Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][CH:14]1C(OCC)=O.[O:24]=O>O1CCCC1.ClCCl.[Zn]>[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][C:14]1=[O:24]
Reactant: CCOC(=O)C1CCN1CC(OC)OC
Reactant: O=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(CN1CCC1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2.2 mmol of lithium diisopropylamide in 15 ml tetrahydrofuran at -78° was added dropwise 0.43 g (2 mmol) of N-(2,2-dimethoxyethyl)-2-carbethoxy azetidine in 3 ml of tetrahydrofuran. After stirring at -78° for 30 minutes, the deep yellow anion was silylated in the usual way and warmed to room temperature. Removal of all volatiles by rotary evaporation with a high vacuum pump gave a purple residue which was redissolved in dichloromethane. Internal photooxidation using 5 g of Photox (trademark for photoconductive lead-free zinc oxides available from The New Jersey Zinc Co.) as the sensitizer required less than 5 minutes for oxygen uptake. The mixture was then filtered free of sensitizer and worked up by aqueous extraction in the usual manner. The pink residue obtained was applied to a 17×2 cm neutral alumina column. Elution with 10:3 ethyl acetate-hexane yielded 0.18 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure. Comparison of its spectral properties (IR, NMR) with those of an authentic known sample confirmed the identity of the product as the expected beta-lactam.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([CH3:7])([CH3:6])[CH:4]=O.[CH2:9]([NH2:11])[CH3:10]>>[CH3:1][N:2]([CH3:8])[C:3]([CH3:7])([CH3:6])[CH2:4][NH:11][CH2:9][CH3:10]
Reactant: CCN
Reactant: CN(C)C(C)(C)C=O
Product: CCNCC(C)(C)N(C)C

Procedure:
Prepared by General Procedure A from 2-(dimethylamino)-2-methylpropanal and ethylamine to get the title compound as colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.63 (q, 2H), 2.50 (s, 2H), 2.19 (s, 6H), 1.11 (t, 3H), 1.01 (s, 6H).
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:5][CH2:6][C:7]1([NH2:11])[CH2:10][NH:9][CH2:8]1)[CH3:4].[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](F)=[O:17]>C(=O)(O)[O-].[Na+].O1CCOCC1.O>[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([C:16]([N:9]2[CH2:10][C:7]([CH2:6][NH:5][CH:3]([CH3:4])[CH3:2])([NH2:11])[CH2:8]2)=[O:17])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)NCC1(N)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)NCC1(N)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine (15 mg, 37% yield). 1H NMR (400 MHz, d4-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H). 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) for C20H22F3IN4O: 519 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1>>[O:10]=[C:8]([N:27]1[CH2:28][CH2:29][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:31][CH2:32]1)[CH2:7][C:6]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:21]=1)([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc2c(c1)CCCC2)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc2c(c1)CCCC2)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 3,3-bis-ethoxycarbonyl-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:22][CH2:23][C:24](NC1SC(C2C=CN=C(NC3C=CC=C([N+]([O-])=O)C=3)N=2)=C(C)N=1)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:25]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine in a manner analogous to that described above for compound [60]. 1H-NMR (DMSO-d6) δ: 2.94 (s, 3H, CH3), 4.75 (s, 2H, CH2), 7.44(m, 3H, pyrimidinyl-H & Ph-H), 8.09 (m, 2H, Ph-H), 8.28 (s, 1H, NH), 8.80 (d, 1H, J=5.2 Hz, pyrimidinyl-H).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nn1
Temperature: 120 °C
Yield: 7.1 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloropyridazine-3-carbonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=1.76 min; m/z: 345 (M+H)+.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)([NH:16][C:17]2[CH2:18][O:19][CH2:20][C:21]([F:42])([F:41])[C@:22]([C:25]3[CH:26]=[C:27]([NH:32][C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[CH:28]=[CH:29][C:30]=3[F:31])([CH3:24])[N:23]=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:16][C:17]1[CH2:18][O:19][CH2:20][C:21]([F:41])([F:42])[C@:22]([C:25]2[CH:26]=[C:27]([NH:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:28]=[CH:29][C:30]=2[F:31])([CH3:24])[N:23]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccc(C#N)cc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(c2cc(Nc3ccc(C#N)cc3)ccc2F)N=C(N)COCC1(F)F
Temperature: 23 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile (intermediate A13A) (21 mg, 31 μmol) in dichloromethane (1 ml) at 23° C. was added trifluoroacetic acid (370 mg, 250 μl, 3.24 mmol) and the mixture was stirred at 23° C. for 1 h. Poured into sat. Na2CO3-sol., extracted thrice with ethyl acetate, dried the combined organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by preparative HPLC (column: Gemini 5μ C18 110 A° AXIA (50×21.2 mm); flow: 40 ml/min; gradient: water (+0.1% TEA)/acetonitrile (90%-10% 1 min plateau; in 3.5 min to 5%-95%); collection: UV-detector 300 nm) to give the title compound (8.9 mg, 76.6%) after trituration with little diethyl ether/pentane as a white solid. MS (ISP): m/z=375.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[CH2:30][C:31](O)=[O:32].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>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([F:29])[CH:26]=[C:27]([F:28])[C:22]=2[F:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
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: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21
Yield: 49.8 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (2,3,5-trifluorophenyl)acetic acid (69.1 mg, 0.363 mmol), HATU (151 mg, 0.396 mmol), DIEA (0.173 mL, 0.991 mmol) was stirred overnight at room temperature. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (72 mg) as a white solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.26-3.32 (m, 2H), 3.94 (s, 3H), 4.06 (s, 2H), 4.28-4.37 (m, 2H), 7.09-7.20 (m, 1H), 7.41-7.52 (m, 2H), 7.53-7.57 (m, 1H), 8.11-8.18 (m, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7](=O)[O:8]C(C)(C)C)[CH3:2].FC(F)(F)C(O)=O.[Cl:22][CH2:23]Cl>>[Cl:22][CH2:23][C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH3:14])=[O:8]
Reactant: ClCCl
Reactant: CCOCCN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOCCN(C)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2-ethoxyethyl)methylcarbamate (1.2 g) in dichloromethane (6 ml) was added trifluoroacetic acid (6 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then the solvent was evaporated in vacuo. Synthesized from the resulting (2-ethoxyethyl)methylamine trifluoroacetate (crude product) (2.3 g) according to an analogous synthetic method to Preparation Example 119, the title compound (799 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C-:23]#[N:24].[Na+]>CN(C)C=O>[C:23]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:24]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Temperature: 0 °C
Yield: 32.6 %

