluted with 100 ml of toluene and filtered. The filtrate was washed with 3×50 ml of saturated sodium bicarbonate and 50 ml of water, dried over sodium sulfate, filtered, and concentrated by rotary evaporation to ~5-10 ml. Crystallization ensued and 3.0 g of crystals were collected. The mother liquor was concentrated giving 1.0 g additional crystals. The two crops were combined and recrystallized from diisopropylether/toluene to give ~3 g (56%) of yellow crystals, m.p. 138°-141° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3cc(OC)ccc32)n1
Product: CCc1nc(NC2CCCc3cc(OC)ccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.26, 6.78, 6.69, 5.33, 4.49, 3.82, 2.89-2.78, 2.55, 2.05-1.84, 1.33-1.26; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1180.
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A solution of Intermediate 54c (171 mg, 0.311 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 132 mg, 0.327 mmol) in 1,4-dioxane (3 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 90° C. for 3 h, and then at 100° C. for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown solid (215 mg, 86%). LCMS (Method 3): Rt 5.70 min, m/z 805.4 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH:17]OCC)[C:6](=[O:16])[C:7]1[C:8]([Cl:15])=[N:9][C:10]([Cl:14])=[C:11]([F:13])[CH:12]=1)[CH3:2].[CH2:22]([CH2:24][NH2:25])[OH:23]>CCOCC>[Cl:15][C:8]1[N:9]=[C:10]([Cl:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6](/[C:5](=[CH:17]/[NH:25][CH2:24][CH2:22][OH:23])/[C:4]([O:3][CH2:1][CH3:2])=[O:21])=[O:16]
Reactant: NCCO
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)nc1Cl
Solvent: CCOCC
Product: CCOC(=O)/C(=C\NCCO)C(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,6-dichloro-α-(ethoxymethylene)-5-fluoro-β-oxo-3-pyridinepropanoic acid ethyl ester (1.00 g; prepared according to EP 132845) was treated with ethanolamine (0.18 mL). After a few minutes, the reaction mixture became sticky and was diluted with Hept/ether (1:1; 10 mL). After further stirring at rt for 1.5 h, the solvents were evaporated under reduced pressure and the crude yellow oil was directly used in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.I[C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: Oc1cccnc1I
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccnc1C1=CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 2-iodo-3-hydroxypyridine (Aldrich, 0.177 g, 0.801 mmol), and tetrakis(triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:21][CH:22]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under protective gas, 1.6 g (0.053 mol) of sodium hydride (80% strength) are suspended in 50 ml of DMF, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation according to EP 324,377) in 100 ml of DMF are added dropwise at 0° C., then the mixture is stirred at 0° C. for 15 min and 18.9 g (0.053 mol) of tertbutyl 2-(4-bromomethylphenyl)-2-cyclopentylacetate in 100 ml of DMF are added dropwise. The mixture is stirred for 2 h at 0° C., the solvent is evaporated, the residue is taken up in diethyl ether, the solid is filtered off and, after concentration, the residue is chromatographed on silica gel 60 using dichloromethane. Yield: 16.2 g (66.7% of theory) Solidification point: 101°-102° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>CCO>[NH2:2]/[C:1](=[N:17]\[OH:18])/[CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC1/C(N)=N/O

Procedure:
A solution of of the product of Step 3 (1 eq.), hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in EtOH (0.5 M) was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in EtOAc and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated giving the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH:36]=[CH:35]1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:34](=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)C=CC(=O)O)C(=O)C=CC(=O)O
Yield: 79.5 %

Procedure:
A reactor was charged with 20 g (0.04 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane and 100 g of xylene, to which 10 g (0.1 mole) of maleic anhydride were then added with stirring to conduct a reaction at 50° C. for 6 hours. After xylene was distilled off under reduced pressure, 300 ml of water were added, and 10% sodium hydroxide was further added to keep the pH of the reaction mixture at 7. Thereafter, the reaction mixture was subjected to electrodialysis and lyophilized, thereby obtaining 22 g (isolation yield: 80%) of 6,10-dihydroxy-4,12-dioctyl-3,13-dioxo-8-sulfoethyl-4,8,12-triaza-1,14-pentadecadiene-1,15-dicarboxylic acid as white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].F[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N+:14]=[N-:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].O.Cl>C(O)C>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCN
Agent: Cl
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NCCCN)c([N+](=O)[O-])c1

