Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[CH2:35]([C@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O1CCNC1=O>C1COCC1.CCCCCC>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([N:43]2[C@@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:15])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a stirring solution at -78° C. of 4-(1,1-dimethylethyl)benzenepropanoic acid (1.29 g, 6.25 mmol) and triethylamine (1.05 mL, 7.51 mmol) in dry THF (26 mL) was added pivaloylchloride (0.77 mL, 6.25 mmol) dropwise. After the addition, the mixture was stirred at -78° C. for 10 minutes and at 0° C. for 30 minutes. During this time metalated oxozolidinone was prepared separately by dropwise addition of n-butyl lithium (4.29 mL of a 1.6M solution in hexane) to a solution of (S)-(-)-4-benzyl-2-oxazolidinone (1.23 g of 99% pure, 6.88 mmol) in dry THF (26 mL). The metalated oxazolidinone solution was then added, at -78° C., via a cannula to the previously prepared reaction mixture and stirred for 1 h at 0° C. The reaction was quenched at 0° C. by addition of saturated NH4Cl solution (16 mL) and was concentrated. Saturated NH4Cl solution (25 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic phases were washed with saturated NaHCO3 (100 mL) and dried (NaSO4). Filtration and concentration provided crude product (2.50 g) which was purified via flash chromatography, eluting with a mixture of EtOAc and hexane (1:3) to provide (S)-3-[3-[4-(1,1-dimethylethyl)phenyl]-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone (1.82 g, 4.98 mmol) in 80% yield, mp 123°-126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9]1.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:11][C:2]([C@@H:3]1[CH2:4][CH:5]=[C:6]([CH2:9][OH:10])[CH2:7][CH2:8]1)=[CH2:1]
Reactant: CC1(C)C2CCC3(CO3)C1C2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)[C@@H]1CC=C(CO)CC1

Procedure:
Among other routes that have been developed to prepare perillyl alcohol from beta pinene oxide is that reported by T. K. Keenan in 1966 who produced perillyl acetate from beta-pinene oxide by refluxing beta-pinene oxide with acetic anhydride and acetic acid for seven hours followed by removal of the acetate to afford a nine percent (9%) yield of perillyl alcohol based on the starting beta-pinene oxide (B.S. Thesis Mass. Institute of Tech.). The applicants found the process to be reproducible albeit in low yield. F. C. Delay in Swiss Patent 5671/84 reported the production of perillyl alcohol in which he treated beta-pinene oxide with nitromethane and ammonium nitrite at a temperature between 20° C. and 90° C. in an overall yield of thirty percent (30%). Two years later Wang and co-workers published in Tetrahedron 1986, 620-638 complete details of this procedure and reported an overall yield of sixty-eight percent (68%) perillyl alcohol.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:8]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[OH-].[Na+]>Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22]
Reactant: CN(C)CCCNc1c(Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNc1c(N)cccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.2 %

Procedure:
A solution containing tin(II) chloride dihydrate (4.040 g) in concentrated hydrochloric acid (5.85 ml) was added to a solution containing N1-(2-chloro-6-nitrophenyl)-N3,N3-dimethyl-1,3-propanediamine (1.289 g) in concentrated hydrochloric acid (4.2 ml) and the mixture was stirred for 14 hours at room temperature. The reaction mixture was alkalified with 10% sodium hydroxide aqueous solution while being cooled with ice and extracted with diethyl ether. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (1.130 g) as orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:11]([OH:10])=[C:12]([O:19][CH3:20])[CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: Nc1cc(Br)cnc1N
Product: COc1cc(-c2nc3cc(Br)cnc3[nH]2)ccc1O

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-hydroxy-3-methoxybenzaldehyde.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[CH:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:24][CH:23]=1>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][C:25]3[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=3)[CH:30]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: Oc1cccc(Nc2ccccc2)c1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2cccc(Nc3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24 Step A and 3-hydroxydiphenylamine in a manner analogous to that described for Example 24, Step B. MS(ES) for C27H27NO4[M+H]+:430.2.
Reaction SMILES: [H-].[Na+].C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.[CH2:24]([C:26]1[C:35]([CH3:36])=[C:34]([O:37][C:38]([CH:40]2CC2)=[O:39])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:44])[C:32]=2[F:43])[N:27]=1)C.O>CN(C)C=O>[CH3:24][C:26]1[C:35]([CH3:36])=[C:34]([O:37][C:38](=[O:39])[CH3:40])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:44])[C:32]=2[F:43])[N:27]=1
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)nc2ccc(F)c(F)c12
Reaction time: 1 h
Yield: 314.2 %