Procedure:
A solution of 3.15 g of 5-chloro-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester and 1.1 g of sodium cyanide in 25 ml of dimethylformamide was heated at approximately 100° C. for four and one-half hours. The reaction mixture also contained approximately 3 g of molecular sieve to insure dryness. The reaction mixture was cooled and poured into approximately 300 ml of ice water. The precipitated solid was collected by filtration and recrystallized from ethanol (charcoal) to provide 1 g of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=70°-72° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:24])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>O.CCOC(C)=O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:24][C:7]1[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)cn2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cn(CCOC3CCCCO3)cn2)n1
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
To a mixture of Intermediate 119b (550 mg) in water (3 mL) and EtOAc (6 mL) was added NaOH (132 mg, 3.30 mmol). After 10 min stirring, 2,2,2-trichloroethyl chloroformate (273 μL, 1.98 mmol) was added and the reaction mixture was stirred at RT for 2 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to afford the title compound (175 mg). LCMS (Method 4): Rt 4.54 min, m/z 508, 510 [MH+].
Reaction SMILES: C(O[C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([Br:13])=[C:8]([O:14][C:15]2[CH:20]=[C:19]([CH:21]([F:23])[F:22])[CH:18]=[C:17]([C:24]#[N:25])[CH:16]=2)[C:7]=1[F:26])C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[CH3:39].NC1C=CC(S(N)(=O)=O)=CC=1>>[Br:13][C:9]1[C:10]([Br:12])=[CH:11][C:6]([CH2:5][C:4]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](=[O:37])(=[O:36])[NH2:38])=[CH:31][C:30]=2[CH3:39])=[O:27])=[C:7]([F:26])[C:8]=1[O:14][C:15]1[CH:20]=[C:19]([CH:21]([F:22])[F:23])[CH:18]=[C:17]([C:24]#[N:25])[CH:16]=1
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: CCOC(=O)Cc1cc(Br)c(Br)c(Oc2cc(C#N)cc(C(F)F)c2)c1F
Agent: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)Cc1cc(Br)c(Br)c(Oc2cc(C#N)cc(C(F)F)c2)c1F

