Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:37])/[CH:23]=[C:24](\[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)/[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:48]>CO>[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](/[CH:23]=[C:24](\[C:29]2[CH:30]=[C:31]([C:35]([NH2:36])=[NH:48])[CH:32]=[CH:33][CH:34]=2)/[C:25]([F:26])([F:27])[F:28])=[O:37])=[CH:19][CH:20]=1)(=[O:7])(=[O:8])[NH2:5]
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)/C=C(\c2cccc(C#N)c2)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N=C(N)c1cccc(/C(=C\C(=O)Nc2ccc(-c3ccccc3S(N)(=O)=O)cc2)C(F)(F)F)c1
Yield: 61.4 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4,4,4-trifluorobut-2-enamide (90 mg, 0.19 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was placed in the refrigerator at 0° C. over the weekend. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated then treated with 10 ml trifluoroacetic acid for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}-1-(trifluoromethyl)vinyl)benzenecarboxamidine (57 mg, 47%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 489.15
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[S:14][C:13]=1Br)=[O:11].C(=O)([O-])[O-].[K+].[K+]>>[CH3:17][C:15]1[S:14][C:13]2[O:1][C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C)c2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(s1)Oc1c(C)cccc1NC2=O

Procedure:
In the same manner as in Example 98 and using N-(2-hydroxy-3-methylphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, 2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:14])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1nnc(-c2ccc(Br)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCCCl)Nc1nnc(-c2ccc(Br)cc2)s1
Yield: 86.6 %

Procedure:
A mixture of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (10.2 g, 0.04 mol), 4-chlorobutyryl chloride (11.3 g, 9.0 ml, 0.08 mol) and potassium carbonate (5.5 g, 0.04 mole) in toluene (100 ml) was heated under reflux for 4 hr. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from toluene to give the required product (12.5 g, 87% yield), mp 187-9° C., m/e 360, 15.7% (consistent with molecular formula C12H11BrClN3OS, calcd. 360.66). 1H NMR (DMSO-d6): δ 1.96-2.22 (m, 2H, —CH2), 2.69-2.81 (m, 2H, —CH2), 3.71-3.72 (m, 2H, —CH2), 7.49-7.88 (dd, 4H, ArH), 12.76 (br s, 1H, NH). 13C NMR: δ 27.3, 32.1, 44.6, 123.8, 128.7, 129.4, 132.3, 158.5, 160.7, 170.7.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[F-].[K+].O1CCOCC1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C(Cl)Cl.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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3nccs3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-Tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min in a microwave reactor. Further 2-tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM]. Fractions containing product were combined, concentrated in vacuo, chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and dried in vacuo to give the title compound as pale yellow film. 1H NMR (CDCl3, 400 MHz): δ=8.61 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.29 (dd, J=4.4, 8.4 Hz, 1H), 7.06 (dd, J=8.4, 9.2 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.83 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=423.96/425.90/427.93 (100/95/27) [MH+], 234.03 (30) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.65 min (polar—5 min, ZQ3).
Reaction SMILES: NC1C=CC(OCCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](CCCCOC2C=CC(N)=CC=2)(C)C)=CC=1.[N+:40]([C:43]1[CH:74]=[CH:73][C:46]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][Si:52]([CH3:72])([CH3:71])[O:53][Si:54]([CH2:57][CH2:58][CH2:59][CH2:60][O:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-])=O)=[CH:64][CH:63]=2)([CH3:56])[CH3:55])=[CH:45][CH:44]=1)([O-])=O>>[NH2:40][C:43]1[CH:74]=[CH:73][C:46]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][Si:52]([CH3:72])([CH3:71])[O:53][Si:54]([CH2:57][CH2:58][CH2:59][CH2:60][O:61][C:62]2[CH:63]=[CH:64][C:65]([NH2:68])=[CH:66][CH:67]=2)([CH3:55])[CH3:56])=[CH:45][CH:44]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)CCCCOc1ccc(N)cc1

