Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=O)[NH2:28])[CH:23]1[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[N:31]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>C(COC)OC>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[S:2])[NH2:28])[CH:23]1[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[N:31]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(C2C(C(N)=O)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
P2S5 (60 mg, 0.27 mmol) was added to a solution of 3-carbamoyl-2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 0.30 mmol) in dimethoxyethane (10 mL) at rt under an atmosphere of N2. The reaction mixture was heated to 100° C. for 2 h then cooled to rt. Water (20 mL) was added and the solution was extracted with DCM (3×30 mL). The combined organics were dried over Na2SO4, filtered and concentrated under vacuum to afford 100 mg (86%) of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCCSc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc(SCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 5.0 g 4-(2-hydroxy-ethylsulfanyl)-phenol (29 mmol) in 100 ml CH2,Cl2 were added at 0° C. 2.6 ml pyridine (32.3 mmol) and 2.34 ml SOCl2 (32.3 mmol), dissolved in 10 ml CH2Cl2. The reaction mixture was stirred for 1 h at r.t. and then quenched by the addition of water. The organic phase was separated and washed twice with sat. NaHCO3-solution. The combined aqueous phases were extracted with CH2Cl2 twice and the combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give 4.6 g product (24.3 mmol, 83%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:38])([F:37])[C:26]1[N:27]=[C:28]2[N:32]([C:33]=1[C:34](O)=[O:35])[CH:31]=[CH:30][S:29]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[N:32]3[C:28]([S:29][CH:30]=[CH:31]3)=[N:27][C:26]=2[C:25]([F:37])([F:24])[F:38])=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1c(C(F)(F)F)nc2sccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C(F)(F)F)nc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Trifluoromethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=545.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Br:16][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C#N)cc1Br
Reaction time: 2 h
Yield: 41 %

Procedure:
A solution of 5.2 g (27 mmol) of 4'-methyl-1,1'-biphenyl-2-nitrile (Step B) in 60 mL of methylene chloride at 0° C. was treated with 6.7 g of silver trifluoroacetate (30 mmol). When all the silver trifluoroacetate was dissolved, 1.6 mL of bromine was added dropwise (4.95 g, 31 mmol) with vigorous stirring. After two hours, the reaction mixture was filtered and the solid washed with methylene chloride. The combined organic layers were washed once with dilute (<1 N) aqueous sodium hydroxide and once with brine. The organic layer was removed, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with 10% etherexane to give 3 g (41%) of product. 1H NMR (200 MHz, CDCl3): δ 2.46 (s, 3H), 7.2-7.8 (m, 7H).
Reaction SMILES: FC1C=CC(O)=C(C2C3C(=CC=CC=3)N(CCCCC)[C:9]2=[O:22])C=1.[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]([C:35]1[C:36]([OH:44])=[CH:37][C:38]3[O:42][CH2:41][CH2:40][C:39]=3[CH:43]=1)[C:28](=[O:34])[NH:29]2>>[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27]([C:35]1[C:36]([OH:44])=[CH:37][C:38]3[O:42][CH2:41][CH2:40][C:39]=3[CH:43]=1)([CH2:9][OH:22])[C:28](=[O:34])[NH:29]2
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2
Reactant: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 14C, and making non-critical variations to replace 3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (16%): Rf=0.21 (EtOAc/Hexanes, 7/3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
3,5-Difluorophenylacetyl chloride was added dropwise to a 0° C. solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction was stirred for 1 h at 0° C. and then overnight at room temperature. The reaction was diluted with water (100 mL), then extracted with ethyl acetate (3×150 mL). The organic layer was then washed with brine (200 mL), dried over MgSO4, and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes afforded the desired product (34.5 g, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[O:14]=[C:13]1[NH:15][C:26]2([CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]1=2
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), N-Boc-piperidin-4-one (0.600 mg, 3.00 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with ethyl acetate-dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.184 g, 92%) as a yellow solid:
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][C:31]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=2)([OH:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC[C@H](C)COCc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC[C@H](C)COCc1ccc(C2(O)CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.32 mmol of 1,2-dibromoethane are added to a suspension of 156.518 mmol of magnesium in 20 ml of tetrahydrofuran under argon at room temperature. The reaction mixture is warmed until the magnesium starts to react and then 3 ml of a solution of 151.509 mmol of 1-bromo-4-((S)-3-methoxy-2-methyl-propoxymethyl)-benzene in 170 ml of tetrahydrofuran, followed by the rest of the solution, is added while maintaining a gentle reflux. After 2 hours, the reaction mixture is cooled to room temperature and then a solution of 125.214 mmol of 1-benzyl-3-trityloxymethyl -piperidin-4-one [234757-27-8] in 170 ml of tetrahydrofuran is slowly added, taking care to keep the internal reaction temperature under 40° C. After overnight stirring at room temperature, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. Ethyl acetate is added to the reaction mixture and the phases separated—the organic phase is washed successively with water and brine. The combined aqueous phases are back-extracted with ethyl acetate—the combined organic phases are dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.30 (EtOAc-heptane-25% ammonia conc. 100:100:1); Rt=5.43 (gradient I).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C=O)C>[CH3:14][C:12]1[O:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[C:18](=[O:28])[C:19]4[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:21]3=[O:23])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=2)[N:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(-c2ccc(CBr)c([N+](=O)[O-])c2)no1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of compound 1c (5.64 g, 19 mmol) and potassium pthalimide (3.9 g, 20.9 mmol) in DMF (42 mL) was heated to 40° C. for 4 h. The reaction mixture was cooled to rt and poured into water (200 mL). The solid was filtered, washed with water (3×), and dried in vacuo to give compound 1d as a white solid (6.2 g, 90%). ESI-MS m/e 365.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([C:33]([OH:35])=[O:34])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
Under nitrogen, a solution of 4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to −78° C. A solution of n-butyllithium (1.5 mL, 1.6M in hexanes) was added dropwise and the mixture maintained at this temperature for 25 minutes. Carbon dioxide gas (generated from dry ice and dried by passage through a column of calcium chloride pellets) was bubbled through the anion solution for 80 minutes then the mixture was allowed to warm to room temperature. The solvents were removed in vacuo then the residue was partitioned between 1N hydrochloric acid and diethyl ether. The organic phase was separated, dried (MgSO4), filtered and concentrated. The combined aqueous phases were further extracted with ethyl acetate, this extract also being dried (MgSO4), filtered, combined with the ethereal extract and concentrated to afford 4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (889 mg); LCMS (PS-A2) Rt 3.52 min [M−tBu+H]+ 360. *This starting material can be made by the method described in Example 14A followed by Example 48A
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)[C:5]([Cl:19])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1>CCCCO>[Cl:19][C:5]1[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: COC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC1COC2C(Nc3nc(Nc4cnn(C)c4)ncc3Cl)COC12
Yield: 42.7 %