Procedure:
[4,5-Dibromo-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (200) was isolated as a byproduct in the Sandmeyer reaction used in the preparation of 186 described in step 1 of example 40. The dibromo compound was converted to I-104 by the procedure described in steps 7 to 9 of example 1 except in the present example, 4-amino-3-methyl-benzenesulfonamide replaced 4-amino-benzenesulfonamide.
Reaction SMILES: [C:1]([C:3]1[C:20]([C:21]#[N:22])=[CH:19][C:6]2[N:7](CCC)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH2:23]([C:26](C1C=CC(C=O)=CC=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:23]([C:26]([C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:6]3[CH:19]=[C:20]([C:21]#[N:22])[C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[CH:11][CH:12]=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]
Reactant: C=CCC(CC=C)(CC=C)c1ccc(C=O)cc1
Reactant: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of 1 (198 mg, 1.25 mmol) in NMP (2.5 mL) and a solution of 2 (300 mg, 1.25 mmol) in NMP (3.5 mL) were combined in a flask fitted with a Hickman still. The mixture was heated at 120° C. and stirred for 2 h. Then FeCl3.6H2O (17 mg, 63 μmol) was added and oxygen was bubbled through the mixture with continued heating and stirring for 20 h. The cooled reaction mixture was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Fractions containing the desired compound were concentrated to give a reddish solid, which was chromatographed over a short plug of alumina (CH2Cl2 w/ethyl acetate gradient of 10-100%) yielding a colorless solid (268 mg, 57%): mp 264-266° C.; 1H NMR (do-acetone) δ 2.57 (d, J=7.2 Hz, 6H), 4.88-5.11 (m, 6H), 5.56-5.69 (m, 3H), 7.65 (d, J=8.8 Hz, 2H), 8.26 (d, J=8.8 Hz, 2H), 12.89 (brs, 1H); 13C NMR (d6-acetone) δ 41.6, 44.0, 108.2, 116.9, 117.7, 126.4, 127.3, 128.0, 134.4, 150.2; FABMS obsd 379.1909, calcd 379.1923 (C25H22N4).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1.[Cu]I.NCC(N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([N:22]2[C:23]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1ccc(F)cc1Br
Agent: [Cu]I
Agent: CC(N)CN
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 260.9 %

Procedure:
2-Bromo-4-fluoroanisole (20 g, 10 mmol, 1 equiv) and carbazole (18.4 g, 11 mmol, 1.1 equiv) were dissolved in 1,4-dioxane (200 mL). Potassium phosphate tribasic hydrate (46 g, 20 mmol, 2 equiv), copper(I) iodide (1 g, 0.5 mmol, 0.05 equiv) and 1,2-diaminopropane (1 mL, 1.3 mmol, 0.13 equiv) were added and the reaction was refluxed for 18 hours. The reaction was cooled to room temperature and filtered through CELITE diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified over silica gel (250 g), eluting with gradient of 0 to 10% ethyl acetate in heptanes to give compound 4 (7.6 g, 26% yield) as an off white solid that was contaminated with carbazole. This material was used subsequently.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1>N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>[CH2:1]=[C:2]1[CH2:12][CH:11]2[CH2:4][CH:3]1[CH:9]=[CH:10]2.[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: C1CCOC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1C=CC(=O)O1
Solvent: CCCCCC
Product: C=C1CC2C=CC1C2
Temperature: 70 °C
Yield: 183.7 %

Procedure:
This synthesis example is directed to the synthesis of polymer (1b) (illustrated below as chemical formulas 14 or 15), a γ-hydroxy carboxylic acid structure. 21.2 g of 5-ethylenebicyclo[2.2.1]hept-2-ene, 19.6 g of maleic anhydride, 2.56 g of 2,2'-azobisisobutyronitrile, and 240 g of tetrahydrofuran were placed in a 500-ml, three-necked flask equipped with a thermometer, a condenser pipe, and a nitrogen inlet pipe, and the mixture was heated under reflux at 70° C. while introducing nitrogen for 8 hr to conduct polymerization. After the completion of the polymerization, the reaction mixture was poured into 1000 ml of n-hexane to precipitate the resultant polymer, which was then dried to give 37.5 g of a 5-methylenebicyclo[2.2.1]hept-2-ene/maleic anhydride copolymer (1a) (yield 92%). The polymer was analyzed by various methods and was found to mainly have a structure represented by the following formula:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[C:29]([F:31])[C:9]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@H:15]3[CH2:27][CH3:28])=[O:13])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[C:29]([F:31])[C:9]([CH2:10][O:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]3[CH2:27][CH3:28])=[O:13])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCC2CC2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@H]1CNCCN1C(=O)OCc1c(F)cc(OCC2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(4-cyclopropylmethoxy-2,6-difluoro-benzyl) ester (400 mg) was dissolved in methanol (5 mL), 1100 μL 4 N HCl in dioxane was added and the mixture was stirred for 18 h at room temperature. The mixture was made alkaline with 2 N NaOH and eluted with ethylacetate over a column containing 10 g ChemElut CE1010. The filtrate was collected, solvent was evaporated to give a yellowish oil (237 mg). This residue was purified by column chromatography (silica gel; dichloromethane/methanol gradient) to yield 186 mg (59%) of the product as a colorless oil. MS (ISP): 355.4 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([Cl:18])=[N:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([NH:19][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:15]([Cl:18])=[N:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzenesulfonyl chloride (2.24 ml, 17.5 mmol) was added dropwise over 5-10 mins to a solution of 5-bromo-2-chloro-3-pyridinamine (2.5 g, 12.1 mmol) and pyridine (1.5 ml, 18.56 mmol) in DCM (25 ml). The reaction was stirred for 18 h at RT before evaporation to dryness in vacuo. The residue was split in two and purified by silica gel chromatography, eluting with 0-100% DCM in cyclohexane. Appropriate fractions were combined and evaporated to give title compound, 1.81 g.