Procedure:
2,3-Dimethyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1.5 g) prepared as described in Example 4 was dissolved in 15 ml of methanol. A 10% aqueous sodium hydroxide solution (15 ml) was added to the solution, and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.1 g of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline. In 5 ml of dimethyl formamide was suspended 11.5 mg of 60% sodium hydride. Separately, 50 mg of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) prepared above was suspended in 5 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 20 mg of acetyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 54.2 mg of 2,3-dimethyl-4-acetoxy-5,6-difluoroquinoline (compound 44). 1H-NMR data are shown in Table 3.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.I[CH3:23]>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH3:23])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CI
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (1 g) was reacted with iodomethane similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-methyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate (0.3 g) was reacted via General Procedure L to provide
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](O)=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: COc1ccc(CC(=O)O)cc1OC
Product: COc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1OC

Procedure:
The product of Example 1B and 2-(3,4-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.92 (q, J=8.3 Hz, 1H), 3.80-3.83 (m, 5H), 3.78 (s, 3H), 3.75 (s, 3H), 3.59 (s, 2H), 3.17 (s, 1H), 3.08-3.10 (m, 3H); MS (ESI−) M/Z 423 (M−H)−.
Reaction SMILES: C(OC1C=C(F)C=C2C=1C(CC(N1CC3C(=CC=CC=3)C1)=O)=C[N:13]2CC)C1C=CC=CC=1.[CH2:33]([N:36]1[C:44]2[C:39](=[C:40]3[O:48][CH2:47][CH2:46][O:45][C:41]3=[CH:42][CH:43]=2)[C:38]([CH2:49][C:50]([OH:52])=O)=[CH:37]1)[CH2:34][CH3:35]>>[CH2:33]([N:36]1[C:44]2[C:39](=[C:40]3[O:48][CH2:47][CH2:46][O:45][C:41]3=[CH:42][CH:43]=2)[C:38]([CH2:49][C:50]([NH2:13])=[O:52])=[CH:37]1)[CH2:34][CH3:35]
Reactant: CCCn1cc(CC(=O)O)c2c3c(ccc21)OCCO3
Reactant: CCn1cc(CC(=O)N2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Product: CCCn1cc(CC(N)=O)c2c3c(ccc21)OCCO3
Yield: 100 %

