Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
120.00 g (0.33 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) of triethylamine were stirred in 1200 ml of toluene at 60° C. for 2 days. The precipitated solid was filtered off with suction and recrystallized from acetone/n-hexane. 102.10 g (71%) of the title compound having a melting point of 243-245° C. were obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:19](=[O:20])[CH2:18][O:17][CH3:16])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and methoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (59 mg, 72%). HPLC, Rt: 2.21 min. (purity 98.2%). LC/MS, M+(ESI): 273.4, M−(ESI): 271.4.
Reaction SMILES: [NH2:1][CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].C(N1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])(OCC)=O.P(=O)(O)(O)O>P([O-])([O-])(O)=O.[K+].[K+].CC(C)=O.O>[C:35]1(=[O:44])[N:1]([CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]2[C:24](=[O:25])[N:11]3[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]23)=[O:7])[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(N)C(=O)O)[C@H]2SC1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(C(=O)O)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 15 grams of 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 150 milliliters of 10 percent potassium hydrogen phosphate buffer solution (adjusted to pH 9.1 by addition of 25 percent potassium phosphate solution) was added 9.9 grams of N-carbethoxy phthalimide in 75 milliliters of acetone. The reaction mixture was stirred at room temperature for one hour at pH 9.1, diluted with water to 300 milliliters, and the pH adjusted to 7.0 by addition of phosphoric acid. The acetone was then evaporated and the reaction mixture extracted with ethyl acetate:ethanol (88:12) to remove the phthalimide. The pH of the aqueous layers was adjusted to 2 by addition of phosphoric acid and the mixture extracted with ethyl acetate:ethanol (88:12). The extract was dried with anhydrous magnesium sulfate and filtered, and the filtrate evaporated to dryness, leaving as a residue the desired 7-(5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid as a foam. It was digested three times with 500-milliliter aliquots of ether. The ether washed product amounted to 17.05 grams.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[CH:9]=[CH2:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:9]=[CH2:10]
Reactant: C1=COCCC1
Reactant: C=CC(O)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C=CC(OC1CCCCO1)c1ccccc1Br

Procedure:
To 1-(2-bromophenyl)prop-2-en-1-ol) (31.0 g; 0.145 mol) in 150 ml of dry THF (tetrahydrofuran) was added 20 ml of 3,4-dihydro-2H-pyran and then 1 ml of POCl3 and the mixture stirred over the weekend at room temperature. The reaction mixture was neutralized with saturated NaHCO3 and concentrated down. The resulting material was partitioned between water and diethyl ether and the aqueous layer extracted again with diethyl ether. The organics were combined and washed with water and then brine and dried over K2CO3 and concentrated. The crude subtitle compound was chromatographed by HPLC using a solvent gradient from pure hexane to 5% ethyl acetate in hexane to afford the subtitle compound.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[NH2:54]>C(O)(=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([N:54]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: COc1ccc(N)cc1OC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1OC
Yield: 59 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (52 mg, 0.22 mmol), triethyl orthoformate (0.45 ml), 3,4-dimethoxyaniline (62.8 mg, 0.41 mmol), and acetic acid (0.06 ml) were used to give 48 mg (0.13 mmol, 59% yield) of the title compound.
Reaction SMILES: ClCl.[F-].[Cl:4][C:5]1[C:6]([F:12])=[C:7](F)[CH:8]=[CH:9][CH:10]=1.[F:13]C1C=C(F)C=CC=1[N+]([O-])=O>>[F:12][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: Fc1cccc(Cl)c1F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: ClCl
Agent: [F-]
Product: Fc1ccc(Cl)c(F)c1
Reaction time: 1.5 h
Yield: 91 %