Procedure:
By the same synthesis procedure as for (3c) in Example 1, the above (2a) was reduced to obtain 1,3-bis(4-aminophenoxybutyl)-1,1,3,3,-tetramethyldisiloxane (3a) (a light brown oily liquid (98% of yield)) represented by the following formula. Various measurements were carried out with regard to the obtained 1,3-bis(4-aminophenoxybutyl)-1,1,3,3,-tetramethyldisiloxane (3a), and results are shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])=[O:9])[CH:5]=[CH:4][C:3]=1[S:23](Cl)(=[O:25])=[O:24].[S:27]1[C:31]([NH2:32])=[N:30][CH:29]=[N:28]1.[OH-].[Na+].O1CCOCC1.O>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:23]([NH:32][C:31]1[S:27][N:28]=[CH:29][N:30]=1)(=[O:25])=[O:24])[C:8]([NH:10][CH2:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH3:13])=[O:9]
Reactant: Nc1ncns1
Reactant: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-Fluoro-4-({[2-(4-fluorophenoxy)-2-methylpropyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 95, 242 mg, 0.599 mmol) was added portion-wise to a solution of 1,2,4-thiadiazol-5-amine (182 mg, 1.80 mmol) and sodium hydroxide (71.9 mg, 1.80 mmol) in 1,4-dioxane (1.9 mL, 24 mmol) and water (0.37 mL, 21 mmol). After stirring 30 min at ambient temperature, the reaction was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (48 mg, 16%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]([F:42])([F:41])[C:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(C)=O)(C)C>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:19][C:18]=3[C:29]([F:31])([F:32])[F:30])(=[O:16])=[O:15])[CH2:11][N:10]2[C:38]([C:35]2([C:34]([F:42])([F:41])[F:33])[CH2:37][CH2:36]2)=[O:39])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2)CC1
Reactant: O=C(O)C1(C(F)(F)F)CC1
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: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
(2S,4R)-4-[4-(2,2,2-Trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (20 mg, 41 umol; example 211a) was dissolved in DMF (0.4 ml) under a N2-atmosphere at ambient temperature. 1-Trifluoromethyl-cyclopropanecarboxylic acid (10 mg, 62 umol; CAS Reg. No. 277756-46-4), HATU (23 mg, 62 umol) and DIEA (10 ul, 62 umol) were added and the reaction mixture was stirred for 48 h at ambient temperature. Ice water/brine 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (13 mg, 21 umol; 51%) as colorless solid. MS (ESI): m/z=622.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:33]>CCOC(C)=O.O1CCOCC1>[ClH:33].[Br:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[O:13])[C:8]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCN(C(=O)OC(C)(C)C)CC3)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)Cn2c3c(c4cccc(Br)c42)CCNCC3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 7-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl }-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.280 g, 0.52 mmol) was dissolved in EtOAc (15 mL). 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at rt under N2. After 1 h, a white solid precipitated from the solution. The precipitate was collected by filtration. Pure 2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide hydrochloride was obtained after recrystallization from 3:1 CH3OH:Et2O (20 mL), as a white solid (0.220 g) in 94% yield. 1H NMR (400 MHz, CD3OD) δ 2.4, 3.22-3.28, 3.49-3.59, 5.7-5.78, 6.88, 7.02, 7.35, 7.54; MS (ESI+) for C18H19BrN4OS m/z 420.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH2:31]([NH:34][CH3:35])[CH:32]=[CH2:33]>>[CH2:31]([N:34]([C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)[CH3:35])[CH:32]=[CH2:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: C=CCNC
Product: C=CCN(C)c1nccc(Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)n1
Temperature: 75 °C

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and N-allyl-N-methylamine (0.25 ml) was stirred and heated to 75° C. for 3 hours. The mixture was cooled to ambient temperature and purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant oil was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound as a solid (0.055 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.95 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 4.1 (d, 2H), 5.04 (m, 2H), 5.75 (m, 1H), 5.91 (m, 1H), 7.07 (m, 1H), 7.17 (m, 2H), 7.19 (m, 1H), 7.86 (m, 1H), 7.98 (m, 1H), 8.25 (m, 1H), 8.42 (s, 1H), 10.17 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: C(OC([NH:8][C:9]([NH:27]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[ClH:35].[F:25][C:23]([F:24])([F:26])[C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:27])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C(F)(F)F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)Nc1cccc(-c2ncccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-trifluoromethylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added 4N hydrogen chloride in 1,4-dioxane (4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-trifluoromethylpyridin-2-yl) phenylguanidine dihydrochloride (111 mg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=O)=[O:4].Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]2[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][CH3:22])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N+:24]=1[O-:25]
Reactant: CCc1cccc(C(=O)c2ccccc2F)c1NC(=O)CBr
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c1NC(=O)C[N+]([O-])=C2c1ccccc1F
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 94.1 %