Procedure:
Following the procedure (step 1, scheme 31) used to prepare compound 31-2, compound 40-5 gave compound 40-6 in 100% yield as yellow oil. LCMS: calc 274.1 found 275.0 [MH]+.
Reaction SMILES: [O:1]([C@@H:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]#[CH:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl-].C([Al+]CC)C.C(N([CH2:36][C:37]1[C:38](=[O:50])[CH2:39][C@@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH:41]=1)CC)C.[Cl-].[NH4+].Cl>CCCCCC.C1(C)C=CC=CC=1>[CH2:36]=[C:37]1[C@@H:41]([C:11]#[C:10][C@@H:9]([O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:40]([O:42][Si:43]([C:46]([CH3:48])([CH3:47])[CH3:49])([CH3:44])[CH3:45])[CH2:39][C:38]1=[O:50]
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: CC[Al+]CC
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (22 ml) of (3S)-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentyne (1.96 g) was added n-butyl lithium (2.5 M, hexane solution, 2.64 ml) at 0° C., followed by stirring at room temperature for 30 minutes. To the solution was added diethylaluminum chloride (0.95 N, hexane solution, 8.10 ml) at 0° C., followed by stirring at room temperature for 30 minutes. To the solution was added (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M, toluene solution, 22.0 ml) at room temperature, followed by stirring for 15 minutes. The reaction solution was poured into a mixture of hexane (53 ml), a saturated aqueous ammonium chloride solution (53 ml) and an aqueous hydrochloric acid solution (3 N, 15.4 ml) with stirring, and the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (20 ml). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=49:1) to give (3R,4R)-2-methylene-3-[(3S)-3-tert-butyldimethylsiloxy-5-phenylpent-1-ynyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (1.65 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].O>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:25]([O:29][CH3:30])=[O:28])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(=O)OC
Solvent: CCO
Solvent: O
Product: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 69.5 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 5 g (0.058 mole) of methyl acrylate in 50 ml of ethanol is heated under reflux for 2 hours. The solution is poured into 10 ml of water and the precipitate is filtered off with suction, washed with methanol and recrystallised from glycol monomethyl ether. 2.9 g (70% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-methoxycarbonylethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 192° to 194° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:25])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Fifty-three grams (0.25 mole) of 3,4-dinitrobenzoic acid, 500 ml. of benzene, 65 g. (0.51 mole) of oxalyl chloride and 1 ml. of pyridine were reacted according to Example 6 (A), first paragraph, to provide 3,4-dinitrobenzoyl chloride as a crude oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)#[CH:2].I[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19]([OH:21])=[O:20].CN(C=O)C.CCN(C(C)C)C(C)C>C(N(CC)CC)C.C(OCC)(=O)C>[CH3:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: C#Cc1cncc(CN2CCCC2)c1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)cc1C#Cc1cncc(CN2CCCC2)c1

Procedure:
can be prepared in a manner similar to that described above for the Sonogashira reaction. 3-Ethynyl-5-(pyrrolidin-1-ylmethyl)pyridine and 3-iodo-4-methylbenzoic acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by triethylamine. The product can be isolated by filtration of the crude reaction mixture. The filter cake is washed sequentially with a solvent such as ethyl acetate and then water, then dried in a vacuum oven. Further purification can be achieved by slurrying the solids in water adjusted to pH 3 with the addition of concentrated HCl. After filtration and water wash, the product can be dried in a vacuum oven.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH2:15]([NH:22][CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:15]([N:22]([CH3:23])[C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: CN(Cc1ccccc1)C(=O)C(=O)c1c[nH]c2ccccc12

Procedure:
N-Benzyl-2-(1H-indol-3-yl)-N-methyl-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and benzyl-methyl-amine. Yield (54%). HPLC ret. time 2.96 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.25 (s, 0.5H), 8.13-8.11 (m, 1.5H), 7.54 (m, 1H), 7.44-7.23 (m, 7H), 4.68 (s, 1H), 4.47 (s, 1H), 2.88 (s, 1.5H), 2.85 (s, 1.5H); ESI-MS 293.3 m/z (MH+).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[F:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[NH:16][C:17]([NH2:1])=[O:18]
Reactant: CCOC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: N
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc(NC(N)=O)c(F)cc1Cl
Yield: 80 %

Procedure:
An ammonia gas was introduced into a solution of 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenyl isocyanate (16.7 g, 64 mmol) in benzene (300 ml) while vigorously stirring on cooling in an ice bath. Precipitation of white solid was immediately observed. After thirty minutes the solid deposited was obtained by filtration and sufficiently washed with benzene and dried. This product was identified as 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenyl urea (14.2 g, yield 80%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([N:30]([CH2:29][C:19]1[CH:20]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:22]=[CH:23][C:18]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:10])=[O:11])[CH3:31])=[O:37]
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(Cl)cc2Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and 2,4-dichlorobenzoic acid (13.1 mg, 0.068 mmol) in 0.68 ml of CH2Cl2, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (20 mg, 48%) as a white solid, m.p. 134°-142° C. (amorphous).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](NC3C=CC(N4CCN(C)CC4)=CC=3)=N2)=[CH:4][CH:3]=1.Br[C:26]1[N:34]2[C:29]([CH:30]=[N:31][C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH:37]=3)=[N:33]2)=[CH:28][CH:27]=1>>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:38]2[CH:37]=[C:36]([NH:35][C:32]3[N:31]=[CH:30][C:29]4=[CH:28][CH:27]=[C:26]([NH:10][CH2:2][C:3]5[CH:8]=[N:7][CH:6]=[CH:5][CH:4]=5)[N:34]4[N:33]=3)[CH:41]=[CH:40][CH:39]=2)[CH2:43][CH2:44]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(Br)n4n3)c2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(NCc5cccnc5)n4n3)c2)CC1