Procedure:
The chlorine gas which is used is employed in anhydrous form. The reaction of the m-difluoronitro-aromatic compounds with the chlorine must be carried out in the absence of Lewis acids or other chlorinating catalysts. The required temperatures are within the range from 80° to 250° C. preferably 100° to 200° C. The reaction can be carried out in the presence or absence of a fluoride-capturing agent. The necessary chlorodifluorobenzene compound (starting compound) can, for example, be prepared as follows: 1800 g (11.3 mol) of 2,4-difluoronitrobenzene (anhydrous and free of Lewis acids) are initially introduced into a 2 l four-neck flask having a stirrer, gas-entry tube and distillation bridge. The reaction solution is brought to 160° C. A stream of chlorine of 4-6 l/h is then passed through the solution at this temperature. After 1-2 h, brown gases are formed which are absorbed in dilute sodium hydroxide solution. After 28 h, the entry of gas is stopped and the reaction solution is distilled (head temperature 127° C). 675.8 g of 2,4-difluorochlorobenzene are obtained, corresponding to a yield of 91%, based on reacted 2,4-difluoronitrobenzene.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.C([OH:14])C=C>>[CH:8]12[CH2:7][CH:6]([CH:10]=[CH:9]1)[CH2:5][CH:4]2[CH2:3][OH:14]
Reactant: C=CCO
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: OCC1CC2C=CC1C2
Temperature: 190 °C
Reaction time: 3.5 h
Yield: 67 %

Procedure:
132 g (1 mol) of dicyclopentadiene and 116.2 g (2 mol) of allyl alcohol were placed into a 300 ml high-pressure reactor and stirred at 190° C. for 3 to 4 hours. The resulting solution was distilled at 80° C. under vacuum to give 5-norbornene-2-methanol. (Yield: 67%, 166 g)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:31][O:32][CH2:33][CH3:34].C1C=CC=CC=1>CCCCCC>[CH2:33]([O:32][CH2:31][N:3]1[C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])[CH3:34]
Reactant: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1
Reactant: CCOCCl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1COCC

Procedure:
By following the same procedure as in Example 25 except that 0.5 g. of diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.5 g. of chloromethoxyethane were used as the starting materials, benzene was used as the eluant, and hexane was used as the solvent for recrystallization, 0.35 g. of colorless acicular crystals of diethyl 1-ethoxymethyl-2-methyl-4-(3-nitrophenyl)-6-propyl-1,4-dihydropyridine-3,5-dicarboxylate melting at 97° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:60])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:57])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2CCN(C4C=CC=CN=4)C[CH2:46]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:58])[C@@H:9]1[OH:59])([CH3:4])([CH3:3])[CH3:2].[N:61]1([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][N:76]=2)[CH2:66][CH2:65][CH:64]([NH:67][C:68]([N:70]2[CH:74]=[CH:73]N=[CH:71]2)=[O:69])[CH2:63][CH2:62]1.N1(C2C=CC=CN=2)CCC(NC(N2CCC(NC(N3C=CN=C3)=O)CC2)=O)CC1>>[C:1]([O:5][C:6](=[O:60])[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:57])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2[CH2:46][CH2:71][N:70]([C:68](=[O:69])[NH:67][CH:64]4[CH2:63][CH2:62][N:61]([C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][N:76]=5)[CH2:66][CH2:65]4)[CH2:74][CH2:73]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:58])[C@@H:9]1[OH:59])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: O=C(NC1CCN(c2ccccn2)CC1)N1CCC(NC(=O)n2ccnc2)CC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to [(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{2-[3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-ureido]-ethylcarbamoyl}-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-carbamic acid tert-butyl ester (Example 12) by replacing imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate C) with 4-[(imidazole-1-carbonyl)-amino]-piperidine-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH2:36]([NH2:38])[CH3:37]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[C:31]([F:34])[C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:38][CH2:36][CH3:37])([CH3:13])[CH3:12])[C:16]3=[O:35])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CCN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Solvent: C1COCCO1
Product: CCNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 252k, 0.5 g) dissolved in 1,4-dioxane (2 mL) was treated with 70% ethylamine (2 mL) in a sealed tube. The resulting mixture was stirred at 100° C. for 1 h in a microwave (100 W). Evaporation and purification by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) gave the title compound (0.255 g).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([OH:21])=O)#[N:2].F[P-](F)(F)(F)(F)F.[N:29]1([O:38][C:39](N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([N:29]([O:38][CH3:39])[CH3:33])=[O:21])#[N:2]
Reactant: N#Cc1c(C(=O)O)n(-c2cccc(F)c2)c2ccccc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
A mixture of 3-cyano-1-(3-fluorophenyl)-1H-indole-2-carboxylic acid (0.12 g, 0.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.32 g, 0.86 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (63 mg, 0.64 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-25% EtOAc/hexane) to give the desired product (90 mg, 65%). LCMS calculated for C18H15FN3O2(M+H)+: m/z=324.1. Found: 324.0.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18]Cl)[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1>CO.O>[NH2:11][C:12]1[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([CH2:18][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:17]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: Sc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(CSc2ccccn2)nc(N)n1