Procedure:
2.5 ml (30 mM) 1,3-diaminopropane was dissolved in 25 ml ethanol. To this solution, was added a solution of 1.82 g (10 mM) 4-fluoro-3-nitrophenyl azide in 25 ml ethanol. The addition was performed dropwise with stirring. The mixture was stirred at room temperature for 16 hours. After this time, 150 ml of water were added and the pH adjusted to between 1 and 2 with concentrated HCl. This solution was filtered to remove the disubstituted amine, cooled on ice and the product was precipitated by the slow addition of concentrated aqueous ammonia with stirring. The product was collected by filtration of the cold mixture, washed with ice-cold water and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 14 %

Procedure:
As described for example 92, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (16 mg, 14%) which was obtained as a light brown solid. MS: m/e=393.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1[NH:33][C:32](=[O:34])[C:31]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:30]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:37]2[CH2:36][CH2:35][C:31]3([N:30]=[C:29]([C:23]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=4[Cl:21])[NH:33][C:32]3=[O:34])[CH2:39][CH2:38]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCN(S(=O)(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
Triethylamine (88 μl, 0.632 mmol) and 4-chlorobenzenesulfonyl chloride (70 mg, 0.332 mmol) were added to a mixed solution of 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (100 mg, 0.299 mmol) in dichloromethane (3 ml). The reaction solution was stirred at room temperature for 16 hours and then diluted with dichloromethane, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give 8-(4-chloro-benzenesulfonyl)-2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (70.8 mg, 96%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: OCCCCCCl
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCCCO)CC1

Procedure:
1-(5-Hydroxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-hydroxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:65][C@@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:68]2[CH2:69][CH2:70][C@@H:66]([F:65])[CH2:67]2)=[O:16])[N:7]=1
Reactant: F[C@@H]1CCNC1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CC[C@@H](F)C3)N2)n1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and (R)-3-fluoropyrrolidine (0.06 mmol, 7.5 mg). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (Compound 85, 13.0 mg, 50%) as light brown solid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.40 (m, 2H) 2.72 (s, 3H) 3.06 (dd, J=16.93, 10.36 Hz, 1H) 3.27-3.38 (m, 1H) 3.39-3.62 (m, 4H) 3.63-3.78 (m, 2H) 3.82 (s, 3H) 4.47-4.67 (m, 2H) 4.87 (dd, J=10.36, 3.03 Hz, 1H) 5.11-5.36 (m, 1H) 6.69 (d, J=8.34 Hz, 1H) 6.97 (d, J=7.33 Hz, 1H) 7.06 (dd, J=9.35, 2.53 Hz, 1H) 7.13 (t, J=8.34 Hz, 1H) 7.50-7.70 (m, 2H). MS (ES) [M+H] calculated for C26H28F2N7O3, 524.53; found 524.50.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 50 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.120 g, 0.41 mmol) in pyridine (4.0 mL) was added phenyl isocyanate (0.055 g, 0.46 mmol) and the reaction mixture was heated to 50° C. After 18 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 0:100 heptane/ethyl acetate, gradient elution) to provide 4-(2-tert-butylphenyl)-N-phenylpiperazine-1-carboxamide (0.093 g, 67%) as an off-white solid, mp 68-72° C.
Reaction SMILES: [CH2:1](Br)[CH2:2]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][CH2:10][CH2:8][NH:9][C:2]2[CH:1]=[CH:11][CH:12]=[C:6]([Cl:5])[CH:7]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: BrCCBr
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(NCCNc2cccc(Cl)c2)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture consisting of 188 gm of ethylene bromide, 383 gm of 3-chloro-aniline and 300 gm of sodium carbonate was stirred at 140° C. for five hours. Thereafter, the reaction mixture was cooled to about 80° C., and by addition of water the inorganic substances were caused to go into solution. The mixture was then extracted with ethyl acetate, the organic extract was dried over sodium sulfate, and the solvent as well as unreacted 3-chloroaniline were distilled off in vacuo, leaving 205 gm (76% of theory) of raw N,N'-bis-(3-chlorophenyl)-ethylenediamine. The raw product may be purified by distillation at 16 mm Hg and about 285° C.