Procedure:
The titled compound was prepared in an analogous fashion to Example 1164 replacing (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine with (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine to give a yellow solid (65 mg, 60%). LCMS (E/I+) 415.19 (M+H). NMR 1H (DMSO-d6)-9.90 (bs, 1H), 1.41 (s, 1H), 8.73 (s, 1H), 8.62 (d, 1H, J=4.97 Hz), 8.4 (s, 1H), 8.06 (d, 1H, J=7.45 Hz), 7.61 (t, 1H, J=5.79 Hz), 7.48 (bs, 1H), 7.37 (d, 1H, J=7.45 Hz), 7.24 (d, 1H, J=7.45 Hz), 7.19 (s, 1H), 7.16 (d, 1H, J=4.97 Hz), 6.70 (d, 1H, J=8.28 Hz), 6.66 (d, 1H, J=4.57 Hz), 4.71 (s, 2H), 3.86 (bs, 2H), 3.47 (bs, 2H), 3.14 (bs, 2H), 2.98 (bs, 4H), 2.86 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[N:4][C:5]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[N:6][CH:7]=1.[ClH:22].B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1B(O)O.Cl.CCOCC>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>[ClH:22].[CH3:15][C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:16]3[CH:20]=[CH:19][O:18][C:17]=3[CH3:21])[C:2]([C:39]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[CH3:33])=[CH:7][N:6]=2)[CH2:9]1
Reactant: Cc1cnccc1B(O)O
Reactant: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: Cc1cnccc1-c1cnc(N2C[C@@H](C)O[C@@H](C)C2)nc1-c1ccoc1C
Temperature: 85 °C
Yield: 29.9 %

Procedure:
cis-4-[5-Bromo-4-(2-methyl-3-furanyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.284 mmol), 3-methyl-4-pyridinyl)boronic acid HCl (54.2 mg, 0.312 mmol), sodium carbonate (75 mg, 0.710 mmol) and tetrakis(triphenylphosphine)palladium(0) (16.40 mg, 0.014 mmol) were added together in 1,4-dioxane (3 mL) and water (0.500 mL) and the resulting mixture was heated at 85° C. under argon for 4 hours. A further amount of (3-methyl-4-pyridinyl)boronic acid HCl (54.2 mg, 0.312 mmol), sodium carbonate (75 mg, 0.710 mmol) and tetrakis (16.40 mg, 0.014 mmol) were added and the resulting mixture was heated at 85° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by Biotage SP4 column chromatography eluting with a gradient of 0-60% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure. The residue was dissolved in methanol (1 ml), treated with 1M HCl in ether (0.1 mL, 0.100 mmol) and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 40° C. for 18 hours to give the title compound (34 mg, 0.085 mmol, 29.9% yield) as a white solid. LC/MS [M+H]+=365; 1H NMR (400 MHz, d4-MeOD): δ 8.68-8.66 (2H, m), 8.33 (1H, s), 7.92-7.90 (1H, d), 7.25-7.24 (1H, d), 5.75-5.74 (1H, d), 4.74-4.70 (2H, m), 3.72-3.64 (2H, m), 2.73-2.67 (2H, m), 2.49 (3H, s), 2.18 (3H, s), 1.25-1.24 (6H, m).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Product: Cc1c(C(=O)O)ccc(F)c1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To fuming nitric acid (20.3 mL, 409 mmol) was slowly added dropwise 4-fluoro-2-methylbenzoic acid (4.50 g, 29.2 mmol) while maintaining the temperature of the reaction mixture at 5-10° C. The reaction solution was stirred at 0-5° C. for 1 hr, and poured into ice. The precipitated solid was recovered, washed with water, and dried under reduced pressure to give 4-fluoro-2-methyl-3-nitrobenzoic acid (5.70 g, purity 25%) as a crudely purified product.