Procedure:
18 g of 30% methanolic sodium methylate solution are added to a solution of 11.1 g of 2-mercaptopyridine in 100 ml of methanol, and stirring is then maintained at 20°-25° C. for 1 hours. To this solution are added portionwise 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and the mixture is stirred at 20°-25° C. for a further 2 hours. In further processing, the mixture is diluted with 1 liter of water, and the precipitating crystalline product is separated and dried. The yield is 22.5 g (91% of theory) of 2-amino-4-methoxy-6-(pyridin-2-yl-thiomethyl)-pyrimidine, m.p. 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: Cc1cccc(C)c1N1CC(C(=O)O)CC1=O
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 2 L, 3-neck flask was added 1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (93 g, 0.40 mol), anhydrous tert-butanol (60 mL, 0.63 mol), TEA (110 mL, 0.79 mol), DMAP (5.0 g, 41 mmol), and CH2Cl2 (800 mL). After the mixture was cooled in an ice bath under nitrogen atmosphere with mechanical stirring, 2,4,6-trichlorobenzoyl chloride (108 g, 0.443 mol) was added in portions over the course of 15 minutes such that the temperature did not exceed 10° C. After the addition was complete, the ice bath was removed, the mixture was allowed to warm to room temperature and stirred for an additional 14 h. TLC and LCMS indicated complete consumption of starting material and formation of desired product. The mixture was filtered and the filter cake was washed with EtOAc (100 mL) and ether (150 mL). The filtrate was washed with two 200 mL portions of 1 M NaHSO4, four 200 mL portions of saturated aqueous NaHCO3, and brine (100 mL). After drying over MgSO4, the organic phase was treated with 24 g of silica gel, and filtered. The filtrate was concentrated to 250 mL and diluted with hexane. A crystalline precipitate began to form, and an initial crop of 66 g was recovered. The filtrate was recovered and recrystallized (ether/hexanes) to afford a second crop (27 g); overall yield, 93 g (81%). LC-MS Rt (retention time): 2.28 min, MS: (ES) m/z 290 (M+H+).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)([C:3]([O:5]CC)=O)=[O:2].O.[NH3:30]>C(O)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)(=[O:2])[C:3]([NH2:30])=[O:5]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Reactant: N
Solvent: O
Solvent: CCO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)C(N)=O)n1
Yield: 26 %