Procedure:
A mixture of 2-bromoacetylamino-3-ethyl-2′-fluorobenzophenone (12.0 g), hydroxylamine hydrochloride (17.65 g), sodium hydroxide (8.58 g) in ethanol was stirred at 30-40° C. for 4.5 hours. Concentrated aqueous hydrochloric acid (14.8 ml) was added to the reaction mixture, which was stirred at room temperature overnight. The mixture was evaporated in vacuo to afford precipitates. Water was added to the resultant mixture. The precipitate was collected by filtration and washed with water to afford 5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (9.25 g, 94.2%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (3.68 g, 11.12 mmol) in DMF (30 mL) was added sodium azide (1.83 g, 27.79 mmol) and the reaction was stirred at 80° C. for 1 hour. After aqueous workup, the mixture was concentrated to give the title compound.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([O-])=O>O.[Fe]>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([CH:11]=1)[NH2:3]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
Iron powder (9.3 g, 0.166 mM) and ammonium chloride (1.7 g, 0.032 mM) were stirred in water (42 ml) at 100° C. for 30 minutes. Commercially available 2-nitro 4-bromo fluorobenzene (9.2 g, 0.42 mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100° C. for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times. The organic layers were combined, dried (MgSO4), passed through a plug of SiO2, and concentrated to afford 4.2 g (53% yield) of the desired product as a red oil. The product was used without further purification. NMR (CHCl3) δ 3.78 (bs, 2H); 6.65–7.07(m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27]>>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[CH3:2]
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Product: CCOC(=O)/C(=C/c1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester [preparation 1a)] was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give (Z)-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-ethoxy-acrylic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[CH:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4]1>CO>[CH3:2][C:3]1([CH3:24])[CH2:4][C:5](=[O:6])[CH2:10][CH2:11][CH:12]1[NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC2(CCC1NC(=O)OCc1ccccc1)OCCO2
Agent: Cl
Solvent: CO
Product: CC1(C)CC(=O)CCC1NC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 91 %

Procedure:
2 M HCl (14 ml) was added to a solution of benzyl 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (1.4 g, 4.3887 mmol, 1 eq) in MeOH (14 ml), and stirring was carried out for 18 h at RT. The solvent was concentrated under reduced pressure and the residue was diluted with water (10 ml) and rendered basic with sat. sodium hydrogen carbonate solution (20 ml). Then extraction with ethyl acetate (2×50 ml) was carried out. The combined organic phases were washed with water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 91% (1.1 g, 4.0 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[C:10]2[C:11](=[O:12])[N:16]3[C:17](=[O:24])[C:18]([CH:21]([CH3:22])[CH3:23])([CH3:20])[N:19]=[C:15]3[C:9]2=[N:8][CH:7]=1
Reactant: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C2c3ncc(C4OCCO4)cc3C(=O)N2C1=O
Yield: 71.9 %

Procedure:
A solution of 5-(1,3-dioxolan-2-yl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (1.0 g, 0.003 mol) and dicyclohexylcarbodiimide (0.65 g, 0.003 mol) in tetrahydrofuran (5 mL) is stirred at reflux temperature for 1.5 hours. After cooling, the reaction mixture is filtered. The filtrate is concentrated in vacuo to afford the title compound (0.68 g, 72%) as a pale yellow solid, mp 102°-104° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:17].[OH-].[Na+].[OH-].[K+]>O=P(Cl)(Cl)Cl>[C:1]([C:4]1[CH:13]=[C:12]([Cl:17])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)cc(C(=O)O)nc2c1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
To 20 mL POCl3 was added 2-carboxy-7-methyl-4-hydroxyquinoline (2.5 g, 12.3 mmol) and PCl5 (11.5 g, 55 mmol). The mixture was heated to 130° C. for 3 hours. The reaction mixture was cooled and poured onto ice. The solution was neutralized with solid NaOH and adjusted to pH 11 with solid KOH. The tan precipitate was filtered, slurried in 250 mL water and adjusted to pH 2 with concentrated HCl. The resultant solid was filtered and dried to afford 2-carboxy-7-methyl-4-chloroquinoline (1.34 g, 50%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][C:16]([NH2:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[C:16]([NH:19][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC(C)(C)C
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3 g, 12.89 mmol), 2-methylpropan-2-amine (1.565 mL, 14.83 mmol) and DIEA (2.93 mL, 16.76 mmol) in ethanol (20 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 4-(tert-butylamino)-2-(methylthio)pyrimidine-5-carboxylate (3.20 g, 11.86 mmol, 92% yield) as a colorless oil. MS (ESI) m/z. 269.5 [M+1]+.