Procedure:
A solution of 2,5-dichloro-N-(6-methoxyhexahydrofuro[3,2-b]furan-3-yl)pyrimidin-4-amine (430 mg, 1.4046 mmol), DIPEA (546.7 mg, 4.23 mmol) and 1-methylpyrazol-4-amine hydrochloride (283.3 mg, 2.12 mmol) in n-BuOH (10 mL) was stirred in a sealed tube at 150° C. for 23 h. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the crude product as a white solid. The crude product was recrystallized from acetone to give the title compound as a white solid (220 mg, 42.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1.N>>[Cl:31][C:28]1[S:27][C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Clc1ccc(Br)s1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(Cl)s3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-bromo-5-chlorothiophene in place of 4-bromothioanisole (yield: 150 mg, 45%). mp 249-251° C. 1H NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 6.92 (d, J=9 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 2H), 7.58 (d, J=6 Hz, 1H), 7.94 (d, J=9 Hz, 2Hz, 2H), 8.04 (s, 1H). MS (DCI/NH3) m/z 477 (M+H)+, 494 (M+NH4)+. Anal. calc. for C21H14Cl2N2O3S2.H2O: C, 50.9; H, 3.03; N, 5.60. Found: C, 50.5; H, 2.79; N, 5.26.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[NH:20]([CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[NH2:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:20]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:21]=1
Reactant: NNCc1cccnc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2cccnc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 5 h with 6.2 g of 3-hydrazinomethylpyridine hydrochloride (57616-01-0) and 13 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxy-phenyl)-1-(pyridin-3-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 174-176° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:12])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc(Cl)ncc1F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A stirred, −78° C. solution of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)ethanone (10.06 g, 57.6 mmol) in tetrahydrofuran (100 mL) under nitrogen is reacted with a 3 M solution of methyl magnesium bromide in diethyl ether (124 mL, 72.04 mmol) and the resulting mixture is stirred at −78° C. for 20 minutes. The reaction is quenched with aqueous saturated ammonium chloride and the mixture is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The crude product is purified over silica gel with a 30 minute, 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (7.06 g, 64%). ES/MS (m/e): (35Cl/37Cl) 191/193 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21](O)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 83A in analogy to the synthesis of the compound of Example 1. 16 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:51]=[N:50]2)[CH2:46]1)(C)(C)C>>[OH:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:51]=[N:50]2)[CH2:46]1
Reactant: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C5CC(O)C5)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 100A).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.C(OCC)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-difluoro-2-nitrobenzen (5.0 g, 31.4 mmol) in 50 mL of dry DMF was added K2CO3 (4.41 g, 32 mmol) and diethyl malonate (3.6 mL, 31.4 mmol). The reaction mixture was heated to 65° C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with 2 N HCl and extrated with diethyl ether. The ether layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified via column chromatograph to afford diethyl (3-fluoro-2-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 7.50˜7.55 (m, 1H), 7.38˜7.40 (rn, 1H), 7.23˜7.28 (m, 1H), 4.82 (s, 1H), 3.77 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: Fc1cnc2[nH]cc(Br)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(F)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) was dissolved in DMF (37.5 mL) and cooled to 0° C. Sodium hydride (1.5 g, 37.2 mmol) was added and the reaction mixture was stirred for 10 minutes and then treated with tosyl chloride (6.6 g, 34.9 mmol). The mixture was stirred for 30 minutes at 0° C. and then at room temperature for another 90 minutes. The reaction mixture was poured into water (100 mL) and the resulting solid was collected, washed with water and hexanes three times and dried in vacuo to afford 8.26 g of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.92 (dd, J=8.4, 2.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:18][C:15]1([CH3:19])[N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13](=[O:20])[N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)[C:16]1=[O:17]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C

Procedure:
Using the procedure of Example 1, 1 g of 1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazolidine-2,5-dione was reacted with a 50% suspension of 170 mg of sodium hydride in oil and 0.7 ml of 1-bromononane to obtain after chromatography on silica 1.08 g of the desired product melting at 63° C.