Procedure:
To 2-ethoxalylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.29 mmol) in ethanol (10 ml) was added ammonia water (2ml). After the addition, the mixture was refluxed for 2 h, evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were dried over and evaporated under reduced pressure to residue, which was chromatographed to afford 2-oxamoylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.121 g, 26% yield) as crystalline material: mp 179.0°-180.0° C.
Reaction SMILES: [C:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#[N:11])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O1CCOCC1>CCOCC>[CH3:17][O:18][C:19](=[O:28])[CH:20]([C:8]1[C:9]([C:10]#[N:11])=[CH:12][C:13]([F:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)Oc1nc(F)c(C#N)cc1F
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC(C)(C)C)c1nc(OC(C)(C)C)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A thick mixture of 6-tert-butoxy-2,5-difluoro-nicotinonitrile (18.22 g, 85.9 mmol), as prepared in Example 1b, malonic acid tert-butyl ester methyl ester sodium salt (34.49 g, 176 mmol), as prepared in the previous step, and dioxane (110 mL) was stirred under argon at 95° C. (oil bath) for 14 h. The resulting homogeneous dark amber solution was allowed to cool to rt, diluted with ether (150 mL), and washed with a solution of 1.0 M NaH2PO4 (200 mL) containing 2.0 M citric acid (40 mL). The aqueous layer was back-extracted with ether (1×100 mL), the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under reduced pressure. Malonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h to afford the title compound as a clear, dark brown viscous oil (32.37 g, approx. 100% crude yield). 1H-NMR (300 MHz, CDCl3) δ 7.48 (d, 1H), 5.06 (s, 1H), 3.80 (s, 3H), 1.62 (s, 9H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:33]1[C:37]2[CH:38]=[CH:39][C:40](B(O)O)=[CH:41][C:36]=2[CH:35]=[CH:34]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([C:40]3[CH:41]=[CH:36][C:35]4[C:39]=3[CH:38]=[CH:37][O:33][CH:34]=4)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc2occc2c1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(-c2ccc3coccc2-3)c1=O
Yield: 40.9 %

Procedure:
A mixture of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.45 mmol), benzofuran-5-boronic acid (120 mg, 0.68 mmol), Pd(PPh3)4 (26 mg, 0.05 mmol) and 2M Na2CO3 (0.9 mL) in 1,4-dioxane (200 mL) was refluxed overnight under N2 atmosphere. The reaction mixture was diluted with water and extracted with EA (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica chromatography to give 100 mg of the title product (42%). [M+H] Calc'd for C30H30FN5O4, 543. Found, 543.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.I[CH2:27]CC>C1COCC1.C(#N)C>[CH3:27][C:6]1[N:5]([CH2:7][CH2:20][CH3:25])[CH:4]=[N:3][CH:2]=1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCI
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCn1cncc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 4-methyl-1-triphenylmethylimidazole (20.0 g) in THF (300 ml) and acetonitrile (300 ml) was added 1-iodopropane (26.2 g) and the mixture was stirred overnight under nitrogen atmosphere at 80° C. The solvent was distilled off under reduced pressure and the residue was dissolved in acetic acid (200 ml), and the mixture was stirred for 3 hours under nitrogen atmosphere at 60° C. The mixture was allowed to be at room temperature, water was added to the mixture, and the insolubles were filtered off. Potassium carbonate was added to the filtrate to make it basic and the mixture was extracted with chloroform three times, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oil was distilled off under reduced pressure (1.5 mmHg, 72° C. to 73° C.), to give 5-methyl-1-propylimidazole (1.9 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:16][CH3:17])[CH:4]=1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1Cl
Temperature: 55 °C
Yield: 99 %

Procedure:
To a solution of 2-chloro-5-bromophenol (WO98/003464 which is incorporated herein by reference, 3.43 g, 16.5 mmol) and K2CO3 (4.57 g, 33.0 mmol) in DMF (20 mL) was added ethyl iodide (1.78 mL, 22.3 mmol) at rt. The mixture was heated at 55° C. for 3.0 h. After cooling to rt, the reaction was diluted with ether, washed with water and brine, and dried over MgSO4. The crude residue was purified by flash column chromatography to give 3.85 g (99%) of 31A as viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.03 Hz, 3H) 4.08 (d, J=7.03 Hz, 2H) 7.03 (m, 2H) 7.22 (d, J=6.15 Hz, 2H).